US20130023662A9 - Ruthenium (ii) catalysts for use in stereoselective cyclopropanations - Google Patents
Ruthenium (ii) catalysts for use in stereoselective cyclopropanations Download PDFInfo
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- US20130023662A9 US20130023662A9 US13/316,729 US201113316729A US2013023662A9 US 20130023662 A9 US20130023662 A9 US 20130023662A9 US 201113316729 A US201113316729 A US 201113316729A US 2013023662 A9 US2013023662 A9 US 2013023662A9
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- unsubstituted
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- alkenyl
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- 239000003054 catalyst Substances 0.000 title claims abstract description 112
- 238000005888 cyclopropanation reaction Methods 0.000 title claims abstract description 45
- YAYGSLOSTXKUBW-UHFFFAOYSA-N ruthenium(2+) Chemical compound [Ru+2] YAYGSLOSTXKUBW-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 230000000707 stereoselective effect Effects 0.000 title claims abstract description 29
- 239000003446 ligand Substances 0.000 claims abstract description 132
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 87
- 229910052751 metal Inorganic materials 0.000 claims abstract description 53
- 239000002184 metal Substances 0.000 claims abstract description 53
- 238000000034 method Methods 0.000 claims abstract description 43
- 238000011065 in-situ storage Methods 0.000 claims abstract description 27
- -1 3,5-di-t-butyl-salicylidene Chemical group 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims description 60
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 47
- 125000000623 heterocyclic group Chemical group 0.000 claims description 45
- YVPJCJLMRRTDMQ-UHFFFAOYSA-N ethyl diazoacetate Chemical group CCOC(=O)C=[N+]=[N-] YVPJCJLMRRTDMQ-UHFFFAOYSA-N 0.000 claims description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims description 41
- 239000001257 hydrogen Substances 0.000 claims description 41
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 38
- 239000000758 substrate Substances 0.000 claims description 37
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 36
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 34
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 33
- 239000002243 precursor Substances 0.000 claims description 31
- WLZOPMPOGRQZCJ-UHFFFAOYSA-N 4-ethenyl-2,3-dihydro-1-benzofuran Chemical compound C=CC1=CC=CC2=C1CCO2 WLZOPMPOGRQZCJ-UHFFFAOYSA-N 0.000 claims description 24
- 125000004429 atom Chemical group 0.000 claims description 24
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 23
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims description 20
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 13
- 125000003282 alkyl amino group Chemical group 0.000 claims description 13
- 150000002500 ions Chemical class 0.000 claims description 13
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 11
- 125000002837 carbocyclic group Chemical group 0.000 claims description 11
- 229910052698 phosphorus Inorganic materials 0.000 claims description 11
- LIKMAJRDDDTEIG-UHFFFAOYSA-N 1-hexene Chemical compound CCCCC=C LIKMAJRDDDTEIG-UHFFFAOYSA-N 0.000 claims description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 10
- 229910021645 metal ion Inorganic materials 0.000 claims description 10
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 9
- LAXRNWSASWOFOT-UHFFFAOYSA-J (cymene)ruthenium dichloride dimer Chemical compound [Cl-].[Cl-].[Cl-].[Cl-].[Ru+2].[Ru+2].CC(C)C1=CC=C(C)C=C1.CC(C)C1=CC=C(C)C=C1 LAXRNWSASWOFOT-UHFFFAOYSA-J 0.000 claims description 9
- 125000004076 pyridyl group Chemical group 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 7
- 239000005977 Ethylene Substances 0.000 claims description 7
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 7
- 239000011574 phosphorus Substances 0.000 claims description 7
- 150000003512 tertiary amines Chemical class 0.000 claims description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 150000004703 alkoxides Chemical class 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 230000006872 improvement Effects 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims 2
- 230000000996 additive effect Effects 0.000 claims 2
- VEUMANXWQDHAJV-UHFFFAOYSA-N 2-[2-[(2-hydroxyphenyl)methylideneamino]ethyliminomethyl]phenol Chemical compound OC1=CC=CC=C1C=NCCN=CC1=CC=CC=C1O VEUMANXWQDHAJV-UHFFFAOYSA-N 0.000 abstract description 37
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 21
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 abstract description 10
- 229910052707 ruthenium Inorganic materials 0.000 abstract description 6
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 abstract description 4
- DHCWLIOIJZJFJE-UHFFFAOYSA-L dichlororuthenium Chemical compound Cl[Ru]Cl DHCWLIOIJZJFJE-UHFFFAOYSA-L 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- 239000000047 product Substances 0.000 description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 25
- 0 [5*]/C=C\[6*] Chemical compound [5*]/C=C\[6*] 0.000 description 25
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 17
- 239000000203 mixture Substances 0.000 description 14
- 150000008049 diazo compounds Chemical group 0.000 description 13
- 238000002474 experimental method Methods 0.000 description 12
- 239000012035 limiting reagent Substances 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 10
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical group [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 229910052723 transition metal Inorganic materials 0.000 description 9
- 150000003624 transition metals Chemical class 0.000 description 9
- 239000002879 Lewis base Substances 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- ZMOXNJBPBINVIF-NWDGAFQWSA-N ethyl (1r,2r)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropane-1-carboxylate Chemical compound CCOC(=O)[C@@H]1C[C@H]1C1=CC=CC2=C1CCO2 ZMOXNJBPBINVIF-NWDGAFQWSA-N 0.000 description 8
- 125000001072 heteroaryl group Chemical group 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- 150000007527 lewis bases Chemical class 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- 229910003827 NRaRb Inorganic materials 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 6
- 150000001336 alkenes Chemical class 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 description 5
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 230000005595 deprotonation Effects 0.000 description 5
- 238000010537 deprotonation reaction Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- FYNXDGNCEBQLGC-LOYHVIPDSA-N 2,4-ditert-butyl-6-[[(1R,2R)-2-[(3,5-ditert-butyl-2-hydroxyphenyl)methylideneamino]cyclohexyl]iminomethyl]phenol Chemical compound CC(C)(C)C1=CC(C(C)(C)C)=CC(C=N[C@H]2[C@@H](CCCC2)N=CC=2C(=C(C=C(C=2)C(C)(C)C)C(C)(C)C)O)=C1O FYNXDGNCEBQLGC-LOYHVIPDSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 125000004430 oxygen atom Chemical group O* 0.000 description 4
- 125000004437 phosphorous atom Chemical group 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000004434 sulfur atom Chemical group 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
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- 229910052701 rubidium Inorganic materials 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
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- 239000000725 suspension Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- JBVSBLLOZVDAAZ-UHFFFAOYSA-N 2-diazonio-1-[(2-methylpropan-2-yl)oxy]ethenolate Chemical compound CC(C)(C)OC([O-])=C[N+]#N JBVSBLLOZVDAAZ-UHFFFAOYSA-N 0.000 description 2
- GLFYYOWJNWFJFE-ZSKYZZNESA-N COC1=C(C(C)(C)C)C=C(C(C)(C)C)C=C1/C=N/[C@H]1CCCC[C@@H]1/N=C/C1=C(C)C(C(C)(C)C)=CC(C(C)(C)C)=C1 Chemical compound COC1=C(C(C)(C)C)C=C(C(C)(C)C)C=C1/C=N/[C@H]1CCCC[C@@H]1/N=C/C1=C(C)C(C(C)(C)C)=CC(C(C)(C)C)=C1 GLFYYOWJNWFJFE-ZSKYZZNESA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
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- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- BXEFQPCKQSTMKA-UHFFFAOYSA-N OC(=O)C=[N+]=[N-] Chemical compound OC(=O)C=[N+]=[N-] BXEFQPCKQSTMKA-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
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- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
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- DURWRTOFTVHEEE-MLSHUHGLSA-L [Li]OC1=C(C(C)(C)C)C=C(C(C)(C)C)C=C1/C=N/[C@H]1CCCC[C@@H]1/N=C/C1=C([Li]O)C(C(C)(C)C)=CC(C(C)(C)C)=C1 Chemical compound [Li]OC1=C(C(C)(C)C)C=C(C(C)(C)C)C=C1/C=N/[C@H]1CCCC[C@@H]1/N=C/C1=C([Li]O)C(C(C)(C)C)=CC(C(C)(C)C)=C1 DURWRTOFTVHEEE-MLSHUHGLSA-L 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
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- 239000006286 aqueous extract Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
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- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
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- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
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- 238000005457 optimization Methods 0.000 description 2
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- 239000011734 sodium Substances 0.000 description 2
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- 238000003860 storage Methods 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- FLEHQRTTWKDNGI-XTJILODYSA-N (1s,3r)-5-[(2e)-2-[(7ar)-1-[(2s)-5-(cyclopropylamino)pentan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-2-methylidenecyclohexane-1,3-diol Chemical compound C([C@H](C)C1[C@]2(CCCC(/C2CC1)=C\C=C1C[C@@H](O)C(=C)[C@@H](O)C1)C)CCNC1CC1 FLEHQRTTWKDNGI-XTJILODYSA-N 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- 125000001831 (C6-C10) heteroaryl group Chemical group 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- WODWCWVOVRDLOO-UHFFFAOYSA-N 1,2,3,4,5-pentamethylcyclopentane;ruthenium Chemical compound [Ru].C[C]1[C](C)[C](C)[C](C)[C]1C.C[C]1[C](C)[C](C)[C](C)[C]1C WODWCWVOVRDLOO-UHFFFAOYSA-N 0.000 description 1
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- NQJHQUYXNPMZCK-UHFFFAOYSA-N 2-diazonio-1-(2,3,4-trimethylpentan-3-yloxy)ethenolate Chemical compound CC(C)C(C)(C(C)C)OC(=O)C=[N+]=[N-] NQJHQUYXNPMZCK-UHFFFAOYSA-N 0.000 description 1
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- ZWFYJXZAIUVVNA-GCTUQQJLSA-N C=CC(=C)/C=C\C.CC[C@@H]1C[C@H]1C1=C2CCOC2=CC=C1.O=C=O.O=C=O.[H]C1C[C@H]1C1=C2CCOC2=CC=C1 Chemical compound C=CC(=C)/C=C\C.CC[C@@H]1C[C@H]1C1=C2CCOC2=CC=C1.O=C=O.O=C=O.[H]C1C[C@H]1C1=C2CCOC2=CC=C1 ZWFYJXZAIUVVNA-GCTUQQJLSA-N 0.000 description 1
- PDTKZHPBAMTSSQ-HKTCBVAVSA-L CC(C)(C)C1=CC2=C(O[Ru]34(N5=CC=CC=C5)(N5=CC=CC=C5)OC5=C(C(C)(C)C)C=C(C(C)(C)C)C=C5/C=N\3[C@H]3CCCC[C@@H]3/N4=C/2)C(C(C)(C)C)=C1 Chemical compound CC(C)(C)C1=CC2=C(O[Ru]34(N5=CC=CC=C5)(N5=CC=CC=C5)OC5=C(C(C)(C)C)C=C(C(C)(C)C)C=C5/C=N\3[C@H]3CCCC[C@@H]3/N4=C/2)C(C(C)(C)C)=C1 PDTKZHPBAMTSSQ-HKTCBVAVSA-L 0.000 description 1
- TUFCMGKRSACJHS-HKTCBVAVSA-N CC(C)(C)C1=CC2=C(O[Ru]34([PH](C5=CC=CC=C5)(C5=CC=CC=C5)C5=CC=CC=C5)([PH](C5=CC=CC=C5)(C5=CC=CC=C5)C5=CC=CC=C5)OC5=C(C(C)(C)C)C=C(C(C)(C)C)C=C5/C=N\3[C@H]3CCCC[C@@H]3/N4=C/2)C(C(C)(C)C)=C1 Chemical compound CC(C)(C)C1=CC2=C(O[Ru]34([PH](C5=CC=CC=C5)(C5=CC=CC=C5)C5=CC=CC=C5)([PH](C5=CC=CC=C5)(C5=CC=CC=C5)C5=CC=CC=C5)OC5=C(C(C)(C)C)C=C(C(C)(C)C)C=C5/C=N\3[C@H]3CCCC[C@@H]3/N4=C/2)C(C(C)(C)C)=C1 TUFCMGKRSACJHS-HKTCBVAVSA-N 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- QKZDXYLAVCWZDL-UHFFFAOYSA-N [(2-diazoacetyl)amino] acetate Chemical compound CC(=O)ONC(=O)C=[N+]=[N-] QKZDXYLAVCWZDL-UHFFFAOYSA-N 0.000 description 1
- WMVSVUVZSYRWIY-UHFFFAOYSA-N [(4-benzoyloxyiminocyclohexa-2,5-dien-1-ylidene)amino] benzoate Chemical compound C=1C=CC=CC=1C(=O)ON=C(C=C1)C=CC1=NOC(=O)C1=CC=CC=C1 WMVSVUVZSYRWIY-UHFFFAOYSA-N 0.000 description 1
- PNDPGZBMCMUPRI-XXSWNUTMSA-N [125I][125I] Chemical compound [125I][125I] PNDPGZBMCMUPRI-XXSWNUTMSA-N 0.000 description 1
- CPNOVDWZRIYWQV-UHFFFAOYSA-N [Li]CCCCCCCC Chemical compound [Li]CCCCCCCC CPNOVDWZRIYWQV-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- KTYVHLCLTPLSGC-UHFFFAOYSA-N amino propanoate Chemical compound CCC(=O)ON KTYVHLCLTPLSGC-UHFFFAOYSA-N 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 229910052790 beryllium Inorganic materials 0.000 description 1
- GPRLTFBKWDERLU-UHFFFAOYSA-N bicyclo[2.2.2]octane Chemical compound C1CC2CCC1CC2 GPRLTFBKWDERLU-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 239000004305 biphenyl Chemical group 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- JYHHJVKGDCZCCL-UHFFFAOYSA-J carbon monoxide;dichlororuthenium Chemical compound [O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].Cl[Ru]Cl.Cl[Ru]Cl JYHHJVKGDCZCCL-UHFFFAOYSA-J 0.000 description 1
- OKTJSMMVPCPJKN-BJUDXGSMSA-N carbon-11 Chemical compound [11C] OKTJSMMVPCPJKN-BJUDXGSMSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- JIXOCHSERUXVMW-UHFFFAOYSA-M chlororuthenium Chemical compound [Ru]Cl JIXOCHSERUXVMW-UHFFFAOYSA-M 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- DMRVBCXRFYZCPR-UHFFFAOYSA-L cycloocta-1,5-diene;ruthenium(2+);dichloride Chemical compound Cl[Ru]Cl.C1CC=CCCC=C1 DMRVBCXRFYZCPR-UHFFFAOYSA-L 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 150000001942 cyclopropanes Chemical class 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- HBIHVBJJZAHVLE-UHFFFAOYSA-L dibromoruthenium Chemical compound Br[Ru]Br HBIHVBJJZAHVLE-UHFFFAOYSA-L 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- HRSOSLBSWOHVPK-UHFFFAOYSA-L diiodoruthenium Chemical compound I[Ru]I HRSOSLBSWOHVPK-UHFFFAOYSA-L 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 229910052730 francium Inorganic materials 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 229940091173 hydantoin Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000004857 imidazopyridinyl group Chemical class N1C(=NC2=C1C=CC=N2)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940044173 iodine-125 Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 238000007250 stereoselective catalysis Methods 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0046—Ruthenium compounds
Definitions
- Chiral catalysts for cyclopropanation, methods of preparation and methods of forming chiral cyclopropyl products are provided herein.
