US20030199688A1 - Macrocyclic module compositions - Google Patents
Macrocyclic module compositions Download PDFInfo
- Publication number
- US20030199688A1 US20030199688A1 US10/226,400 US22640002A US2003199688A1 US 20030199688 A1 US20030199688 A1 US 20030199688A1 US 22640002 A US22640002 A US 22640002A US 2003199688 A1 US2003199688 A1 US 2003199688A1
- Authority
- US
- United States
- Prior art keywords
- group
- synthons
- alkyl
- hydrogen
- independently selected
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 121
- 239000011148 porous material Substances 0.000 claims abstract description 101
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 65
- 125000000524 functional group Chemical group 0.000 claims description 92
- 229910052739 hydrogen Inorganic materials 0.000 claims description 77
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 74
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 66
- 239000001257 hydrogen Substances 0.000 claims description 49
- -1 aluminas Substances 0.000 claims description 44
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 36
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 33
- 125000004429 atom Chemical group 0.000 claims description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- 239000002253 acid Substances 0.000 claims description 26
- 229930195733 hydrocarbon Natural products 0.000 claims description 26
- 239000004215 Carbon black (E152) Substances 0.000 claims description 25
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 25
- 229920006395 saturated elastomer Polymers 0.000 claims description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 24
- 238000005859 coupling reaction Methods 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 239000007787 solid Substances 0.000 claims description 22
- 230000008878 coupling Effects 0.000 claims description 21
- 238000010168 coupling process Methods 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 18
- 229910052751 metal Inorganic materials 0.000 claims description 18
- 239000002184 metal Substances 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 18
- 229910052710 silicon Inorganic materials 0.000 claims description 17
- 229910052782 aluminium Inorganic materials 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 150000002739 metals Chemical class 0.000 claims description 16
- 230000002441 reversible effect Effects 0.000 claims description 16
- 239000003513 alkali Substances 0.000 claims description 15
- 229910052796 boron Inorganic materials 0.000 claims description 15
- 229910052698 phosphorus Inorganic materials 0.000 claims description 15
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 15
- 229910052740 iodine Inorganic materials 0.000 claims description 14
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 150000002430 hydrocarbons Chemical class 0.000 claims description 12
- 125000005647 linker group Chemical group 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 239000007790 solid phase Substances 0.000 claims description 8
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 7
- 239000000377 silicon dioxide Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 6
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims description 6
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 claims description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims description 6
- JFNLZVQOOSMTJK-KNVOCYPGSA-N norbornene Chemical compound C1[C@@H]2CC[C@H]1C=C2 JFNLZVQOOSMTJK-KNVOCYPGSA-N 0.000 claims description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 claims description 4
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 4
- 230000000295 complement effect Effects 0.000 claims description 4
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 claims description 4
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims description 4
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 claims description 4
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 4
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- AEBWATHAIVJLTA-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydropentalene Chemical compound C1CCC2CCCC21 AEBWATHAIVJLTA-UHFFFAOYSA-N 0.000 claims description 2
- WGGHTQJCLFQFTA-UHFFFAOYSA-N 1,2,3,3a,4,5-hexahydropentalene Chemical compound C1CC=C2CCCC21 WGGHTQJCLFQFTA-UHFFFAOYSA-N 0.000 claims description 2
- DUXAVVSOUJIVFH-UHFFFAOYSA-N 1,3-diazabicyclo[2.2.1]heptane Chemical compound C1NC2CCN1C2 DUXAVVSOUJIVFH-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- SNZSSCZJMVIOCR-UHFFFAOYSA-N 7-azabicyclo[2.2.1]heptane Chemical compound C1CC2CCC1N2 SNZSSCZJMVIOCR-UHFFFAOYSA-N 0.000 claims description 2
- 229920000936 Agarose Polymers 0.000 claims description 2
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- 229920005654 Sephadex Polymers 0.000 claims description 2
- 239000012507 Sephadex™ Substances 0.000 claims description 2
- 229920002684 Sepharose Polymers 0.000 claims description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 2
- SLGBZMMZGDRARJ-UHFFFAOYSA-N Triphenylene Natural products C1=CC=C2C3=CC=CC=C3C3=CC=CC=C3C2=C1 SLGBZMMZGDRARJ-UHFFFAOYSA-N 0.000 claims description 2
- NGDCLPXRKSWRPY-UHFFFAOYSA-N Triptycene Chemical compound C12=CC=CC=C2C2C3=CC=CC=C3C1C1=CC=CC=C12 NGDCLPXRKSWRPY-UHFFFAOYSA-N 0.000 claims description 2
- 239000003875 Wang resin Substances 0.000 claims description 2
- 125000000539 amino acid group Chemical group 0.000 claims description 2
- VIQRCOQXIHFJND-UHFFFAOYSA-N bicyclo[2.2.2]oct-2-ene Chemical compound C1CC2CCC1C=C2 VIQRCOQXIHFJND-UHFFFAOYSA-N 0.000 claims description 2
- GPRLTFBKWDERLU-UHFFFAOYSA-N bicyclo[2.2.2]octane Chemical compound C1CC2CCC1CC2 GPRLTFBKWDERLU-UHFFFAOYSA-N 0.000 claims description 2
- UTODCSRVEOLXKS-UHFFFAOYSA-N bicyclo[3.2.2]non-4-ene Chemical compound C1CC(CC2)CCC2=C1 UTODCSRVEOLXKS-UHFFFAOYSA-N 0.000 claims description 2
- GNTFBMAGLFYMMZ-UHFFFAOYSA-N bicyclo[3.2.2]nonane Chemical compound C1CC2CCC1CCC2 GNTFBMAGLFYMMZ-UHFFFAOYSA-N 0.000 claims description 2
- SIVKZPBURVINMX-UHFFFAOYSA-N bicyclo[3.3.1]non-4-ene Chemical compound C1CC=C2CCCC1C2 SIVKZPBURVINMX-UHFFFAOYSA-N 0.000 claims description 2
- WNTGVOIBBXFMLR-UHFFFAOYSA-N bicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1C2 WNTGVOIBBXFMLR-UHFFFAOYSA-N 0.000 claims description 2
- ZUDPATVLKVXKSZ-UHFFFAOYSA-N bicyclo[4.2.2]decane Chemical compound C1CC2CCC1CCCC2 ZUDPATVLKVXKSZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000919 ceramic Substances 0.000 claims description 2
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims description 2
- 239000000017 hydrogel Substances 0.000 claims description 2
- 229910003480 inorganic solid Inorganic materials 0.000 claims description 2
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 claims description 2
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 claims description 2
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 claims description 2
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 claims description 2
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004065 semiconductor Substances 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- PHICBFWUYUCFKS-UHFFFAOYSA-N spiro[4.4]nonane Chemical compound C1CCCC21CCCC2 PHICBFWUYUCFKS-UHFFFAOYSA-N 0.000 claims description 2
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 claims description 2
- 125000005580 triphenylene group Chemical group 0.000 claims description 2
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 30
- 150000002431 hydrogen Chemical class 0.000 claims 10
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 claims 2
- RRKODOZNUZCUBN-CCAGOZQPSA-N (1z,3z)-cycloocta-1,3-diene Chemical compound C1CC\C=C/C=C\C1 RRKODOZNUZCUBN-CCAGOZQPSA-N 0.000 claims 1
- GWYPDXLJACEENP-UHFFFAOYSA-N 1,3-cycloheptadiene Chemical compound C1CC=CC=CC1 GWYPDXLJACEENP-UHFFFAOYSA-N 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims 1
- 108010058846 Ovalbumin Proteins 0.000 claims 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims 1
- 239000004202 carbamide Substances 0.000 claims 1
- 150000004696 coordination complex Chemical class 0.000 claims 1
- 229940109239 creatinine Drugs 0.000 claims 1
- CHVJITGCYZJHLR-UHFFFAOYSA-N cyclohepta-1,3,5-triene Chemical compound C1C=CC=CC=C1 CHVJITGCYZJHLR-UHFFFAOYSA-N 0.000 claims 1
- ZXIJMRYMVAMXQP-UHFFFAOYSA-N cycloheptene Chemical compound C1CCC=CCC1 ZXIJMRYMVAMXQP-UHFFFAOYSA-N 0.000 claims 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- ICPMUWPXCAVOOQ-UHFFFAOYSA-N cycloocta-1,3,5-triene Chemical compound C1CC=CC=CC=C1 ICPMUWPXCAVOOQ-UHFFFAOYSA-N 0.000 claims 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 claims 1
- 239000004914 cyclooctane Substances 0.000 claims 1
- KDUIUFJBNGTBMD-VXMYFEMYSA-N cyclooctatetraene Chemical compound C1=C\C=C/C=C\C=C1 KDUIUFJBNGTBMD-VXMYFEMYSA-N 0.000 claims 1
- URYYVOIYTNXXBN-UPHRSURJSA-N cyclooctene Chemical compound C1CCC\C=C/CC1 URYYVOIYTNXXBN-UPHRSURJSA-N 0.000 claims 1
- 239000004913 cyclooctene Substances 0.000 claims 1
- 239000008103 glucose Substances 0.000 claims 1
- 229960001031 glucose Drugs 0.000 claims 1
- 229940092253 ovalbumin Drugs 0.000 claims 1
- 235000012431 wafers Nutrition 0.000 claims 1
- 230000002153 concerted effect Effects 0.000 abstract description 7
- 239000000243 solution Substances 0.000 description 96
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 90
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 89
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 80
- 0 C.C*C1=CC=CC(*C)=C1 Chemical compound C.C*C1=CC=CC(*C)=C1 0.000 description 75
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 60
- 241000894007 species Species 0.000 description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
- 235000019439 ethyl acetate Nutrition 0.000 description 34
- 239000002904 solvent Substances 0.000 description 33
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 29
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 26
- 150000002466 imines Chemical class 0.000 description 26
- 239000010408 film Substances 0.000 description 25
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 229910052786 argon Inorganic materials 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 20
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 238000013459 approach Methods 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000012528 membrane Substances 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 230000002829 reductive effect Effects 0.000 description 16
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 14
- 238000000926 separation method Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 125000001931 aliphatic group Chemical group 0.000 description 13
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
- 239000000758 substrate Substances 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- 238000006969 Curtius rearrangement reaction Methods 0.000 description 11
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 11
- 239000011780 sodium chloride Substances 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- 230000000717 retained effect Effects 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 150000008064 anhydrides Chemical class 0.000 description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 125000006850 spacer group Chemical group 0.000 description 8
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- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- MMYYTPYDNCIFJU-UHFFFAOYSA-N calix[6]arene Chemical compound C1C(C=2)=CC=CC=2CC(C=2)=CC=CC=2CC(C=2)=CC=CC=2CC(C=2)=CC=CC=2CC(C=2)=CC=CC=2CC2=CC=CC1=C2 MMYYTPYDNCIFJU-UHFFFAOYSA-N 0.000 description 1
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- GCSHUYKULREZSJ-UHFFFAOYSA-N phenyl(pyridin-2-yl)methanone Chemical compound C=1C=CC=NC=1C(=O)C1=CC=CC=C1 GCSHUYKULREZSJ-UHFFFAOYSA-N 0.000 description 1
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- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
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- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical group C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
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- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
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- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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- NNBZCPXTIHJBJL-MGCOHNPYSA-N trans-decalin Chemical compound C1CCC[C@@H]2CCCC[C@H]21 NNBZCPXTIHJBJL-MGCOHNPYSA-N 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- PGAJYUDRKAPMPA-UHFFFAOYSA-N trimethylsilyl n-ethylcarbamate Chemical compound CCNC(=O)O[Si](C)(C)C PGAJYUDRKAPMPA-UHFFFAOYSA-N 0.000 description 1
- JSPLKZUTYZBBKA-UHFFFAOYSA-N trioxidane Chemical class OOO JSPLKZUTYZBBKA-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D259/00—Heterocyclic compounds containing rings having more than four nitrogen atoms as the only ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
- C07C211/49—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring having at least two amino groups bound to the carbon skeleton
- C07C211/50—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring having at least two amino groups bound to the carbon skeleton with at least two amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/74—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C215/76—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton of the same non-condensed six-membered aromatic ring
- C07C215/78—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton of the same non-condensed six-membered aromatic ring containing at least two hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/74—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C215/76—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton of the same non-condensed six-membered aromatic ring
- C07C215/80—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton of the same non-condensed six-membered aromatic ring containing at least two amino groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
Definitions
- This invention is related to the fields of organic chemistry and nanotechnology. In particular, it relates to materials and methods for the preparation of synthons used to construct macrocyclic module compositions.
- One area of nanotechnology is to develop chemical building blocks from which hierarchical molecules of predicted properties can be assembled.
- An approach to making chemical building blocks or nanostructures begins at the atomic and molecular level by designing and synthesizing starting materials with highly tailored properties. Precise control at the atomic level is the foundation for development of rationally tailored synthesis-structure-property relationships which can provide materials of unique structure and predictable properties.
- This approach to nanotechnology is inspired by nature where, for example, from twenty common amino acids found in natural proteins, more than 10 5 stable and unique proteins are made.
- Nanotechnology has also been described by K. Eric Drexler in Engines of Creation as “the knowledge and means for designing, fabricating and employing molecular scale devices by the manipulation and placement of individual atoms and molecules with precision on the atomic scale.”
- a quest of nanotechnology is to prepare molecular architectures capable of performing on a nanometer scale functions normally observed for large-scale constructs.
- rotaxanes and polyrotaxanes are molecules that are interlocked, but not chemically bound to one another, which act like nano-machines.
- carbon nanotubes and similar constructs have been created which may function as molecular scaffold units, or as transport channels, storage units, or encapsulators for various atoms and molecules.
- the use of biological processes is also being studied as an approach to the assembly of non-biological nano-devices.
- U.S. Pat. No. 5,468,851 discloses building various structures from polynucleotide segments.
- membranes used in a variety of separation processes can be made selectively permeable to various molecular species.
- the permeation properties of conventional membranes generally depend on the pathways of transport of species through the membrane structure. While the diffusion pathway in conventional selectively permeable materials can be made tortuous in order to control permeation, porosity is not well defined or controlled by conventional methods.
- the ability to fabricate regular or unique pore structures of membranes is a long-standing goal of separation technology.
- Resistance to flow of species through a membrane may also be governed by the flow path length. Resistance can be greatly reduced by using a very thin film as a membrane, at the cost of reduced mechanical strength of the membrane material.
- Conventional membranes may have a barrier thickness of at least one to two hundred nanometers, and often up to millimeter thickness. In general, a thin film of membrane barrier material can be deposited on a porous substrate of greater thickness to restore material strength.
- Membrane separation processes are used to separate components from a fluid in which atomic or molecular components having sizes smaller than a certain “cut-off” size can be separated from components of larger size. Normally, species smaller than the cut-off size are passed by the membrane.
- the cut-off size may be an approximate empirical value which reflects the phenomenon that the rate of transport of components smaller than the cut-off size is merely faster than the rate of transport of larger components.
- the primary factors affecting separation of components are size, charge, and diffusivity of the components in the membrane structure.
- the driving force for separation is a concentration gradient, while in electrodialysis electromotive force is applied to ion selective membranes.
- a macrocyclic module composition which may be made from three to about twenty-four cyclic synthons.
- the synthons of the macrocyclic module composition form a closed ring.
- a macrocyclic module composition may include functional groups for coupling to other macrocyclic modules.
- a composition may include two or more closed rings coupled together.
- one or more functional groups may be coupled to one or more of the cyclic synthons of a macrocyclic module composition, the functional group(s) located at the pore of the composition, where the macrocyclic module composition may have a first pore dimension in a first conformation when a first group of substituents is located at the pore and a second pore dimension in a second conformation when a second group of substituents is located at the pore.
- a composition may include a closed ring, a functional group coupled to the closed ring at the pore, and a selected species to be transported through the pore.
- a method is provided to make a composition to transport selected species through the composition, by selecting a first cyclic synthon substituted with at least one functional group and selecting from two to about twenty-three additional cyclic synthons, then incorporating the cyclic synthons into a macrocyclic module composition in which the functional group of the first cyclic synthon is located at the pore of the composition.
- a macrocyclic module composition may be coupled to a solid support.
- a macrocyclic module composition having from three to twenty-four cyclic synthons forming a closed ring of cyclic synthons which retains film area after a period of time on a Langmuir trough.
- a linkage is formed between coupled cyclic synthons.
- a method for making a macrocyclic module composition wherein a plurality of a first cyclic synthon is contacted with a plurality of a second cyclic synthon, and the macrocyclic module composition is isolated therefrom.
- a linker molecule may be contacted with the mixture of synthons.
- a method for making a macrocyclic module composition wherein a plurality of a first cyclic synthon is contacted with a plurality of a second cyclic synthon, and a plurality of the first cyclic synthon is contacted with the mixture.
- the first cyclic synthon may be supported on a solid phase.
- a method for making a macrocyclic module composition wherein a plurality of a first cyclic synthon is contacted with a plurality of a second cyclic synthon, and a plurality of a third cyclic synthon is contacted with the mixture.
- the first cyclic synthon may be supported on a solid phase.
- a method for making a macrocyclic module includes a template for bringing together synthons.
- FIG. 1A shows a representation of an example of the structure of an embodiment of a hexamer macrocyclic module.
- FIG. 1B shows a representation of an example of the structure of an embodiment of a hexamer macrocyclic module.
- FIG. 2A shows an example of the Langmuir isotherm of an embodiment of a hexamer macrocyclic module.
- FIG. 2B shows an example of the isobaric creep of an embodiment of a hexamer macrocyclic module.
- FIG. 3A shows an example of the Langmuir isotherm of an embodiment of a hexamer macrocyclic module.
- FIG. 3B shows an example of the isobaric creep of an embodiment of a hexamer macrocyclic module.
- alkyl refers to a branched or unbranched monovalent hydrocarbon radical.
- An “n-mC” alkyl or “(nC-mC)alkyl” refers to all alkyl groups containing from n to m carbon atoms.
- a 1-4C alkyl refers to a methyl, ethyl, propyl, or butyl group. All possible isomers of an indicated alkyl are also included.
- propyl includes isopropyl
- butyl includes n-butyl, isobutyl and t-butyl, and so on.
- alkyl includes substituted alkyls.
- substituted alkyl refers to an alkyl group with an additional group or groups attached to any carbon of the alkyl group. Additional groups attached to a substituted alkyl may include one or more functional groups such as alkyl, aryl, acyl, halogen, alkylhalo, hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, aryloxy, aryloxyalkyl, mercapto, both saturated and unsaturated cyclic hydrocarbons, heterocycles, and others.
- functional groups such as alkyl, aryl, acyl, halogen, alkylhalo, hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, aryloxy, aryloxyalkyl, mercapto, both saturated and unsaturated cyclic hydrocarbons, heterocycles, and others.
- R refers to a hydrogen or an organic group, each independently selected, unless stated otherwise.
- aryl refers to an aromatic group which may be a single aromatic ring or multiple aromatic rings which are fused together, linked covalently, or linked to a common group such as a methylene, ethylene, or carbonyl, and includes polynuclear ring structures.
- An aromatic ring or rings may include substituted or unsubstituted phenyl, naphthyl, biphenyl, diphenylmethyl, and benzophenone groups, among others.
- aryl includes substituted aryls.
- heteroaryl refers to an aromatic ring(s) in which one or more carbon atoms of the aromatic ring(s) are substituted by a heteroatom such as nitrogen, oxygen, or sulfur.
- Heteroaryl refers to structures which may include a single aromatic ring, multiple aromatic rings, or one or more aromatic rings coupled to one or more nonaromatic rings. It includes structures having multiple rings, fused or unfused, linked covalently, or linked to a common group such as a methylene or ethylene group, or linked to a carbonyl as in phenyl pyridyl ketone.
- heteroaryl includes rings such as thiophene, pyridine, isoxazole, phthalimide, pyrazole, indole, furan, or benzo-fused analogues of these rings.
- saturated cyclic hydrocarbon refers to ring structures cyclopropyl, cyclobutyl, cyclopentyl groups, and others, including substituted groups. Substituents to saturated cyclic hydrocarbons include substituting one or more carbon atoms of the ring with a heteroatom such as nitrogen, oxygen, or sulfur. Saturated cyclic hydrocarbons include bicyclic structures such as bicycloheptanes and bicyclooctanes, and multicyclic structures.
- the term “unsaturated cyclic hydrocarbon” refers to a monovalent nonaromatic group with at least one double bond, such as cyclopentene, cyclohexene, and others, including substituted groups. Substituents to unsaturated cyclic hydrocarbons include substituting one or more carbon atoms of the ring with a heteroatom such as nitrogen, oxygen, or sulfur. As used herein, the term “cyclic hydrocarbon” includes substituted and unsubstituted, saturated and unsaturated cyclic hydrocarbons, and multicyclic structures. Unsaturated cyclic hydrocarbons include bicyclic structures such as bicycloheptenes and bicyclooctenes, and multicyclic structures.
- amphiphile or “amphiphilic” refer to a species which exhibits both hydrophilic and lipophilic character. In general, an amphiphile contains a lipophilic moiety and a hydrophilic moiety. An amphiphile may form a Langmuir film.
- hydrophilic moieties include, without limitation, hydroxyl, methoxy, phenol, carboxylic acids and salts thereof, methyl and ethyl esters of carboxylic acids, amides, amino, cyano, ammonium salts, monoalkyl-substituted amino groups, di-alkyl-substituted amino groups, —NRR′, —N ⁇ C, —NHR, sulfonium salts, phosphonium salts, polyethyleneglycols, polypropyleneglycols, epoxy groups, acrylates, sulfonamides, nitro, —OP(O)(OCH 2 CH 2 N + RR′R′′)O ⁇ , guanidinium, aminate, acrylamide, and pyridinium.
- Such hydrophilic moieties may include groups such as polyethylene glycols, or for example, polymethylene chains substituted with alcohol, carboxylate, acrylate, methacrylate, or
- Hydrophilic moieties may also include alkyl chains having internal amino or substituted amino groups, for example, internal —NH—, —NC(O)R—, or —NC(O)CH ⁇ CH 2 — groups.
- Hydrophilic moieties may also include polycaprolactones, polycaprolactone diols, poly(acetic acid)s, poly(vinyl acetates)s, poly(2-vinyl pyridine)s, cellulose esters, cellulose hydroxyl ethers, poly(L-lysine hydrobromide)s, poly(itaconic acid)s, poly(maleic acid)s, poly(styrenesulfonic acid)s, poly(aniline)s, or poly(vinyl phosphonic acid)s.
- Examples of lipophilic moieties include, without limitation, linear or branched alkyls, including 1-28C hydrocarbons.
- Examples of groups which may be coupled to a synthon or macrocyclic module as a lipophilic group include alkyls, —CH ⁇ CH—R, —C ⁇ C—R, —OC(O)—R, —C(O)O—R, —NHC(O)—R, —C(O)NH—R, and —O—R, where R is 4-18C alkyl.
- Each chain may independently comprise, without limitation, alkenyl, alkynyl, saturated and unsaturated cyclic hydrocarbons, or aromatic groups.
- Each chain may also contain, interspersed among the carbons of the chain, one or more silicon atoms substituted with alkyl, alkenyl, alkynyl, saturated and unsaturated cyclic hydrocarbons, or aryl groups.
- the carbon atoms of each chain may independently be substituted with one or more fluorine atoms.
- the carbon atoms of an alkyl group may be interrupted by one or more functional groups such as, for example, —S—, double bond, triple bond or —SiR′R′′— groups, any of which may be substituted with one or more fluorine atoms, and any combination of such functional groups may be used.