- Cyclopropanes are particularly challenging to synthesize enantiomerically pure. Especially for commercial applications, stereoselective cyclopropanations must give good diastereo- and enantioselectivity in high yield and purity at a reasonable cost.
- One approach that is particularly efficient, is stereoselective catalysis because a small amount of a chiral catalyst can be used to produce a large quantity of the desired chiral cyclopropyl compound. Transition metal catalysts are typically employed to catalyze the reaction between a diazoester and an olefin substrate to form a chiral cyclopropyl product.
- the olefin substrates are often complex and require multi-step syntheses.
- using an excess of the olefin substrate not only wastes material, but also increases cost and lowers the throughput of the chemical process.
- using a large excess of the diazoester to drive the reaction to completion is undesirable due to safety concerns on large scale.
- use of excess reagents can lead to increased impurities and purification difficulties.
- the use of an isolated chiral catalyst can be undesirable in commercial applications because of the increased number of steps in a chemical process, increasing cycle time, as well as safety issues associated with handling transition metal catalysts. What is needed, are efficient transition metal catalyzed stereoselective cyclopropanation methods employing mild and safe conditions.
- a method of stereoselective cyclopropanation comprises combining a carbene precursor and an alkenyl substrate in the presence of a chiral catalyst to form a cyclopropyl product.
- the chiral catalyst is formed in situ by combining an alkenyl ligand with a deprotonated chiral ligand and a ruthenium (II) metal.
- a catalyst for stereoselective reactions is provided.
- the catalyst is prepared in situ by combining an alkenyl ligand and a deprotonated chiral ligand in the presence of a ruthenium (II) metal.
- the alkenyl ligand is of formula (I):
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , M 1 and M 2 are defined below.
- a method of stereoselective cyclopropanation comprising the step of combining a carbene precursor and an alkenyl substrate in the presence of a chiral catalyst to form a cyclopropyl product, the chiral catalyst is prepared in situ by the step of combining an alkenyl ligand and a deprotonated chiral ligand in the presence of a ruthenium (II) metal; wherein the alkenyl ligand is of formula (I):
- R 5 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 6-10 aryl, C 5-10 heteroaryl, C 3-10 heterocycle; and where R 6 is selected from the group consisting of hydrogen, and C 1-8 alkyl; and where R 5 and R 6 together with the atoms to which they are attached may form a carbocyclic ring; wherein the deprotonated chiral ligand is of formula (III):
- R 1 and R 2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 3-10 heterocyclyl, substituted or unsubstituted C 5-10 heteroaryl; where R 3 and R 4 are each independently selected from the group consisting of substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, C 1-10 alkoxy, C 1-12 alkylamino, substituted or unsubstituted C 3-10 heterocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 5-10 heteroaryl and substituted or unsubstituted arylalkyl; where R 3 and R 4 together with the atoms to which they are attached may form a ring; and where M 1 and M 2 are each a counterion independently selected
- R 5 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 6-10 aryl, C 5-10 heteroaryl, C 3-10 heterocycle; and where R 6 is selected from the group consisting of hydrogen, and C 1-6 alkyl; and where R 5 and R 6 together with the atoms to which they are attached may form a carbocyclic ring; wherein the deprotonated chiral ligand is of formula (III):
- R 1 and R 2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 3-10 heterocyclyl, substituted or unsubstituted C 5-10 heteroaryl; where R 3 and R 4 are each independently selected from the group consisting of substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, C 1-10 alkoxy, C 1-12 alkylamino, substituted or unsubstituted C 10 heterocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 5-10 heteroaryl and substituted or unsubstituted arylalkyl; where R 3 and R 4 together with the atoms to which they are attached may form a ring; and where M 1 and M 2 are each a counterion independently selected from
- R 5 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 6-10 aryl, C 5-10 heteroaryl, C 3-10 heterocycle; and where R 6 is selected from the group consisting of hydrogen, and C 1-6 alkyl; and where R 5 and R 6 together with the atoms to which they are attached may form a carbocyclic ring; where R 1 and R 2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 3-10 heterocyclyl, substituted or unsubstituted C 5-10 heteroaryl; where R 3 and R 4 are each independently selected from the group consisting of substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-6 cycloalkyl, C 1-10 alkoxy, C 1-12 alkylamino, substituted or unsubstituted C 3-10 heterocycl
- a catalyst for stereoselective reactions prepared by the step of combining an alkenyl ligand and a deprotonated chiral ligand in the presence of a ruthenium (II) metal; wherein the alkenyl ligand is of formula (I):
- R 5 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 6-10 aryl, C 5-10 heteroaryl, C 3-10 heterocycle; and where R 6 is selected from the group consisting of hydrogen, and C 1-8 alkyl; and where R 5 and R 6 together with the atoms to which they are attached may form a carbocyclic ring; wherein the deprotonated chiral ligand is of formula (III):
- R 1 and R 2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 3-10 heterocyclyl, substituted or unsubstituted C 5-10 heteroaryl; where R 3 and R 4 are each independently selected from the group consisting of substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, C 1-10 alkoxy, C 1-12 alkylamino, substituted or unsubstituted C 3-10 heterocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 5-10 heteroaryl and substituted or unsubstituted arylalkyl; where R 3 and R 4 together with the atoms to which they are attached may form a ring; and where M 1 and M 2 are each a counterion independently selected
- Alkyl by itself or as part of another substituent refers to a saturated hydrocarbon group which may be linear, cyclic, or branched or a combination thereof having the number of carbon atoms designated (i.e., C 1-8 means one to eight carbon atoms).
- alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, cyclopentyl, (cyclohexyl)methyl, cyclopropylmethyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.
- Alkyl groups can be substituted or unsubstituted, unless otherwise indicated. Examples of substituted alkyl include haloalkyl, perhaloalkyls, thioalkyl, aminoalkyl, and the like.
- Alkoxy refers to —O-alkyl. Examples of an alkoxy group include methoxy, ethoxy, n-propoxy etc.
- Alkylamino refers to —NHR′ and —NR′R′′ where R′ is alkyl and R is hydrogen or alkyl.
- alkylamino groups include methylamine, ethylamine, isopropylamine, butylamine, dimethyl amine, diisopropylamine and the like.
- Alkenyl refers to an unsaturated hydrocarbon group which may be linear, cyclic or branched or a combination thereof. Alkenyl groups with 2-8 carbon atoms are preferred. The alkenyl group may contain 1, 2 or 3 carbon-carbon double bonds. Examples of alkenyl groups include ethenyl, 11-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl, cyclohexenyl, cyclopentenyl and the like. Alkenyl groups can be substituted or unsubstituted, unless otherwise indicated.
- Aryl refers to a polyunsaturated, aromatic hydrocarbon group having a single ring (monocyclic) or multiple rings (bicyclic), which can be fused together or linked covalently.
- Aryl groups with 6-10 carbon atoms are preferred, where this number of carbon atoms can be designated by C 6-10 , for example.
- Examples of aryl groups include phenyl and naphthalene-1-yl, naphthalene-2-yl, biphenyl and the like.
- Aryl groups can be substituted or unsubstituted, unless otherwise indicated.
- Heterocyclyl refers to a saturated or unsaturated non-aromatic ring containing at least one heteroatom (typically 1 to 5 heteroatoms) selected from nitrogen, oxygen, sulfur or silicon.
- the heterocyclyl ring may be monocyclic or bicyclic.
- these groups contain 0-5 nitrogen atoms, 0-2 sulfur atoms and 0-2 oxygen atoms. More preferably, these groups contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygen atoms.
- heterocycle groups include pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-dioxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine and the like.
- Heteroaryl refers to an aromatic group containing at least one heteroatom, where the heteroaryl group may be monocyclic or bicyclic. Examples include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiazolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, is
- Heterocyclyl and heteroaryl can be attached at any available ring carbon or heteroatom.
- Each heterocyclyl and heteroaryl may have one or more rings. When multiple rings are present, they can be fused together or linked covalently.
- Each heterocyclyl and heteroaryl must contain at least one heteroatom (typically 1 to 5 heteroatoms) selected from nitrogen, oxygen or sulfur. Preferably, these groups contain 0-5 nitrogen atoms, 0-2 sulfur atoms and 0-2 oxygen atoms. More preferably, these groups contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygen atoms.
- Heterocyclyl and heteroaryl groups can be substituted or unsubstituted, unless otherwise indicated. For substituted groups, the substitution may be on a carbon or heteroatom.
- R′, R and R′′ each independently refer to a variety of groups including hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryloxyalkyl.
- R′ and R′′ When R′ and R′′ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring (for example, —NR′R′′ includes 1-pyrrolidinyl and 4-morpholinyl). Furthermore, R′ and R′′, R and R′, or R′ and R′′′ may together with the atom(s) to which they are attached, form a substituted or unsubstituted 5-, 6- or 7-membered ring.
- Heteroatom is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
- the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-11 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
- radioactive isotopes such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-11 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
- asymmetric refers to a molecule lacking all traditional elements of symmetry.
- carbocyclic ring refers to a 5-10 membered ring in which the all of the ring atoms are carbons.
- a carbocyclic ring may be aromatic or nonaromatic.
- catalysis refers to a process in which a relatively small amount of a material increases the rate of a chemical reaction and is not itself consumed in the reaction.
- catalytic amount refers to a substoichiometric amount of the catalyst relative to a reactant.
- chiral refers to a molecule or conformation which is not superimposable with its mirror image partner.
- Chiral catalyst refers to a molecule which is not superimposable with its mirror image partner and that increases the rate of a chemical reaction without itself being consumed. In a stereoselective catalytic reaction, the chiral catalyst will serve to catalyze the reaction, while also providing enantioselectivity.
- Chiral ligand refers to a molecule or ion that surrounds a metal, especially a transition metal, in a metal ion complex as a Lewis base, where the molecule in one which is not superimposable with its mirror image partner.
- “Complex” refers to a coordination compound formed by the union of one or more electronically rich molecules or atoms capable of independent existence with one or more electronically poor molecules or atoms, which is also capable of independent existence.
- Diastereomer refers to one of a group of stereoisomers which is not related to another stereoisomer of the group as a mirror image.
- Diastereoselective refers to a process which favors production of one of the two possible diastereomers of a reaction product. For example, a chemical reaction would be diastereoselective if it produces the two diastereomers of a chiral product in unequal amounts. Such a reaction is said to exhibit diastereoselectivity.
- Enantiomer refers to one of a pair of molecular species that are mirror images of each other and not superimposable.
- Enantiomerically enriched refers to a mixture of enantiomers, in which one of the enantiomers is present in a greater amount than the partner enantiomer.
- An “enantiomerically enriched” product will have an enantiomeric excess (“% ee”), of more than 0 but less than 100%.
- “Enantiomeric excess” (ee) is equal to 100 times the mole fraction of the major enantiomer minus the mole fraction of the minor enantiomer. In a mixture of a pure enantiomer (R or S) and a racemate, ee is the percent excess of the enantiomer over the racemate.
- an enantiomerically enriched sample is a mixture of 25% of one enantiomer and 75% of the partner enantiomer.
- the mole fractions of each enantiomer are 0.25 and 0.75 respectively.
- the enantiomerically enriched sample has an ee of 50%.
- Enantioselective refers to a process which favors production of one of the two possible enantiomers of a reaction product. For example, a chemical reaction would be enantioselective if it produces the two enantiomers of a chiral product in unequal amounts. Such a reaction is said to exhibit enantioselectivity.
- Ligand refers to a molecule or ion that surrounds a metal, especially a transition metal, in a complex and serves as a Lewis base (i.e. an electron pair donor).
- Metal refers to elements located in Groups 5 and 6 of the periodic table with atomic numbers of 23 to 74.
- Phosphorus donating ligand refers to a ligand containing a phosphorus atom, where the phosphorus atom can act as the Lewis base and electron pair donor to form a complex with a metal. Examples include triphenylphosphine, tributylphosphine and the like.
- “Pyridyl donating ligand” refers to a pyridine compound which can act as a ligand, where the nitrogen atom of the pyridine ring can act as the Lewis base and electron pair donor to form a complex with a metal.
- a pyridyl donor ligand can be substituted or unsubstituted.