- the terms “coupling” and “coupled” with respect to molecular moieties or species, molecules, synthons, and macrocyclic modules refers to their attachment or association with other molecular moieties or species, atoms, molecules, synthons, or macrocyclic modules, whether the attachment or association is specific or non-specific, reversible or non-reversible, is the result of chemical reaction, or the result of direct or indirect physical interactions, complexation, charge transfer, or as the result of magnetic, electrostatic, or electromagnetic interaction.
- Coupling may be specific or non-specific, and the bonds formed by a coupling reaction are often covalent bonds, or polar-covalent bonds, or mixed ionic-covalent bonds, and may sometimes be Coulombic forces, ionic or electrostatic forces or interactions.
- the term “functional group” includes, but is not limited to, chemical groups, organic groups, inorganic groups, organometallic groups, aryl groups, heteroaryl groups, cyclic hydrocarbon groups, amino (—NH 2 ), hydroxyl (—OH), cyano (—C ⁇ N), nitro (NO 2 ), carboxyl (—COOH), formyl (—CHO), keto (—CH 2 C(O)CH 2 —), alkenyl (—C ⁇ C—), alkynyl, (—C ⁇ C—), and halo (F, Cl, Br and I) groups.
- synthon refers to a molecule used to make a macrocyclic module.
- a synthon may be substantially one isomeric configuration, for example, a single enantiomer.
- a synthon may be substituted with functional groups which are used to couple a synthon to another synthon or synthons, and which are part of the synthon.
- a synthon may be substituted with an atom or group of atoms which are used to impart hydrophilic, lipophilic, or amphiphilic character to the synthon or to species made from the synthon.
- a synthon may be substituted with an atom or group of atoms to form one or more functional groups on the synthon which may be used to couple the synthon to another synthon or synthons.
- the synthon before being substituted with functional groups or groups used to impart hydrophilic, lipophilic, or amphiphilic character may be called the core synthon.
- the term “synthon” refers to a core synthon, and also refers to a synthon substituted with functional groups or groups used to impart hydrophilic, lipophilic, or amphiphilic character.
- cyclic synthon refers to a synthon having one or more ring structures.
- ring structures include aryl, heteroaryl, and cyclic hydrocarbon structures including bicyclic ring structures and multicyclic ring structures.
- core cyclic synthons include, but are not limited to, benzene, cyclohexadiene, cyclopentadiene, naphthalene, anthracene, phenylene, phenanthracene, pyrene, triphenylene, phenanthrene, pyridine, pyrimidine, pyridazine, biphenyl, bipyridyl, cyclohexane, cyclohexene, decalin, piperidine, pyrrolidine, morpholine, piperazine, pyrazolidine, quinuclidine, tetrahydropyran, dioxane, tetrahydrothiophene, tetrahydrofuran, pyrrole, cyclopentane, cyclopentene, triptycene, adamantane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo
- a core synthon comprises all isomers or arrangements of coupling the core synthon to other synthons.
- the core synthon benzene includes synthons such as 1,2- and 1,3-substituted benzenes, where the linkages between synthons are formed at the 1,2- and 1,3-positions of the benzene ring, respectively.
- the core synthon benzene includes 1,3-substituted synthons such as
- L is a linkage between synthons and the 2,4,5,6 positions of the benzene ring may also have substituents.
- a condensed linkage between synthons involves a direct coupling between a ring atom of one cyclic synthon to a ring atom of another cyclic synthon, for example, where synthons M—X and M—X couple to form M—M, where M is a cyclic synthon and X is halogen; as for example when M is phenyl resulting in the condensed linkage
- activated acid refers to a —C(O)R moiety in which the R group is readily displaced by a nucleophile to form a covalent bond between the —C(O)— and the nucleophile.
- activated acids include acid chlorides, acid fluorides, p-nitrophenyl esters, pentafluorophenyl esters, and N-hydroxysuccinimide esters.
- amino acid residue refers to the product formed when a species comprising at least one amino (—NH 2 ) and at least one carboxyl (—C(O)O—) group couples through either of its amino or carboxyl groups with an atom or functional group of a synthon. Whichever of the amino or carboxyl groups is not involved in the coupling may be blocked with a removable protective group.
- a macrocyclic module is a closed ring of coupled synthons.
- synthons may be substituted with functional groups to couple the synthons to form a macrocyclic module.
- Synthons may also be substituted with functional groups which will remain in the structure of the macrocyclic module.
- Functional groups which remain in the macrocyclic module may be used to couple the macrocyclic module to other macrocyclic modules.
- a macrocyclic module may contain from three to about twenty-four cyclic synthons.
- a first cyclic synthon may be coupled to a second cyclic synthon
- the second cyclic synthon may be coupled to a third cyclic synthon
- the third cyclic synthon may be coupled to a fourth cyclic synthon, if four cyclic synthons are present in the macrocyclic module, the fourth to a fifth, and so on, until an n th cyclic synthon may be coupled to its predecessor, and the n th cyclic synthon may be coupled to the first cyclic synthon to form a closed ring of cyclic synthons.
- the closed ring of the macrocyclic module may be formed with a linker molecule.
- a macrocyclic module may be an amphiphilic macrocyclic module when hydrophilic and lipophilic functional groups exist in the structure.
- the amphiphilic character of a macrocyclic module may arise from atoms in the synthons, in the linkages between synthons, or in functional groups coupled to the synthons or linkages.
- one or more of the synthons of a macrocyclic module may be substituted with one or more lipophilic moieties, while one or more of the synthons may be substituted with one or more hydrophilic moieties, thereby forming an amphiphilic macrocyclic module.
- Lipophilic and hydrophilic moieties may be coupled to the same synthon or linkage in an amphiphilic macrocyclic module.
- Lipophilic and hydrophilic moieties may be coupled to the macrocyclic module before or after formation of the closed ring of the macrocyclic module.
- lipophilic or hydrophilic moieties may be added to the macrocyclic module after formation of the closed ring by substitution of a synthon or linkage.
- the amphiphilicity of a macrocyclic module may be characterized in part by its ability to form a stable Langmuir film.
- a Langmuir film may be formed on a Langmuir trough at a particular surface pressure measured in milliNewtons per meter (mN/m) with a particular barrier speed measured in millimeters per minute (mm/min), and the isobaric creep or change in film area at constant surface pressure can be measured to characterize stability of the film.
- mN/m milliNewtons per meter
- mm/min millimeters per minute
- a stable Langmuir film of macrocyclic modules on a water subphase may have an isobaric creep at 5-15 mN/m such that the majority of the film area is retained over a period of time of about one hour.
- Examples of stable Langmuir films of macrocyclic modules on a water subphase may have isobaric creep at 5-15 mN/m such that about 70% of the film area is retained over a period of time of about 30 minutes, sometimes about 70% of the film area is retained over a period of time of about 40 minutes, sometimes about 70% of the film area is retained over a period of time of about 60 minutes, and sometimes about 70% of the film area is retained over a period of time of about 120 minutes.
- stable Langmuir films of macrocyclic modules on a water subphase may have isobaric creep at 5-15 mN/m such that about 80% of the film area is retained over a period of time of about thirty minutes, sometimes about 85% of the film area is retained over a period of time of about thirty minutes, sometimes about 90% of the film area is retained over a period of time of about thirty minutes, sometimes about 95% of the film area is retained over a period of time of about thirty minutes, and sometimes about 98% of the film area is retained over a period of time of about thirty minutes.
- an individual macrocyclic module may include a pore in its structure.
- Each macrocyclic module may define a pore of a particular size, depending on the conformation and state of the module.
- Various macrocyclic modules may be prepared which define pores of different sizes.
- a macrocyclic module may include a flexibility in its structure. Flexibility may permit a macrocyclic module to more easily form linkages with other macrocyclic modules by coupling reactions. Flexibility of a macrocyclic module may also play a role in regulating passage of species through the pore of the macrocyclic module. For example, flexibility may affect the dimension of the pore of a macrocyclic module since various conformations may be available to the structure. For example, a macrocyclic module may have a certain pore dimension in one conformation when no substituents are located at the pore, and have a different pore dimension in another conformation when one or more substituents are located at the pore.
- a macrocyclic module may have a certain pore dimension in one conformation when one group of substituents are located at the pore, and have a different pore dimension in a different conformation when a different group of substituents are located at the pore.
- the “one group” of substituents located at the pore may be three alkoxy groups arranged in one regioisomer, while the “different group” of substituents may be two alkoxy groups arranged in another regioisomer.
- the effect of the “one group” of substituents located at the pore and the “different group” of substituents located at the pore is to provide a macrocyclic module composition which may regulate transport and filtration, in conjunction with other regulating factors.
- the synthons may be used as a substantially pure single isomer, for example, as a pure single enantiomer.
- one or more coupling linkages are formed between adjacent synthons.
- the linkage formed between synthons may be the product of the coupling of one functional group on one synthon to a complementary functional group on a second synthon.
- a hydroxyl group of a first synthon may couple with an acid group or acid halide group of a second synthon to form an ester linkage between the two synthons.
- Another example is an imine linkage, —CH ⁇ N—, resulting from the reaction of an aldehyde, —CH ⁇ O, on one synthon with an amine, —NH 2 , on another synthon. Examples of complementary functional groups and linkages between synthons are shown in Table 1.
- R and R′ represent hydrogen or organic groups, and X is halogen or other good leaving groups.
- a macrocyclic module may have functional groups for coupling to other macrocyclic modules which were coupled to the macrocyclic module after initial preparation of the closed ring.
- an imine linkage of a macrocyclic module may be substituted with one of various functional groups to produce additional macrocyclic modules. Examples of linkages between synthons having functional groups for coupling macrocyclic modules are shown in Table 2. TABLE 2 Examples of functional groups of synthons and synthon linkages Functional Group of Macrocyclic Substituted Module Linkage Reagent Linkage X— ⁇ —H
- the functional groups of synthons used to form linkages between synthons may be separated from the synthon by a spacer.
- a spacer can be any atom or group of atoms which couples the functional group to the synthon, and does not interfere with the linkage-forming reaction.
- a spacer is part of the functional group, and becomes part of the linkage between synthons.
- An example of a spacer is a methylene group, —CH 2 —.
- the spacer may be said to extend the linkage between synthons. For example, if one methylene spacer were inserted in an imine linkage, —CH ⁇ N—, the resulting imine linkage may be —CH 2 CH ⁇ N—.
- a linkage between synthons may also contain one or more atoms provided by an external moiety other than the two functional groups of the synthons.
- An external moiety may be a linker molecule which may couple with the functional group of one synthon to form an intermediate which couples with a functional group on another synthon to form a linkage between the synthons, such as, for example, to form a closed ring of synthons from a series of coupled synthons.
- An example of a linker molecule is formaldehyde.
- amino groups on two synthons may undergo Mannich reaction in the presence of formaldehyde as the linker molecule to produce the linkage —NHCH 2 NH—.
- a macrocyclic module may be a closed ring composition of the formula:
- the closed ring comprises a total of from three to twenty-four synthons Q; J is 2-23;
- Q 1 are synthons each independently selected from the group consisting of (a) aryl synthons, (b) heteroaryl synthons, (c) saturated cyclic hydrocarbon synthons, (d) unsaturated cyclic hydrocarbon synthons, (e) saturated bicyclic hydrocarbon synthons, (f) unsaturated bicyclic hydrocarbon synthons, (g) saturated multicyclic hydrocarbon synthons, and (h) unsaturated multicyclic hydrocarbon synthons; wherein ring positions of each Q 1 which are not coupled to a linkage L are substituted with hydrogen or organic functional groups containing atoms selected from the group of C, H, N, O, Si, P, S, B, Al, halogens, and metals from the alkali and alkaline earth groups;
- Q 2 is a synthon independently selected from the group consisting of (a) aryl synthons, (b) heteroaryl synthons, (c) saturated cyclic hydrocarbon synthons, (d) unsaturated cyclic hydrocarbon synthons, (e) saturated bicyclic hydrocarbon synthons, (f) unsaturated bicyclic hydrocarbon synthons, (g) saturated multicyclic hydrocarbon synthons, and (h) unsaturated multicyclic hydrocarbon synthons; wherein ring positions of Q 2 which are not coupled to an L are substituted with hydrogen or organic functional groups containing atoms selected from the group consisting of C, H, N, O, Si, P, S, B, Al, halogens, and metals from the alkali and alkaline earth groups;
- L are linkages between the synthons each independently selected from the group consisting of synthon-synthon, —NRC(O)—, —OC(O)—, —O—, —S—S—, —S—, —NR—, —(CRR′) p —, —CH 2 NH—, —C(O)S—, —C(O)O—, —C ⁇ C—, —C ⁇ C—C ⁇ C—, —CH(OH)—, —HC ⁇ CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH 2 NH—, —NHCH 2 CH(OH)CH 2 NH—, —N ⁇ CH(CH 2 ) p CH ⁇ N—, —CH 2 CH(OH)CH 2 —, —N ⁇ CH(CH 2 ) h CH ⁇ N— where h is 1-4, —CH ⁇ N—NH—, —OC(O)O—, —
- R and R′ are each independently selected from the group of hydrogen and alkyl; wherein the linkages L are each independently configured with respect to the Q 1 and Q 2 synthons, each L having either of its two possible configurations with respect to the synthons it couples together, the forward and reverse configurations of the linkage with respect to the immediately adjacent synthons to which it couples, for example, Q 1 a —NHC(O)—Q 1 b and Q 1 a —C(O)NH—Q 1 b , if the two configurations are isomerically different structures.
- Synthons Q 1 when independently selected, may be any cyclic synthon as described, so that the J synthons Q 1 may be found in the closed ring in any order, for example, cyclohexyl--1,2-phenyl--piperidinyl--1,2-phenyl--1,2-phenyl--cyclohexyl, and so on, and the J linkages L may also be independently selected and configured in the closed ring.
- the macrocyclic modules represented and encompassed by the formula include all stereoisomers of the synthons involved, so that a wide variety of stereoisomers of the macrocyclic module are included for each closed ring composition of synthons.
- a macrocyclic module may include functional groups for coupling the macrocyclic module to a solid surface, substrate, or support.
- functional groups of macrocyclic modules which can be used to couple to a substrate or surface include amine, carboxylic acid, carboxylic ester, benzophenone and other light activated crosslinkers, alcohol, glycol, vinyl, styryl, olefin styryl, epoxide, thiol, magnesium halo or Grignard, acrylate, acrylamide, diene, aldehyde, and mixtures thereof.
- These functional groups may be coupled to the closed ring of the macrocyclic module, and may optionally be attached by a spacer group.
- solid surfaces include metal surfaces, ceramic surfaces, polymer surfaces, semiconductor surfaces, silicon wafer surfaces, alumina surfaces, and so on.
- functional groups of macrocyclic modules which can be used to couple to a substrate or surface further include those described in the left hand column of Tables 1 and 2. Methods of initiating coupling of the modules to the substrate include chemical, thermal, photochemical, electrochemical, and irradiative methods.
- spacer groups include polyethylene oxides, polypropylene oxides, polysaccharides, polylysines, polypeptides, poly(amino acids), polyvinylpyrrolidones, polyesters, polyvinylchlorides, polyvinylidene fluorides, polyvinylalcohols, polyurethanes, polyamides, polyimides, polysulfones, polyethersulfones, polysulfonamides, and polysulfoxides.
- a substrate may have functional groups which couple to the macrocyclic modules.
- the functional groups of the substrate may be surface groups or linking groups bound to the substrate, which may be formed by reactions which bind the surface groups or linking groups to the substrate.
- Surface groups may also be created on the substrate by a variety of treatments such as cold plasma treatment, surface etching methods, solid abrasion methods, or chemical treatments. Some methods of plasma treatment are given in Inagaki, Plasma Surface Modification and Plasma Polymerization , Technomic, Lancaster, Pa., 1996.
- the functional groups of the macrocyclic modules and the surface may be blocked with protecting groups until needed.
- a photoreactive group such as a benzophenone group is bound to the surface or substrate.
- the photoreactive group may be activated with light, for example, ultraviolet light to provide a reactive species which couples to a macrocyclic module.
- modules useful as building blocks are shown in Table 3.
- TABLE 3 Examples of macrocyclic modules Macrocyclic Module Structure Hexamer 1a Hexamer 1dh Hexamer 3j - amine Hexamer 1jh Hexamer 2j - amine/ester Hexamer 1dh - acryl Octamer 5jh - aspartic Octamer 4jh - acryl
- An individual macrocyclic module may include a pore in its structure.
- the size of the pore may determine the size of molecules or other species which can pass through the macrocyclic module.
- the size of a pore in a macrocyclic module may depend on the structure of the synthons used to make the macrocyclic module, the linkages between synthons, the number of synthons in a module, the structure of any linker molecules used to make the macrocyclic module, and other structural features of the macrocyclic module whether inherent in the preparation of the macrocyclic module or added in later steps or modifications.
- Stereoisomerism of macrocyclic modules may also be used to regulate the size of a pore of a macrocyclic module by variation of the stereoisomer of each synthon used to prepare the closed ring of the macrocyclic module.
- the dimension of a pore in a macrocyclic module may be varied by changing the combination of synthons used to form the macrocyclic module, or by varying the number of synthons in the closed ring.
- the dimension of a pore may also be varied by substituents on the synthons or linkages. The pore may therefore be made large enough or small enough to achieve an effect on transport of species through the pore.
- Species which may be transported through the pore of a macrocyclic module include atoms, molecules, biomolecules, ions, charged particles, and photons.
- the size of a species may not be the sole determinant of whether it will be able to pass through a pore of a macrocyclic module.
- Groups or moieties located in or near the pore structure of a macrocyclic module may regulate or affect transport of a species through the pore by various mechanisms.
- transport of a species through the pore may be affected by groups of the macrocyclic module which interact with the species, by ionic or other interaction, such as chelating groups, or by complexing the species.
- a charged group such as a carboxylate anion or ammonium group may couple an oppositely-charged species and affect its transport.
- Substituents of synthons in a macrocyclic module may affect the passage of a species through the pore of the macrocyclic module.
- Groups of atoms which render the pore of a macrocyclic module more or less hydrophilic or lipophilic may affect transport of a species through the pore.
- An atom or group of atoms may be located within or proximate to a pore to sterically slow or block the passage of a species through the pore.
- hydroxyl or alkoxy groups may be coupled to a cyclic synthon and located in the pore of the structure of the macrocyclic module, or may be coupled to a linkage between synthons and located in the pore.
- a wide range of functional groups may be used to sterically slow or block the passage of a species through the pore, including organic functional groups containing atoms selected from the group consisting of C, H, N, O, Si, P, S, B, Al, halogens, and metals from the alkali and alkaline earth groups.
- Blocking and slowing passage of a species through the pore may involve reducing the dimension of the pore by steric blocking, as well as slowing the passage of species by creating a path through the pore which is not linear, and providing interaction between the functional group and the species to slow transport.
- the stereochemical structure of the portion of the macrocyclic module which defines the pore and its interior may also affect transport.
- Any groups or moieties which affect transport of a species through the pore of a macrocyclic module may be introduced as part of the synthons used to prepare the macrocyclic module, or may be added later by various means.
- S7-1 could be reacted with ClC(O)(CH 2 ) 2 C(O)OCH 2 CH 3 to convert the phenol groups to succinyl ester groups.
- molecular dynamical motion of the synthons and linkages of a partly flexible macrocyclic module may affect transport of a species through the pore of the module.
- Transport behavior may not be described solely by the structure of the macrocyclic module itself since the presence of the species which is to be transported through the pore affects the flexibility, conformation, and dynamical motions of a macrocyclic module.
- solvent may also affect transport of solutes through a pore.
- Macrocyclic modules and arrays of macrocyclic modules may be useful in size exclusion separations, ion separation, gas separation, separation of enantiomers, small molecule separation, water purification, filtration of bacteria, fungi, or viruses, sewage treatment, and toxin removal, among other uses.
- stereospecific or at least stereoselective coupling reactions may be employed in the preparation of the synthons of this invention.
- the following are examples of synthetic schemes for several classes of synthons useful in the preparation of macrocyclic modules of this invention. In general, the core synthons are illustrated, and lipophilic moieties are not shown on the structures, however, it is understood that all of the following synthetic schemes might encompass additional lipophilic or hydrophilic moieties used to prepare amphiphilic and other modified macrocyclic modules. Species are numbered in relation to the scheme in which they appear; for example, “S1-1” refers to the structure 1 in Scheme 1.
- symmetrical diester S1-1 is used to give enantiomerically pure S1-2.
- S1-2 is subjected to the Curtius reaction and then quenched with benzyl alcohol to give protected amino acid S1-3.
- Iodolactonization of carboxylic acid S1-4 followed by dehydrohalogenation gives unsaturated lactone S1-6.
- Opening of the lactone ring with sodium methoxide gives alcohol S1-7, which is converted with inversion of configuration to S1-8 in a one-pot reaction involving mesylation, SN 2 displacement with azide, reduction and protection of the resulting amine with di-tert-butyl dicarbonate.
- S1-10 Epimerization of S1-8 to the more stable diequatorial configuration followed by saponification gives carboxylic acid S1-10.
- S1-10 is subjected to the Curtius reaction.
- a mixed anhydride is prepared using ethyl chloroformate followed by reaction with aqueous NaN 3 to give the acyl azide, which is thermally rearranged to the isocyanate in refluxing benzene.
- the isocyanate is quenched with 2-trimethylsilylethanol to give differentially protected tricarbamate S1-11.
- Reaction with trifluoroacetic acid (TFA) selectively deprotects the 1,3-diamino groups to provide the desired synthon S1-12.
- TFA trifluoroacetic acid
- Norbornanes may be used to prepare synthons of this invention, and stereochemically controlled multifunctionalization of norbornanes can be achieved.
- Diels-Alder cycloaddition may be used to form norbornanes incorporating various functional groups having specific, predictable stereochemistry.
- Enantiomerically enhanced products may also be obtained through the use of appropriate reagents, thus limiting the need for chiral separations.
- Synthons maybe coupled to one another to form macrocyclic modules.
- the coupling of synthons may be accomplished in a concerted scheme.
- Preparation of a macrocyclic module by the concerted route requires at least two types of synthons, each type having at least two functional groups for coupling to other synthons.
- the functional groups may be selected so that a functional group of one type of synthon can couple only to a functional group of the other type of synthon.
- a macrocyclic module may be formed having alternating synthons of different types.
- Scheme 7 illustrates a concerted module synthesis.
- 1,2-Diaminocyclohexane, S7-1 is a synthon having two amino functional groups for coupling to other synthons
- 2,6-diformyl-4-dodec-1-ynylphenol, S7-2 is a synthon having two formyl groups for coupling to other synthons.
- An amino group may couple with a formyl group to form an imine linkage.
- a concerted product hexamer macrocyclic module is shown.
- a mixture of tetramer, hexamer, and octamer macrocyclic modules may be formed in the concerted scheme.
- the yields of these macrocyclic modules can be varied by changing the concentration of various synthons in the reagent mixture, and among other factors, by changing the solvent, temperature, and reaction time.
- the imine groups of S7-3 can be reduced, e.g. with sodium borohydride, to give amine linkages. If the reaction is carried out using 2,6-di(chlorocarbonyl)-4-dodec-1-ynylphenol instead of 2,6-diformyl-4-dodec-1-ynylphenol, the resulting module will contain amide linkages. Similarly, if 1,2-dihydroxycyclohexane is reacted with 2,6-di(chlorocarbonyl)-4-dodec-1-ynylphenol, the resulting module will contain ester linkages.
- the coupling of synthons may be accomplished in a stepwise scheme.
- a first type of synthon is substituted with one protected functional group and one unprotected functional group.
- a second type of synthon is substituted with an unprotected functional group that will couple with the unprotected functional group on the first synthon.
- the product of contacting the first type of synthon with the second type of synthon may be a dimer, which is made of two coupled synthons.
- the second synthon may also be substituted with another functional group which is either protected, or which does not couple with the first synthon when the dimer is formed.