- Stepoisomer refers to isomers of identical constitution (i.e. bond connectivity), but which differ in their arrangement in space.
- Steposelective refers to preferentially forming one stereoisomer over another in a chemical reaction. If the stereoisomers are enantiomers, the chemical reaction is an enantioselective reaction. If the stereoisomers are diastereomers, the chemical reaction is a diastereoselective reaction.
- Tertiary amine ligand refers to nitrogen atom which is substituted with three groups other than hydrogen. Suitable substituents include alkyl and aryl groups. The tertiary amine ligand contains a nitrogen atom that can act as a Lewis base and electron pair donor to form a complex with a metal.
- carbene precursor refers to a compound used to generate a carbene at the coordination site of a transition metal.
- a chiral catalyst is formed by combining a deprotonated chiral ligand, an alkenyl ligand and a ruthenium (II) metal.
- a ruthenium (II) metal is any ruthenium metal with an oxidation state of 2 Examples of ruthenium (II) metals include ruthenium (I) chloride (RuCl 2 ); ruthenium (II) bromide (RuBr 2 ); ruthenium (II) iodide (RuI 2 ); tricarbonyldichlorodiruthenium(II) dimmer ([RuCl 2 (CO) 3 ] 2 ); K 4 [Ru(CN) 6 ].3H 2 O; bis(cyclopentadienyl)ruthenium (II) (Ru(C 5 H 5 ) 2 ); bis(pentamethylcyclopentadienyl)ruthenium (II) (Ru(C 5 Me).
- an alkenyl ligand is provided of the formula (I):
- R 5 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 5-10 heteroaryl, and substituted or unsubstituted C 3-10 -heterocycle;
- R 6 is selected from the group consisting of hydrogen and substituted or unsubstituted C 1-8 alkyl; or
- R 5 and R 6 together with the atoms to which they are attached may form a carbocyclic ring.
- the alkenyl ligand is of formula II:
- the alkenyl ligand is selected from the group consisting of ethylene, cyclohexene, 1-hexene and 2,3-dihydro-4-vinylbenzofuran.
- R 5 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, and substituted or unsubstituted C 3-10 heterocycle.
- R 6 is hydrogen
- R 6 is hydrogen, and R 5 is other than hydrogen.
- R 6 is hydrogen, and R 5 is substituted or unsubstituted C 3-10 heterocycle.
- R 6 is hydrogen, and R 5 is substituted or unsubstituted C 1-8 alkyl.
- R 6 and R 5 are each independently substituted or unsubstituted C 1-8 alkyl.
- the deprotonated chiral ligand of the present invention is of the formula (III)
- R 1 and R 2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-10 aryl, substituted or unsubstituted C 3-10 heterocyclyl, and substituted or unsubstituted C 5-10 heteroaryl;
- R 3 and R 4 are each independently selected from the group consisting of substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, C 1-10 alkoxy, C 1-12 alkylamino, substituted or unsubstituted C 3-10 heterocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 5-10 heteroaryl, and substituted or unsubstituted arylalkyl; or R 3 and R 4 together with the atoms to which they are attached may form a ring;
- M 1 and M 2 are each a counterion.
- M 1 and M 2 are the same but they may be different.
- M 1 and M 2 are each independently selected from Group I or Group II metal ions.
- Group I metals are Li, Na, K, Rb, Cs and Fr.
- Group II metals are Be, Mg, Ca, Sr, Ba, and Ra.
- M 1 and M 2 are selected from the group consisting of Li + , Na + , MgCl + and MgBr + .
- M 1 and M 2 are each Li + .
- the deprotonated chiral ligand is of the formula (IV):
- the chiral ligand is the (1R,2R)-( ⁇ ) enantiomer.
- the (1S,2S)-(+) enantiomer is preferred.
- R 1 and R 2 are each independently selected from the group consisting of substituted or unsubstituted C 1-8 alkyl, and substituted or unsubstituted C 6-10 aryl.
- R 1 and R 2 are each independently substituted or unsubstituted C 1-8 alkyl.
- R 1 and R 2 are each independently a perfluoro C 1-8 alkyl.
- R 1 and R 2 are each t-butyl.
- R 3 and R 4 are each independently selected from the group consisting of substituted or unsubstituted C 1-8 alkyl, and substituted or unsubstituted C 6-10 aryl.
- R 3 and R 4 are each independently a substituted or unsubstituted C 1-8 alkyl.
- R 3 and R 4 together with the atoms to which they are attached form a cyclohexane ring.
- the chiral catalyst was prepared by combining the ruthenium (II) metal, the deprotonated chiral ligand and alkenyl ligand.
- the deprotonated chiral ligand, formula (III) where M 1 and M 2 are metal ions from Group I or Group II, may be formed by deprotonating the phenolic groups of the chiral ligand with a suitable base as shown in Scheme 1.
- the chiral ligand was deprotonated with a base, with deprotonation occurring at both hydroxyl groups to form phenoxide anions.
- a base Any suitable base known to one skilled in the art to deprotonate a phenol may be employed to deprotonate the chiral ligand.
- Suitable bases include metal amines, including for example, lithium diisopropylamine (LiN(CH(CH 3 )) 2 ; metal alkoxides including for example potassium tert-butoxide, sodium ethoxide, sodium methoxide; and metal alkyls, including for example methyl lithium, n-butyl lithium, t-butyl lithium, hexyl lithium, octyl lithium, methylmagnesium bromide, methylmagnesium chloride and the like.
- the base is lithium diisopropylamide (LiN(CH(CH 3 ) 2 ) 2 ).
- at least two mole equivalents of base are used as compared to the chiral ligand.
- the deprotonation of the chiral ligand may be performed in any suitable inert solvent known to one skilled in the art.
- the solvent is tetrahydrofuran (THF).
- THF tetrahydrofuran
- the deprotonation is conducted at a suitable temperature to deprotonate the phenol groups of the chiral ligand.
- the deprotonation is conducted at about less than 15° C., more preferably less than about 10° C., even more preferably between about 0 and about 10° C.
- the deprotonated phenoxide groups of the chiral ligand coordinate with the ruthenium (II) metal to form a complex. Due to the chirality of the chiral ligand, complexation of the deprotonated chiral ligand with the ruthenium (II) metal imparts chirality to the ruthenium catalyst. The chiral nature of the catalyst influences the stereoselectivity of the cyclopropanation reaction.
- alkenyl ligand was also combined with ruthenium (II) metal and the deprotonated chiral ligand. Without wishing to be bound by theory, the alkenyl ligand is believed to coordinate to the ruthenium (II) metal and occupy an axial coordination site, forming a catalyst of formula (V) or (VI), depending upon whether one or two alkenyl ligands coordinate.
- ruthenium (II) catalysts Strong donor ligands such as pyridyl donating ligands, phosphorus donating ligands and tertiary amine ligands have been used previously with ruthenium (II) catalysts and are thought to occupy an axial coordination position on the ruthenium (II) metal.
- Pyridyl donating ligands are pyridine compounds which can act as a ligand, where the nitrogen atom of the pyridine ring acts as the Lewis base and electron pair donor to form a complex with the ruthenium metal.
- a phosphorus donating ligand is a ligand containing a phosphorus atom, where the phosphorus atom can act as the Lewis base and electron pair donor to form a complex with the ruthenium metal.
- a tertiary amine ligand is where the nitrogen atom acts as a Lewis base and electron pair donor to form a complex with the ruthenium metal.
- the present invention provides alkenyl ligands which are thought to occupy an axial coordination position on the ruthenium (II) metal.
- Pyridyl donating ligands, phosphorus donating ligands and tertiary amine ligands are preferably not employed in the catalyst preparation or cyclopropanation reaction.
- Better stereoselectivity such as enantioselectivity and higher yields have been found in the present invention when alkenyl ligands are used as compared to pyridyl or phosphorus donating ligands.
- the combination of the alkenyl ligand, ruthenium (II) metal and deprotonated chiral ligand forms a catalyst which is active.
- the catalyst is formed in situ, not isolated, and not purified prior to use in the cyclopropanation reaction.
- Generating the catalyst in situ offers advantages over using a isolated catalyst such as: (i) convenience; and (ii) minimal handling of a catalyst which may be air or moisture sensitive.
- the properties which make a catalyst stable enough for isolation may also decrease the reactivity of the catalyst.
- Using an in situ catalyst may allow a more reactive catalyst to be used that gives better selectivity, yield and turnover than using an isolated catalyst.
- the formula of the alkenyl ligand is the same as the formula of the alkenyl substrate to be used in the cyclopropanation reaction. This minimizes the generation of impurities.
- the alkenyl ligand can enter into transition metal catalyzed side reactions known to one skilled in the art, and form impurities.
- impurities are minimized.
- the combining of the ruthenium (II) metal, alkenyl ligand, and deprotonated chiral ligand may be done in any suitable order. In some aspects it may be desirable to generate the deprotonated chiral ligand in the presence of the ruthenium (II) metal and or alkenyl ligand, for example, when ruthenium (II) metal and the functional groups on the alkenyl ligand are compatible with the deprotonation conditions.
- the deprotonated chiral ligand is formed by deprotonating the phenol groups of the chiral ligand with a suitable base as discussed previously.
- the catalyst preparation reaction is carried out with various amounts of metal, deprotonated chiral ligand and alkenyl ligand.
- the amount of deprotonated chiral ligand used can be greater than the amount of ruthenium (II) metal.
- Preferably at least one equivalent of the deprotonated chiral ligand relative to the ruthenium (II) metal is used.
- the amount of alkenyl ligand is at least twice the amount of the ruthenium (II) metal, preferably at least 5 equivalents, more preferably at least 6 equivalent of the alkenyl ligand relative to the ruthenium (II) metal.
- a large excess of alkenyl ligand may be employed relative to the ruthenium (II) metal.
- the combining of the ruthenium (II) metal, deprotonated chiral ligand and alkenyl ligand is preferably done in a suitable solvent, for a suitable length of time, and at a suitable temperature.
- suitable solvents include tetrahydrofuran (THF), and combinations of THF/cyclohexane.
- the ruthenium (II) metal, deprotonated chiral ligand and alkenyl ligand are combined at a suitable temperature.
- a suitable temperature for combining the ruthenium (II) metal, deprotonated chiral ligand and alkenyl ligand is between about ⁇ 10° C. and about 30° C., preferably between about 0° C.
- the mixture is stirred for a suitable amount of time to allow the catalyst to form.
- the mixture is stirred for at least 12 h, preferably at least 1 h, more preferably at least 5 minutes.
- a method of stereoselective cyclopropanation is provided.
- the catalyst is contacted with a carbene precursor in the presence of an alkenyl substrate.
- a carbene precursor is a compound used to generate a carbene at the coordination site of a transition metal, in particular at the coordination site of ruthenium.
- the carbene precursor is a diazo compound wherein the carbene is generated by the removal of N 2 as nitrogen gas from the solution.
- diazo compounds which are carbene precursors include ethyl diazoacetate, t-butyl diazoacetate, 2,3,4-trimethyl-3-pentyl diazoacetate, menthyl diazoacetate, 2,5-dimethyl-4-hexen-2-yl diazoacetate, 3-(diazoacetyl)amino propionate, and diazoacetylamino acetate.
- the carbene precursor is a diazoester.
- the carbene precursor is selected from the group consisting of ethyl diazoacetate, t-butyl diazoacetate, and menthyl diazoacetate.
- the carbene precursor is ethyl diazoacetate.
- the carbene precursor is of the formula (VII):
- R 7 is selected from the group consisting of substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, C 1-10 alkoxy, C 1-12 alkylamino, substituted or unsubstituted C 3-10 heterocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 6-10 heteroaryl and substituted or unsubstituted arylakyl.
- R 7 is selected from the group consisting of substituted or unsubstituted C 1-8 alkyl, C 1-10 alkoxy, C 1-12 alkylamino, and substituted or unsubstituted C 6-10 aryl.
- R 7 is selected from the group consisting of substituted or unsubstituted C 1-8 alkyl, and C 1-10 alkoxy.
- R 7 is C 1-10 alkoxy.
- R 7 is selected from the group consisting of —OEt, -OtBu, and —O-(menthyl).
- the catalyst is contacted with the carbene precursor in the presence of an alkenyl substrate.
- the carbon atoms of the alkenyl substrate form two of the carbon atoms of the cyclopropyl ring that is formed.
- Any suitable alkenyl substrate can be used which leads a cyclopropyl product which is enriched in one stereoisomer.
- the alkenyl substrate is a terminal alkene of formula (VIII):
- R 8 is selected from the group consisting of halogen, —CN, —C(O)R a , —CO 2 R a , —C(O)NR a R b , —OR a , —OC(0)R a , —OC(O)NR a R b , —SR a , —S(0)R a , —S(O) 2 R a , —S(O) 2 NR a R b , —NO 2 , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —NR a S(O) 2 R b , —NR a C(O)NR b R c , substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substitute
- R 9 is selected from the group consisting of hydrogen, and C 1-6 alkyl.
- the alkenyl substrate is of formula (II):
- VBF 2,3-dihydro-4-vinylbenzofuran and VBF, herein.
- R 8 is selected from the group consisting of halogen, —CN, —C(O)R a , —CO 2 R a , —C(O)NR a R b , —S(0)R a , —S(O) 2 R a , —S(O) 2 NR a R b , and —NO 2 .
- R 8 is selected from the group consisting of —OR a , —SR a , and —NR a R b .
- R 8 is selected from the group consisting of substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl.
- R 8 is selected from the group consisting of substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl.
- R 8 is substituted or unsubstituted 3- to 10-membered heterocyclyl.
- R 9 is hydrogen
- R 9 is C 1-8 alkyl.
- R 9 is methyl
- a cyclopropyl product is formed which is enriched in one stereoisomer.