- the dimer may be isolated and purified, or the preparation may proceed as a one-pot method.
- the dimer may be contacted with a third synthon having two functional groups, only one of which may couple with the remaining functional group of either the first or second synthons to form a trimer, which is made of three coupled synthons.
- Such stepwise coupling of synthons may be repeated to form macrocyclic modules of various ring sizes.
- the n th synthon which was coupled to the product may be substituted with a second functional group which may couple with the second functional group of a previously coupled synthon that has not been coupled, which may be deprotected for that step.
- the stepwise method may be carried out with synthons on solid phase support.
- Scheme 8 illustrates a stepwise preparation of module SC8-1.
- Deprotection/coupling is repeated, alternating synthons S8-3 and S8-6 until a linear construct with eight residues is obtained.
- the remaining acid and amine protecting groups on the 8-mer are removed and the oligomer is cyclized, see e.g., Caba, J. M., et al., J. Org. Chem. , 2001, 66:7568 (PyAOP cyclization) and Tarver, J. E. et al., J. Org. Chem ., 2001, 66:7575 (active ester cyclization).
- the R group is H or an organic functional group
- X is N, O, or S.
- solid supports examples include Wang resin, hydrogels, silica gels, sepharose, sephadex, agarose, and inorganic solids. Using a solid support might simplify the procedure by obviating purification of intermediates along the way. The final cyclization may be done in a solid phase mode.
- a “safety-catch linker” approach (Bourne, G. T., et al., J. Org. Chem ., 2001, 66:7706) may be used to obtain cyclization and resin cleavage in a single operation.
- a concerted method involves contacting two or more different synthons and a linker molecule as shown in Scheme 9, where R may be an alkyl group or other lipophilic group.
- a stepwise linear method involves various synthons and a solid phase support as shown in Scheme 10.
- a stepwise convergent method involves synthon trimers and a solid phase support as shown in Scheme 11. This method can also be done without the solid phase support using trimers in solution.
- a template method involves synthons brought together by a template as shown in Scheme 12.
- a linker molecule method involves cyclizing synthons in solution as shown in Scheme 13.
- S1-1 (15.0 g, 75.7 mmol) was suspended in pH 7 phosphate buffer (950 mL). Pig liver esterase (2909 units) was added, and the mixture stirred at ambient temperature for 72 h with the pH maintained at 7 by addition of 2M NaOH. The reaction mixture was washed with ethyl acetate (200 mL), acidified to pH 2 with 2M HCl, and extracted with ethyl acetate (3 ⁇ 200 mL). The extracts were combined, dried, and evaporated to afford 13.8 g (99%) of S1-2.
- S1-9 (0.85 g, 2.1 mmol) was suspended in 50:50 MeOH/dichloromethane (5 mL) and cooled to 0° C. under N 2 after which 2M NaOH (2.0 mL) was added and the mixture stirred at ambient temperature for 16 h. The mixture was acidified with 2M HCl upon which a white precipitate formed. The precipitate was collected, washed with water and hexane, and dried to give 0.74 g (90%) of S1-10.
- S1-11 (2.5 g, 4.9 mmol) was added to TFA (10 mL) and the solution stirred at ambient temperature for 16 h after which the solution was evaporated. The residue was dissolved in water (20 mL), basified to pH 14 with KOH and extracted with dichloromethane (3 ⁇ 50 mL). The extracts were combined, washed with water (20 mL), dried and evaporated to give 1.1 g (85%) of S1-12.
- the mixture was stirred at room temperature and work-up initiated when the starting material S1b-1 was completely consumed (Using a solvent system of 66% EtOAc/33% Hexane and developing with phosphomolybdic acid reagent (Aldrich #31,927-9) the starting material S1b-1 has an Rf of 0.88 and the product streaks with an Rf of approx. 0.34 to 0.64.).
- the reaction usually takes 2 days.
- Work-Up The THF was removed by vacuum transfer until about the same volume is left as water added to the reaction, in this case 50 mL. During this the reaction solution forms a white mass that adheres to the stir bar surrounded by clear yellow solution.
- a separatory funnel is set up including a funnel to pour in the reaction solution and an Erlenmeyer flask is placed underneath the separatory funnel. Into the Erlenmeyer flask is added some anhydrous Na 2 SO 4 .
- This apparatus should be set up before acidification is started. (It is important to set up the separatory funnel and Erlenmeyer flask etc. before acidification of the reaction solution to enable separation of phases and extraction of the product away from the acid quickly once the solution attains a pH close to 1.
- the stopcock is turned to release the CH 2 Cl 2 phase (bottom) into the Erlenmeyer flask and swirl the flask to allow the drying agent to absorb water in the solution.
- 80 mL of 1N HCl was used.
- the aqueous phase is extracted with CH 2 Cl 2 (2 ⁇ 100 mL), dried over anhydrous Na 2 SO 4 and the volatiles removed to produce 5.37 g/9.91 mmoles of a beautiful white microcrystals reflecting a 99.1% yield.
- This product can not be purified by chromatography since that process would also hydrolyze the Boc functional group on the column.
- S4-29 (0.220 g, 0.00050 mol) was added to a mixture of tetrahydrofuran (1.5 mL), water (0.5 mL), and methanol (0.5 mL). Potassium hydroxide (0.036 g, 0.00065 mol) was added and the solution stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue purified by column chromatography (10% ethyl acetate/hexanes) to give S4-30 (0.050 g, 0.00012 mol, 23% yield).
- Mass Spec calculated for C 26 H 34 O 5 426.24; found 425.4 (M ⁇ 1) and 851.3 (2M ⁇ 1).
- reaction S5-40 is converted to the corresponding mesylate with methanesulfonyl chloride, sodium azide added to displace the mesylate to give exo-azide, which is followed by reduction with tributyl phosphine to give the free amine, which is protected as the t-Boc derivative to give S5-41.
- the benzyl ether protecting group is removed by catalytic hydrogenolysis of S5-41 with 10% Pd/C in methanol at room temperature for 6 hours. Filtration of the catalyst and removal of the solvent yields crude S5-42.
- S6-50 formic acid, and a catalytic amount of p-toluenesulfonic acid is heated at 90° C. overnight. Acetic anhydride is added to the reaction mixture, and it is refluxed for an additional 6 hours. Removal of the solvents and washing with ether affords S6-51.
- one method to approximate pore size of a macrocyclic module is quantum mechanical (QM) and molecular mechanical (MM) computations.
- QM quantum mechanical
- MM molecular mechanical
- the root mean square deviations in the pore areas were computed over dynamic runs.
- each module was first optimized using the MM+ force field approach of Allinger (JACS, 1977, 99:8127) and Burkert, et al., (Molecular Mechanics, ACS Monograph 177, 1982). They were then re-optimized using the AM1 Hamiltonian (Dewar, et al., JACS, 1985, 107:3903; Dewar, et al., JACS, 1986, 108:8075; Stewart, J. Comp. Aided Mol. Design, 1990, 4:1). To verify the nature of the potential energy surface in the vicinity of the optimized structures, the associated Hessian matrices were computed using numerical double-differencing.
- Macrocyclic module pore areas derived from QM and MM computations for various linkages and macrocyclic module pore size are shown in Table 4.
- the macrocyclic modules had alternating synthons “A” and “B.”
- Synthon “A” is a benzene synthon coupled to linkages L at 1,3-phenyl positions, and Synthon “B” is shown in the left-hand column of the table.
- FIGS. 1A and 1B An example of the energy-minimized conformations of some hexamer macrocyclic modules having groups of substituents are shown in FIGS. 1A and 1B.
- a Hexamer 1-h-(OH) 3 is shown having a group of —OH substituents.
- FIG. 1B a Hexamer 1-h-(OEt) 3 is shown having a group of —OEt substituents.
- This macrocyclic module results in a composition which may be used to regulate pores. Selection of ethoxy synthon substituents over hydroxy synthon substituents for this hexamer composition is a method which may be used for transporting selected species.
- the pore size of macrocyclic modules was determined experimentally using a voltage-clamped bilayer procedure.
- a quantity of a macrocyclic module was inserted into a lipid bilayer formed by phosphatidylcholine and phosphatidylethanolamine.
- On one side of the bilayer was placed a solution containing the cationic species to be tested.
- On the other side was a solution containing a reference cationic species known to be able to pass through the pore of the macrocyclic module.
- Anions required for charge balance were selected which could not pass through the pores of the macrocyclic module.
- a hexameric macrocyclic module comprised of 1R,2R-( ⁇ )-transdiaminocyclohexane and 2,6-diformal-4-(1-dodec-1-ynyl)phenol synthons, having imine groups as the linkages (the first module in Table 3) was tested for transport of various ionic species. The results are shown in Table 6. TABLE 6 Voltage-clamped bilayer test for macrocyclic module pore size Calculated van der Calculated van der Waals radius of ionic Waals radius of species with one Does ionic species Ionic species ionic species ( ⁇ ) water shell ( ⁇ ) pass through pore?
- CH 3 NH 3 + having a radius of 2.0 ⁇ , passed through the pore while CH 3 CH 2 NH 3 + , with a radius of 2.6 ⁇ , did not.
- the observed ability of hydrated ions to pass through the pore may be due to partial dehydration of the species to enter the pore, transport of water molecules and ions through the pore separately or with reduced interaction during transport, and re-coordination of water molecules and ions after transport.
- the details of pore structure, composition, and chemistry, the flexibility of the macrocyclic module, and other interactions may affect the transport process.
- the relative stability of the Langmuir film of Hexamer 1a-Me is illustrated by the isobaric creep data shown in FIG. 2B.
- the area of the film decreased by about 30% after about 30 min at 5 mN/m surface pressure.
- the Langmuir isotherm and isobaric creep for Hexamer 1a-C15 are shown in FIGS. 3A and 3B, respectively.
- the relative stability of the Langmuir film of Hexamer 1a-C15 is illustrated by the isobaric creep data shown in FIG. 3B.
- the area of the film decreased by about 1-2% after about 30 min at 10 mN/m surface pressure, and by about 2% after about 60 min.
- the collapse pressure was about 18 mN/m for Hexamer 1a-C15.
- Hexamer 1jh To a 100 mL pear-shaped flask with magnetic stirbar under argon, Hexamer 1j (0.387 mmol, 0.594 g) was added and dissolved in THF:MeOH (7:3, 28:12 mL, respectively). Next, NaBH 4 (2.32 mmol, 0.088 g) was added slowly in portions at room temperature for 6.5 h. The solvent was removed by roto-evaporation, the residue dissolved in 125 mL ethyl acetate and washed 3 ⁇ 50 mL of H 2 O. The organic layer was separated, dried over Na 2 SO 4 and the solvent removed by roto-evaporation.
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Abstract
Macrocyclic module compositions are made from cyclic synthons. The macrocyclic module structures are prepared by stepwise or concerted schemes which couple synthons in a closed ring. The macrocyclic module structures may have a pore of nanometer dimensions.
Description
- This is a continuation-in-part of application Ser. No. 10/071,377, filed Feb. 7, 2002, now abandoned.
- This invention is related to the fields of organic chemistry and nanotechnology. In particular, it relates to materials and methods for the preparation of synthons used to construct macrocyclic module compositions.
- One area of nanotechnology is to develop chemical building blocks from which hierarchical molecules of predicted properties can be assembled. An approach to making chemical building blocks or nanostructures begins at the atomic and molecular level by designing and synthesizing starting materials with highly tailored properties. Precise control at the atomic level is the foundation for development of rationally tailored synthesis-structure-property relationships which can provide materials of unique structure and predictable properties. This approach to nanotechnology is inspired by nature where, for example, from twenty common amino acids found in natural proteins, more than 105 stable and unique proteins are made.
- Nanotechnology has also been described by K. Eric Drexler inEngines of Creation as “the knowledge and means for designing, fabricating and employing molecular scale devices by the manipulation and placement of individual atoms and molecules with precision on the atomic scale.” A quest of nanotechnology is to prepare molecular architectures capable of performing on a nanometer scale functions normally observed for large-scale constructs. For example, rotaxanes and polyrotaxanes are molecules that are interlocked, but not chemically bound to one another, which act like nano-machines. In other examples, carbon nanotubes and similar constructs have been created which may function as molecular scaffold units, or as transport channels, storage units, or encapsulators for various atoms and molecules. The use of biological processes is also being studied as an approach to the assembly of non-biological nano-devices. For example, U.S. Pat. No. 5,468,851 discloses building various structures from polynucleotide segments.
- In U.S. Pat. No. 5,876,830 an approach to the construction of macromolecular structures by coupling molecular modules using connectors, spacers, and binders is described. The modules were adhered to a surface and reacted to form grids or nets on the surface.
- International Patent Application WO 01/27028 A1 describes structural sub-units or synthons which could be used to prepare molecular nanostructures, machines and devices. Synthons used were closo-carboranes, which are rigid polyhedral structures, selected for their availability and requisite substitutional control and structural diversity.
- Some aspects of nanotechnology are described inChemical Reviews, 1999(7).
- One field that will benefit from nanotechnology is filtration using membranes. Conventional membranes used in a variety of separation processes can be made selectively permeable to various molecular species. The permeation properties of conventional membranes generally depend on the pathways of transport of species through the membrane structure. While the diffusion pathway in conventional selectively permeable materials can be made tortuous in order to control permeation, porosity is not well defined or controlled by conventional methods. The ability to fabricate regular or unique pore structures of membranes is a long-standing goal of separation technology.
- In one example, the formation of selectively permeable membranes of monomolecular thickness was described by Hendel, et al.,Journal of the Amer. Chem. Soc., 1997, 119:6909-18, who reported preparation of calix[6]arenes and their deposition as Langmuir-Blodgett films on a porous poly[1(trimethylsilyl)-1-propyne] substrate, where the calix[6]arene molecules are not coupled or bound to each other in the film. A selectively permeable membrane was described for which the ratio of the normalized flux of helium gas to nitrogen gas was found to significantly exceed the conventional Graham's law prediction.
- Resistance to flow of species through a membrane may also be governed by the flow path length. Resistance can be greatly reduced by using a very thin film as a membrane, at the cost of reduced mechanical strength of the membrane material. Conventional membranes may have a barrier thickness of at least one to two hundred nanometers, and often up to millimeter thickness. In general, a thin film of membrane barrier material can be deposited on a porous substrate of greater thickness to restore material strength.
- Membrane separation processes are used to separate components from a fluid in which atomic or molecular components having sizes smaller than a certain “cut-off” size can be separated from components of larger size. Normally, species smaller than the cut-off size are passed by the membrane. The cut-off size may be an approximate empirical value which reflects the phenomenon that the rate of transport of components smaller than the cut-off size is merely faster than the rate of transport of larger components. In conventional pressure-driven membrane separation processes, the primary factors affecting separation of components are size, charge, and diffusivity of the components in the membrane structure. In dialysis, the driving force for separation is a concentration gradient, while in electrodialysis electromotive force is applied to ion selective membranes.
- Thus, what is needed is an approach to making chemical building blocks or nanostructures from starting materials with tailored properties.
- In one aspect, a macrocyclic module composition is provided which may be made from three to about twenty-four cyclic synthons. The synthons of the macrocyclic module composition form a closed ring.
- In some variations, a macrocyclic module composition may include functional groups for coupling to other macrocyclic modules. A composition may include two or more closed rings coupled together.
- In other variations, one or more functional groups may be coupled to one or more of the cyclic synthons of a macrocyclic module composition, the functional group(s) located at the pore of the composition, where the macrocyclic module composition may have a first pore dimension in a first conformation when a first group of substituents is located at the pore and a second pore dimension in a second conformation when a second group of substituents is located at the pore.
- In further variations, a composition may include a closed ring, a functional group coupled to the closed ring at the pore, and a selected species to be transported through the pore.
- In another aspect, a method is provided to make a composition to transport selected species through the composition, by selecting a first cyclic synthon substituted with at least one functional group and selecting from two to about twenty-three additional cyclic synthons, then incorporating the cyclic synthons into a macrocyclic module composition in which the functional group of the first cyclic synthon is located at the pore of the composition.
- In one variation, a macrocyclic module composition may be coupled to a solid support.
- In one aspect, a macrocyclic module composition is provided having from three to twenty-four cyclic synthons forming a closed ring of cyclic synthons which retains film area after a period of time on a Langmuir trough.
- In another aspect, a linkage is formed between coupled cyclic synthons.
- In another aspect, a method for making a macrocyclic module composition is provided wherein a plurality of a first cyclic synthon is contacted with a plurality of a second cyclic synthon, and the macrocyclic module composition is isolated therefrom. A linker molecule may be contacted with the mixture of synthons.
- In another variation, a method for making a macrocyclic module composition is provided wherein a plurality of a first cyclic synthon is contacted with a plurality of a second cyclic synthon, and a plurality of the first cyclic synthon is contacted with the mixture. The first cyclic synthon may be supported on a solid phase.
- In another variation, a method for making a macrocyclic module composition is provided wherein a plurality of a first cyclic synthon is contacted with a plurality of a second cyclic synthon, and a plurality of a third cyclic synthon is contacted with the mixture. The first cyclic synthon may be supported on a solid phase.
- In another variation, a method for making a macrocyclic module includes a template for bringing together synthons.
- FIG. 1A shows a representation of an example of the structure of an embodiment of a hexamer macrocyclic module.
- FIG. 1B shows a representation of an example of the structure of an embodiment of a hexamer macrocyclic module.
- FIG. 2A shows an example of the Langmuir isotherm of an embodiment of a hexamer macrocyclic module.
- FIG. 2B shows an example of the isobaric creep of an embodiment of a hexamer macrocyclic module.
- FIG. 3A shows an example of the Langmuir isotherm of an embodiment of a hexamer macrocyclic module.
- FIG. 3B shows an example of the isobaric creep of an embodiment of a hexamer macrocyclic module.
- Synthons for Macrocyclic Modules
- As used herein, the term “alkyl” refers to a branched or unbranched monovalent hydrocarbon radical. An “n-mC” alkyl or “(nC-mC)alkyl” refers to all alkyl groups containing from n to m carbon atoms. For example, a 1-4C alkyl refers to a methyl, ethyl, propyl, or butyl group. All possible isomers of an indicated alkyl are also included. Thus, propyl includes isopropyl, butyl includes n-butyl, isobutyl and t-butyl, and so on. The term alkyl includes substituted alkyls. As used herein, the term “substituted alkyl” refers to an alkyl group with an additional group or groups attached to any carbon of the alkyl group. Additional groups attached to a substituted alkyl may include one or more functional groups such as alkyl, aryl, acyl, halogen, alkylhalo, hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, aryloxy, aryloxyalkyl, mercapto, both saturated and unsaturated cyclic hydrocarbons, heterocycles, and others.
- As used herein, the terms “R,” “R′,” and “R″” in a chemical formula refer to a hydrogen or an organic group, each independently selected, unless stated otherwise.
- As used herein, the term “aryl” refers to an aromatic group which may be a single aromatic ring or multiple aromatic rings which are fused together, linked covalently, or linked to a common group such as a methylene, ethylene, or carbonyl, and includes polynuclear ring structures. An aromatic ring or rings may include substituted or unsubstituted phenyl, naphthyl, biphenyl, diphenylmethyl, and benzophenone groups, among others. The term “aryl” includes substituted aryls.
- As used herein, the term “heteroaryl” refers to an aromatic ring(s) in which one or more carbon atoms of the aromatic ring(s) are substituted by a heteroatom such as nitrogen, oxygen, or sulfur. Heteroaryl refers to structures which may include a single aromatic ring, multiple aromatic rings, or one or more aromatic rings coupled to one or more nonaromatic rings. It includes structures having multiple rings, fused or unfused, linked covalently, or linked to a common group such as a methylene or ethylene group, or linked to a carbonyl as in phenyl pyridyl ketone. As used herein, the term “heteroaryl” includes rings such as thiophene, pyridine, isoxazole, phthalimide, pyrazole, indole, furan, or benzo-fused analogues of these rings.
- As used herein, the term “saturated cyclic hydrocarbon” refers to ring structures cyclopropyl, cyclobutyl, cyclopentyl groups, and others, including substituted groups. Substituents to saturated cyclic hydrocarbons include substituting one or more carbon atoms of the ring with a heteroatom such as nitrogen, oxygen, or sulfur. Saturated cyclic hydrocarbons include bicyclic structures such as bicycloheptanes and bicyclooctanes, and multicyclic structures.
- As used herein, the term “unsaturated cyclic hydrocarbon” refers to a monovalent nonaromatic group with at least one double bond, such as cyclopentene, cyclohexene, and others, including substituted groups. Substituents to unsaturated cyclic hydrocarbons include substituting one or more carbon atoms of the ring with a heteroatom such as nitrogen, oxygen, or sulfur. As used herein, the term “cyclic hydrocarbon” includes substituted and unsubstituted, saturated and unsaturated cyclic hydrocarbons, and multicyclic structures. Unsaturated cyclic hydrocarbons include bicyclic structures such as bicycloheptenes and bicyclooctenes, and multicyclic structures.
- As used herein, the terms “amphiphile” or “amphiphilic” refer to a species which exhibits both hydrophilic and lipophilic character. In general, an amphiphile contains a lipophilic moiety and a hydrophilic moiety. An amphiphile may form a Langmuir film.
- Examples of hydrophilic moieties include, without limitation, hydroxyl, methoxy, phenol, carboxylic acids and salts thereof, methyl and ethyl esters of carboxylic acids, amides, amino, cyano, ammonium salts, monoalkyl-substituted amino groups, di-alkyl-substituted amino groups, —NRR′, —N≡C, —NHR, sulfonium salts, phosphonium salts, polyethyleneglycols, polypropyleneglycols, epoxy groups, acrylates, sulfonamides, nitro, —OP(O)(OCH2CH2N+RR′R″)O−, guanidinium, aminate, acrylamide, and pyridinium. Such hydrophilic moieties may include groups such as polyethylene glycols, or for example, polymethylene chains substituted with alcohol, carboxylate, acrylate, methacrylate, or
- groups, where y is 1-6. Hydrophilic moieties may also include alkyl chains having internal amino or substituted amino groups, for example, internal —NH—, —NC(O)R—, or —NC(O)CH═CH2— groups. Hydrophilic moieties may also include polycaprolactones, polycaprolactone diols, poly(acetic acid)s, poly(vinyl acetates)s, poly(2-vinyl pyridine)s, cellulose esters, cellulose hydroxyl ethers, poly(L-lysine hydrobromide)s, poly(itaconic acid)s, poly(maleic acid)s, poly(styrenesulfonic acid)s, poly(aniline)s, or poly(vinyl phosphonic acid)s.
- Examples of lipophilic moieties include, without limitation, linear or branched alkyls, including 1-28C hydrocarbons. Examples of groups which may be coupled to a synthon or macrocyclic module as a lipophilic group include alkyls, —CH═CH—R, —C≡C—R, —OC(O)—R, —C(O)O—R, —NHC(O)—R, —C(O)NH—R, and —O—R, where R is 4-18C alkyl. Each chain may independently comprise, without limitation, alkenyl, alkynyl, saturated and unsaturated cyclic hydrocarbons, or aromatic groups. Each chain may also contain, interspersed among the carbons of the chain, one or more silicon atoms substituted with alkyl, alkenyl, alkynyl, saturated and unsaturated cyclic hydrocarbons, or aryl groups. The carbon atoms of each chain may independently be substituted with one or more fluorine atoms. The carbon atoms of an alkyl group may be interrupted by one or more functional groups such as, for example, —S—, double bond, triple bond or —SiR′R″— groups, any of which may be substituted with one or more fluorine atoms, and any combination of such functional groups may be used.
- As used herein, the terms “coupling” and “coupled” with respect to molecular moieties or species, molecules, synthons, and macrocyclic modules refers to their attachment or association with other molecular moieties or species, atoms, molecules, synthons, or macrocyclic modules, whether the attachment or association is specific or non-specific, reversible or non-reversible, is the result of chemical reaction, or the result of direct or indirect physical interactions, complexation, charge transfer, or as the result of magnetic, electrostatic, or electromagnetic interaction. Coupling may be specific or non-specific, and the bonds formed by a coupling reaction are often covalent bonds, or polar-covalent bonds, or mixed ionic-covalent bonds, and may sometimes be Coulombic forces, ionic or electrostatic forces or interactions.
- As used herein, the term “functional group” includes, but is not limited to, chemical groups, organic groups, inorganic groups, organometallic groups, aryl groups, heteroaryl groups, cyclic hydrocarbon groups, amino (—NH2), hydroxyl (—OH), cyano (—C≡N), nitro (NO2), carboxyl (—COOH), formyl (—CHO), keto (—CH2C(O)CH2—), alkenyl (—C═C—), alkynyl, (—C≡C—), and halo (F, Cl, Br and I) groups.
- As used herein, the term “synthon” refers to a molecule used to make a macrocyclic module. A synthon may be substantially one isomeric configuration, for example, a single enantiomer. A synthon may be substituted with functional groups which are used to couple a synthon to another synthon or synthons, and which are part of the synthon. A synthon may be substituted with an atom or group of atoms which are used to impart hydrophilic, lipophilic, or amphiphilic character to the synthon or to species made from the synthon. A synthon may be substituted with an atom or group of atoms to form one or more functional groups on the synthon which may be used to couple the synthon to another synthon or synthons. The synthon before being substituted with functional groups or groups used to impart hydrophilic, lipophilic, or amphiphilic character may be called the core synthon. As used herein, the term “synthon” refers to a core synthon, and also refers to a synthon substituted with functional groups or groups used to impart hydrophilic, lipophilic, or amphiphilic character.
- As used herein, the term “cyclic synthon” refers to a synthon having one or more ring structures. Examples of ring structures include aryl, heteroaryl, and cyclic hydrocarbon structures including bicyclic ring structures and multicyclic ring structures. Examples of core cyclic synthons include, but are not limited to, benzene, cyclohexadiene, cyclopentadiene, naphthalene, anthracene, phenylene, phenanthracene, pyrene, triphenylene, phenanthrene, pyridine, pyrimidine, pyridazine, biphenyl, bipyridyl, cyclohexane, cyclohexene, decalin, piperidine, pyrrolidine, morpholine, piperazine, pyrazolidine, quinuclidine, tetrahydropyran, dioxane, tetrahydrothiophene, tetrahydrofuran, pyrrole, cyclopentane, cyclopentene, triptycene, adamantane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo[2.2.2]octane, bicyclo[2.2.2]octene, bicyclo[3.3.0]octane, bicyclo[3.3.0]octene, bicyclo[3.3.1]nonane, bicyclo[3.3.1]nonene, bicyclo[3.2.2]nonane, bicyclo[3.2.2]nonene, bicyclo[4.2.2]decane, 7-azabicyclo[2.2.1]heptane, 1,3-diazabicyclo[2.2.1]heptane, and spiro[4.4]nonane. A core synthon comprises all isomers or arrangements of coupling the core synthon to other synthons. For example, the core synthon benzene includes synthons such as 1,2- and 1,3-substituted benzenes, where the linkages between synthons are formed at the 1,2- and 1,3-positions of the benzene ring, respectively. For example, the core synthon benzene includes 1,3-substituted synthons such as
- where L is a linkage between synthons and the 2,4,5,6 positions of the benzene ring may also have substituents. A condensed linkage between synthons involves a direct coupling between a ring atom of one cyclic synthon to a ring atom of another cyclic synthon, for example, where synthons M—X and M—X couple to form M—M, where M is a cyclic synthon and X is halogen; as for example when M is phenyl resulting in the condensed linkage
- As used herein, the term “activated acid” refers to a —C(O)R moiety in which the R group is readily displaced by a nucleophile to form a covalent bond between the —C(O)— and the nucleophile. Examples of activated acids include acid chlorides, acid fluorides, p-nitrophenyl esters, pentafluorophenyl esters, and N-hydroxysuccinimide esters.
- As used herein, the term “amino acid residue” refers to the product formed when a species comprising at least one amino (—NH2) and at least one carboxyl (—C(O)O—) group couples through either of its amino or carboxyl groups with an atom or functional group of a synthon. Whichever of the amino or carboxyl groups is not involved in the coupling may be blocked with a removable protective group.
- Macrocyclic Modules
- A macrocyclic module is a closed ring of coupled synthons. To make a macrocyclic module, synthons may be substituted with functional groups to couple the synthons to form a macrocyclic module. Synthons may also be substituted with functional groups which will remain in the structure of the macrocyclic module. Functional groups which remain in the macrocyclic module may be used to couple the macrocyclic module to other macrocyclic modules.
- A macrocyclic module may contain from three to about twenty-four cyclic synthons. In the closed ring of a macrocyclic module, a first cyclic synthon may be coupled to a second cyclic synthon, the second cyclic synthon may be coupled to a third cyclic synthon, the third cyclic synthon may be coupled to a fourth cyclic synthon, if four cyclic synthons are present in the macrocyclic module, the fourth to a fifth, and so on, until an nth cyclic synthon may be coupled to its predecessor, and the nth cyclic synthon may be coupled to the first cyclic synthon to form a closed ring of cyclic synthons. In one variation, the closed ring of the macrocyclic module may be formed with a linker molecule.
- A macrocyclic module may be an amphiphilic macrocyclic module when hydrophilic and lipophilic functional groups exist in the structure. The amphiphilic character of a macrocyclic module may arise from atoms in the synthons, in the linkages between synthons, or in functional groups coupled to the synthons or linkages.
- In some variations, one or more of the synthons of a macrocyclic module may be substituted with one or more lipophilic moieties, while one or more of the synthons may be substituted with one or more hydrophilic moieties, thereby forming an amphiphilic macrocyclic module. Lipophilic and hydrophilic moieties may be coupled to the same synthon or linkage in an amphiphilic macrocyclic module. Lipophilic and hydrophilic moieties may be coupled to the macrocyclic module before or after formation of the closed ring of the macrocyclic module. For example, lipophilic or hydrophilic moieties may be added to the macrocyclic module after formation of the closed ring by substitution of a synthon or linkage.
- The amphiphilicity of a macrocyclic module may be characterized in part by its ability to form a stable Langmuir film. A Langmuir film may be formed on a Langmuir trough at a particular surface pressure measured in milliNewtons per meter (mN/m) with a particular barrier speed measured in millimeters per minute (mm/min), and the isobaric creep or change in film area at constant surface pressure can be measured to characterize stability of the film. For example, a stable Langmuir film of macrocyclic modules on a water subphase may have an isobaric creep at 5-15 mN/m such that the majority of the film area is retained over a period of time of about one hour. Examples of stable Langmuir films of macrocyclic modules on a water subphase may have isobaric creep at 5-15 mN/m such that about 70% of the film area is retained over a period of time of about 30 minutes, sometimes about 70% of the film area is retained over a period of time of about 40 minutes, sometimes about 70% of the film area is retained over a period of time of about 60 minutes, and sometimes about 70% of the film area is retained over a period of time of about 120 minutes. Other examples of stable Langmuir films of macrocyclic modules on a water subphase may have isobaric creep at 5-15 mN/m such that about 80% of the film area is retained over a period of time of about thirty minutes, sometimes about 85% of the film area is retained over a period of time of about thirty minutes, sometimes about 90% of the film area is retained over a period of time of about thirty minutes, sometimes about 95% of the film area is retained over a period of time of about thirty minutes, and sometimes about 98% of the film area is retained over a period of time of about thirty minutes.
- In one aspect, an individual macrocyclic module may include a pore in its structure. Each macrocyclic module may define a pore of a particular size, depending on the conformation and state of the module. Various macrocyclic modules may be prepared which define pores of different sizes.
- A macrocyclic module may include a flexibility in its structure. Flexibility may permit a macrocyclic module to more easily form linkages with other macrocyclic modules by coupling reactions. Flexibility of a macrocyclic module may also play a role in regulating passage of species through the pore of the macrocyclic module. For example, flexibility may affect the dimension of the pore of a macrocyclic module since various conformations may be available to the structure. For example, a macrocyclic module may have a certain pore dimension in one conformation when no substituents are located at the pore, and have a different pore dimension in another conformation when one or more substituents are located at the pore. Likewise, a macrocyclic module may have a certain pore dimension in one conformation when one group of substituents are located at the pore, and have a different pore dimension in a different conformation when a different group of substituents are located at the pore. For example, the “one group” of substituents located at the pore may be three alkoxy groups arranged in one regioisomer, while the “different group” of substituents may be two alkoxy groups arranged in another regioisomer. The effect of the “one group” of substituents located at the pore and the “different group” of substituents located at the pore is to provide a macrocyclic module composition which may regulate transport and filtration, in conjunction with other regulating factors.
- In making macrocyclic modules from synthons, the synthons may be used as a substantially pure single isomer, for example, as a pure single enantiomer.
- In making macrocyclic modules from synthons, one or more coupling linkages are formed between adjacent synthons. The linkage formed between synthons may be the product of the coupling of one functional group on one synthon to a complementary functional group on a second synthon. For example, a hydroxyl group of a first synthon may couple with an acid group or acid halide group of a second synthon to form an ester linkage between the two synthons. Another example is an imine linkage, —CH═N—, resulting from the reaction of an aldehyde, —CH═O, on one synthon with an amine, —NH2, on another synthon. Examples of complementary functional groups and linkages between synthons are shown in Table 1.
TABLE 1 Examples of functional groups of synthons and synthon linkages Functional Group A Functional Group B Linkage Formed —NH2 —C(O)H —N═CH— —NH2 —CO2H —NHC(O)— —NHR —CO2H —NRC(O)— —OH —CO2H —OC(O)— —X —O Na —O— —SH —SH —S—S— —X —(NR)Li —NR— —X —S Na —S— —X —NHR —NR— —X —CH2CuLi —CH2— —X —(CRR′)n=1-6CuLi —(CRR′)n— synthon-X synthon-X synthon—synthon —CH2X —CH2X —CH2CH2— —ONa —C(O)OR —C(O)O— —SNa —C(O)OR —C(O)S— —X —C≡ CH —C≡ C— —C≡ CH —C≡ CH —C≡ C—C≡ C— —MgX —C(O)H —CH(OH)— synthon-NH2 synthon-MgX synthon-X —C(O)H —C(O)H —HC═CH— (CH3)2C═CH-synthon synthon-C(O)Cl —N═C═O —NH2 —NHC(O)NH— —N═C═O HO— —NHC(O)O— —C(O)H —NHNH2 —CH═N—NH— —OH —OC(O)X —OC(O)O— (CH3)2C═CH-synthon synthon-SH (CH3)2CHC(O)O-synthon synthon-CH(O) synthon-CH2C(O)OH synthon-CH2C(O)OH R2SiH-synthon —OP(O)(OH)2 —OH —OP(O)(OH)O— - In Table 1, R and R′ represent hydrogen or organic groups, and X is halogen or other good leaving groups.
- In another variation, a macrocyclic module may have functional groups for coupling to other macrocyclic modules which were coupled to the macrocyclic module after initial preparation of the closed ring. For example, an imine linkage of a macrocyclic module may be substituted with one of various functional groups to produce additional macrocyclic modules. Examples of linkages between synthons having functional groups for coupling macrocyclic modules are shown in Table 2.
TABLE 2 Examples of functional groups of synthons and synthon linkages Functional Group of Macrocyclic Substituted Module Linkage Reagent Linkage X—≡—H - In Table 2, X is halogen.
- The functional groups of synthons used to form linkages between synthons may be separated from the synthon by a spacer. A spacer can be any atom or group of atoms which couples the functional group to the synthon, and does not interfere with the linkage-forming reaction. A spacer is part of the functional group, and becomes part of the linkage between synthons. An example of a spacer is a methylene group, —CH2—. The spacer may be said to extend the linkage between synthons. For example, if one methylene spacer were inserted in an imine linkage, —CH═N—, the resulting imine linkage may be —CH2CH═N—.
- A linkage between synthons may also contain one or more atoms provided by an external moiety other than the two functional groups of the synthons. An external moiety may be a linker molecule which may couple with the functional group of one synthon to form an intermediate which couples with a functional group on another synthon to form a linkage between the synthons, such as, for example, to form a closed ring of synthons from a series of coupled synthons. An example of a linker molecule is formaldehyde. For example, amino groups on two synthons may undergo Mannich reaction in the presence of formaldehyde as the linker molecule to produce the linkage —NHCH2NH—.
-
- wherein:
- the closed ring comprises a total of from three to twenty-four synthons Q; J is 2-23;
- Q1 are synthons each independently selected from the group consisting of (a) aryl synthons, (b) heteroaryl synthons, (c) saturated cyclic hydrocarbon synthons, (d) unsaturated cyclic hydrocarbon synthons, (e) saturated bicyclic hydrocarbon synthons, (f) unsaturated bicyclic hydrocarbon synthons, (g) saturated multicyclic hydrocarbon synthons, and (h) unsaturated multicyclic hydrocarbon synthons; wherein ring positions of each Q1 which are not coupled to a linkage L are substituted with hydrogen or organic functional groups containing atoms selected from the group of C, H, N, O, Si, P, S, B, Al, halogens, and metals from the alkali and alkaline earth groups;
- Q2 is a synthon independently selected from the group consisting of (a) aryl synthons, (b) heteroaryl synthons, (c) saturated cyclic hydrocarbon synthons, (d) unsaturated cyclic hydrocarbon synthons, (e) saturated bicyclic hydrocarbon synthons, (f) unsaturated bicyclic hydrocarbon synthons, (g) saturated multicyclic hydrocarbon synthons, and (h) unsaturated multicyclic hydrocarbon synthons; wherein ring positions of Q2 which are not coupled to an L are substituted with hydrogen or organic functional groups containing atoms selected from the group consisting of C, H, N, O, Si, P, S, B, Al, halogens, and metals from the alkali and alkaline earth groups;
-
- wherein p is 1-6;
- wherein R and R′ are each independently selected from the group of hydrogen and alkyl; wherein the linkages L are each independently configured with respect to the Q1 and Q2 synthons, each L having either of its two possible configurations with respect to the synthons it couples together, the forward and reverse configurations of the linkage with respect to the immediately adjacent synthons to which it couples, for example, Q1 a—NHC(O)—Q1 b and Q1 a—C(O)NH—Q1 b, if the two configurations are isomerically different structures. Synthons Q1, when independently selected, may be any cyclic synthon as described, so that the J synthons Q1 may be found in the closed ring in any order, for example, cyclohexyl--1,2-phenyl--piperidinyl--1,2-phenyl--1,2-phenyl--cyclohexyl, and so on, and the J linkages L may also be independently selected and configured in the closed ring. The macrocyclic modules represented and encompassed by the formula include all stereoisomers of the synthons involved, so that a wide variety of stereoisomers of the macrocyclic module are included for each closed ring composition of synthons.
- A macrocyclic module may include functional groups for coupling the macrocyclic module to a solid surface, substrate, or support. Examples of functional groups of macrocyclic modules which can be used to couple to a substrate or surface include amine, carboxylic acid, carboxylic ester, benzophenone and other light activated crosslinkers, alcohol, glycol, vinyl, styryl, olefin styryl, epoxide, thiol, magnesium halo or Grignard, acrylate, acrylamide, diene, aldehyde, and mixtures thereof. These functional groups may be coupled to the closed ring of the macrocyclic module, and may optionally be attached by a spacer group. Examples of solid surfaces include metal surfaces, ceramic surfaces, polymer surfaces, semiconductor surfaces, silicon wafer surfaces, alumina surfaces, and so on. Examples of functional groups of macrocyclic modules which can be used to couple to a substrate or surface further include those described in the left hand column of Tables 1 and 2. Methods of initiating coupling of the modules to the substrate include chemical, thermal, photochemical, electrochemical, and irradiative methods.
- Examples of spacer groups include polyethylene oxides, polypropylene oxides, polysaccharides, polylysines, polypeptides, poly(amino acids), polyvinylpyrrolidones, polyesters, polyvinylchlorides, polyvinylidene fluorides, polyvinylalcohols, polyurethanes, polyamides, polyimides, polysulfones, polyethersulfones, polysulfonamides, and polysulfoxides.
- A substrate may have functional groups which couple to the macrocyclic modules. The functional groups of the substrate may be surface groups or linking groups bound to the substrate, which may be formed by reactions which bind the surface groups or linking groups to the substrate. Surface groups may also be created on the substrate by a variety of treatments such as cold plasma treatment, surface etching methods, solid abrasion methods, or chemical treatments. Some methods of plasma treatment are given in Inagaki,Plasma Surface Modification and Plasma Polymerization, Technomic, Lancaster, Pa., 1996. The functional groups of the macrocyclic modules and the surface may be blocked with protecting groups until needed. In one variation, a photoreactive group such as a benzophenone group is bound to the surface or substrate. The photoreactive group may be activated with light, for example, ultraviolet light to provide a reactive species which couples to a macrocyclic module.
-
- Macrocyclic Module Pores
- An individual macrocyclic module may include a pore in its structure. The size of the pore may determine the size of molecules or other species which can pass through the macrocyclic module. The size of a pore in a macrocyclic module may depend on the structure of the synthons used to make the macrocyclic module, the linkages between synthons, the number of synthons in a module, the structure of any linker molecules used to make the macrocyclic module, and other structural features of the macrocyclic module whether inherent in the preparation of the macrocyclic module or added in later steps or modifications. Stereoisomerism of macrocyclic modules may also be used to regulate the size of a pore of a macrocyclic module by variation of the stereoisomer of each synthon used to prepare the closed ring of the macrocyclic module.
- The dimension of a pore in a macrocyclic module may be varied by changing the combination of synthons used to form the macrocyclic module, or by varying the number of synthons in the closed ring. The dimension of a pore may also be varied by substituents on the synthons or linkages. The pore may therefore be made large enough or small enough to achieve an effect on transport of species through the pore. Species which may be transported through the pore of a macrocyclic module include atoms, molecules, biomolecules, ions, charged particles, and photons.
- The size of a species may not be the sole determinant of whether it will be able to pass through a pore of a macrocyclic module. Groups or moieties located in or near the pore structure of a macrocyclic module may regulate or affect transport of a species through the pore by various mechanisms. For example, transport of a species through the pore may be affected by groups of the macrocyclic module which interact with the species, by ionic or other interaction, such as chelating groups, or by complexing the species. For example, a charged group such as a carboxylate anion or ammonium group may couple an oppositely-charged species and affect its transport. Substituents of synthons in a macrocyclic module may affect the passage of a species through the pore of the macrocyclic module. Groups of atoms which render the pore of a macrocyclic module more or less hydrophilic or lipophilic may affect transport of a species through the pore. An atom or group of atoms may be located within or proximate to a pore to sterically slow or block the passage of a species through the pore. For example, hydroxyl or alkoxy groups may be coupled to a cyclic synthon and located in the pore of the structure of the macrocyclic module, or may be coupled to a linkage between synthons and located in the pore. A wide range of functional groups may be used to sterically slow or block the passage of a species through the pore, including organic functional groups containing atoms selected from the group consisting of C, H, N, O, Si, P, S, B, Al, halogens, and metals from the alkali and alkaline earth groups. Blocking and slowing passage of a species through the pore may involve reducing the dimension of the pore by steric blocking, as well as slowing the passage of species by creating a path through the pore which is not linear, and providing interaction between the functional group and the species to slow transport. The stereochemical structure of the portion of the macrocyclic module which defines the pore and its interior may also affect transport. Any groups or moieties which affect transport of a species through the pore of a macrocyclic module may be introduced as part of the synthons used to prepare the macrocyclic module, or may be added later by various means. For example, S7-1 could be reacted with ClC(O)(CH2)2C(O)OCH2CH3 to convert the phenol groups to succinyl ester groups. Further, molecular dynamical motion of the synthons and linkages of a partly flexible macrocyclic module may affect transport of a species through the pore of the module. Transport behavior may not be described solely by the structure of the macrocyclic module itself since the presence of the species which is to be transported through the pore affects the flexibility, conformation, and dynamical motions of a macrocyclic module. In general, solvent may also affect transport of solutes through a pore.
- Macrocyclic modules and arrays of macrocyclic modules may be useful in size exclusion separations, ion separation, gas separation, separation of enantiomers, small molecule separation, water purification, filtration of bacteria, fungi, or viruses, sewage treatment, and toxin removal, among other uses.
- The following examples further describe and demonstrate variations within the scope of the present invention. All examples described in this specification, both in the description above and the examples below, as well as in the figures, are given solely for the purpose of illustration and are not to be construed as limiting the present invention. While there have been described illustrative variations of this invention, those skilled in the art will recognize that they may be changed or modified without departing from the spirit and scope of this invention, and it is intended to cover all such changes, modifications, and equivalent arrangements that fall within the true scope of the invention as set forth in the appended claims.
- All chemical structures illustrated and described in this specification, both in the description above and the examples below, as well as in the figures, are intended to encompass and include all variations and isomers of the structure which are foreseeable, including all stereoisomers and constitutional or configurational isomers when the illustration, description, or figure is not explicitly limited to any particular isomer.
- All documents referenced herein, including applications for patent, patent references, publications, articles, books, and treatises, are specifically incorporated by reference herein in their entirety.
- Methods to Prepare Cyclic Synthons
- To avoid the need to separate single configurational or enantiomeric isomers from complex mixtures resulting from non-specific reactions, stereospecific or at least stereoselective coupling reactions may be employed in the preparation of the synthons of this invention. The following are examples of synthetic schemes for several classes of synthons useful in the preparation of macrocyclic modules of this invention. In general, the core synthons are illustrated, and lipophilic moieties are not shown on the structures, however, it is understood that all of the following synthetic schemes might encompass additional lipophilic or hydrophilic moieties used to prepare amphiphilic and other modified macrocyclic modules. Species are numbered in relation to the scheme in which they appear; for example, “S1-1” refers to the structure 1 in Scheme 1.
-
- symmetrical diester S1-1 is used to give enantiomerically pure S1-2. S1-2 is subjected to the Curtius reaction and then quenched with benzyl alcohol to give protected amino acid S1-3. Iodolactonization of carboxylic acid S1-4 followed by dehydrohalogenation gives unsaturated lactone S1-6. Opening of the lactone ring with sodium methoxide gives alcohol S1-7, which is converted with inversion of configuration to S1-8 in a one-pot reaction involving mesylation, SN2 displacement with azide, reduction and protection of the resulting amine with di-tert-butyl dicarbonate. Epimerization of S1-8 to the more stable diequatorial configuration followed by saponification gives carboxylic acid S1-10. S1-10 is subjected to the Curtius reaction. A mixed anhydride is prepared using ethyl chloroformate followed by reaction with aqueous NaN3 to give the acyl azide, which is thermally rearranged to the isocyanate in refluxing benzene. The isocyanate is quenched with 2-trimethylsilylethanol to give differentially protected tricarbamate S1-11. Reaction with trifluoroacetic acid (TFA) selectively deprotects the 1,3-diamino groups to provide the desired synthon S1-12.
-
- Some aspects of these preparations are given in Suami et al.,J. Org. Chem. 1975, 40, 456 and Kavadias et al. Can. J. Chem. 1978, 56, 404.
-
- This synthon will remain “Z-protected” until the macrocyclic module has been cyclized. Subsequent deprotection to yield a macrocyclic module with amine functional groups is done by a hydrogenation protocol.
- Norbornanes (bicycloheptanes) may be used to prepare synthons of this invention, and stereochemically controlled multifunctionalization of norbornanes can be achieved. For example, Diels-Alder cycloaddition may be used to form norbornanes incorporating various functional groups having specific, predictable stereochemistry. Enantiomerically enhanced products may also be obtained through the use of appropriate reagents, thus limiting the need for chiral separations.