- the cyclopropatiion method is enantioselective wherein one enantiomer is formed preferentially as compared to the partner enantiomer.
- a cyclopropyl product of formula (IX) is formed according to the following scheme:
- R 7 , R 8 , and R 9 are as defined above.
- the cyclopropyl product is formed in at least 50% yield, preferably at least 80%, more preferably at least 90% and even more preferably at least 95%.
- the cyclopropyl product has a cis or trans configuration, depending on the relative size and nature of R 8 and R 9 .
- R 9 is hydrogen
- the trans product is formed as shown in the following scheme.
- the amount of trans cyclopropyl product formed in comparison to cis cyclopropyl product is determined by dividing the amount of trans cyclopropyl product by the sum of the amount of cis and trans cyclopropyl products, and multiplying this number by 100.
- the amount of cis or trans product can be measured in either moles or mass.
- the trans cyclopropyl product is formed in greater than about 80%, more preferably greater than about 90% and even more preferably greater than about 95%.
- Enantiomeric excess is equal to 100 times the mole fraction of the major enantiomer minus the mole fraction of the minor enantiomer.
- the enantiomeric excess is preferably greater than about 80%, more preferably greater than about 90%.
- the stereoselective cyclopropanation reaction is carried out with various amounts of catalyst, carbene precursor and alkenyl substrate.
- the amount of carbene precursor and alkenyl substrate may be the same or one may be used in excess.
- the reagent present in the lesser amount is referred to as the limiting reagent.
- the alkenyl substrate is the limiting reagent.
- An advantage of the present invention is that the cyclopropanation reaction can be carried out with good stereoselectivity and in high yield when the alkenyl substrate is used as the limiting reagent. This is particularly important when the alkenyl substrate requires a laborious synthesis or is costly to synthesize or purchase.
- Another advantage of the present invention is that the cyclopropanation reaction can be carried out with good stereoselectivity and in high yield without using a large excess of the carbene precursor. Often a reaction is driven to completion by using a large excess of the non-limiting reagent, for example 5-fold, 10-fold or even greater excess of the non-limiting reagent.
- the non-limiting reagent is the carbene precursor, such as a diazo compound
- use of an excess of the diazo compound creates an unsafe operating condition, especially on large scale such as in a manufacturing plant.
- diazo compound such as diazoesters
- diazo compounds can be explosive and the reactor concentration of this reagent must be kept low
- the rapid addition of the diazo compound can lead to an exothermic reaction that can be difficult to control
- for each mole of the diazo compound that is consumed, a mole of nitrogen is released; a rapid increase in the rate of the reaction in the presence of a high concentration of the diazo compound could release a bulbous amount of nitrogen that may not be able to be effectively vented from the reactor, thus leading to a pressure build-up in the reactor and creating an unsafe condition
- the use of a large excess of diazo compound creates an unsafe condition, requires the handling, transporting and storage of excess diazo compound than theoretically required in the reaction which is significant at manufacturing scale, requires extra monitoring to determine the fate of the excess diazo compound used in the reaction, and is inefficient.
- the alkenyl substrate is used as the limiting reagent and less than about 2.0 equivalents of the carbene precursor is used in the stereoselective cyclopropanation reaction.
- the alkenyl substrate is the limiting reagent
- between about 1.05 and about 2.0 equivalents of the carbene precursor are used as compared to the limiting reagent, preferably between about 1.1 and about 1.8, more preferably between about 1.2 and about 1.5 equivalents, even more preferably about 1.3 equivalents.
- the metal catalyst is used in amount of at least 0.05 mole % of the limiting reagent, preferably between about 0.05% to about 10%, more preferably between about 0.1 to about 5%, even more preferably between about 0.5% and 3%.
- reaction solvent is THF or toluene, or a combination thereof. Additional solvents such as cyclohexane may also be present. A single solvent may be used, or a combination of solvents may be used.
- the stereoselective cyclopropanation reaction is preferably carried out at a suitable reaction temperature. Any suitable temperature may be chosen which affords the desired yield and stereoselectivity of the cyclopropyl product.
- the reaction temperature is usually below or at the boiling point of the solvent. Preferably the reaction temperature is between about 0° C. and about 40° C., more preferably between about 20° C. and about 30° C.
- the stereoselective cyclopropanation reaction is carried out for a suitable time to afford the desired yield and stereoselectivity of the cyclopropyl product.
- the reaction can be carried out for a suitable time to consume the limiting reagent.
- the reaction time is at least 1 h, preferably between about 1 h and about 10 h, more preferably between abut 2 h and about 5 h.
- optimization of the yield and the stereoselectivity can be achieved by altering the reaction conditions.
- optimization can include changing the solvent, the temperature of various stages of the reaction, the equivalents the metal catalyst, the equivalents of the carbene precursor, and the equivalents of the alkenyl substrate.
- Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA) unless otherwise indicated. The salen complex was obtained from Strem Chemicals, Inc. 1 H-NMR were recorded on an NMR spectrometer. Significant peaks are tabulated in the order: multiplicity (br, broad; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet) and number of protons. Mass spectrometry results are reported as the ratio of mass over charge, followed by the relative abundance of each ion (in parenthesis). A single mle value is reported for the M+H (or, as noted, M ⁇ H, or M+Na) ion containing the most common atomic isotopes. Isotope patterns correspond to the expected formula in all cases.
- dichloro(p-cymene)ruthenium(II) dimer (1.21 g, 2 mmol), cyclohexene (0.92 g, 11.2 mmol) and anhydrous THF (60 mL).
- the mixture was stirred.
- the salen solution was added in one portion to the stirred suspension at ambient temperature.
- the salen reaction flask was rinsed with 10 mL of THF and the rinse solution was transferred to the 250-mL flask.
- the resultant mixture was stirred overnight.
- the catalyst solution can be used without further work-up in the cyclopropanation reaction as described below. Alternatively, the solution can be concentrated to dryness to provide a green solid that can be used in the cyclopropanation reaction.
- dichloro(p-cymene)ruthenium (II) dimer 300 mg, 0.5 mmol
- VBF 0.4 g, 2.8 mmol
- the catalyst solution can be used without further work-up in the cyclopropanation reaction as described below.
- the solution can be concentrated to dryness to provide a green solid that can be used in the cyclopropanation reaction.
- the Ru/salen/1-hexene catalyst was prepared according to the procedure for Ru/salen/cyclohexene except that 1-hexene was used in place of cyclohexene.
- the resulting catalyst solution was found to be active in the cyclopropanation reaction of 4-vinyl-2,3-dihydrobenzofuran with ethyl diazoacetate.
- the Ru/salen/ethylene catalyst was prepared according to the procedure for Ru/salen/cyclohexene except that ethylene was used in place of cyclohexene. Excess ethylene gas was bubbled through a solution of dichloro(p-cymene)ruthenium(II) dimer in anhydrous THF, followed by addition of the deprotonated salen ligand. The resulting catalyst solution was found to be active in the cyclopropanation reaction of 4-vinyl-2,3-dihydrobenzofuran with ethyl diazoacetate.
- the combined aqueous extracts were extracted with of toluene.
- the aqueous phase was combined with MTBE and cooled to 10° C.
- the pH of the aqueous phase was adjusted to 2-3 with phosphoric acid.
- the phases were mixed and then separated.
- the MTBE phase was washed with water.
- the MTBE phase was filtered through Whatman Qualitative #1 filter paper.
- the MTBE phase was concentrated to an oil
- the Ru/salen/4-vinyl-2,3-dihydrobenzofuran catalyst was prepared according to the procedure for Ru/salen/cyclohexene except that 4-vinyl-2,3-dihydrobenzofuran was used in place of cyclohexene.
- the resulting catalyst solution was found to be active in the cyclopropanation reaction of 4-vinyl-2,3-dihydrobenzofuran with ethyl diazoacetate.
- the MTBE phase was washed with 4 ⁇ 50 mL of water.
- the MTBE phase was filtered through Whatman Qualitative #1 filter paper.
- the MTBE phase was concentrated to an oil that solidified upon standing to give 22.13 g (95%) of a mixture of cyclopropyl acid isomers. 97.7:2.3 trans/cis by HPLC area counts; trans isomer (1R,2R) 91.8%:trans enantiomer (1S,2S):8.2% by HPLC area counts; % enantiomeric purity (83.6% ee)
- the isolated Ru/salen/pyridine catalyst was obtained from SonBinh Nguyen prepared according to the method of Miller et al (Angew. Chem Int. Ed. 2002, 41, 2953-2956). According to Miller et al. the Rulsalenlpyridine catalyst has the structure:
- the isolated Ru/salen/triphenylphosphine catalyst was obtained from SonBinh Nguyen prepared according to the method of Miller et al. (Angew. Chem Int. Ed. 2002, 41, 2953-2956). According to Miller et al. the Rulsalenltriphenylphosphinecatalyst has the structure:
- Examples 15 and 17 illustrate the use of isolated Ru/salen/pyridine and Rulsalenltriphenylphosphinein the stereoselective cyclopropanation of 4-vinyl-2,3-dihydrobenzofuran. Neither of these isolated catalysts provided satisfactory results. Specifically, the reaction with the isolated Ru/salen/pyridine catalyst provided none of the desired (1R,2R)-ethyl 2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxylate product.
- the reaction with the isolated Rulsalenltriphenylphosphine catalyst provided only a small amount of the desired (1R,2R)-ethyl 2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxylate product.
- the isolated Rulsalenlpyridine catalyst and isolated Rulsalenltriphenylphosphine catalyst may be unstable. The catalysts may degrade over time or due to exposure to air or moisture. Further experiments were conducted by generating the Rulsalenlpyridine catalyst in situ as detailed below.
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Abstract
Chiral ruthenium catalysts comprising salen and alkenyl ligands are provided for stereoselective cyclopropanation, and methods of cyclopropanation are provided. The chiral ruthenium catalyst is prepared in situ by combining an alkenyl ligand, a deprotonated chiral salen ligand, and a ruthenium (II) metal. A preferred catalyst is prepared in situ by combining 2,3-dihydro-4-venylbenzofuran, deprotonated 1,2-cyclohexanediamino-N,N′-bis(3,5-di-t-butyl-salicylidene) and RuCl2(p-cymene)]2.
Description
- This application is a continuation application of co-pending U.S. patent application Ser. No. 12/783,935, filed 20 May 2010, which is hereby incorporated herein.
- Chiral catalysts for cyclopropanation, methods of preparation and methods of forming chiral cyclopropyl products are provided herein.
- The biological activities of many pharmaceuticals, fragrances, food additives and agrochemicals are often associated with their absolute molecular configuration. While one enantiomer gives a desired biological function through interactions with natural binding sites, another enantiomer usually does not have the same function and sometimes has deleterious side effects. As such, chemical synthesis of biologically active compounds are usually directed at the desired enantiomercally pure form.
- Cyclopropanes are particularly challenging to synthesize enantiomerically pure. Especially for commercial applications, stereoselective cyclopropanations must give good diastereo- and enantioselectivity in high yield and purity at a reasonable cost. One approach that is particularly efficient, is stereoselective catalysis because a small amount of a chiral catalyst can be used to produce a large quantity of the desired chiral cyclopropyl compound. Transition metal catalysts are typically employed to catalyze the reaction between a diazoester and an olefin substrate to form a chiral cyclopropyl product.
- Current stereoselective cyclopropanation methods using transition metal catalysis, are nonoptimal for commercialization due to the use of a large excess olefin substrate or diazoester in order to drive the reaction to completion. Miller et el. (Angew. Chem Int Ed. 2002, 41, 2953-2956) report an isolated ruthenium catalyst formed from a chiral salen ligand and pyridine or phosphine ligands. The stereoselective cyclopropanation method of Miller et al. employs an isolated chiral ruthenium catalyst and five equivalents of the olefin substrate relative to the amount of diazoester employed. In commercial applications, the olefin substrates are often complex and require multi-step syntheses. As a result, using an excess of the olefin substrate not only wastes material, but also increases cost and lowers the throughput of the chemical process. On the other hand, using a large excess of the diazoester to drive the reaction to completion is undesirable due to safety concerns on large scale. Furthermore, use of excess reagents can lead to increased impurities and purification difficulties. Finally, the use of an isolated chiral catalyst can be undesirable in commercial applications because of the increased number of steps in a chemical process, increasing cycle time, as well as safety issues associated with handling transition metal catalysts. What is needed, are efficient transition metal catalyzed stereoselective cyclopropanation methods employing mild and safe conditions.
- In one embodiment, a method of stereoselective cyclopropanation is provided. The stereoselective cyclopropanation reaction comprises combining a carbene precursor and an alkenyl substrate in the presence of a chiral catalyst to form a cyclopropyl product. The chiral catalyst is formed in situ by combining an alkenyl ligand with a deprotonated chiral ligand and a ruthenium (II) metal.
- In another embodiment, a catalyst for stereoselective reactions is provided. The catalyst is prepared in situ by combining an alkenyl ligand and a deprotonated chiral ligand in the presence of a ruthenium (II) metal. The alkenyl ligand is of formula (I):
- and the deprotonated ligand is of formula (III):
- where R1, R2, R3, R4, R5, R6, M1 and M2 are defined below.
- Thus, there is disclosed a method of stereoselective cyclopropanation comprising the step of combining a carbene precursor and an alkenyl substrate in the presence of a chiral catalyst to form a cyclopropyl product, the chiral catalyst is prepared in situ by the step of combining an alkenyl ligand and a deprotonated chiral ligand in the presence of a ruthenium (II) metal; wherein the alkenyl ligand is of formula (I):
- where R5 is selected from the group consisting of hydrogen, C1-8 alkyl, C6-10 aryl, C5-10 heteroaryl, C3-10 heterocycle; and where R6 is selected from the group consisting of hydrogen, and C1-8 alkyl; and where R5 and R6 together with the atoms to which they are attached may form a carbocyclic ring; wherein the deprotonated chiral ligand is of formula (III):
- where R1 and R2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C5-10 heteroaryl; where R3 and R4 are each independently selected from the group consisting of substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C3-8 cycloalkyl, C1-10 alkoxy, C1-12 alkylamino, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C5-10 heteroaryl and substituted or unsubstituted arylalkyl; where R3 and R4 together with the atoms to which they are attached may form a ring; and where M1 and M2 are each a counterion independently selected from the group consisting of Group I metal ions and Group II metal ions.
- There is further disclosed a method of stereoselective cyclopropanation consisting of the steps of combining an alkenyl ligand and a deprotonated chiral ligand in the presence of a ruthenium (II) metal to form a chiral catalyst in situ; wherein the alkenyl ligand is of formula (I):
- where R5 is selected from the group consisting of hydrogen, C1-8 alkyl, C6-10 aryl, C5-10 heteroaryl, C3-10 heterocycle; and where R6 is selected from the group consisting of hydrogen, and C1-6 alkyl; and where R5 and R6 together with the atoms to which they are attached may form a carbocyclic ring; wherein the deprotonated chiral ligand is of formula (III):
- where R1 and R2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C5-10 heteroaryl; where R3 and R4 are each independently selected from the group consisting of substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C3-8 cycloalkyl, C1-10 alkoxy, C1-12 alkylamino, substituted or unsubstituted C10 heterocyclyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C5-10 heteroaryl and substituted or unsubstituted arylalkyl; where R3 and R4 together with the atoms to which they are attached may form a ring; and where M1 and M2 are each a counterion independently selected from the group consisting of Group I metal ions and Group II metal ions; and combining a carbene precursor and an alkenyl substrate in the presence of the chiral catalyst to form a cyclopropyl product.
- Also disclosed is the stereoselective cyclopropanation of a carbene precursor and an alkenyl substrate with a chiral catalyst of the formulae (V) or (VI):
- where R5 is selected from the group consisting of hydrogen, C1-8 alkyl, C6-10 aryl, C5-10 heteroaryl, C3-10 heterocycle; and where R6 is selected from the group consisting of hydrogen, and C1-6 alkyl; and where R5 and R6 together with the atoms to which they are attached may form a carbocyclic ring; where R1 and R2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C5-10 heteroaryl; where R3 and R4 are each independently selected from the group consisting of substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C3-6 cycloalkyl, C1-10 alkoxy, C1-12 alkylamino, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C5-10 heteroaryl and substituted or unsubstituted arylalkyl; where R3 and R4 together with the atoms to which they are attached may form a ring; and where M1 and M2 are each a counterion independently selected from the group consisting of Group I metal ions and Group II metal ions; the improvement comprising generating the chiral catalyst in situ.
- Further, there is disclosed a catalyst for stereoselective reactions prepared by the step of combining an alkenyl ligand and a deprotonated chiral ligand in the presence of a ruthenium (II) metal; wherein the alkenyl ligand is of formula (I):
- where R5 is selected from the group consisting of hydrogen, C1-8 alkyl, C6-10 aryl, C5-10 heteroaryl, C3-10 heterocycle; and where R6 is selected from the group consisting of hydrogen, and C1-8 alkyl; and where R5 and R6 together with the atoms to which they are attached may form a carbocyclic ring; wherein the deprotonated chiral ligand is of formula (III):
- where R1 and R2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C5-10 heteroaryl; where R3 and R4 are each independently selected from the group consisting of substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C3-8 cycloalkyl, C1-10 alkoxy, C1-12 alkylamino, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C5-10 heteroaryl and substituted or unsubstituted arylalkyl; where R3 and R4 together with the atoms to which they are attached may form a ring; and where M1 and M2 are each a counterion independently selected from the group consisting of Group I metal ions and Group II metal ions.
- “Alkyl” by itself or as part of another substituent refers to a saturated hydrocarbon group which may be linear, cyclic, or branched or a combination thereof having the number of carbon atoms designated (i.e., C1-8 means one to eight carbon atoms). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, cyclopentyl, (cyclohexyl)methyl, cyclopropylmethyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. Alkyl groups can be substituted or unsubstituted, unless otherwise indicated. Examples of substituted alkyl include haloalkyl, perhaloalkyls, thioalkyl, aminoalkyl, and the like.
- “Alkoxy” refers to —O-alkyl. Examples of an alkoxy group include methoxy, ethoxy, n-propoxy etc.
- “Alkylamino” refers to —NHR′ and —NR′R″ where R′ is alkyl and R is hydrogen or alkyl. Examples of alkylamino groups include methylamine, ethylamine, isopropylamine, butylamine, dimethyl amine, diisopropylamine and the like.
- “Alkenyl” refers to an unsaturated hydrocarbon group which may be linear, cyclic or branched or a combination thereof. Alkenyl groups with 2-8 carbon atoms are preferred. The alkenyl group may contain 1, 2 or 3 carbon-carbon double bonds. Examples of alkenyl groups include ethenyl, 11-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl, cyclohexenyl, cyclopentenyl and the like. Alkenyl groups can be substituted or unsubstituted, unless otherwise indicated.
- “Aryl” refers to a polyunsaturated, aromatic hydrocarbon group having a single ring (monocyclic) or multiple rings (bicyclic), which can be fused together or linked covalently. Aryl groups with 6-10 carbon atoms are preferred, where this number of carbon atoms can be designated by C6-10, for example. Examples of aryl groups include phenyl and naphthalene-1-yl, naphthalene-2-yl, biphenyl and the like. Aryl groups can be substituted or unsubstituted, unless otherwise indicated.
- “Heterocyclyl” refers to a saturated or unsaturated non-aromatic ring containing at least one heteroatom (typically 1 to 5 heteroatoms) selected from nitrogen, oxygen, sulfur or silicon. The heterocyclyl ring may be monocyclic or bicyclic. Preferably, these groups contain 0-5 nitrogen atoms, 0-2 sulfur atoms and 0-2 oxygen atoms. More preferably, these groups contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygen atoms. Examples of heterocycle groups include pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-dioxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine and the like.
- “Heteroaryl” refers to an aromatic group containing at least one heteroatom, where the heteroaryl group may be monocyclic or bicyclic. Examples include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiazolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl or thienyl.
- Heterocyclyl and heteroaryl can be attached at any available ring carbon or heteroatom. Each heterocyclyl and heteroaryl may have one or more rings. When multiple rings are present, they can be fused together or linked covalently. Each heterocyclyl and heteroaryl must contain at least one heteroatom (typically 1 to 5 heteroatoms) selected from nitrogen, oxygen or sulfur. Preferably, these groups contain 0-5 nitrogen atoms, 0-2 sulfur atoms and 0-2 oxygen atoms. More preferably, these groups contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygen atoms. Heterocyclyl and heteroaryl groups can be substituted or unsubstituted, unless otherwise indicated. For substituted groups, the substitution may be on a carbon or heteroatom.
- Suitable substituents for substituted alkyl, substituted alkenyl, and substituted alkynyl include halogen, —CN, —CO2R′, —C(O)R, —C(O)NR′R″, oxo (=0 or —O−), —OR′, —OC(O)R′, —OC(O)NR′R″—NO2, —NR′C(O)R′, —NR′″C(O)NR′R″, —NR′R″, —NR′CO2R″, —NR′S(O)R′, —NR′S(O)2R′″, —NR′″S(O)NR′R″, —NR′″S(O)2NR′R″, —SR′, —S(O)R′, —S(O)2R′, —S(O)2NR′R″, —NR′—C(NHR″)═NR′″, —SiR′R″R′″, —N3, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl. The number of possible substituents range from zero to (2m′+1), where m′ is the total number of carbon atoms in such radical.
- Suitable substituents for substituted aryl, substituted heteroaryl and substituted heterocyclyl include halogen, —CN, —CO2R′, —C(O)R′, —C(O)NR′R″, oxo (=0 or —O−), —OR′, —OC(O)R′, —OC(O)NR′R″, —NO2, —NR′C(O)R″, —NR′″C(O)NR′R″, —NR′R″, —NR′CO2R″, —NR′S(O)R″, —NR′S(O)2R″, —NR′″S(O)NR′R″, —NR′″S(O)2NR′R″, —SR′, —S(O)R′, —S(O)2R′, —S(O)2NR′R″, —NR′—C(NHR″)═NR′″, —SIR′R″R′″, —N3, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10 membered heterocyclyl. The number of possible substituents range from zero to the total number of open valences on the aromatic ring system.
- As used above, R′, R and R″ each independently refer to a variety of groups including hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryloxyalkyl. When R′ and R″ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring (for example, —NR′R″ includes 1-pyrrolidinyl and 4-morpholinyl). Furthermore, R′ and R″, R and R′, or R′ and R′″ may together with the atom(s) to which they are attached, form a substituted or unsubstituted 5-, 6- or 7-membered ring.
- “Heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
- It will be apparent to one skilled in the art that certain compounds of the present invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention. Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention. The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-11 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
- The term “asymmetric” refers to a molecule lacking all traditional elements of symmetry.
- The term “carbocyclic ring” refers to a 5-10 membered ring in which the all of the ring atoms are carbons. A carbocyclic ring may be aromatic or nonaromatic.
- The term catalysis or “catalyzed” refers to a process in which a relatively small amount of a material increases the rate of a chemical reaction and is not itself consumed in the reaction.
- The term “catalytic amount” refers to a substoichiometric amount of the catalyst relative to a reactant.
- The term “chiral” refers to a molecule or conformation which is not superimposable with its mirror image partner.
- “Chiral catalyst” refers to a molecule which is not superimposable with its mirror image partner and that increases the rate of a chemical reaction without itself being consumed. In a stereoselective catalytic reaction, the chiral catalyst will serve to catalyze the reaction, while also providing enantioselectivity.
- “Chiral ligand” refers to a molecule or ion that surrounds a metal, especially a transition metal, in a metal ion complex as a Lewis base, where the molecule in one which is not superimposable with its mirror image partner.
- “Complex” refers to a coordination compound formed by the union of one or more electronically rich molecules or atoms capable of independent existence with one or more electronically poor molecules or atoms, which is also capable of independent existence.
- “Diastereomer” refers to one of a group of stereoisomers which is not related to another stereoisomer of the group as a mirror image.
- “Diastereoselective” refers to a process which favors production of one of the two possible diastereomers of a reaction product. For example, a chemical reaction would be diastereoselective if it produces the two diastereomers of a chiral product in unequal amounts. Such a reaction is said to exhibit diastereoselectivity.
- “Enantiomer” refers to one of a pair of molecular species that are mirror images of each other and not superimposable.
- “Enantiomerically enriched” refers to a mixture of enantiomers, in which one of the enantiomers is present in a greater amount than the partner enantiomer. An “enantiomerically enriched” product will have an enantiomeric excess (“% ee”), of more than 0 but less than 100%. “Enantiomeric excess” (ee) is equal to 100 times the mole fraction of the major enantiomer minus the mole fraction of the minor enantiomer. In a mixture of a pure enantiomer (R or S) and a racemate, ee is the percent excess of the enantiomer over the racemate. Representative of an enantiomerically enriched sample is a mixture of 25% of one enantiomer and 75% of the partner enantiomer. The mole fractions of each enantiomer are 0.25 and 0.75 respectively. The enantiomeric excess is calculated as (0.75−0.25)×100=50. Thus, the enantiomerically enriched sample has an ee of 50%.
- “Enantioselective” refers to a process which favors production of one of the two possible enantiomers of a reaction product. For example, a chemical reaction would be enantioselective if it produces the two enantiomers of a chiral product in unequal amounts. Such a reaction is said to exhibit enantioselectivity.
- “Ligand” refers to a molecule or ion that surrounds a metal, especially a transition metal, in a complex and serves as a Lewis base (i.e. an electron pair donor).
- “Metal” refers to elements located in Groups 5 and 6 of the periodic table with atomic numbers of 23 to 74.
- “Phosphorus donating ligand” refers to a ligand containing a phosphorus atom, where the phosphorus atom can act as the Lewis base and electron pair donor to form a complex with a metal. Examples include triphenylphosphine, tributylphosphine and the like.
- “Pyridyl donating ligand refers to a pyridine compound which can act as a ligand, where the nitrogen atom of the pyridine ring can act as the Lewis base and electron pair donor to form a complex with a metal. A pyridyl donor ligand can be substituted or unsubstituted.
- “Stereoisomer” refers to isomers of identical constitution (i.e. bond connectivity), but which differ in their arrangement in space.
- “Stereoselective” refers to preferentially forming one stereoisomer over another in a chemical reaction. If the stereoisomers are enantiomers, the chemical reaction is an enantioselective reaction. If the stereoisomers are diastereomers, the chemical reaction is a diastereoselective reaction.
- “Tertiary amine ligand” refers to nitrogen atom which is substituted with three groups other than hydrogen. Suitable substituents include alkyl and aryl groups. The tertiary amine ligand contains a nitrogen atom that can act as a Lewis base and electron pair donor to form a complex with a metal.
- The term “carbene precursor” refers to a compound used to generate a carbene at the coordination site of a transition metal.
- In a first aspect of the first embodiment, a chiral catalyst is formed by combining a deprotonated chiral ligand, an alkenyl ligand and a ruthenium (II) metal. A ruthenium (II) metal is any ruthenium metal with an oxidation state of 2 Examples of ruthenium (II) metals include ruthenium (I) chloride (RuCl2); ruthenium (II) bromide (RuBr2); ruthenium (II) iodide (RuI2); tricarbonyldichlorodiruthenium(II) dimmer ([RuCl2(CO)3]2); K4[Ru(CN)6].3H2O; bis(cyclopentadienyl)ruthenium (II) (Ru(C5H5)2); bis(pentamethylcyclopentadienyl)ruthenium (II) (Ru(C5Me5)2); dichloro(η4-cyloocta 1,5-diene)ruthenium(II); dichloro(1,5-cyclooctadiene)ruthenium(II); tetrachlorobis(4-cymene)diruthenium(II), and tetrachlorobis(η6-p-cymene)diruthenium(II) ([RuCl2(p-cymene)]2). Preferably the ruthenium (II) metal is [RuCl2(p-cymene)]2.