-
- diethylaluminum chloride Lewis acid complex of di-(l)-menthyl fumarate (S2-14) at low temperature to give the diastereomerically pure norbornene S2-15. Saponification with potassium hydroxide in aqueous ethanol gives the diacid S2-16, which is subjected to a tandem Curtius reaction with diphenylphosphoryl azide (DPPA), the reaction product is quenched with 2-trimethylsilylethanol to give the biscarbamate S2-17. Deprotection with TFA gives diamine S2-18.
- Another approach to this synthon class is outlined in Scheme 3. Opening of anhydride S3-19 with methanol in the presence of quinidine gives the enantiomerically pure ester acid S3-20. Epimerization of the ester group with sodium methoxide (NaOMe) gives S3-21. A Curtius reaction with DPPA followed by quenching with trimethylsilylethanol gives carbamate S3-22. Saponification with NaOH gives the acid S3-23, which undergoes a Curtius reaction,
- then quenched with benzyl alcohol to give differentially protected biscarbamate S3-24. Compound S3-24 can be fully deprotected to provide the diamine or either of the carbamates can be selectively deprotected.
- An approach to preparing synthons of endo, endo-1,3-Diaminonorbornane is shown in
Scheme 4. 5-Trimethylsilyl-1,3-cyclopentadiene (S4-25) is reacted with the diethylaluminum chloride Lewis acid complex of di-(l)-menthyl fumarate at low temperature to give nearly diastereomerically pure norbornene S4-26. Crystallization of S4-26 from alcohol results in recovery of greater than 99% of the single diastereomer. Bromolactonization followed by silver mediated rearrangement gives mixed diester S4-28 with an alcohol moiety at the 7-position. Protection of the alcohol with benzyl bromide and selective deprotection of the methyl ester gives the free carboxylic acid S4-30. A Curtius reaction results in trimethylsilylethyl carbamate norbornene S4-31. Biscarbonylation of the olefin in methanol, followed by a single-step deprotection and dehydration gives the mono-anhydride S4-33. Quinidine mediated opening of the anhydride with methanol gives S4-34. Curtius transformation of S4-34 gives the biscarbamate S4-35, which is deprotected with TFA or tetrabutylammonium fluoride (TBAF) to give diamine S4-36. - Another approach to this class of synthons is outlined in
Scheme 5. Benzyl alcohol opening of S3-19 in the presence of quinidine gives S5-37 in high enantiomeric excess. Iodolactonization followed by NaBH4 reduction gives lactone S5-39. Treatment with NaOMe liberates the methyl ester and the free alcohol to generate S5-40. Transformation of the alcohol S5-40 to the inverted t-butyl carbamate protected amine S5-41 is accomplished in a one-pot reaction by azide deplacement of the mesylate S5-40 followed by reduction to the amine, which is protected with di-tert-butyl dicarbonate. Hydrogenolytic cleavage of the benzyl ester and epimerization of the methyl ester to the exo configuration is followed by protection of the free acid with benzyl bromide to give S5-44. Saponification of the methyl ester followed by a trimethylsilylethanol quenched Curtius reaction - gives the biscarbamate S5-46, which is cleaved with TFA to give the desired diamine S5-47.
- An approach to preparing synthons of exo,endo-1,3-Diaminonorbornane is shown in
Scheme 6. p-Methoxybenzyl alcohol opening of norbornene anhydride S3-19 in the presence of quinidine gives monoester S6-48 in high enantiomeric excess. Curtius reaction of the free acid gives protected all endo monoacid-monoamine S6-49. Biscarbonylation and anhydride formation gives exo-monoanhydride S6-51. Selective methanolysis in the presence of quinine gives S6-52. A trimethylsilylethanol quenched Curtius reaction gives biscarbamate S6-53. Epimerization of the two esters results in the more sterically stable S6-54. Cleavage of the carbamate groups provides synthon S6-55. - Methods to Prepare Macrocyclic Modules
- Synthons maybe coupled to one another to form macrocyclic modules. In one variation, the coupling of synthons may be accomplished in a concerted scheme. Preparation of a macrocyclic module by the concerted route requires at least two types of synthons, each type having at least two functional groups for coupling to other synthons. The functional groups may be selected so that a functional group of one type of synthon can couple only to a functional group of the other type of synthon. When two types of synthons are used, a macrocyclic module may be formed having alternating synthons of different types. Scheme 7 illustrates a concerted module synthesis.
- Referring to Scheme 7, 1,2-Diaminocyclohexane, S7-1, is a synthon having two amino functional groups for coupling to other synthons, and 2,6-diformyl-4-dodec-1-ynylphenol, S7-2, is a synthon having two formyl groups for coupling to other synthons. An amino group may couple with a formyl group to form an imine linkage. In Scheme 7, a concerted product hexamer macrocyclic module is shown.
- In one variation, a mixture of tetramer, hexamer, and octamer macrocyclic modules may be formed in the concerted scheme. The yields of these macrocyclic modules can be varied by changing the concentration of various synthons in the reagent mixture, and among other factors, by changing the solvent, temperature, and reaction time.
- The imine groups of S7-3 can be reduced, e.g. with sodium borohydride, to give amine linkages. If the reaction is carried out using 2,6-di(chlorocarbonyl)-4-dodec-1-ynylphenol instead of 2,6-diformyl-4-dodec-1-ynylphenol, the resulting module will contain amide linkages. Similarly, if 1,2-dihydroxycyclohexane is reacted with 2,6-di(chlorocarbonyl)-4-dodec-1-ynylphenol, the resulting module will contain ester linkages.
- In some variations, the coupling of synthons may be accomplished in a stepwise scheme. In the stepwise preparation of macrocyclic modules, a first type of synthon is substituted with one protected functional group and one unprotected functional group. A second type of synthon is substituted with an unprotected functional group that will couple with the unprotected functional group on the first synthon. The product of contacting the first type of synthon with the second type of synthon may be a dimer, which is made of two coupled synthons. The second synthon may also be substituted with another functional group which is either protected, or which does not couple with the first synthon when the dimer is formed. The dimer may be isolated and purified, or the preparation may proceed as a one-pot method. The dimer may be contacted with a third synthon having two functional groups, only one of which may couple with the remaining functional group of either the first or second synthons to form a trimer, which is made of three coupled synthons. Such stepwise coupling of synthons may be repeated to form macrocyclic modules of various ring sizes. To cyclize or close the ring of the macrocyclic module, the nth synthon which was coupled to the product may be substituted with a second functional group which may couple with the second functional group of a previously coupled synthon that has not been coupled, which may be deprotected for that step. The stepwise method may be carried out with synthons on solid phase support.
Scheme 8 illustrates a stepwise preparation of module SC8-1. -
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-
-
-
-
- Reagents for the following examples were obtained from Aldrich Chemical Company and VWR Scientific Products. All reactions were carried out under nitrogen or argon atmosphere unless otherwise noted. Solvent extracts of aqueous solutions were dried over anhydrous Na2SO4. Solutions were concentrated under reduced pressure using a rotary evaporator. Thin layer chromatography (TLC) was done on Analtech Silica gel GF (0.25 mm) plates or on Machery-Nagel Alugram Sil G/UV (0.20 mm) plates. Chromatograms were visualized with either UV light, phosphomolybdic acid, or KMnO4. All compounds reported were homogenous by TLC unless otherwise noted. HPLC analyses were performed on a Hewlett Packard 1100 system using a reverse phase C-18 silica column. Enantiomeric excess was determined by HPLC using a reverse phase (l)-leucine silica column from Regis Technologies. All 1[H] and 13[C] NMR spectra were collected at 400 MHz on a Varian Mercury system. Electrospray mass spectra were obtained by Synpep Corp., or on a Thermo Finnigan LC-MS system.
- 2,6-Diformyl-4-bromophenol
- Hexamethylenetetramine (73.84 g, 526 mmol) was added to TFA (240 mL) with stirring. 4-Bromophenol (22.74 g, 131 mmol) was added in one portion and the solution heated in an oil bath to 120° C. and stirred under argon for 48 h. The reaction mixture was then cooled to ambient temperature. Water (160 mL) and 50% aqueous H2SO4 (80 mL) were added and the solution stirred for an additional 2 h. The reaction mixture was poured into water (1600 mL) and the resulting precipitate collected on a Büchner funnel. The precipitate was dissolved in ethyl acetate (EtOAc) and the solution was dried over MgSO4. The solution was filtered and the solvent removed on a rotary evaporator. Purification by column chromatography on silica gel (400 g) using a gradient of 15-40% ethyl acetate in hexanes resulted in a isolation of the product as a yellow solid (18.0 g, 60%).
-
- 2,6-Diformyl-4-(dodecyn-1-yl)phenol
- 2,6-Diformyl-4-bromophenol (2.50 g, 10.9 mmol), 1-dodecyne (2.00 g, 12.0 mmol), CuI (65 mg, 0.33 mmol), and bis(triphenylphosphine)palladium)II) dichloride were suspended in degassed acetonitrile (MeCN) (5 mL) and degassed benzene (1 mL). The yellow suspension was sparged with argon for 30 min and degassed Et3N (1 mL) was added. The resulting brown suspension was sealed in a pressure vial, warmed to 80° C. and held there for 12 h. The mixture was then partitioned between EtOAc and KHSO4 solution. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated under reduced pressure. The dark yellow oil was purified by column chromatography on silica gel (25% Et2O in hexanes) to give 1.56 g (46%) of the title compound.
-
-
- MS (FAB): Calcd. for C20H27O3 315.1960; found 315.1958 [M+H]+.
- 2,6-Diformyl-4-(dodecen-1-yl)phenol
- 2,6-Diformyl-4-bromophenol (1.00 g, 4.37 mmol), 1-dodecene (4.8 mL, 21.7 mmol), 1.40 g tetrabutylammonium bromide (4.34 mmol), 0.50 g NaHCO3 (5.95 mmol), 1.00 g LiCl (23.6 mmol) and 0.100 g palladium diacetate (Pd(OAc)2) (0.45 mmol) were combined in 30 mL degassed anhydrous dimethylformamide (DMF). The mixture was sparged with argon for 10 min and then sealed in a pressure vial which was warmed to 82° C. and held for 40 h. The crude reaction mixture was partitioned between CH2Cl2 and 0.1 M HCl solution. The organic layer was washed with 0.1 M HCl (2×), brine (2×), and saturated aqueous NaHCO3 (2×), dried over MgSO4 and concentrated under reduced pressure. The dark yellow oil was purified by column chromatography on silica gel (25% hexanes in Et2O) to give 0.700 g (51%) of the title compound as primarily the Z isomer.
-
- MS (FAB): Calcd. for C20H27O3 315.20; found 315.35 [M−H]−.
- (1R,6S)-6-Methoxycarbonyl-3-cyclohexene-1-carboxylic Acid (S1-2)
- S1-1 (15.0 g, 75.7 mmol) was suspended in pH 7 phosphate buffer (950 mL). Pig liver esterase (2909 units) was added, and the mixture stirred at ambient temperature for 72 h with the pH maintained at 7 by addition of 2M NaOH. The reaction mixture was washed with ethyl acetate (200 mL), acidified to
pH 2 with 2M HCl, and extracted with ethyl acetate (3×200 mL). The extracts were combined, dried, and evaporated to afford 13.8 g (99%) of S1-2. -
- Methyl (1S, 6R)-6-Benzyloxycarbonylaminocyclohex-3-enecarboxylate (S1-3)
- S1-2 (10.0 g, 54.3 mmol) was dissolved in benzene (100 mL) under N2. Triethylamine (13.2 g, 18.2 mL, 130.3 mmol) was added followed by DPPA (14.9 g, 11.7 mL, 54.3 mmol). The solution was refluxed for 20 h. Benzyl alcohol (5.9 g, 5.6 mL, 54.3 mmol) was added and reflux continued for 20 h. The solution was diluted with EtOAc (200 mL), washed with saturated aqueous NaHCO3 (2×50 mL), water (20 mL), and saturated aqueous NaCl (20 mL), dried and evaporated to give 13.7 g (87%) of S1-3.
-
- (1S, 6R)-6-Benzyloxycarbonylaminocyclohex-3-enecarboxylic acid (S1-4)
- S1-3 (23.5 g, 81.3 mmol) was dissolved in MeOH (150 mL) and the solution cooled to 0° C. 2M NaOH (204 mL, 0.41 mol) was added, the mixture allowed to come to ambient temperature and then it was stirred for 48 h. The reaction mixture was diluted with water (300 mL), acidified with 2M HCl, and extracted with dichloromethane (250 mL), dried, and evaporated. The residue was recrystallized from diethyl ether to give 21.7 (97%) of S1-4.
-
- (1S,2R,4R,5R)-2-Benzyloxycarbonylamino-4-iodo-7-oxo-6-oxabicyclo[3.2.1]octane (S1-5)
- S1-4 (13.9 g, 50.5 mmol) was dissolved in dichloromethane (100 mL) under N2, 0.5 M NaHCO3 (300 mL), KI (50.3 g, 303.3 mmol), and iodine (25.6 g, 101 mmol) were added and the mixture stirred at ambient temperature for 72 h. The mixture was diluted with dichloromethane (50 mL) and the organic phase separated. The organic phase was washed with saturated aqueous Na2S2O3 (2×50 mL), water (30 mL), and saturated aqueous NaCl (20 mL), dried and evaporated to afford 16.3 g (80%) of S1-5.
-
- (1S,2R,5R)-2-Benzyloxycarbonylamino-7-oxo-6-oxabicyclo[3.2.1]oct-3-ene (S1-6).
- S1-5 (4.0 g, 10 mmol) was dissolved in benzene (50 mL) under N2. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (1.8 g, 12 mmol) was added and the solution refluxed for 16 h. The precipitate was filtered and the filtrate was diluted with EtOAc (200 mL). The filtrate was washed with 1 M HCl (20 mL), saturated aqueous Na2S2O3 (20 mL), water (20 mL), and saturated aqueous NaCl (20 mL), dried and evaporated to give 2.2 g (81%) S1-6.
-
- (1S,2R,5R)-Methyl 2-Benzyloxycarbonylamino-5-hydroxycyclohex-3-enecarboxylate (S1-7)
- S1-6 (9.0 g, 33 mmol) was suspended in MeOH (90 mL) and cooled to 0° C. NaOMe (2.8 g, 52.7 mmol) was added and the mixture stirred for 3 h during which time a solution gradually formed. The solution was neutralized with 2M HCl, diluted with saturated aqueous NaCl (200 mL), and extracted with dichloromethane (2×100 mL). The extracts were combined, washed with water (20 mL) and saturated aqueous NaCl (20 ml), dried, and evaporated. The residue was flash chromatographed (silica gel (250 g), 50:50 hexane/EtOAc) to give 8.5 g (85%) of S1-7.
-
- (1S,2R,5S)-Methyl 2-Benzyloxycarbonylamino-5-t-butoxycarbonylaminocyclohex-3-enecarboxylate (S1-8).
- S1-7 (7.9 g, 25.9 mmol) was dissolved in dichloromethane (150 mL) and cooled to 0° C. under N2. Triethylamine (6.3 g, 8.7 mL, 62.1 mmol) and methanesulfonyl chloride (7.1 g, 62.1 mmol) were added and the mixture stirred at 0° C. for 2 h. (n-Bu)4NN3 (14.7 g, 51.7 mmol) in dichloromethane (50 mL) was added and stirring continued at 0° C. for 3 h followed by 15 h at ambient temperature. The mixture was cooled to 0° C. and P(n-Bu)3 (15.7 g, 19.3 mL, 77.7 mmol) and water (1 mL)were added and the mixture stirred at ambient temperature for 24 h. Di-tert-butyl dicarbonate (17.0 g, 77.7 mmol) was added and stirring continued for 24 h. The solvent was removed, the residue dissolved in 2:1 hexane/EtOAc (100 mL), the solution filtered, and evaporated. The residue was flash chromatographed (silica gel (240 g), 67:33 hexane/EtOAc) to give 5.9 g (56%) of S1-8.
-
- (1R,2R,5S)-Methyl 2-Benzyloxycarbonylamino-5-t(butoxycarbonylaminocyclohex-3-enecarboxylate (S1-9)
- S1-8 (1.1 g, 2.7 mmol) was suspended in MeOH (50 mL). NaOMe (0.73 g, 13.6 mmol) was added and the mixture refluxed for 18 h after which 0.5 M NH4Cl (50 mL) was added and the resulting precipitate collected. The filtrate was evaporated and the residue triturated with water (25 mL). The insoluble portion was collected and combined with the original precipitate to give 0.85 g (77%) of S1-9.
-
- (1R,2R,5S-)-2-Benzyloxycarbonylamino-5-t-butoxycarbonylaminocyclohex-3-enecarboxylic acid (S1-10)
- S1-9 (0.85 g, 2.1 mmol) was suspended in 50:50 MeOH/dichloromethane (5 mL) and cooled to 0° C. under N2 after which 2M NaOH (2.0 mL) was added and the mixture stirred at ambient temperature for 16 h. The mixture was acidified with 2M HCl upon which a white precipitate formed. The precipitate was collected, washed with water and hexane, and dried to give 0.74 g (90%) of S1-10.
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- (1R,2R,5S)-2-Benzyloxycarbonylamino-5-t-butoxycarbonylamino-1-(2-trimethylsilyl)ethoxycarbonylaminocyclohex-3-ene (S1-11)
- S1-10 (3.1 g, 7.9 mmol) was dissolved in THF (30 mL) under N2 and cooled to 0° C. Triethylamine (1.6 g, 2.2 mL, 15.9 mmol) was added followed by ethyl chloroformate (1.3 g, 1.5 mL, 11.8 mmol). The mixture was stirred at 0° C. for 1 h. A solution of NaN3 (1.3 g, 19.7 mmol) in water (10 mL) was added and stirring at 0° C. was continued for 2 h. The reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was separated, dried, and evaporated. The residue was dissolved in benzene (50 mL) and refluxed for 2 h. 2-Trimethylsilylethanol (1.0 g, 1.2 mL, 8.7 mmol) was added and reflux continued for 3 h. The reaction mixture was diluted with EtOAc (200 mL), washed with saturated aqueous NaHCO3 (50 mL), water (20 mL), and saturated aqueous NaCl (20 mL), dried and evaporated. The residue was flash chromatographed (silica gel (100 g), 67:33 hexane/EtOAc) to give 3.1 g (77%) of S1-11.
-
- (1R,2R,5S)-2-Benzyloxycarbonylamino-1,5-diaminocyclohex-3-ene (S1-12)
- S1-11 (2.5 g, 4.9 mmol) was added to TFA (10 mL) and the solution stirred at ambient temperature for 16 h after which the solution was evaporated. The residue was dissolved in water (20 mL), basified to
pH 14 with KOH and extracted with dichloromethane (3×50 mL). The extracts were combined, washed with water (20 mL), dried and evaporated to give 1.1 g (85%) of S1-12. -
- Isolation of S1b-2 was accomplished using the following procedure: Using Schlenk technique 5.57 g (10.0 mmol) of methyl ester compound, S1b-1, was dissolved in 250 mL of THF. In another flask LiOH (1.21 g, 50.5 mmol) was dissolved in 50 mL water and de- gassed by bubbling N2 through the solution using a needle for 20 minutes. The reaction was started transferring the base solution into the flask containing S1b-1 over one minute with rapid stirring. The mixture was stirred at room temperature and work-up initiated when the starting material S1b-1 was completely consumed (Using a solvent system of 66% EtOAc/33% Hexane and developing with phosphomolybdic acid reagent (Aldrich #31,927-9) the starting material S1b-1 has an Rf of 0.88 and the product streaks with an Rf of approx. 0.34 to 0.64.). The reaction usually takes 2 days. Work-Up: The THF was removed by vacuum transfer until about the same volume is left as water added to the reaction, in this
case 50 mL. During this the reaction solution forms a white mass that adheres to the stir bar surrounded by clear yellow solution. As the THF is being removed a separatory funnel is set up including a funnel to pour in the reaction solution and an Erlenmeyer flask is placed underneath the separatory funnel. Into the Erlenmeyer flask is added some anhydrous Na2SO4. This apparatus should be set up before acidification is started. (It is important to set up the separatory funnel and Erlenmeyer flask etc. before acidification of the reaction solution to enable separation of phases and extraction of the product away from the acid quickly once the solution attains a pH close to 1. If the separation is not preformed rapidly the Boc functional group will be hydrolyzed significantly reducing the yield.) Once the volatiles are sufficiently removed, CH2Cl2 (125 mL) and water (65 mL) are added and the reaction flask cooled in an ice bath. The solution is stirred rapidly and 5 mL aliquots of 1N HCl are added by syringe and the reaction solution tested with pH paper. Acid is added until the spot on the pH paper shows red (not orange) around the edge indicating a pH is 1 to 2 has been achieved (The solution being tested is a mixture of CH2Cl2 and water so the pH paper will show the accurate measurement at the edge of the spot and not the center.) and the phases are separated by quickly pouring the solution into the separatory funnel. As the phases separate the stopcock is turned to release the CH2Cl2 phase (bottom) into the Erlenmeyer flask and swirl the flask to allow the drying agent to absorb water in the solution. (At this scale of thisprocedure 80 mL of 1N HCl was used.) Soon after phase separation the aqueous phase is extracted with CH2Cl2 (2×100 mL), dried over anhydrous Na2SO4 and the volatiles removed to produce 5.37 g/9.91 mmoles of a beautiful white microcrystals reflecting a 99.1% yield. This product can not be purified by chromatography since that process would also hydrolyze the Boc functional group on the column. -
- IR (crystalline, cm−) 3326 br w, 3066 w, 3033 w; 2975 w, 2940 w sh, 1695 vs, 1506 vs, 1454 m sh, 1391 w, 1367 m, 1300 m sh, 1278 m sh, 1236 s, 1213 w sh, 1163 vs, 1100 w, 1053 m, 1020 m, 981 w sh, 910 w, 870 m, 846 w, 817 w, 775 w sh, 739 m, 696 m.
- Di-(l)-menthyl bicyclo[2.2.1]hept-5-ene-7-anti-(trimethylsilyl)-2-endo-3-exo-dicarboxylate (S4-26)
- To a solution of S4-25 (6.09 g, 0.0155 mol) in toluene (100 mL) was added diethylaluminum chloride (8.6 mL of a 1.8 M solution in toluene) at −78° C. under nitrogen and the mixture was stirred for 1 hour. To the resulting orange solution was added S2-14 (7.00 g, 0.0466 mol) dropwise as a −78° C. solution in toluene (10 mL). The solution was kept at −78° C. for 2 hours, followed by slow warming to room temperature overnight. The aluminum reagent was quenched with a saturated solution of ammonium chloride (50 mL). The aqueous layer was separated and extracted with methylene chloride (100 mL) which was subsequently dried over magnesium sulfate. Evaporation of the solvent left a yellow solid that was purified by column chromatography (10% ethyl acetate/hexanes) to give S4-26 as a while solid (7.19 g, 0.0136 mol, 87% yield).
-
- 5-exo-Bromo-3-exo-(l)-menthylcarboxybicyclo[2.2.1]heptane-7-anti-(trimethylsilyl)-2,6-carbolactone (S4-27)
- A solution of bromine (3.61 g, 0.0226 mol) in methylene chloride (20 mL) was added to a stirring solution of S4-26 (4.00 g, 0.00754 mol) in methylene chloride (80 mL). Stirring was continued at room temperature overnight. The solution was treated with 5% sodium thiosulfate (150 mL), and the organic layer separated and dried over magnesium sulfate. The solvent was evaporated at reduced pressure, and the crude product purified by column chromatography (5% ethyl acetate/hexanes) to give S4-27 as a white solid (3.53 g, 0.00754 mol, 99% yield).