- In one aspect of the first embodiment of the present invention an alkenyl ligand is provided of the formula (I):
- where R5 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C5-10 heteroaryl, and substituted or unsubstituted C3-10-heterocycle; and
- R6 is selected from the group consisting of hydrogen and substituted or unsubstituted C1-8 alkyl; or
- R5 and R6 together with the atoms to which they are attached may form a carbocyclic ring.
- In one embodiment, the alkenyl ligand is of formula II:
- which is also referred to as 2,3-dihydro-4-vinylbenzofuran.
- In another embodiment, the alkenyl ligand is selected from the group consisting of ethylene, cyclohexene, 1-hexene and 2,3-dihydro-4-vinylbenzofuran.
- In one embodiment, R5 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-8 alkyl, and substituted or unsubstituted C3-10 heterocycle.
- In one embodiment, R6 is hydrogen.
- In one embodiment, R6 is hydrogen, and R5 is other than hydrogen.
- In another embodiment, R6 is hydrogen, and R5 is substituted or unsubstituted C3-10 heterocycle.
- In another embodiment R6 is hydrogen, and R5 is substituted or unsubstituted C1-8 alkyl.
- In another embodiment, R6 and R5 are each independently substituted or unsubstituted C1-8 alkyl.
- The deprotonated chiral ligand of the present invention is of the formula (III)
- where R1 and R2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C1-10 aryl, substituted or unsubstituted C3-10 heterocyclyl, and substituted or unsubstituted C5-10 heteroaryl;
- R3 and R4 are each independently selected from the group consisting of substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C3-8 cycloalkyl, C1-10 alkoxy, C1-12 alkylamino, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C5-10 heteroaryl, and substituted or unsubstituted arylalkyl; or R3 and R4 together with the atoms to which they are attached may form a ring;
- M1 and M2 are each a counterion. Preferably, M1 and M2 are the same but they may be different. More preferably, M1 and M2 are each independently selected from Group I or Group II metal ions. Group I metals are Li, Na, K, Rb, Cs and Fr. Group II metals are Be, Mg, Ca, Sr, Ba, and Ra. Even more preferably, M1 and M2 are selected from the group consisting of Li+, Na+, MgCl+ and MgBr+. Most preferably, M1 and M2 are each Li+.
- In one embodiment, the deprotonated chiral ligand is of the formula (IV):
- also referred to as 1,2-cyclohexanediamino-N,N′-bis(3,5-di-t-butyl-salicylidene). Preferably, the chiral ligand is the (1R,2R)-(−) enantiomer. In other embodiments, the (1S,2S)-(+) enantiomer is preferred.
- In one embodiment, R1 and R2 are each independently selected from the group consisting of substituted or unsubstituted C1-8 alkyl, and substituted or unsubstituted C6-10 aryl.
- In another embodiment, R1 and R2 are each independently substituted or unsubstituted C1-8 alkyl.
- In another embodiment, R1 and R2 are each independently a perfluoro C1-8 alkyl.
- In a highly preferred embodiment, R1 and R2 are each t-butyl.
- In one embodiment, R3 and R4 are each independently selected from the group consisting of substituted or unsubstituted C1-8 alkyl, and substituted or unsubstituted C6-10 aryl.
- In another embodiment, R3 and R4 are each independently a substituted or unsubstituted C1-8 alkyl.
- In a highly preferred embodiment, R3 and R4 together with the atoms to which they are attached form a cyclohexane ring.
- In an illustrative embodiment, the chiral catalyst was prepared by combining the ruthenium (II) metal, the deprotonated chiral ligand and alkenyl ligand. The deprotonated chiral ligand, formula (III) where M1 and M2 are metal ions from Group I or Group II, may be formed by deprotonating the phenolic groups of the chiral ligand with a suitable base as shown in Scheme 1.
- To promote complexation of the chiral ligand with the ruthenium (II) metal, the chiral ligand was deprotonated with a base, with deprotonation occurring at both hydroxyl groups to form phenoxide anions. Any suitable base known to one skilled in the art to deprotonate a phenol may be employed to deprotonate the chiral ligand. Suitable bases include metal amines, including for example, lithium diisopropylamine (LiN(CH(CH3))2; metal alkoxides including for example potassium tert-butoxide, sodium ethoxide, sodium methoxide; and metal alkyls, including for example methyl lithium, n-butyl lithium, t-butyl lithium, hexyl lithium, octyl lithium, methylmagnesium bromide, methylmagnesium chloride and the like. Preferably the base is lithium diisopropylamide (LiN(CH(CH3)2)2). Preferably at least two mole equivalents of base are used as compared to the chiral ligand.
- The deprotonation of the chiral ligand may be performed in any suitable inert solvent known to one skilled in the art. Preferably the solvent is tetrahydrofuran (THF). The deprotonation is conducted at a suitable temperature to deprotonate the phenol groups of the chiral ligand. Preferably the deprotonation is conducted at about less than 15° C., more preferably less than about 10° C., even more preferably between about 0 and about 10° C.
- The deprotonated phenoxide groups of the chiral ligand coordinate with the ruthenium (II) metal to form a complex. Due to the chirality of the chiral ligand, complexation of the deprotonated chiral ligand with the ruthenium (II) metal imparts chirality to the ruthenium catalyst. The chiral nature of the catalyst influences the stereoselectivity of the cyclopropanation reaction.
- An alkenyl ligand was also combined with ruthenium (II) metal and the deprotonated chiral ligand. Without wishing to be bound by theory, the alkenyl ligand is believed to coordinate to the ruthenium (II) metal and occupy an axial coordination site, forming a catalyst of formula (V) or (VI), depending upon whether one or two alkenyl ligands coordinate.
- Strong donor ligands such as pyridyl donating ligands, phosphorus donating ligands and tertiary amine ligands have been used previously with ruthenium (II) catalysts and are thought to occupy an axial coordination position on the ruthenium (II) metal. Pyridyl donating ligands are pyridine compounds which can act as a ligand, where the nitrogen atom of the pyridine ring acts as the Lewis base and electron pair donor to form a complex with the ruthenium metal. A phosphorus donating ligand is a ligand containing a phosphorus atom, where the phosphorus atom can act as the Lewis base and electron pair donor to form a complex with the ruthenium metal. A tertiary amine ligand is where the nitrogen atom acts as a Lewis base and electron pair donor to form a complex with the ruthenium metal.
- Without wishing to be bound by theory, the present invention provides alkenyl ligands which are thought to occupy an axial coordination position on the ruthenium (II) metal. Pyridyl donating ligands, phosphorus donating ligands and tertiary amine ligands are preferably not employed in the catalyst preparation or cyclopropanation reaction. Better stereoselectivity such as enantioselectivity and higher yields have been found in the present invention when alkenyl ligands are used as compared to pyridyl or phosphorus donating ligands.
- The combination of the alkenyl ligand, ruthenium (II) metal and deprotonated chiral ligand forms a catalyst which is active. Although in some cases it may be desirable to isolate the catalyst, preferably the catalyst is formed in situ, not isolated, and not purified prior to use in the cyclopropanation reaction. Generating the catalyst in situ offers advantages over using a isolated catalyst such as: (i) convenience; and (ii) minimal handling of a catalyst which may be air or moisture sensitive. Without wishing to be bound by theory, the properties which make a catalyst stable enough for isolation, may also decrease the reactivity of the catalyst. Using an in situ catalyst may allow a more reactive catalyst to be used that gives better selectivity, yield and turnover than using an isolated catalyst.
- In one embodiment, the formula of the alkenyl ligand is the same as the formula of the alkenyl substrate to be used in the cyclopropanation reaction. This minimizes the generation of impurities. For example, when the alkenyl ligand is different than the alkenyl substrate, the alkenyl ligand can enter into transition metal catalyzed side reactions known to one skilled in the art, and form impurities. When the alkenyl ligand is the same as the alkenyl substrate, impurities are minimized.
- The combining of the ruthenium (II) metal, alkenyl ligand, and deprotonated chiral ligand may be done in any suitable order. In some aspects it may be desirable to generate the deprotonated chiral ligand in the presence of the ruthenium (II) metal and or alkenyl ligand, for example, when ruthenium (II) metal and the functional groups on the alkenyl ligand are compatible with the deprotonation conditions. The deprotonated chiral ligand is formed by deprotonating the phenol groups of the chiral ligand with a suitable base as discussed previously.
- The catalyst preparation reaction is carried out with various amounts of metal, deprotonated chiral ligand and alkenyl ligand. The amount of deprotonated chiral ligand used can be greater than the amount of ruthenium (II) metal. Preferably at least one equivalent of the deprotonated chiral ligand relative to the ruthenium (II) metal is used. The amount of alkenyl ligand is at least twice the amount of the ruthenium (II) metal, preferably at least 5 equivalents, more preferably at least 6 equivalent of the alkenyl ligand relative to the ruthenium (II) metal. In aspects where the alkenyl ligand is the same as the alkenyl substrate, a large excess of alkenyl ligand may be employed relative to the ruthenium (II) metal.
- The combining of the ruthenium (II) metal, deprotonated chiral ligand and alkenyl ligand is preferably done in a suitable solvent, for a suitable length of time, and at a suitable temperature. Suitable solvents include tetrahydrofuran (THF), and combinations of THF/cyclohexane. The ruthenium (II) metal, deprotonated chiral ligand and alkenyl ligand are combined at a suitable temperature. A suitable temperature for combining the ruthenium (II) metal, deprotonated chiral ligand and alkenyl ligand is between about −10° C. and about 30° C., preferably between about 0° C. and about 25° C., more preferably between about 0° C. and about 5° C. After combining the ruthenium (II) metal, deprotonated chiral ligand and alkenyl ligand, the mixture is stirred for a suitable amount of time to allow the catalyst to form. The mixture is stirred for at least 12 h, preferably at least 1 h, more preferably at least 5 minutes.
- In one embodiment of the present invention, a method of stereoselective cyclopropanation is provided. In the cyclopropanation method, the catalyst is contacted with a carbene precursor in the presence of an alkenyl substrate.
- A carbene precursor is a compound used to generate a carbene at the coordination site of a transition metal, in particular at the coordination site of ruthenium. Preferably, the carbene precursor is a diazo compound wherein the carbene is generated by the removal of N2 as nitrogen gas from the solution. Examples of diazo compounds which are carbene precursors include ethyl diazoacetate, t-butyl diazoacetate, 2,3,4-trimethyl-3-pentyl diazoacetate, menthyl diazoacetate, 2,5-dimethyl-4-hexen-2-yl diazoacetate, 3-(diazoacetyl)amino propionate, and diazoacetylamino acetate.
- In one embodiment, the carbene precursor is a diazoester.
- In one embodiment, the carbene precursor is selected from the group consisting of ethyl diazoacetate, t-butyl diazoacetate, and menthyl diazoacetate.
- In another embodiment, the carbene precursor is ethyl diazoacetate.
- In one embodiment, the carbene precursor is of the formula (VII):
- where R7 is selected from the group consisting of substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C3-8 cycloalkyl, C1-10 alkoxy, C1-12 alkylamino, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C6-10 heteroaryl and substituted or unsubstituted arylakyl.
- In one embodiment, R7 is selected from the group consisting of substituted or unsubstituted C1-8 alkyl, C1-10 alkoxy, C1-12 alkylamino, and substituted or unsubstituted C6-10 aryl.
- In another embodiment, R7 is selected from the group consisting of substituted or unsubstituted C1-8 alkyl, and C1-10 alkoxy.
- In one preferred embodiment, R7 is C1-10 alkoxy.
- In another preferred embodiment, R7 is selected from the group consisting of —OEt, -OtBu, and —O-(menthyl).
- In the stereoselective cyclopropanation method, the catalyst is contacted with the carbene precursor in the presence of an alkenyl substrate. The carbon atoms of the alkenyl substrate form two of the carbon atoms of the cyclopropyl ring that is formed. Any suitable alkenyl substrate can be used which leads a cyclopropyl product which is enriched in one stereoisomer. Preferably the alkenyl substrate is a terminal alkene of formula (VIII):
- where R8 is selected from the group consisting of halogen, —CN, —C(O)Ra, —CO2Ra, —C(O)NRaRb, —ORa, —OC(0)Ra, —OC(O)NRaRb, —SRa, —S(0)Ra, —S(O)2Ra, —S(O)2NRaRb, —NO2, —NRaRb, —NRaC(O)Rb, —NRaC(O)ORb, —NRaS(O)2Rb, —NRaC(O)NRbRc, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl;
-
- where Ra, Rb, and Rc are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;
- Ra and Rb, Rb and Rc or Ra and Rc may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring; and
- where R9 is selected from the group consisting of hydrogen, and C1-6 alkyl.
- In one embodiment, the alkenyl substrate is of formula (II):
- which is also referred to as 2,3-dihydro-4-vinylbenzofuran and VBF, herein.
- In one embodiment, R8 is selected from the group consisting of halogen, —CN, —C(O)Ra, —CO2Ra, —C(O)NRaRb, —S(0)Ra, —S(O)2Ra, —S(O)2NRaRb, and —NO2.
- In another embodiment, R8 is selected from the group consisting of —ORa, —SRa, and —NRaRb.
- In another embodiment, R8 is selected from the group consisting of substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl.
- In another embodiment, R8 is selected from the group consisting of substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl.
- In another embodiment, R8 is substituted or unsubstituted 3- to 10-membered heterocyclyl.
- In one embodiment, R9 is hydrogen.