-
- Bicyclo[2.2.1]hept-5-ene-7-syn-(hydroxy)-2-exo-methyl-3-endo-(l)-menthyl dicarboxylate (S4-28)
- S4-27 (3.00 g, 0.00638 mol) was dissolved in anhydrous methanol (150 mL), silver nitrate (5.40 g, 0.0318 mol) added and the suspension refluxed for 3 days. The mixture was cooled, filtered through Celite and the solvent evaporated to give an oily residue. Purification by column chromatography gave S4-28 as a light yellow oil (1.72 g, 0.00491 mol, 77% yield).
-
- 2-exo-Methyl-3-endo-(l)-menthylbicyclo[2.2.1]hept-5-ene-7-syn-(benzyloxy) dicarboxylate (S4-29)
- Benzyl bromide (1.20 g, 0.0070 mol) and silver oxide (1.62 g, 0.0070 mol) were added to a stirring solution of S4-28 (0.490 g, 0.00140 mol) in DMF (25 mL). The suspension was stirred overnight and then diluted with ethyl acetate (100 mL). The solution was washed repeatedly with water followed by 1 N lithium chloride. The organic layer was separated and dried with magnesium sulfate. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography on silica gel to give S4-29 as an oil (0.220 g, 0.000500 mol, 36% yield).
-
- Bicyclo[2.2.1]hept-5-ene-7-syn-(benzyloxy)-2-exo-carboxy-3-endo-(l)-menthyl carboxylate (S4-30)
- S4-29 (0.220 g, 0.00050 mol) was added to a mixture of tetrahydrofuran (1.5 mL), water (0.5 mL), and methanol (0.5 mL). Potassium hydroxide (0.036 g, 0.00065 mol) was added and the solution stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue purified by column chromatography (10% ethyl acetate/hexanes) to give S4-30 (0.050 g, 0.00012 mol, 23% yield).
-
- Mass Spec: calculated for C26H34O5 426.24; found 425.4 (M−1) and 851.3 (2M−1).
- Bicyclo[2.2.1]hept-5-ene-7-syn-(benzyloxy)-2-exo-(trimethylsilylethoxycarbonyl)-amino-3-endo-(l)-menthyl carboxylate (S4-31)
- To a solution of S4-30 in benzene is added triethylamine and diphenylphosphoryl azide. The solution is refluxed for 24 hours then cooled to room temperature. Trimethylsilylethanol is added, and the solution refluxed for an additional 48 hours. The benzene solution is partitioned between ethyl acetate and 1 M sodium bicarbonate. The organic layers are combined, washed with 1 M sodium bicarbonate and dried over sodium sulfate. The solvent is evaporated under reduced pressure to give the crude Curtius reaction product.
- Bicyclo[2.2.1]heptane-7-syn-(benzyloxy)-2-exo-(trimethylsilylethoxycarbonyl)-amino-3-endo-(l)-menthyl-5-exo-methyl-6-exo-methyl tricarboxylate (S4-32)
- S4-31, dry copper(II) chloride, 10% Pd/C, and dry methanol are added to a flask with vigorous stirring. After degassing, the flask is charged with carbon monoxide to a pressure just above 1 atm., which is maintained for 72 hours. The solids are filtered and the residue worked up in the usual way to afford the biscarbonylation product.
- Bicyclo[2.2.1]heptane-7-syn-(benzyloxy)-2-exo-(trimethylsilylethoxycarbonyl)-amino-3-endo-(l)-menthylcarbox-5-exo-6-exo-dicarboxylic anhydride (S4-33)
- A mixture of S4-32, formic acid, and a catalytic amount of p-toluenesulfonic acid is stirred at 90° C. overnight. Acetic anhydride is added and the reaction mixture refluxed for 6 hours. Removal of the solvents and washing with ether gives the desired anhydride.
- Bicyclo[2.2.1]heptane-7-syn-(benzyloxy)-2-exo-(trimethylsilylethoxycarbonyl)-amino-3-endo-(l)-menthyl-6-exo-carboxy-5-exo-methyl dicarboxylate (S4-33)
- To a solution of S4-32 in equal amounts of toluene and carbon tetrachloride is added quinidine. The suspension is cooled to −65° C. and stirred for 1 hour. Three equivalents of methanol are slowly added over 30 minutes. The suspension is stirred at −65° C. for 4 days followed by removal of the solvents under reduced pressure. The resulting white solid is partitioned between ethyl acetate and 2M HCl. The quinine is recovered from the acid layer and S4-33 obtained from the organic layer.
- Bicyclo[12.2.1]heptane-7-syn-(benzyloxy)-2-exo-(trimethylsilylethoxycarbonyl)-amino-3-endo-(l)-menthyl-6-exo-(trimethylsilylethoxycarbonyl)amino-5-exo-methyl dicarboxylate (S4-35)
- To a solution of S4-34 in benzene is added triethylamine and diphenylphosphoryl azide. The solution is refluxed for 24 hours. After cooling to room temperature, 2-trimethylsilylethanol is added and the solution refluxed for 48 hours. The benzene solution is partitioned between ethyl acetate and 1M sodium bicarbonate. The organic layers are combined, washed with 1M sodium bicarbonate, and dried over sodium sulfate. The solvent is evaporated under reduced pressure to give the crude Curtius reaction product.
- endo-Bicyclo[2.2.1]hept-5-ene-2-benzylcarboxylate-3-carboxylic acid (S5-37)
- Compound S3-19 (4.00 g, 0.0244 mol) and quinidine (8.63 g, 0.0266 mol) were suspended in equal amounts of toluene (50 mL) and carbon tetrachloride (50 mL). The suspension was cooled to −55° C. after which benzyl alcohol (7.90 g, 0.0732 mol) was added over 15 minutes. The reaction mixture became homogenous after 3 hours and was stirred at −55° C. for an additional 96 hours. After removal of the solvents, the residue was partitioned between ethyl acetate (300 mL) and 2M hydrochloric acid (100 mL). The organic layer was washed with water (2×50 mL) and saturated aqueous sodium chloride (1×50 mL). Drying over magnesium sulfate and evaporation of the solvent gave S5-37 (4.17 g, 0.0153 mol, 63% yield).
-
- 2-endo-Benzylcarboxy-6-exo-iodobicyclo[2.2.1]heptane-3,5-carbolactone (S5-38)
- S5-37 (4.10 g, 0.0151 mol) was dissolved in 0.5 M sodium bicarbonate solution (120 mL) and cooled to 0° C. Potassium iodide (15.0 g, 0.090 mol) and iodine (7.66 g, 0.030 mol) were added followed by methylene chloride (40 mL). The solution was stirred at room temperature overnight. After dilution with methylene chloride (100 mL), sodium thiosulfate was added to quench the excess iodine. The organic layer was separated and washed with water (100 mL) and sodium chloride solution (100 mL). Drying over magnesium sulfate and evaporation of the solvent gave S5-38 (5.44 g, 0.0137 mol, 91% yield).
-
-
- S5-38 (0.30 g, 0.75 mmol) was placed in DMSO under N2, NaBH4 (85 mg, 2.25 mmol) added and the solution stirred at 85° C. for 2 h. The mixture was cooled, diluted with water (50 mL) and extracted with dichloromethane (3×20 mL). The extracts were combined, washed with water (4×15 mL) and saturated aqueous NaCl (10 mL), dried, and evaporated to give 0.14 g (68%) of S5-39.
- 5-endo-hydroxybicyclo[2.2.1]heptane-2-endo-benzyl-3-endo-methyl dicarboxylate (S5-40)
- Compound S5-39 is dissolved in methanol and sodium methoxide added with stirring. Removal of the solvent gives S5-40.
- Bicyclo[2.2.1]heptane-2-endo-benzyl-3-endo-methyl-5-exo-(t-butoxycarbonyl)-amino dicarboxylate (S5-41)
- In a one-pot reaction S5-40 is converted to the corresponding mesylate with methanesulfonyl chloride, sodium azide added to displace the mesylate to give exo-azide, which is followed by reduction with tributyl phosphine to give the free amine, which is protected as the t-Boc derivative to give S5-41.
- Bicyclo[2.2.1]heptane-2-endo-carboxy-3-exo-methyl-5-exo-(t-butoxycarbonyl)-amino carboxylate (S5-42)
- The benzyl ether protecting group is removed by catalytic hydrogenolysis of S5-41 with 10% Pd/C in methanol at room temperature for 6 hours. Filtration of the catalyst and removal of the solvent yields crude S5-42.
- Bicyclo[2.2.1]heptane-2-endo-carboxy-3-exo-methyl-5-exo-(t-butoxycarbonyl)-amino carboxylate (S5-43)
- Sodium is dissolved in methanol to generate sodium methoxide. S5-42 is added and the mixture stirred at 62° C. for 16 hr. The mixture is cooled and acetic acid added with cooling to neutralize the excess sodium methoxide. The mixture is diluted with water and extracted with ethyl acetate. The extract is dried and evaporated to give S5-43.
- Bicyclo[2.2.1]heptane-2-endo-benzyl-3-exo-methyl-5-exo-(t-butoxycarbonyl)amino dicarboxylate (S5-44)
- Compound S5-43 is reacted with benzyl bromide and cesium carbonate in tetrahydrofuran at room temperature to give benzyl ester S5-44, which is isolated by acid work-up of the crude reaction mixture.
- Bicyclo[2.2.1]heptane-2-endo-benzyl-3-exo-carboxy-5-exo-(t-butoxycarbonyl)-amino carboxylate (S5-45)
- Compound S5-44 is dissolved in methanol and cooled to 0° C. under N2. 2M NaOH (2 equivalents) is added dropwise, the mixture allowed to come to ambient temperature and is stirred for 5 h. The solution is diluted with water, acidified with 2M HCl and extracted with ethyl acetate. The extract is washed with water, saturated aqueous NaCl, dried and evaporated to give S5-45.
- Bicyclo[2.2.1]heptane-2-endo-benzyl-3-exo-(trimethylsilylethoxycarbonyl)amino-5-exo-(t-butoxycarbonyl)amino carboxylate (S5-46)
- To a solution of S5-45 in benzene is added triethylamine and diphenylphosphoryl azide. The solution is refluxed for 24 hours and then cooled to room temperature. Trimethylsilylethanol is added and the solution refluxed for 48 hours. The solution is partitioned between ethyl acetate and 1M sodium bicarbonate. The organic layer is washed with 1M sodium bicarbonate and dried over sodium sulfate. The solvent is evaporated under reduced pressure to give crude Curtius product S5-46.
- endo-Bicyclo[2.2.1]hept-5-ene-2-(4-methoxy)benzylcarboxylate-3-carboxylic acid (S6-48)
- Compound S3-19 and quinidine are suspended in equal amounts of toluene and carbon tetrachloride and cooled to −55° C. p-Methoxybenzyl alcohol is added over 15 minutes and the solution stirred at −55° C. for 96 hours. After removal of the solvents, the residue is partitioned between ethyl acetate and 2 M hydrochloric acid. The organic layer is washed with water and saturated aqueous sodium chloride. Drying over magnesium sulfate and removal of the solvent gives S6-48.
- endo-Bicyclo[2.2.1]hept-5-ene-2-(4-methoxy)benzyl-3-(trimethylsilylethoxycarbonyl)amino carboxylate (S6-49)
- To a solution of S6-48 in benzene is added triethylamine and diphenylphosphoryl azide. The solution is refluxed for 24 hours, cooled to room temperature, trimethylsilylethanol is added, and the solution is refluxed for an additional 48 hours. The benzene solution is partitioned between ethyl acetate and 1 M sodium bicarbonate. The organic layers are combined, washed with 1 M sodium bicarbonate, and dried with sodium sulfate. The solvent is evaporated under reduced pressure to give crude Curtius product S6-49.
- Bicyclo[2.2.1]heptane-2-endo-(4-methoxy)benzyl-3-endo-(trimethylsilylethoxycarbonyl)amino-5-exo-methyl-6-exo-methyl tricarboxylate (S6-50).
- S6-49, copper(II) chloride, 10% Pd/C, and dry methanol are added to a flask with vigorous stirring. After degassing the suspension, the flask is charged with carbon monoxide to a pressure just above 1 atm. The pressure of carbon monoxide is maintained over 72 hours. The solids are filtered off, and the crude reaction mixture worked up in the usual way to afford S6-50.
- Bicyclo[2.2.1]heptane-2-endo-(4-methoxy)benzyl-3-endo-(trimethylsilylethoxycarbonyl)amino-5-exo-6-exo-dicarboxylic anhydride (S6-51).
- S6-50, formic acid, and a catalytic amount of p-toluenesulfonic acid is heated at 90° C. overnight. Acetic anhydride is added to the reaction mixture, and it is refluxed for an additional 6 hours. Removal of the solvents and washing with ether affords S6-51.
- Bicyclo[2.2.1]heptane-2-endo-(4-methoxy)benzyl-3-endo-(trimethylsilylethoxycarbonyl)amino-5-exo-carboxy-6-exo-methyl dicarboxylate (S6-52).
- To a solution of S6-51 in equal amounts of toluene and carbon tetrachloride is added quinine. The suspension is cooled to −65° C. and stirred for 1 hour. Three equivalents of methanol are added slowly over 30 minutes. The suspension is stirred at −65° C. for 4 days followed by removal of the solvents. The resulting white solid is partitioned between ethyl acetate and 2 M HCl, with S6-52 worked up from the organic layer.
- Bicyclo[2.2.1]heptane-2-endo-(4-methoxy)benzyl-3-endo-(trimethylsilylethoxycarbonyl)amino-5-exo-(trimethylsilylethoxycarbonyl)amino-6-exo-methyl dicarboxylate (S6-53).
- To a solution of S6-52 in benzene is added triethylamine and diphenylphosphoryl azide. The solution is refluxed for 24 hours then cooled to room temperature. 2-Trimethylsilylethanol is added, and the solution is refluxed for an additional 48 hours. The benzene solution is partitioned between ethyl acetate and 1 M sodium bicarbonate. The organic layers are combined, washed with 1 M sodium bicarbonate, and dried with sodium sulfate. The solvent is evaporated under reduced pressure to give S6-53.
- Bicyclo[2.2.1]heptane-2-exo-(4-methoxy)benzyl-3-endo-(trimethylsilylethoxycarbonyl)amino-5-exo-(trimethylsilylethoxycarbonyl)amino-6-endo-methyl dicarboxylate (S6-54).
- To a solution of S6-53 in tetrahydrofuran is carefully added potassium tert-butoxide. The basic solution is refluxed for 24 hours followed by addition of acetic acid. Standard extraction methods give the double epimerized product S6-54.
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- To 0.300 g (1R, 2R)-(−)-trans-1,2-diaminocyclohexane (2.63 mmol) in 5 mL CH2Cl2 at 0° C. was added 0.600 g of 2,6-diformyl-4-bromophenol (2.62 mmol) in 5 mL of CH2Cl2. The yellow solution was allowed to warm to room temperature and stirred for 48 hours. The reaction solution was decanted, and added to 150 mL of methanol. After standing for 30 minutes, the yellow precipitate was collected, washed with methanol, and air-dried (0.580 g; 72% yield).
-
- MS (FAB): Calcd for C42H46N6O3Br3 923.115; found 923.3 [M+H]+.
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- To 0.300 g (1R, 2R)-(−)-trans-1,2-diaminocyclohexane (2.63 mmol) in 6 mL CH2Cl2 at 0° C. was added 0.826 g of 2,6-diformyl-4-(1-dodec-1-yne)phenol (2.63 mmol) in 6 mL of CH2Cl2. The orange solution was stirred at 0° C. for 1 hour and then allowed to warm to room temperature after which stirring was continued for 16 hours. The reaction solution was decanted and added to 150 mL of methanol. A sticky yellow solid was obtained after decanting the methanol solution. Chromatographic cleanup of the residue gave a yellow powder.
-
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- MS (FAB): Calcd for C78H109N6O3 1177.856; found: 1177.8 [M+H]+.
-
- To 0.240 g of 2,6-diformyl-4-(1-dodecene)phenol (0.76 mmol) in 10 mL of benzene was added a 10 mL benzene solution of (1R,2R)-(−)-trans-1,2-diaminocyclohexane (0.087g, 0.76 mmol). The solution was stirred at room temperature for 48 hours shielded from the light. The orange solution was taken to dryness and chromatographed (silica, 50/50 acetone/Et2O) to give a yellow sticky solid (33% yield).
-
- MS (FAB): Calcd for C78H115N6O3 1183.90; found: 1184.6 [M+H]+.
-
-
- Triethylamine (0.50 mL, 3.59 mmol) and (1R, 2R)-(−)-trans-1,2-diaminocyclohexane (0.190 g, 1.66 mmol) were combined in 150 mL EtOAc and purged with N2 for 5 minutes. To this solution was added 0.331 g isophthalolyl chloride (1.66 mmol) dissolved in 100 mL EtOAc dropwise over six hours. The solution was filtered and the filtrate taken to dryness. TLC (5% methanol/CH2Cl2) shows the product mixture to be primarily composed of two macrocyclic compositions. Chromatographic separation (silica, 5% methanol/CH2Cl2) gave the above tetramer (0.020 g, 5% yield) and hexamer (about 10%).
- Tetramer:
-
- MS (ESI): Calcd for C28H33N4O4 489.25; found 489.4 [M+H]+.
- Hexamer:
- MS (ESI): Calcd for C42H49N6O6 733.37; found 733.5 [M+H]+.
-
- n=2, Tetramer 1 f-methoxy
- n=3, Hexamer 1 f-methoxy
- n=4, Octamer 1 f-methoxy
- To a 5 mL dichloromethane solution of 4-dodecyl-2,6-diformyl anisole (24 mg; 0.072 mmol) was added a 5 mL dichloromethane solution of (1R, 2R)-(−)-trans-1,2-diaminocyclohexane (8.5 mg; 0.074 mmol). This solution was stirred at room temperature for 16 hours and then added to the top of a short silica column. Elution with diethyl ether and then removal of solvent led to the isolation of 22 mg of an off-white solid. Positive ion electrospray mass spectrometry demonstrated the presence of the tetramer (m/z 822, MH+), hexamer (m/z 1232, MH+), and the octamer (m/z 1643, MH+) in the off-white solid. Calculated molecular weights were as follows: tetramer+H (C54H85N4O2, 821.67); hexamer+H (C81H127N6O3, 1232.00); octamer+H (C108H169N8O4, 1643.33).
- Without intending to be bound by any one particular theory, one method to approximate pore size of a macrocyclic module is quantum mechanical (QM) and molecular mechanical (MM) computations. In this example, macrocyclic modules having two types of synthons, “A” and “B,” were used and all linkages between synthons were assumed to be the same. For the purposes of QM and MM computations, the root mean square deviations in the pore areas were computed over dynamic runs.
- For QM, each module was first optimized using the MM+ force field approach of Allinger (JACS, 1977, 99:8127) and Burkert, et al., (Molecular Mechanics, ACS Monograph 177, 1982). They were then re-optimized using the AM1 Hamiltonian (Dewar, et al., JACS, 1985, 107:3903; Dewar, et al., JACS, 1986, 108:8075; Stewart, J. Comp. Aided Mol. Design, 1990, 4:1). To verify the nature of the potential energy surface in the vicinity of the optimized structures, the associated Hessian matrices were computed using numerical double-differencing.
- For MM, the OPLS-AA force field approach (Jorgensen, et al., JACS, 1996, 118:11225) was used. For imine linkages, the dihedral angle was confined to 180°±10°. The structures were minimized and equilibrated for one picosecond using 0.5 femtosecond time steps. Then a 5 nanosecond dynamics run was carried out with a 1.5 femtosecond time step. Structures were saved every picosecond. The results are shown in Tables 4 and 5.
- Macrocyclic module pore areas derived from QM and MM computations for various linkages and macrocyclic module pore size are shown in Table 4. In Table 4, the macrocyclic modules had alternating synthons “A” and “B.” Synthon “A” is a benzene synthon coupled to linkages L at 1,3-phenyl positions, and Synthon “B” is shown in the left-hand column of the table.
TABLE 4 Pore areas for various macrocyclic modules (Å2) TETRAMER TETRAMER HEXAMER HEXAMER OCTAMER OCTAMER SYNTHON B QM MM QM MM QM MM trans-1,2- imine (trans) Imine (trans) cyclohexane 14.3 Å2 13.2 ± 1.4 Å2 trans-1,2- Acetylene cyclohexane 14.3 Å2 trans-1,2- Amine Amine cyclohexane 23.1 Å2 13.9 ± 1.9 Å2 trans-1,2- Amide Amide cyclohexane 19.7 Å2 17.5 ± 2.0 Å2 trans-1,2- Ester Ester cyclohexane 18.9 Å2 19.6 ± 2.0 Å2 Equatorial-1,3- imine (trans) Imine (trans) imine (trans) Imine (trans) cyclohexane 18.1 Å2 21.8 ± 1.6 Å2 66.2 Å2 745 ± 7.7 Å2 Equatorial-1,3- Amine Amine cyclohexane 14.7 Å2 19.9 ± 26 Å2 Equatorial-1,3- Amide Amide cyclohexane 24.8 Å2 21.7 ± 1.8 Å2 Equatorial-1,3- Ester Ester cyclohexane 22.9 Å2 22.8 ± 24 Å2 Equatorial-3- imine (trans) imine (trans) imine (trans) Imine (trans) imine (trans) Imine (trans) amino- oxygen- oxygen-oxygen 18.4 Å2 21.0 ± 1.5 Å2 56.7 Å2 60.5+-8.3 Å2 cyclohexene oxygen distance distance 37 ± 3Å 2481 Å trans-1,2- imine (trans) Imine (trans) pyrrolidine 10.4 Å2 92 ± 14 Å2 Equatorial-1,3 imine (trans) Imine (trans) piperidene 19.2 Å2 209 ± 11 Å2 Endo-exo-1,2- imine (trans) Imine (trans) bicycloheptane 11.1 Å2 14.1 ± 11 Å2 Endo-endo-1,3- imine (trans) Imine (trans) bicycloheptane 18.8 Å2 207 ± 1.4 Å2 Endo-exo-1,3- Imine Imine bicycloheptane 19.5 Å2 10.1 ± 4.9 Å2 Equatorial-1,3- Amine Amine cyclohexane 9.8 Å2 9.9 ± 2.4 Å2 Endo-endo-1,3- imine (trans) Imine (trans) bicyclooctene 18.9 Å2 21.6 ± 1.5 Å2 Endo-exo-1,3- imine (trans) Imine (trans) bicyclooctene 15.6 Å2 187 ± 1.6 Å2 Equatorial-3,9- imine (trans) Imine (trans) decalin 35.4 Å2 40.0 ± 2.2 Å2 - Further macrocyclic module pore areas derived from QM and MM computations for various linkages and macrocyclic module pore size are shown in Table 5. In Table 5, the macrocyclic modules had alternating synthons “A” and “B.” In Table 5, Synthon “A” is a naphthalene synthon coupled to linkages L at 2,7-naphthyl positions, and Synthon “B” is shown in the left-hand column of the table.
TABLE 5 Pore areas for various macrocyclic modules (Å2) HEXAMER HEXAMER SYNTHON B QM MM Trans-1,2- imine (trans) imine (trans) cyclohexane 23.5 Å2 25.4 ± 4.9 Å2 Endo-endo-1,3- imine (trans) imine (trans) bicycloheptane 30.1 Å2 30.0 ± 3.6 Å2 -
- The pore size of macrocyclic modules was determined experimentally using a voltage-clamped bilayer procedure. A quantity of a macrocyclic module was inserted into a lipid bilayer formed by phosphatidylcholine and phosphatidylethanolamine. On one side of the bilayer was placed a solution containing the cationic species to be tested. On the other side was a solution containing a reference cationic species known to be able to pass through the pore of the macrocyclic module. Anions required for charge balance were selected which could not pass through the pores of the macrocyclic module. When a positive electrical potential was applied to the solution on the side of the lipid bilayer containing the test species, if the test species passed through the pores in the macrocyclic modules, a current was detected. The voltage was then reversed to detect current due to transport of the reference species through the pores, thereby confirming that the bilayer is a barrier to transport and that the pores of the macrocyclic modules provide transport of species.