- In another embodiment, R9 is C1-8 alkyl.
- In another embodiment, R9 is methyl.
- In the stereoselective cyclopropanation method, a cyclopropyl product is formed which is enriched in one stereoisomer. Preferably the cyclopropatiion method is enantioselective wherein one enantiomer is formed preferentially as compared to the partner enantiomer. As an illustrative example, when the carbene precursor is of formula (VII) and the alkenyl substrate is of formula (VIII), a cyclopropyl product of formula (IX) is formed according to the following scheme:
- where R7, R8, and R9 are as defined above. The cyclopropyl product is formed in at least 50% yield, preferably at least 80%, more preferably at least 90% and even more preferably at least 95%.
- The cyclopropyl product has a cis or trans configuration, depending on the relative size and nature of R8 and R9. When R9 is hydrogen, preferably the trans product is formed as shown in the following scheme.
- The amount of trans cyclopropyl product formed in comparison to cis cyclopropyl product is determined by dividing the amount of trans cyclopropyl product by the sum of the amount of cis and trans cyclopropyl products, and multiplying this number by 100. The amount of cis or trans product can be measured in either moles or mass. Preferably the trans cyclopropyl product is formed in greater than about 80%, more preferably greater than about 90% and even more preferably greater than about 95%.
- Each of the cis and trans isomers can be evaluated for enantiomeric excess. Enantiomeric excess (ee) is equal to 100 times the mole fraction of the major enantiomer minus the mole fraction of the minor enantiomer. The enantiomeric excess is preferably greater than about 80%, more preferably greater than about 90%.
- The stereoselective cyclopropanation reaction is carried out with various amounts of catalyst, carbene precursor and alkenyl substrate. The amount of carbene precursor and alkenyl substrate may be the same or one may be used in excess. In this case, the reagent present in the lesser amount is referred to as the limiting reagent. Preferably the alkenyl substrate is the limiting reagent.
- An advantage of the present invention is that the cyclopropanation reaction can be carried out with good stereoselectivity and in high yield when the alkenyl substrate is used as the limiting reagent. This is particularly important when the alkenyl substrate requires a laborious synthesis or is costly to synthesize or purchase.
- Another advantage of the present invention is that the cyclopropanation reaction can be carried out with good stereoselectivity and in high yield without using a large excess of the carbene precursor. Often a reaction is driven to completion by using a large excess of the non-limiting reagent, for example 5-fold, 10-fold or even greater excess of the non-limiting reagent. When the non-limiting reagent is the carbene precursor, such as a diazo compound, use of an excess of the diazo compound creates an unsafe operating condition, especially on large scale such as in a manufacturing plant. The use of excess diazo compound such as diazoesters is undesirable due to: (i) the build-up of the diazo compound in the reactor; diazo compounds can be explosive and the reactor concentration of this reagent must be kept low; (ii) the rapid addition of the diazo compound can lead to an exothermic reaction that can be difficult to control; (iii) for each mole of the diazo compound that is consumed, a mole of nitrogen is released; a rapid increase in the rate of the reaction in the presence of a high concentration of the diazo compound could release a bulbous amount of nitrogen that may not be able to be effectively vented from the reactor, thus leading to a pressure build-up in the reactor and creating an unsafe condition; (iv) the use of a large excess of diazo compound creates an unsafe condition, requires the handling, transporting and storage of excess diazo compound than theoretically required in the reaction which is significant at manufacturing scale, requires extra monitoring to determine the fate of the excess diazo compound used in the reaction, and is inefficient.
- Accordingly, preferably the alkenyl substrate is used as the limiting reagent and less than about 2.0 equivalents of the carbene precursor is used in the stereoselective cyclopropanation reaction. In another embodiment, when the alkenyl substrate is the limiting reagent, between about 1.05 and about 2.0 equivalents of the carbene precursor are used as compared to the limiting reagent, preferably between about 1.1 and about 1.8, more preferably between about 1.2 and about 1.5 equivalents, even more preferably about 1.3 equivalents.
- The metal catalyst is used in amount of at least 0.05 mole % of the limiting reagent, preferably between about 0.05% to about 10%, more preferably between about 0.1 to about 5%, even more preferably between about 0.5% and 3%.
- The stereoselective cyclopropanation reaction is carried out in a solvent, with organic solvents being preferred. Preferably reaction solvent is THF or toluene, or a combination thereof. Additional solvents such as cyclohexane may also be present. A single solvent may be used, or a combination of solvents may be used.
- The stereoselective cyclopropanation reaction is preferably carried out at a suitable reaction temperature. Any suitable temperature may be chosen which affords the desired yield and stereoselectivity of the cyclopropyl product. The reaction temperature is usually below or at the boiling point of the solvent. Preferably the reaction temperature is between about 0° C. and about 40° C., more preferably between about 20° C. and about 30° C.
- The stereoselective cyclopropanation reaction is carried out for a suitable time to afford the desired yield and stereoselectivity of the cyclopropyl product. Alternatively, the reaction can be carried out for a suitable time to consume the limiting reagent. The reaction time is at least 1 h, preferably between about 1 h and about 10 h, more preferably between abut 2 h and about 5 h.
- It is important to note that one skilled in the art would realize that optimization of the yield and the stereoselectivity can be achieved by altering the reaction conditions. For example, such optimization can include changing the solvent, the temperature of various stages of the reaction, the equivalents the metal catalyst, the equivalents of the carbene precursor, and the equivalents of the alkenyl substrate.
- The following examples are offered to illustrate, but not to limit, the claimed invention.
- Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA) unless otherwise indicated. The salen complex was obtained from Strem Chemicals, Inc. 1H-NMR were recorded on an NMR spectrometer. Significant peaks are tabulated in the order: multiplicity (br, broad; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet) and number of protons. Mass spectrometry results are reported as the ratio of mass over charge, followed by the relative abundance of each ion (in parenthesis). A single mle value is reported for the M+H (or, as noted, M−H, or M+Na) ion containing the most common atomic isotopes. Isotope patterns correspond to the expected formula in all cases.
- In a 50-mL 3-neck neck round bottom flask fitted with a temperature probe, nitrogen inlet, magnetic stir bar and a septum was added (1R,2R)-(−)-1,2-cyclohexanediamino-N,N′-bis-(3,5-di-t-butylsalicyl idene) (salen; 2.17 g, 4 mmol) and 25 mL of anhydrous THF. The resultant solution was cooled to 0-5° C. Lithium diisopropylamide(tetrahydrofuran) (1.5 M solution in cyclohexane; 5.3 mL, 8 mmol) was added slowly at a rate that the reaction temperature was kept below 5° C. The solution was stirred for 1 hour at 0-5° C.
- In a 250-mL round bottom flask was charged dichloro(p-cymene)ruthenium(II) dimer (1.21 g, 2 mmol), cyclohexene (0.92 g, 11.2 mmol) and anhydrous THF (60 mL). The mixture was stirred. The salen solution was added in one portion to the stirred suspension at ambient temperature. The salen reaction flask was rinsed with 10 mL of THF and the rinse solution was transferred to the 250-mL flask. The resultant mixture was stirred overnight. The catalyst solution can be used without further work-up in the cyclopropanation reaction as described below. Alternatively, the solution can be concentrated to dryness to provide a green solid that can be used in the cyclopropanation reaction.
- In a 50-mL round bottom flask fitted with a temperature probe, nitrogen inlet, magnetic stir bar and a septum was added (1R,2R)-(−)-1,2-cyclohexanediamino-N,N′-bis-(3,5-di-t-butylsalicylidene) (salen, 540 mg, 1 mmol) and 23.5 mL of anhydrous THF. The resulting solution was cooled to 0-5° C. To this was added LDA (1.5 M in cyclohexane, 1.34 mL, 2 mmol) at a rate that allowed the reaction temperature to be maintained below 5° C. The reaction mixture was stirred for 0.5 hour at 0-5° C. To this was added dichloro(p-cymene)ruthenium (II) dimer (300 mg, 0.5 mmol), followed by VBF (0.4 g, 2.8 mmol). After the addition, the mixture was stirred at ambient temperature. The catalyst solution can be used without further work-up in the cyclopropanation reaction as described below. Alternatively, the solution can be concentrated to dryness to provide a green solid that can be used in the cyclopropanation reaction.
- The Ru/salen/1-hexene catalyst was prepared according to the procedure for Ru/salen/cyclohexene except that 1-hexene was used in place of cyclohexene. The resulting catalyst solution was found to be active in the cyclopropanation reaction of 4-vinyl-2,3-dihydrobenzofuran with ethyl diazoacetate.
- The Ru/salen/ethylene catalyst was prepared according to the procedure for Ru/salen/cyclohexene except that ethylene was used in place of cyclohexene. Excess ethylene gas was bubbled through a solution of dichloro(p-cymene)ruthenium(II) dimer in anhydrous THF, followed by addition of the deprotonated salen ligand. The resulting catalyst solution was found to be active in the cyclopropanation reaction of 4-vinyl-2,3-dihydrobenzofuran with ethyl diazoacetate.
- In a 3-neck neck round bottom flask fitted with a temperature probe, nitrogen inlet, magnetic stir bar and a septum was added (1R,2R)-(−)-1,2-cyclohexanediamino-N,N′-bis-(3,5-di-t-butylsalicylidene) (salen) and anhydrous THF. The resultant solution was cooled to 0-5° C. Lithium diisopropylamide(tetrahydrofuran) (1.5 M solution in cyclohexane; 2 equivalents) was added slowly at a rate that the reaction temperature was kept below 5° C. The solution was stirred for 1 hour at 0-5° C.
- In a round bottom flask was charged dichloro(p-cymene)ruthenium(II) dimer (0.5 equivalents relative to the salen) and anhydrous THF and ethylene gas was bubbled through the solution. The mixture was stirred. The salen solution was added in one portion to the stirred suspension at ambient temperature. The salen reaction flask was rinsed with THF and the rinse solution was transferred to the round bottom flask. The resultant mixture was stirred overnight.
- To a mixture of the in situ generated catalyst prepared in the previous paragraph was charged 4-vinyl-2,3-dihydrobenzofuran and toluene. To the stirred solution was added a solution of EDA in toluene. In some experiments, a second aliquot of EDA was charged. The solution was concentrated to remove the THF from the reaction solution. The remaining solution was transferred to a 3-neck round bottom flask equipped with a mechanical stirrer and temperature probe connected to a J-Kem controller. To the solution was added a solution of sodium hydroxide followed by tetra-n-butylammonium hydroxide. The mixture was stirred and heated to 60° C. The phases were separated and the organic phase was washed with water. The combined aqueous extracts were extracted with of toluene. The aqueous phase was combined with MTBE and cooled to 10° C. The pH of the aqueous phase was adjusted to 2-3 with phosphoric acid. The phases were mixed and then separated. The MTBE phase was washed with water. The MTBE phase was filtered through Whatman Qualitative #1 filter paper. The MTBE phase was concentrated to an oil
-
TABLE 1 Cyclopropanation of VBF with in situ Rulsalenlethyene catalyst Exp. Reaction Temp. Cis Trans VBF Remaining 5 60° C.a 4.3% 83.8% 11.8% 6b RT 4.7% 92.8% 2.5% 7 0-5° C. for 6 hours, 6.4% 94.6% None Detected then RT overnight.c 8d RT 5.1% 94.9% None Detected 9e RT 4.8% 92.6% 2.6% 10f RT 4.5% 95.5% None Detected 11g RT 4.8% 95.2% None Detected aStarted at RT and heated to 60° C. bSlow addition of EDA. Mild exotherm observed. cThe reaction is slow at 0-5° C. and after warming to RT the reaction rate increases. dCatalyst solution filtered through silica gel. eUnfiltered catalyst solution used in Exp. 8. fUsed 1.2 eq of salen in catalyst synthesis. gSame catalyst solution as used in exp. 10, except stored under N2 at RT for 10 days prior to use. - The experiments in Table 1 used 2.6 equivalents of EDA relative to VBF, and 0.1-0.2 equivalents of catalyst. Experiments 5-6 illustrate that adding EDA at lower temperatures led to higher consumption of VBF. Experiments 9-10 illustrate that filtering the in situ catalyst solution led to higher consumption of VBF. Experiment 11 illustrates that freshly prepared in situ catalyst gives similar results to in situ catalyst that has been stored for 10 days.
- The Ru/salen/4-vinyl-2,3-dihydrobenzofuran catalyst was prepared according to the procedure for Ru/salen/cyclohexene except that 4-vinyl-2,3-dihydrobenzofuran was used in place of cyclohexene. The resulting catalyst solution was found to be active in the cyclopropanation reaction of 4-vinyl-2,3-dihydrobenzofuran with ethyl diazoacetate.
-
- One mmol of the Ru/salen/4-vinyl-2,3-dihydrobenzofuran catalyst was prepared in situ in a total of 50 mL of anhydrous THF as described above in a 250 mL round bottom flask equipped with a mechanical stirrer, a temperature probe, a Claisen head fitted with a nitrogen inlet and an inlet for the addition of an ethyl diazoacetate (EDA) solution. To the in situ catalyst solution was charged 4-vinyl-2,3-dihydrobenzofuran (14.64 g, 100 mmol) in 15 mL of toluene. To the stirred solution was slowly added a solution of EDA (20.19 g, 180 mmol) in 90 mL of toluene via a Masterflex pump. A slight exotherm was noted but was easily controlled by the adjustment of the rate of EDA addition. After 3 hours, the VBF was consumed and 32 mL of the EDA solution was remaining. The remaining EDA solution was not added to the reaction vessel. Approximately 130 mmol of EDA or 1.3 equivalents were required to consume the VBF. The solution was concentrated to remove the THF from the reaction solution. Approximately 40 mL of solvent was removed. The remaining solution was transferred to a 500-mL 3-neck round bottom flask equipped with a mechanical stirrer and temperature probe connected to a J-Kem controller. To the solution was added a solution of sodium hydroxide (29.54 g 370 mmol, of 50% aqueous sodium hydroxide solution diluted with 120 mL of water) followed by tetra-n-butylammonium hydroxide (16.12 g, 33 mmol). The mixture was stirred and heated to 60° C. for 280 mins. The phases were separated and the organic phase was washed with 75 mL of water. The combined aqueous extracts were extracted with 75 mL of toluene. The aqueous phase was combined with 200 mL of MTBE and cooled to 10° C. The pH of the aqueous phase was adjusted to 2-3 with phosphoric acid. The phases were mixed and then separated. The MTBE phase was washed with 4×50 mL of water. The MTBE phase was filtered through Whatman Qualitative #1 filter paper. The MTBE phase was concentrated to an oil that solidified upon standing to give 22.13 g (95%) of a mixture of cyclopropyl acid isomers. 97.7:2.3 trans/cis by HPLC area counts; trans isomer (1R,2R) 91.8%:trans enantiomer (1S,2S):8.2% by HPLC area counts; % enantiomeric purity (83.6% ee)
- The isolated Ru/salen/pyridine catalyst was obtained from SonBinh Nguyen prepared according to the method of Miller et al (Angew. Chem Int. Ed. 2002, 41, 2953-2956). According to Miller et al. the Rulsalenlpyridine catalyst has the structure:
- To the isolated Ru/salen/pyridine (4 mg, 0.005 mmol) catalyst was charged 4-vinyl-2,3-dihydrobenzofuran (0.37 g, 2.53 mmol) in 4.44 mL of toluene. To the stirred solution was slowly added a solution of EDA (0.32 g, 2.80 mmol) in 1.0 mL of toluene over 30 minutes. After 2.5 hours, an aliquot was removed, and the sample was analyzed by in-process HPLC. The desired cyclopropane ethyl ester was not formed, and only VBF was detected. The catalyst was not active in the promotion of the cyclopropanation of VBF.
- The isolated Ru/salen/triphenylphosphine catalyst was obtained from SonBinh Nguyen prepared according to the method of Miller et al. (Angew. Chem Int. Ed. 2002, 41, 2953-2956). According to Miller et al. the Rulsalenltriphenylphosphinecatalyst has the structure:
- To the isolated Ru/salen/triphenylphosphine (4 mg, 0.005 mmol) catalyst was charged 4-vinyl-2,3-dihydrobenzofuran (0.37 g, 2.53 mmol) in 4.4 mL of toluene. To the stirred solution was slowly added a solution of EDA (0.32 g, 2.80 mmol) in 1.0 mL of toluene over 15 minutes. After 2 hours, an aliquot was removed and analyzed by in-process HPLC. The cyclopropane ethyl ester was formed in just 4% (% AUC) yield, and after 20 hours the yield of the ethyl ester was unchanged.
- Examples 15 and 17 illustrate the use of isolated Ru/salen/pyridine and Rulsalenltriphenylphosphinein the stereoselective cyclopropanation of 4-vinyl-2,3-dihydrobenzofuran. Neither of these isolated catalysts provided satisfactory results. Specifically, the reaction with the isolated Ru/salen/pyridine catalyst provided none of the desired (1R,2R)-ethyl 2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxylate product. The reaction with the isolated Rulsalenltriphenylphosphine catalyst provided only a small amount of the desired (1R,2R)-ethyl 2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxylate product. Without wishing to be bound by theory, the isolated Rulsalenlpyridine catalyst and isolated Rulsalenltriphenylphosphine catalyst may be unstable. The catalysts may degrade over time or due to exposure to air or moisture. Further experiments were conducted by generating the Rulsalenlpyridine catalyst in situ as detailed below.
- In a 3-neck neck round bottom flask fitted with a temperature probe, nitrogen inlet, magnetic stir bar and a septum was added (1R,2R)-(−)-1,2-cyclohexanediamino-N,N′-bis-(3,5-di-t-butylsalicylidene) (salen) and anhydrous THF. The resultant solution was cooled to 0-5° C. Lithium diisopropylamide(tetrahydrofuran) (1.5 M solution in cyclohexane; 2 equivalents) was added slowly at a rate that the reaction temperature was kept below 5° C. The solution was stirred for 1 hour at 0-5° C.
- In a round bottom flask was charged dichloro(p-cymene)ruthenium(II) dimer (0.5 equivalents relative to the salen), pyridine (10 equivalents relative to the salen) and anhydrous THF. The mixture was stirred. The salen solution was added in one portion to the stirred suspension at ambient temperature. The salen reaction flask was rinsed with THF and the rinse solution was transferred to the round bottom flask. The resultant mixture was stirred overnight.
- To a mixture of the in situ generated catalyst prepared in the previous paragraph was charged 4-vinyl-2,3-dihydrobenzofuran and toluene. To the stirred solution was added a solution of EDA in toluene. In some experiments, a second aliquot of EDA was charged. The solution was concentrated to remove the THF from the reaction solution. The residue was analyzed by in-process HPLC.
-
TABLE 2 Results of in situ Rulsalenlpyridine catalyst in the cyclopropanation of 4-vinyl-2,3-dihydrobenzofuran Eq. % Ru/ conversion Salen/ Addition Time of VBF to Exp. pyr Eq. EDA Temp for EDA CPA1 19 0.04 1.1 60° C. Slow-overnight 21% 20 0.04 2.5 60° C. Rapid addition; 50% (First) (First) 2.5 60° C. 2nd addition 100% (Second) over 1 hour (Second) 21 0.04 2.5 60° C. Slow 1 hour 17% (First) (First) 2.5 60° C. addition; 50% (Second) 2nd rapid (Second) addition over 7 min 22 0.04 5 60° C. Rapid addition 97% over 9 minutes 1CPA = (1R,2R)-ethyl 2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxylate - The results in Table 2 illustrate that the Ru/salen/pyridine catalyst generated in situ is active in the cyclopropanation reaction. Experiment 19 illustrates that the slow addition of ethyl diazoacetate (EDA) affords only a 21% yield of the product. Experiment 20 illustrates that rapid addition of 2.5 equivalents afforded a 50% conversion to product. When an additional 2.5 eq. of EDA was added over 1 h, the reaction went to 100% completion. Experiment 21 illustrates that the slow addition of 2.5 eq. of EDA over 1 h afforded only 17% conversion to product. Even after adding an additional 2.5 equivalents of EDA over 7 min. the reaction was still incomplete, with only a 50% conversion to product.
- In experiment 22, 97% conversion was obtained using 5 equivalents of EDA with a rapid addition over 9 minutes. However, the need for a rapid addition of EDA to the reaction creates an unsafe operating condition especially on large scale such as in a pilot plant or manufacturing facility due to: (i) the build-up of EDA in the reactor; EDA is explosive and the reactor concentration of this reagent must be kept low; (ii) the rapid addition of EDA leads to an exothermic reaction that would be difficult to control; (iii) for each mole of EDA that is consumed, a mole of nitrogen is released; a rapid increase in the rate of the reaction in the presence of a high concentration of EDA could release a bulbous amount of nitrogen that may not be able to be effectively vented from the reactor, thus leading to a pressure build-up in the reactor and creating an unsafe condition; (iv) 5 equivalents of EDA were necessary to drive the reaction to completion; the use of such an excess of EDA creates an unsafe condition, requires the handling, transporting and storage of 4 times the amount of EDA than theoretically required in the reaction which is significant at manufacturing scale, requires extra monitoring to determine the fate of the excess EDA used in the reaction, and is inefficient. For at least these reasons, an alternative cyclopropanation catalyst and method was developed. In particular, conditions which gave high yields and stereoselectivity which utilized the alkenyl substrate as the limiting reagent and minimized the amount of the carbene precursor were developed.
- It is therefore intended that the foregoing detailed description be regarded as illustrative rather than limiting, and that it be understood that it is the following claims, including all equivalents, that are intended to define the spirit and scope of this invention.
Claims (17)
1. A method of stereoselective cyclopropanation comprising the step of:
combining a carbene precursor and an alkenyl substrate in the presence of a chiral catalyst to form a cyclopropyl product, the chiral catalyst is prepared in situ by the step of:
combining an alkenyl ligand and a deprotonated chiral ligand in the presence of a ruthenium (II) metal;
wherein the alkenyl ligand is of formula (I):
where R5 is selected from the group consisting of hydrogen, C1-8 alkyl, C6-10 aryl, C5-10 heteroaryl, C3-10 heterocycle; and
where R6 is selected from the group consisting of hydrogen, and C1-8 alkyl; and
where R5 and R6 together with the atoms to which they are attached may form a carbocyclic ring;
wherein the deprotonated chiral ligand is of formula (III):
where R1 and R2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C5-10 heteroaryl;
where R3 and R4 are each independently selected from the group consisting of substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C3-8 cycloalkyl, C1-10 alkoxy, C1-12 alkylamino, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C5-10 heteroaryl and substituted or unsubstituted arylalkyl; where R3 and R4 together with the atoms to which they are attached may form a ring; and
where M1 and M2 are each a counterion independently selected from the group consisting of Group I metal ions and Group II metal ions.
2. The method of claim 1 , wherein the deprotonated chiral ligand is formed by deprotonating a chiral ligand of formula (III) where M1 and M2 are hydrogen with a base selected from the group consisting of consisting of metal alkoxides, metal amines, and metal alkyls, wherein the metal is selected from the group consisting of Group I or Group II metals.
3. The method of claim 1 , wherein the alkenyl ligand is the same as the alkenyl substrate.
4. The method of claim 1 , wherein the catalyst is prepared in the absence of an additive selected from the group consisting of a pyridyl donating ligand, a phosphorus donating ligand and a tertiary amine ligand.
5. The method of claim 3 , wherein the carbene precursor is an alkyl diazoacetate.
6. The method of claim 5 , wherein the cyclopropyl product is at least 90% trans.
7. The method of claim 1 , wherein the molar amount of carbene precursor is greater than the molar amount of the alkenyl substrate.
9. The method of claim 8 , wherein the alkenyl ligand is selected from the group consisting of ethylene, cyclohexene, 1-hexene and 2,3-dihydro-4-vinylbenzofuran.
11. The method of claim 10 , wherein the molar amount of carbene precursor is greater than the molar amount of the alkenyl substrate.
12. A method of stereoselective cyclopropanation consisting of the steps of:
combining an alkenyl ligand and a deprotonated chiral ligand in the presence of a ruthenium (II) metal to form a chiral catalyst in situ;
wherein the alkenyl ligand is of formula (I):
where R5 is selected from the group consisting of hydrogen, C1-8 alkyl, C6-10 aryl, C5-10 heteroaryl, C3-10 heterocycle; and
where R6 is selected from the group consisting of hydrogen, and C1-8 alkyl; and
where R5 and R6 together with the atoms to which they are attached may form a carbocyclic ring;
wherein the deprotonated chiral ligand is of formula (III):
where R1 and R2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C5-10 heteroaryl;
where R3 and R4 are each independently selected from the group consisting of substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C3-8 cycloalkyl, C1-10 alkoxy, C1-12 alkylamino, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C5-10 heteroaryl and substituted or unsubstituted arylalkyl; where R3 and R4 together with the atoms to which they are attached may form a ring; and
where M1 and M2 are each a counterion independently selected from the group consisting of Group I metal ions and Group II metal ions; and
combining a carbene precursor and an alkenyl substrate in the presence of the chiral catalyst to form a cyclopropyl product.
13. In the stereoselective cyclopropanation of a carbene precursor and an alkenyl substrate with a chiral catalyst of the formulae (V) or (VI):
where R5 is selected from the group consisting of hydrogen, C1-8 alkyl, C6-10 aryl, C5-10 heteroaryl, C3-10 heterocycle; and
where R6 is selected from the group consisting of hydrogen, and C1-8 alkyl; and
where R5 and R6 together with the atoms to which they are attached may form a carbocyclic ring;
where R1 and R2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C5-10 heteroaryl;
where R3 and R4 are each independently selected from the group consisting of substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C3-8 cycloalkyl, C1-10 alkoxy, C1-12 alkylamino, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C5-10 heteroaryl and substituted or unsubstituted arylalkyl; where R3 and R4 together with the atoms to which they are attached may form a ring; and
where M1 and M2 are each a counterion independently selected from the group consisting of Group I metal ions and Group II metal ions;
the improvement comprising generating the chiral catalyst in situ.
14. A catalyst for stereoselective reactions prepared by the step of combining an alkenyl ligand and a deprotonated chiral ligand in the presence of a ruthenium (II) metal;
wherein the alkenyl ligand is of formula (I):
where R5 is selected from the group consisting of hydrogen, C1-8 alkyl, C6-10 aryl, C5-10 heteroaryl, C3-10 heterocycle; and
where R6 is selected from the group consisting of hydrogen, and C1-8 alkyl; and
where R1 and R6 together with the atoms to which they are attached may form a carbocyclic ring;
wherein the deprotonated chiral ligand is of formula (III):
where R1 and R2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C5-10 heteroaryl;
where R3 and R4 are each independently selected from the group consisting of substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C3-8 cycloalkyl, C1-10 alkoxy, C1-12 alkylamino, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C5-10 heteroaryl and substituted or unsubstituted arylalkyl; where R3 and R4 together with the atoms to which they are attached may form a ring; and
where M1 and M2 are each a counterion independently selected from the group consisting of Group I metal ions and Group II metal ions.
15. The catalyst of claim 14 , wherein the combining occurs in the absence of an additive selected from the group consisting of a pyridyl donating ligand, a phosphorus donating ligand and a tertiary amine ligand.
16. The catalyst of claim 14 , wherein the alkenyl ligand is selected from the group consisting of ethylene, cyclohexene, 1-hexene and 2,3-dihydro-4-vinylbenzofuran.
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