- Using the above technique, a hexameric macrocyclic module comprised of 1R,2R-(−)-transdiaminocyclohexane and 2,6-diformal-4-(1-dodec-1-ynyl)phenol synthons, having imine groups as the linkages (the first module in Table 3) was tested for transport of various ionic species. The results are shown in Table 6.
TABLE 6 Voltage-clamped bilayer test for macrocyclic module pore size Calculated van der Calculated van der Waals radius of ionic Waals radius of species with one Does ionic species Ionic species ionic species (Å) water shell (Å) pass through pore? Na+ 1.0 2.2 Yes K+ 1.3 2.7 Yes Ca2+ 1.0 2.7 Yes NH4 + 1.9 2.9 Yes Cs+ 1.7 3.0 Yes MeNH3 + 2.0 3.0 Yes EtNH 3 +2.6 3.6 No NMe4 + 2.6 3.6 No Aminoguanidinium 3.1 4.1 No NEt 4 +3.9 4.4 No Choline 3.8 4.8 No Glucosamine 4.2 5.2 No - The results in Table 6 show that the cut-off for passage through the pore in the selected module is a van der Waals radius of between 2.0 and 2.6 Å. In Table 4, the QM and MM computed pore sizes are given as areas. Using the equation for area of a circle, A=πr2, the computed area of the pore in the first module of Table 4, 14.3 Å2, gives a value for r of 2.13 Å. Ions having van der Waals radii of less than 2.13 Å would be expected to traverse the pore and those with larger radii would not, and that is what was observed. CH3NH3 +, having a radius of 2.0 Å, passed through the pore while CH3CH2NH3 +, with a radius of 2.6 Å, did not. Without being held to a particular theory, and recognizing that several factors influence pore transport, the observed ability of hydrated ions to pass through the pore may be due to partial dehydration of the species to enter the pore, transport of water molecules and ions through the pore separately or with reduced interaction during transport, and re-coordination of water molecules and ions after transport. The details of pore structure, composition, and chemistry, the flexibility of the macrocyclic module, and other interactions may affect the transport process.
- Pore properties of 1,2-imine-linked and 1,2-amine-linked hexamer macrocyclic modules are illustrated in Table 7. Referring to Table 7, the bilayer clamp data indicates that the passage and exclusion of certain species through the pore of the modules correlates with the computational size of the pores. Further, these surprising data show that a very small change in the placement of atoms and/or structural features can lead to a discrete change in transport properties and allow regulation of transport through the pore by variation of synthons and linkages among other factors.
TABLE 7 Voltage-clamped bilayer test for macrocyclic module pore size Radius of solute with H2O Hexamer 1a Hexamer 1jh Radius of (radius of 2nd hydration (1,2-imine) (1,2-amine) Solute species Solute shell in parentheses) Radius = 3.3Å Radius = 3.9Å Li+ 0.6 2.0 (5.6) No Yes Na+ 1.0 2.2 Yes Yes K+ 1.3 2.7 Yes Yes Ca2+ 1.0 2.7 Yes Yes Mg2+ 0.7 2.8 (5.5) No Yes NH3 + 1.9 2.9 Yes Yes Cs+ 1.7 3 Yes Yes MeNH 3 + 2 3 Yes Yes EtNH3 + 2.6 3.6 No Yes NMe4 + 2.6 3.6 No Yes Aminoguanidine 3.1 4.1 No Yes Choline 3.8 4.8 No Yes NEt4 + 3.9 4.4 No No Glucosamine 4.2 5.2 No No NPr4 + — — — No -
- The relative stability of the Langmuir film of Hexamer 1a-Me is illustrated by the isobaric creep data shown in FIG. 2B. The area of the film decreased by about 30% after about 30 min at 5 mN/m surface pressure. The Langmuir isotherm and isobaric creep for Hexamer 1a-C15 are shown in FIGS. 3A and 3B, respectively. The relative stability of the Langmuir film of Hexamer 1a-C15 is illustrated by the isobaric creep data shown in FIG. 3B. The area of the film decreased by about 1-2% after about 30 min at 10 mN/m surface pressure, and by about 2% after about 60 min. The collapse pressure was about 18 mN/m for Hexamer 1a-C15.
-
- Templated Imine Octamer. To a 3
neck 100 mL round bottomed flask with stirbar, fitted with condenser and addition funnel under argon, amphiphilic dialdehyde phenol 1 (500 mg, 1.16 mmol) was added. Next, Mg(NO3)2. 6 H2O (148 mg, 0.58 mmol) 2 and Mg(OAc)2. 4 H2O (124 mg, 0.58 mmol) were successively added. The flask was put under vacuo and backfilled with argon 3×. Anhydrous methanol was transferred to the flask via syringe under argon and the resulting suspension stirred. The mixture was then refluxed for 10 min affording a homogeneous solution. The reaction was allowed to cool to room temperature under positive argon pressure. (1R, 2R)-(−)-trans-1,2-diaminocyclohexane 4 was added to the addition funnel followed by cannula transfer of anhydrous MeOH (11.6 mL) under argon. The diamine/MeOH solution was added to the stirred homogeneous metal template/dialdehyde solution drop wise over a period of 1 h affording an orange oil. The addition funnel was replaced with a glass stopper and the mixture was refluxed for 3 days. The solvent was removed in vacuo affording a yellow crystalline solid that was used without further purification. - Amine Octamer. To a 50 mL schlenk flask with stirbar under argon Imine Octamer (314 mg, 0.14 mmol) was added. Next anhydrous THF (15 mL) and MeOH (6.4 mL) were added via syringe under argon and the suspension stirred at room temperature. To the homogeneous solution, NaBH4 (136 mg, 3.6 mmol) was added in portions and the mixture stirred at room temperature for 12 h. The solution was filtered, followed by addition of 19.9 mL H2O. The pH was adjusted to ca. 2 by addition of 4 M HCl, then 6.8 mL of an ethylenediamine tetraaceticacid disodium salt dihydrate (0.13 M in H2O) was added and the mixture stirred for 5 min. To the solution, 2.0% ammonium hydroxide was added and stirring continued for an additional 5 min. The solution was extracted with ethyl acetate (3×100 mL) the organic layer separated, dried over Na2SO4 and the solvent removed via rotoevaporation affording a pale yellow solid. Recrystallization from chloroform and hexanes afforded the Amine Octamer. Molecular weight was confirmed by ESIMS M+H=experimental=2058.7 m/z, calcd=2058.7 m/z.
-
- Hexamer 1j. The two substrates, (−)-R,R-1,2-trans-diaminocyclohexane (0.462 mmol, 0.053 g) and 2,6-diformyl-4-hexadecyl benzylphenol carboxylate (0.462 mmol, 0.200 g) were added to a 10 mL vial containing a magnetic stirbar followed by the addition of 2 mL of CH2Cl2. The yellow solution was stirred at room temperature. After 24 h the reaction solution was plugged through silica gel with diethyl ether, and the solvent removed via roto-evaporation. (232 mg; 98% yield). 1H NMR (400 MHz, CDCl3): δ 14.11 (s, 3 H, OH), 8.67 (s, 3 H, CH═N), 8.23 (s, 3 H, CH═N), 7.70 (s, 3 H, ArH), 7.11 (s, 3 H, ArH), 4.05-3.90 (t, 6 H, 3J=6.6 Hz, CH2C(O)OCH2(CH2)14CH3), 3.44 (s, 6 H, CH2C(O)OCH2(CH2)14CH3), 3.30-3.42 (m, 6 H, CH2—CH—N), 1.21-1.90 (m, 108 H, aliphatic) 0.92-0.86 (t, 9 H, 3j=6.6 Hz. ESIMS (+) Calcd for C96H151N6O9: 1533; Found: 1534 [M+H]+.
- Hexamer 1jh. To a 100 mL pear-shaped flask with magnetic stirbar under argon, Hexamer 1j (0.387 mmol, 0.594 g) was added and dissolved in THF:MeOH (7:3, 28:12 mL, respectively). Next, NaBH4 (2.32 mmol, 0.088 g) was added slowly in portions at room temperature for 6.5 h. The solvent was removed by roto-evaporation, the residue dissolved in 125 mL ethyl acetate and washed 3×50 mL of H2O. The organic layer was separated, dried over Na2SO4 and the solvent removed by roto-evaporation. The resulting residue was recrystallized from CH2Cl2 and MeOH affording a white solid (0.440 g; 74% yield). 1H NMR (400 MHz, CDCl3): δ 6.86 (s, 6 H, ArH), 4.10-4.00 (t, 6 H, 3J=6.6 Hz, CH2C(O)OCH2(CH2)14CH3), 3.87-3.69 (dd, 6 H, 3J=13.7 Hz, 3J (CNH)=42.4 Hz CH2—CH—N), 3.43 (s, 6 H, CH2C(O)OCH2(CH2)14CH3), 2.40-2.28 (m, 6 H, aliphatic), 2.15-1.95 (m, 6 H, aliphatic), 1.75-1.60 (m, 6 H, aliphatic), 1.60-1.55 (m, 6 H, aliphatic) 1.37-1.05 (m, 84 H, aliphatic) 0.92-0.86 (t, 9 H, 3J=6.8 Hz. ESIMS (+) Calcd for C96H163N6O9: 1544; Found: 1545 [M+H]+.
-
- Hexamer 1A-Me. A solution of 2-hydroxy-5-methyl-1,3-benzenedicarboxaldehye (53 mg, 0.32 mmol) in dichloromethane (0.6 mL) was added to a solution of (1R,2R)-(−)-1,2-diaminocyclohexane (37 mg, 0.32 mmol) in dichloromethane (0.5 mL). The mixture was stirred at ambient temperature for 16 h, added dropwise to methanol (75 mL) and chilled (4° C.) for 4 h. The precipitate was collected to afford 71 mg (92%) of hexamer 1A-Me.1H NMR (CDCl3): δ 13.88 (s, 3H, OH), 8.66 (s, 3H, ArCH═N), 8.19 (s, 3H, ArCH═N), 7.52 (d, 3H, J=2 Hz, Ar H), 6.86 (d, 3H, J=2 Hz, Ar H), 3.35 (m, 6H, cyclohexane 1,2-H's), 2.03 (3, 9H, Me), 1.6-1.9 (m, 18H, cyclohexane 3,6-H2 and 4eq,5eq-H's), 1.45 (m, 6H,
cyclohexane 4ax, 5ax-H's); 13C NMR δ 63.67, 159.55, 156.38, 134.42, 129.75, 127.13, 119.00, 75.68, 73.62, 33.68, 33.41, 24.65, 24.57, 20.22; ESI(+) MS m/e (%) 727 M+H (100); IR 1634 cm−1.
Claims (40)
1. A macrocyclic module composition comprising:
from three to about twenty-four cyclic synthons coupled to form a closed ring;
at least two functional groups for coupling the closed ring to complementary functional groups on at least two other closed rings;
wherein each functional group and each complementary functional group comprises an organic functional group containing atoms selected from the group consisting of C, H, N, O, Si, P, S, B, Al, halogens, and metals from the alkali and alkaline earth groups.
2. The composition of claim 1 , comprising at least two closed rings coupled through said functional groups.
3. The composition of claim 1 , comprising at least three closed rings coupled through said functional groups.
4. A macrocyclic module composition comprising:
from three to about twenty-four cyclic synthons coupled to form a closed ring defining a pore;
the closed ring having a first pore dimension in a first conformation when a first group of substituents is located at the pore and a second pore dimension in a second conformation when a second group of substituents is located at the pore;
wherein each substituent of each group comprises an organic functional group containing atoms selected from the group consisting of C, H, N, O, Si, P, S, B, Al, halogens, and metals from the alkali and alkaline earth groups.
5. A composition, comprising:
(a) from three to about twenty-four cyclic synthons coupled to form a closed ring defining a pore;
(b) at least one functional group coupled to the closed ring at the pore and selected to transport a selected species through the pore, wherein the at least one functional group comprises an organic functional group containing atoms selected from the group consisting of C, H, N, O, Si, P, S, B, Al, halogens, and metals from the alkali and alkaline earth groups;
(c) a selected species to be transported through the pore.
6. The composition of claim 5 , wherein the selected species is selected from the group of ovalbumin, glucose, creatinine, H2PO4 −, HPO4 −2, HCO3 −, urea, Na+, Li+, and K+.
7. A method of preparing a composition to transport a selected species through the composition, comprising:
selecting a first cyclic synthon, wherein the first cyclic synthon is substituted with at least one functional group comprising an organic functional group containing atoms selected from the group consisting of C, H, N, O, Si, P, S, B, Al, halogens, and metals from the alkali and alkaline earth groups;
selecting from two to about twenty-three additional cyclic synthons;
incorporating the first cyclic synthon and the additional cyclic synthons into a macrocyclic module composition comprising:
from three to about twenty-four cyclic synthons coupled to form a closed ring defining a pore;
wherein the at least one functional group of the first cyclic synthon is located at the pore of the macrocyclic module composition and is selected to transport the selected species through the pore.
8. The composition as in any one of claims 1-4 coupled to a solid support selected from the group of Wang resins, hydrogels, aluminas, metals, ceramics, polymers, silica gels, sepharose, sephadex, agarose, inorganic solids, semiconductors, and silicon wafers.
9. The composition as in any one of claims 1-4, wherein the macrocyclic module composition retains at least 85% of film area after thirty minutes on a Langmuir trough at 5-15 mN/m.
10. The composition as in any one of claims 1-4, wherein the macrocyclic module composition retains at least 95% of film area after thirty minutes on a Langmuir trough at 5-15 mN/m.
11. The composition as in any one of claims 1-4, wherein the macrocyclic module composition retains at least 98% of film area after thirty minutes on a Langmuir trough at 5-15 mN/m.
12. The composition as in any one of claims 1-5, wherein the cyclic synthons are each independently selected from the group consisting of benzene, cyclohexadiene, cyclohexene, cyclohexane, cyclopentadiene, cyclopentene, cyclopentane, cycloheptane, cycloheptene, cycloheptadiene, cycloheptatriene, cyclooctane, cyclooctene, cyclooctadiene, cyclooctatriene, cyclooctatetraene, naphthalene, anthracene, phenylene, phenanthracene, pyrene, triphenylene, phenanthrene, pyridine, pyrimidine, pyridazine, biphenyl, bipyridyl, decalin, piperidine, pyrrolidine, morpholine, piperazine, pyrazolidine, quinuclidine, tetrahydropyran, dioxane, tetrahydrothiophene, tetrahydrofuran, pyrrole, triptycene, adamantane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo[2.2.2]octane, bicyclo[2.2.2]octene, bicyclo[3.3.0]octane, bicyclo[3.3.0]octene, bicyclo[3.3.1]nonane, bicyclo[3.3.1]nonene, bicyclo[3.2.2]nonane, bicyclo[3.2.2]nonene, bicyclo[4.2.2]decane, 7-azabicyclo[2.2.1]heptane, 1,3-diazabicyclo[2.2.1]heptane, and spiro[4.4]nonane.
13. The composition as in any one of claims 1, 4, or 5, wherein each coupled cyclic synthon is independently coupled to two adjacent synthons by a linkage selected from the group consisting of (a) a condensed linkage, and (b) a linkage selected from the group consisting of —NRC(O)—, —OC(O)—, —O—, —S—S—, —S—, —NR—, —(CRR′)p—, —CH2NH—, —C(O)S—, —C(O)O—, —C≡C—, —C≡C—C≡C—, —CH(OH)—, —HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH2NH—, —NHCH2CH(OH)CH2NH—, —N═CH(CH2)pCH═N—, —CH2CH(OH)CH2—, —N═CH(CH2)hCH═N— where h is 1-4, —CH═N—NH—, —OC(O)O—, —OP(O)(OH)O—, —CH(OH)CH2NH—, —CH(OH)CH2—, —CH(OH)C(CH3)2C(O)O—,
wherein p is 1-6;
wherein R and R′ are each independently selected from the group of hydrogen and alkyl;
wherein the linkage is independently configured in either of two possible configurations, forward and reverse, with respect to the synthons it couples together, if the two configurations are different structures;
wherein Q is one of the synthons connected by the linkage.
14. A closed ring composition of the formula:
wherein:
J is 2-23;
Q1 are synthons each independently selected from the group consisting of (a) phenyl synthons coupled to linkages L at 1,2-phenyl positions, (b) phenyl synthons coupled to linkages L at 1,3-phenyl positions, (c) aryl synthons other than phenyl synthons, (d) heteroaryl synthons other than pyridinium synthons, (e) saturated cyclic hydrocarbon synthons, (f) unsaturated cyclic hydrocarbon synthons, (g) saturated bicyclic hydrocarbon synthons, (h) unsaturated bicyclic hydrocarbon synthons, (i) saturated multicyclic hydrocarbon synthons, and (j) unsaturated multicyclic hydrocarbon synthons; wherein ring positions of each Q1 which are not coupled to a linkage L are substituted with hydrogen or organic functional groups containing atoms selected from the group of C, H, N, O, Si, P, S, B, Al, halogens, and metals from the alkali and alkaline earth groups;
Q2 is a synthon independently selected from the group consisting of (a) aryl synthons other than phenyl synthons and naphthalene synthons coupled to linkages L at 2,7-naphthyl positions, (b) heteroaryl synthons other than pyridine synthons coupled to linkages L at 2,6-pyridino positions, (c) saturated cyclic hydrocarbon synthons other than cyclohexane synthons coupled to linkages L at 1,2-cyclohexyl positions, (d) unsaturated cyclic hydrocarbon synthons other than pyrrole synthons coupled to linkages L at 2,5-pyrrole positions, (e) saturated bicyclic hydrocarbon synthons, (f) unsaturated bicyclic hydrocarbon synthons, (g) saturated multicyclic hydrocarbon synthons, and (h) unsaturated multicyclic hydrocarbon synthons; wherein ring positions of Q2 which are not coupled to an L are substituted with hydrogen or organic functional groups containing atoms selected from the group consisting of C, H, N, O, Si, P, S, B, Al, halogens, and metals from the alkali and alkaline earth groups;
L are linkages between the synthons each independently selected from the group consisting of (a) a condensed linkage, and (b) a linkage selected from the group consisting of —NRC(O)—, —OC(O)—, —O—, —S—S—, —S—, —NR—, —(CRR′)p—, —CH2NH—, —C(O)S—, —C(O)O—, —C≡C—, —C≡C—C≡C—, —CH(OH)—, —HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH2NH—, —NHCH2CH(OH)CH2NH—, —N═CH(CH2)pCH═N—, —CH2CH(OH)CH2—, —N═CH(CH2)hCH═N— where h is 1-4, —CH═N—NH—, —OC(O)O—, —OP(O)(OH)O—, —CH(OH)CH2NH—, —CH(OH)CH2—, —CH(OH)C(CH3)2C(O)O—,
wherein p is 1-6;
wherein R and R′ are each independently selected from the group of hydrogen and alkyl;
wherein linkages L are each independently configured in either of two possible configurations, forward and reverse, with respect to the synthons it couples together, if the two configurations are different structures;
wherein y is 1 or 2, and Qy are each independently one of the Q1 or Q2 synthons connected by the linkage.
15. The composition of claim 14 , wherein the organic functional groups are each independently selected from the group consisting of hydrogen, an activated acid, —OH, —C(O)OH, —C(O)H, —C(O)OCH3, —C(O)Cl, —NRR, —NRRR+, —MgX, —Li, —OLi, —OK, —ONa, —SH, —C(O)(CH2)2C(O)OCH3, —NH-alkyl-C(O)CH2CH(NH2)CO2-alkyl, —CH═CH2, —CH═CHR, —CH═CR2, 4-vinylaryl, —C(O)CH═CH2, —NHC(O)CH═CH2, —C(O)CH═CH(C6H5),
—OH, —OC(O)(CH2)2C(O)OCH3, —OC(O)CH═CH2, —P(O)(OH)(OX), —P(═O)(O−)O(CH2)sNR3 +;
wherein R are each independently selected from the group consisting of hydrogen and 1-6C alkyl; X is selected from the group consisting of Cl, Br, and I; r is 1-50; and s is 1-4.
16. The composition of claim 14 , wherein the macrocyclic module composition retains at least 85% of film area after thirty minutes on a Langmuir trough at 5-15 mN/m.
17. The composition of claim 14 , wherein the macrocyclic module composition retains at least 95% of film area after thirty minutes on a Langmuir trough at 5-15 mN/m.
18. The composition of claim 14 , wherein the macrocyclic module composition retains at least 98% of film area after thirty minutes on a Langmuir trough at 5-15 mN/m.
19. A closed ring composition of the formula:
wherein:
J is 2-23;
Q1 are synthons each independently selected from the group consisting of (a) phenyl synthons coupled to linkages L at 1,2-phenyl positions, (b) phenyl synthons coupled to linkages L at 1,3-phenyl positions, and (c) cyclohexane synthons coupled to linkages L at 1,2-cyclohexyl positions; wherein ring positions of each Q1 which are not coupled to a linkage L are substituted with hydrogen or organic functional groups containing atoms selected from the group of C, H, N, O, Si, P, S, B, Al, halogens, and metals from the alkali and alkaline earth groups;
Q2 is a cyclohexane synthon coupled to linkages L at 1,2-cyclohexyl positions; wherein ring positions of Q2 which are not coupled to an L are substituted with organic functional groups containing atoms selected from the group consisting of C, H, N, O, Si, P, S, B, Al, halogens, and metals from the alkali and alkaline earth groups;
L are linkages between the synthons each independently selected from the group consisting of (a) a condensed linkage, and (b) a linkage selected from the group consisting of —NRC(O)—, —OC(O)—, —O—, —S—S—, —S—, —NR—, —(CRR′)p—, —CH2NH—, —C(O)S—, —C(O)O—, —C≡C—, —C≡C—C≡C—, —CH(OH)—, —HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH2NH—, —NHCH2CH(OH)CH2NH—, —N═CH(CH2)pCH═N—, —CH2CH(OH)CH2—, —N═CH(CH2)hCH═N— where h is 1-4, —CH═N—NH—, —OC(O)O—, —OP(O)(OH)O—, —CH(OH)CH2NH—, —CH(OH)CH2—, —CH(OH)C(CH3)2C(O)O—,
wherein p is 1-6;
wherein R and R′ are each independently selected from the group of hydrogen and alkyl;
wherein linkages L are each independently configured in either of two possible configurations, forward and reverse, with respect to the synthons it couples together, if the two configurations are different structures;
wherein y is 1 or 2, and Qy are each independently one of the Q1 or Q2 synthons connected by the linkage.
20. The composition of claim 19 , wherein the organic functional groups are each independently selected from the group consisting of hydrogen, an activated acid, —OH, —C(O)OH, —C(O)H, —C(O)OCH3, —C(O)Cl, —NRR, —NRRR+, —MgX, —Li, —OLi, —OK, —ONa, —SH, —C(O)(CH2)2C(O)OCH3, —NH-alkyl-C(O)CH2CH(NH2)CO2-alkyl, —CH═CH2, —CH═CHR, —CH═CR2, 4-vinylaryl, —C(O)CH═CH2, —NHC(O)CH═CH2, —C(O)CH═CH(C6H5),
—OH, —OC(O)(CH2)2C(O)OCH3, —OC(O)CH═CH2, —P(O)(OH)(OX), —P(═O)(O−)O(CH2),NR3 +;
wherein R are each independently selected from the group consisting of hydrogen and 1-6C alkyl; X is selected from the group consisting of Cl, Br, and I; r is 1-50; and s is 1-4.
21. The composition of claim 19 , wherein the macrocyclic module composition retains at least 85% of film area after thirty minutes on a Langmuir trough at 5-15 mN/m.
22. The composition of claim 19 , wherein the macrocyclic module composition retains at least 95% of film area after thirty minutes on a Langmuir trough at 5-15 mN/m.
23. The composition of claim 19 , wherein the macrocyclic module composition retains at least 98% of film area after thirty minutes on a Langmuir trough at 5-15 mN/m.
24. A closed ring composition of the formula:
wherein:
J is 2-23;
Q1 are synthons each independently selected from the group consisting of (a) phenyl synthons coupled to linkages L at 1,4-phenyl positions, (b) aryl synthons other than phenyl synthons, (c) heteroaryl synthons, (d) saturated cyclic hydrocarbon synthons, (e) unsaturated cyclic hydrocarbon synthons, (f) saturated bicyclic hydrocarbon synthons, (g) unsaturated bicyclic hydrocarbon synthons, (h) saturated multicyclic hydrocarbon synthons, and (i) unsaturated multicyclic hydrocarbon synthons; wherein at least one of Q1 is a phenyl synthon coupled to linkages L at 1,4-phenyl positions, and wherein ring positions of each Q1 which are not coupled to a linkage L are substituted with organic functional groups containing atoms selected from the group of C, H, N, O, Si, P, S, B, Al, halogens, and metals from the alkali and alkaline earth groups;
Q2 is a synthon independently selected from the group consisting of (a) aryl synthons other than phenyl synthons and naphthalene synthons coupled to linkages L at 2,7-naphthyl positions, (b) heteroaryl synthons, (c) saturated cyclic hydrocarbon synthons other than cyclohexane synthons coupled to linkages L at 1,2-cyclohexyl positions, (d) unsaturated cyclic hydrocarbon synthons, (e) saturated bicyclic hydrocarbon synthons, (f) unsaturated bicyclic hydrocarbon synthons, (g) saturated multicyclic hydrocarbon synthons, and (h) unsaturated multicyclic hydrocarbon synthons; wherein ring positions of Q2 which are not coupled to an L are substituted with hydrogen or organic functional groups containing atoms selected from the group consisting of C, H, N, O, Si, P, S, B, Al, halogens, and metals from the alkali and alkaline earth groups;
L are linkages between the synthons each independently selected from the group consisting of (a) a condensed linkage, and (b) a linkage selected from the group consisting of —NRC(O)—, —OC(O)—, —O—, —S—S—, —S—, —NR—, —(CRR′)p—, —CH2NH—, —C(O)S—, —C(O)O—, —C≡C—, —C≡C—C≡C—, —CH(OH)—, —HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH2NH—, —NHCH2CH(OH)CH2NH—, —N═CH(CH2)pCH═N—, —CH2CH(OH)CH2—, —N═CH(CH2)hCH═N— where h is 1-4, —CH═N—NH—, —OC(O)O—, —OP(O)(OH)O—, —CH(OH)CH2NH—, —CH(OH)CH2—, —CH(OH)C(CH3)2C(O)O—,
wherein p is 1-6;
wherein R and R′ are each independently selected from the group of hydrogen and alkyl;
wherein linkages L are each independently configured in either of two possible configurations, forward and reverse, with respect to the synthons it couples together, if the two configurations are different structures;
wherein y is 1 or 2, and Qy are each independently one of the Q1 or Q2 synthons connected by the linkage.
25. The composition of claim 24 , wherein the organic functional groups are each independently selected from the group consisting of hydrogen, an activated acid, —OH, —C(O)OH, —C(O)H, —C(O)OCH3, —C(O)Cl, —NRR, —NRRR+, —MgX, —Li, —OLi, —OK, —ONa, —SH, —C(O)(CH2)2C(O)OCH3, —NH-alkyl-C(O)CH2CH(NH2)CO2-alkyl, —CH═CH2, —CH═CHR, —CH═CR2, 4-vinylaryl, —C(O)CH═CH2, —NHC(O)CH═CH2, —C(O)CH═CH(C6H5),
—OH, —OC(O)(CH2)2C(O)OCH3, —OC(O)CH═CH2, —P(O)(OH)(OX), —P(═O)(O−)O(CH2)sNR3 +;
wherein R are each independently selected from the group consisting of hydrogen and 1-6C alkyl; X is selected from the group consisting of Cl, Br, and I; r is 1-50; and s is 1-4.
26. A closed ring composition of the formula:
wherein:
Q is
J is from 1-22, and n is from 1-24;
X and Rn are each independently selected from the group consisting of organic functional groups containing atoms selected from the group consisting of C, H, N, O, Si, P, S, B, Al, halogens, and metals from the alkali and alkaline earth groups;
Z are each independently hydrogen or a lipophilic group;
L are linkages between synthons each independently selected from the group consisting of (a) a condensed linkage, and (b) a linkage selected from the group consisting of —N═CR—, —NRC(O)—, —OC(O)—, —O—, —S—S—, —S—, —NR—, —(CRR′)p—, —CH2NH—, —C(O)S—, —C(O)O—, —C≡C—, —C≡C—C≡C—, —CH(OH)—, —HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH2NH—, —NHCH2CH(OH)CH2NH—, —N═CHCH2CH═N— —N═CH(CH2)hCH═N— where h is 1-4, —CH═N—NH—, —OC(O)O—, —P(O)(OH)2O—, —CH(OH)CH2NH—, —CH(OH)CH2—, —CH(OH)C(CH3)2C(O)O—,
wherein p is 1-6;
wherein R and R′ are each independently selected from the group of hydrogen and alkyl;
wherein linkages L are each independently configured in either of two possible configurations, forward and reverse, with respect to the synthons it couples together, if the two configurations are different structures.
27. The composition of claim 26 , wherein X and Rn are each independently selected from the group consisting of hydrogen, an activated acid, —OH, —C(O)OH, —C(O)H, —C(O)OCH3, —C(O)Cl, —NRR, —NRRR+, —MgX, —Li, —OLi, —OK, —ONa, —SH, —C(O)(CH2)2C(O)OCH3, —NH-alkyl-C(O)CH2CH(NH2)CO2-alkyl, —CH═CH2, —CH═CHR, —CH═CR2, 4-vinylaryl,
—C(O)CH═CH2, —NHC(O)CH═CH2, —C(O)CH═CH(C6H5),
—OH, —OC(O)(CH2)2C(O)OCH3, —OC(O)CH═CH2, and, —P(O)(OH)(OX), —P(═O)(O−)O(CH2)sNR3 +;
wherein R are each independently selected from the group consisting of hydrogen and 1-6C alkyl; X is selected from the group consisting of Cl, Br, and I; r is 1-50; and s is 1-4.
28. A closed ring composition of the formula:
wherein:
J is from 1-22, and n is from 1-48;
X and Rn are each independently selected from the group consisting of organic functional groups containing atoms selected from the group consisting of C, H, N, O, Si, P, S, B, Al, halogens, and metals from the alkali and alkaline earth groups;
Z are each independently hydrogen or a lipophilic group;
L are linkages between the synthons each independently selected from the group consisting of (a) a condensed linkage, and (b) a linkage selected from the group consisting of —NRC(O)—, —OC(O)—, —O—, —S—S——S—, —NR—, —(CRR′)p—, —CH2NH—, —C(O)S—, —C(O)—, —C≡C—, —C≡C—C≡C—, —CH(OH)—, —HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH2NH—, —NHCH2CH(OH)CH2NH—, —N═CH(CH2)pCH═N—, —CH2CH(OH)CH2—, —N═CH(CH2)hCH═N— where h is 1-4, —CH═N—NH—, —OC(O)O—, —OP(O)(OH)O—, —CH(OH)CH2NH—, —CH(OH)CH2—, —CH(OH)C(CH3)2C(O)O—,
wherein p is 1-6;
wherein R and R′ are each independently selected from the group of hydrogen and alkyl;
wherein linkages L are each independently configured in either of two possible configurations, forward and reverse, with respect to the synthons it couples together, if the two configurations are different structures.
29. The composition of claim 28 , wherein X and Rn are each independently selected from the group consisting of hydrogen, an activated acid, —OH, —C(O)OH, —C(O)H, —C(O)OCH3, —C(O)Cl, —NRR, —NRRR+, —MgX, —Li, —OLi, —OK, —ONa, —SH, —C(O)(CH2)2C(O)OCH3, —NH-alkyl-C(O)CH2CH(NH2)CO2-alkyl, —CH═CH2, —CH═CHR, —CH═CR2, 4-vinylaryl,
—C(O)CH═CH2, —NHC(O)CH═CH2, —C(O)CH═CH(C6H5),
—OH, —OC(O)(CH2)2C(O)OCH3, —OC(O)CH═CH2, and, —P(O)(OH)(OX), —P(═O)(O−)O(CH2)sNR3 +;
wherein R are each independently selected from the group consisting of hydrogen and 1-6C alkyl; X is selected from the group consisting of Cl, Br, and I; r is 1-50; and s is 1-4.
30. The composition of claim 14 having the formula:
wherein:
J is from 1-11, and n is from 1-12;
X and Rn are each independently selected from the group consisting of hydrogen, an activated acid, —OH, —C(O)OH, —C(O)H, —C(O)OCH3, —C(O)Cl, —NRR, —NRRR+, —MgX, —Li, —OLi, —OK, —ONa, —SH, —C(O)(CH2)2C(O)OCH3, —NH-alkyl-C(O)CH2CH(NH2)CO2-alkyl, —CH═CH2, —CH═CHR, —CH═CR2, 4-vinylaryl, —C(O)CH═CH2, —NHC(O)CH═CH2,
—C(O)CH═CH(C6H5),
—OC(O)(CH2)2C(O)OCH3, —OC(O)CH═CH2,
wherein R are each independently selected from the group consisting of hydrogen and 1-6C alkyl; X is selected from the group consisting of Cl, Br, and I; r is 1-50; and s is 1-4;
Z are each independently hydrogen or a lipophilic group;
L are linkages between synthons each independently selected from the group consisting of (a) a condensed linkage, and (b) a linkage selected from the group consisting of —NRC(O)—, —OC(O)—, —O—, —S—S—, —S—, —NR—, —(CRR′)p—, —CH2NH—, —C(O)S—, —C(O)O—, —C≡C—, —C≡C—C≡C—, —CH(OH)—, —HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH2NH—, —NHCH2CH(OH)CH2NH—, —N═CH(CH2)pCH═N—, —CH2CH(OH)CH2—, —N═CH(CH2)hCH═N— where h is 1-4, —CH═N—NH—, —OC(O)O—, —OP(O)(OH)O—, —CH(OH)CH2NH—, —CH(OH)CH2—, —CH(OH)C(CH3)2C(O)O—,
wherein p is 1-6;
wherein R and R′ are each independently selected from the group of hydrogen and alkyl;
wherein linkages L are each independently configured in either of two possible configurations, forward and reverse, with respect to the synthons it couples together, if the two configurations are different structures.
31. The composition of claim 19 having the formula:
wherein:
J is from 1-11, and n is from 1-12;
X and Rn are each independently selected from the group consisting of hydrogen, an activated acid, —OH, —C(O)OH, —C(O)H, —C(O)OCH3, —C(O)Cl, —NRR, —NRRR+, —MgX, —Li, —OLi, —OK, —ONa, —SH, —C(O)(CH2)2C(O)OCH3, —NH-alkyl-C(O)CH2CH(NH2)CO2-alkyl, —CH═CH2, —CH═CHR, —CH═CR2, 4-vinylaryl, —C(O)CH═CH2, —NHC(O)CH═CH2,
—C(O)CH═CH(C6H5),
—OC(O)(CH2)2C(O)OCH3, —OC(O)CH═CH2,
wherein R are each independently selected from the group consisting of hydrogen and 1-6C alkyl; X is selected from the group consisting of Cl, Br, and I; r is 1-50; and s is 1-4;
Z are each independently hydrogen or a lipophilic group;
L are linkages between the synthons each independently selected from the group consisting of (a) a condensed linkage, and (b) a linkage selected from the group consisting of —NRC(O)—, —OC(O)—, —O—, —S—S—, —S—, —NR—, —(CRR′)p—, —CH2NH—, —C(O)S—, —C(O)O—, —C≡C—, —C≡C—C≡C—, —CH(OH)—, —HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH2NH—, —NHCH2CH(OH)CH2NH—, —N═CH(CH2)pCH═N—, —CH2CH(OH)CH2—, —N═CH(CH2)hCH═N— where h is 1-4, —CH═N—NH—, —OC(O)O—, —OP(O)(OH)O—, —CH(OH)CH2NH—, —CH(OH)CH2—, —CH(OH)C(CH3)2C(O)O—,
wherein p is 1-6;
wherein R and R′ are each independently selected from the group of hydrogen and alkyl;
wherein linkages L are each independently configured in either of two possible configurations, forward and reverse, with respect to the synthons it couples together, if the two configurations are different structures.
32. The composition of claim 14 having the formula:
wherein:
J is from 1-11, and n is from 1-12;
X is —NX1— or —CX2X3, where
X1 is selected from the group consisting of an amino acid residue, —CH2C(O)CH2CH(NH2)CO2-alkyl, and —C(O)CH═CH2;
X2 and X3 are each independently selected from the group consisting of hydrogen, —OH, —NH2, —SH, —(CH2)tOH, —(CH2)tNH2 and —(CH2)tSH, wherein t is 1-4, and X2 and X3 are not both hydrogen;
Rn are each independently selected from the group consisting of hydrogen, an activated acid, —OH, —C(O)OH, —C(O)H, —C(O)OCH3, —C(O)Cl, —NRR, —NRRR+, —MgX, —Li, —OLi, —OK, —ONa, —SH, —C(O)(CH2)2C(O)OCH3, —NH-alkyl-C(O)CH2CH(NH2)CO2-alkyl, —CH═CH2, —CH═CHR, —CH═CR2, 4-vinylaryl, —C(O)CH═CH2, —NHC(O)CH═CH2, —C(O)CH═CH(C6H5),
—OH, —OC(O)(CH2)2C(O)OCH3, —OC(O)CH═CH2, —P(O)(OH)(OX), —P(═O)(O31 )O(CH2)sNR3 +;
wherein R are each independently selected from the group consisting of hydrogen and 1-6C alkyl; X is selected from the group consisting of Cl, Br, and I; r is 1-50; and s is 1-4;
Z are each independently hydrogen or a lipophilic group;
L are linkages between synthons each independently selected from the group consisting of (a) a condensed linkage, and (b) a linkage selected from the group consisting of —NRC(O)—, —OC(O)—, —O—, —S—S—, —S—, —NR—, —(CRR′)p—, —CH2NH—, —C(O)S—, —C(O)O—, —C≡C—, —C≡C—C≡C—, —CH(OH)—, —HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH2NH—, —NHCH2CH(OH)CH2NH—, —N═CH(CH2)pCH═N—, —CH2CH(OH)CH2—, —N═CH(CH2)hCH═N— where h is 1-4, —CH═N—NH—, —OC(O)O—, —OP(O)(OH)O—, —CH(OH)CH2NH—, —CH(OH)CH2—, —CH(OH)C(CH3)2C(O)O—,
wherein p is 1-6;
wherein R and R′ are each independently selected from the group of hydrogen and alkyl;
wherein linkages L are each independently configured in either of two possible configurations, forward and reverse, with respect to the synthons it couples together, if the two configurations are different structures.
33. The composition of claim 14 having the formula:
wherein:
J is from 1-11, and n is from 1-12;
X and Rn are each independently selected from the group consisting of hydrogen, an activated acid, —OH, —C(O)OH, —C(O)H, —C(O)OCH3, —C(O)Cl, —NRR, —NRRR+, —MgX, —Li, —OLi, —OK, —ONa, —SH, —C(O)(CH2)2C(O)OCH3, —NH-alkyl-C(O)CH2CH(NH2)CO2-alkyl, —CH═CH2, —CH═CHR, —CH═CR2, 4-vinylaryl, —C(O)CH═CH2, —NHC(O)CH═CH2, —C(O(CH═CH(C6H5),
—OC(O)(CH2)2C(O)OCH3, —OC(O)CH═CH2,
wherein R are each independently selected from the group consisting of hydrogen and 1-6C alkyl; X is selected from the group consisting of Cl, Br, and I; r is 1-50; and s is 1-4;
Z and Y are each independently hydrogen or a lipophilic group;
L are linkages between the synthons each independently selected from the group consisting of (a) a condensed linkage, and (b) a linkage selected from the group consisting of —NRC(O)—, —OC(O)—, —O—, —S—S—, —S—, —NR—, —(CRR′)p—, —CH2NH—, —C(O)S—, —C(O)O—, —C≡C—, —C≡C—C≡C—, —CH(OH)—, —HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH2NH—, —NHCH2CH(OH)CH2NH—, —N═CH(CH2)pCH═N—, —CH2CH(OH)CH2—, —N═CH(CH2)hCH═N— where h is 1-4, —CH═N—NH—, —OC(O)O—, —OP(O)(OH)O—, —CH(OH)CH2NH—, —CH(OH)CH2—, —CH(OH)C(CH3)2C(O)O—,
wherein p is 1-6;
wherein R and R′ are each independently selected from the group of hydrogen and alkyl;
wherein linkages L are each independently configured in either of two possible configurations, forward and reverse, with respect to the synthons it couples together, if the two configurations are different structures.
34. The composition of claim 14 having the formula:
wherein:
J is from 1-11, and n is from 1-12;
X and Rn are each independently selected from the group consisting of hydrogen, an activated acid, —OH, —C(O)OH, —C(O)H, —C(O)OCH3, —C(O)Cl, —NRR, —NRRR+, —MgX, —Li, —OLi, —OK, —ONa, —SH, —C(O)(CH2)2C(O)OCH3, —NH-alkyl-C(O)CH2CH(NH2)CO2-alkyl, —CH═CH2, —CH═CHR, —CH═CR2, 4-vinylaryl, —C(O)CH═CH2, —NHC(O)CH═CH2,
—C(O)CH═CH(C6H5), —OC(O)(CH2)2C(O)OCH3, —OC(O)CH═CH2, —P(O)(OH)(OX), —P(═O)(O31 )O(CH2)sNR3 +;
wherein R are each independently selected from the group consisting of hydrogen and 1-6C alkyl; X is selected from the group consisting of Cl, Br, and I; r is 1-50; and s is 1-4;
Z and Y are each independently hydrogen or a lipophilic group;
L are linkages between synthons each independently selected from the group consisting of (a) a condensed linkage, and (b) a linkage selected from the group consisting of —NRC(O)—, —OC(O)—, —O—, —S—S—, —S—, —NR—, —(CRR′)p—, —CH2NH—, —C(O)S—, —C(O)O—, —C≡C—, —C≡C—C≡C—, —CH(OH)—, —HC═CH—, —NHC(O)NH—, —NHC(O)O—, —NHCH2NH—, —NHCH2CH(OH)CH2NH—, —N═CH(CH2)pCH═N—, —CH2CH(OH)CH2—, —N═CH(CH2)hCH═N— where h is 1-4, —CH═N—NH—, —OC(O)O—, —OP(O)(OH)O—, —CH(OH)CH2NH—, —CH(OH)CH2—, —CH(OH)C(CH3)2C(O)O—,
wherein p is 1-6;
wherein R and R′ are each independently selected from the group of hydrogen and alkyl;
wherein linkages L are each independently configured in either of two possible configurations, forward and reverse, with respect to the synthons it couples together, if the two configurations are different structures.
35. A method for making a macrocyclic module composition comprising:
(a) providing a plurality of a first cyclic synthon;
(b) contacting a plurality of a second cyclic synthon with the first cyclic synthons;
(c) isolating the macrocyclic module composition.
36. The method of claim 35 , further comprising contacting a linker molecule with the mixture in (a) or (b).
37. A method for making a macrocyclic module composition comprising:
(a) providing a plurality of a first cyclic synthon;
(b) contacting a plurality of a second cyclic synthon with the first cyclic synthons;
(c) contacting a plurality of the first cyclic synthon with the mixture from (b).
38. A method for making a macrocyclic module composition comprising:
(a) providing a plurality of a first cyclic synthon;
(b) contacting a plurality of a second cyclic synthon with the first cyclic synthons;
(c) contacting a plurality of a third cyclic synthon with the mixture from (b).
39. The method of claim 37 or 38, further comprising supporting a cyclic synthon or coupled synthons on a solid phase.
40. A method for making a macrocyclic module composition comprising:
(a) contacting a plurality of cyclic synthons with a metal complex template;
(b) isolating the macrocyclic module composition.
Priority Applications (23)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/226,400 US20030199688A1 (en) | 2002-02-07 | 2002-08-23 | Macrocyclic module compositions |
PCT/US2003/003830 WO2003066646A2 (en) | 2002-02-07 | 2003-02-07 | Macrocyclic module compositions |
EP03709017A EP1481268A4 (en) | 2002-02-07 | 2003-02-07 | Nanofilm and membrane compositions |
EA200401045A EA007470B1 (en) | 2002-02-07 | 2003-02-07 | Nanofilm and membrane compositions |
KR1020047012272A KR100979423B1 (en) | 2002-02-07 | 2003-02-07 | Macrocyclic module compositions |
PCT/US2003/003829 WO2003067286A2 (en) | 2002-02-07 | 2003-02-07 | Nanofilm and membrane compositions |
US10/359,894 US7432371B2 (en) | 2002-02-07 | 2003-02-07 | Nanofilm and membrane compositions |
AU2003212973A AU2003212973B2 (en) | 2002-02-07 | 2003-02-07 | Nanofilm and membrane compositions |
AU2003212974A AU2003212974B2 (en) | 2002-02-07 | 2003-02-07 | Macrocyclic module compositions |
CN03807571.7A CN1646116A (en) | 2002-02-07 | 2003-02-07 | Macrocyclic module compositions |
MXPA04007679A MXPA04007679A (en) | 2002-02-07 | 2003-02-07 | Nanofilm and membrane compositions. |
EA200401044A EA200401044A1 (en) | 2002-02-07 | 2003-02-07 | MACROCYCLIC MODULAR COMPOSITIONS |
JP2003566582A JP4688418B2 (en) | 2002-02-07 | 2003-02-07 | Nanofilm and membrane composition |
MXPA04007680A MXPA04007680A (en) | 2002-02-07 | 2003-02-07 | Macrocyclic module compositions. |
CA002475567A CA2475567A1 (en) | 2002-02-07 | 2003-02-07 | Nanofilm and membrane compositions |
JP2003566017A JP2005517017A (en) | 2002-02-07 | 2003-02-07 | Macrocyclic module composition |
EP03709018A EP1480635A4 (en) | 2002-02-07 | 2003-02-07 | Macrocyclic module compositions |
CNA038075407A CN1646501A (en) | 2002-02-07 | 2003-02-07 | Nanofilm and membrane compositions |
CA002475646A CA2475646A1 (en) | 2002-02-07 | 2003-02-07 | Macrocyclic module compositions |
KR10-2004-7012275A KR20050009981A (en) | 2002-02-07 | 2003-02-07 | Nanofilm and membrane compositions |
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US12/183,469 US8110679B2 (en) | 2002-02-07 | 2008-07-31 | Nanofilm and membrane compositions |
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ZA200406352B (en) | 2005-08-11 |
KR100979423B1 (en) | 2010-09-02 |
US20040034223A1 (en) | 2004-02-19 |
KR20050013097A (en) | 2005-02-02 |
US20100152438A1 (en) | 2010-06-17 |
US20060270846A1 (en) | 2006-11-30 |
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US7563890B2 (en) | 2009-07-21 |
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