WO1998027051A9 - Catalytic asymmetric amidohydroxylation of olefins with n-halo carboxamides - Google Patents
Catalytic asymmetric amidohydroxylation of olefins with n-halo carboxamidesInfo
- Publication number
- WO1998027051A9 WO1998027051A9 PCT/US1997/023511 US9723511W WO9827051A9 WO 1998027051 A9 WO1998027051 A9 WO 1998027051A9 US 9723511 W US9723511 W US 9723511W WO 9827051 A9 WO9827051 A9 WO 9827051A9
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- asymmetric
- bromo
- iodo
- amide
- product
- Prior art date
Links
- -1 -halo carboxamides Chemical class 0.000 title claims abstract description 122
- 150000001336 alkenes Chemical class 0.000 title claims abstract description 50
- 230000003197 catalytic Effects 0.000 title claims description 22
- 230000027455 binding Effects 0.000 claims abstract description 79
- 239000003446 ligand Substances 0.000 claims abstract description 77
- 239000000758 substrate Substances 0.000 claims abstract description 44
- 229910052762 osmium Inorganic materials 0.000 claims abstract description 30
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 claims abstract description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 28
- 229960000811 hydroquinidine Drugs 0.000 claims description 54
- 125000000217 alkyl group Chemical group 0.000 claims description 43
- 238000006243 chemical reaction Methods 0.000 claims description 42
- 229960004251 hydroquinine Drugs 0.000 claims description 38
- 150000001408 amides Chemical class 0.000 claims description 34
- 239000002904 solvent Substances 0.000 claims description 33
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 26
- 238000007792 addition Methods 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 20
- VUVGYHUDAICLFK-UHFFFAOYSA-N Perosmic oxide Chemical compound O=[Os](=O)(=O)=O VUVGYHUDAICLFK-UHFFFAOYSA-N 0.000 claims description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 19
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 17
- 239000003054 catalyst Substances 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 14
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 14
- VBTQNRFWXBXZQR-UHFFFAOYSA-N N-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 claims description 13
- XSXHWVKGUXMUQE-UHFFFAOYSA-N dioxoosmium Chemical compound O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- PJANXHGTPQOBST-VAWYXSNFSA-N (E)-Stilbene Chemical compound C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 8
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-Butanol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl radical Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- PPBRXRYQALVLMV-UHFFFAOYSA-N styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- FLYWSBDBTKARFZ-UHFFFAOYSA-N N-bromobenzamide Chemical compound BrNC(=O)C1=CC=CC=C1 FLYWSBDBTKARFZ-UHFFFAOYSA-N 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- 239000011591 potassium Substances 0.000 claims description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 5
- AMQJEAYHLZJPGS-UHFFFAOYSA-N n-pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 4
- PJANXHGTPQOBST-QXMHVHEDSA-N (Z)-Stilbene Chemical compound C=1C=CC=CC=1/C=C\C1=CC=CC=C1 PJANXHGTPQOBST-QXMHVHEDSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- ONTKXYYYJHVACC-UHFFFAOYSA-N 2-bromo-N-fluoroacetamide Chemical compound FNC(=O)CBr ONTKXYYYJHVACC-UHFFFAOYSA-N 0.000 claims description 3
- UDDAXMWIURQYDZ-UHFFFAOYSA-N 2-bromo-N-iodoacetamide Chemical compound BrCC(=O)NI UDDAXMWIURQYDZ-UHFFFAOYSA-N 0.000 claims description 3
- HDTJLQGMONOXOF-UHFFFAOYSA-N 2-chloro-N-fluoroacetamide Chemical compound FNC(=O)CCl HDTJLQGMONOXOF-UHFFFAOYSA-N 0.000 claims description 3
- SWHODQMVGAQHMB-UHFFFAOYSA-N 2-chloro-N-iodoacetamide Chemical compound ClCC(=O)NI SWHODQMVGAQHMB-UHFFFAOYSA-N 0.000 claims description 3
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 3
- AUOCNVNYZAIMOY-UHFFFAOYSA-N N,2-dibromoacetamide Chemical compound BrCC(=O)NBr AUOCNVNYZAIMOY-UHFFFAOYSA-N 0.000 claims description 3
- ISOKSVZBBCWLED-UHFFFAOYSA-N N,2-diiodoacetamide Chemical compound ICC(=O)NI ISOKSVZBBCWLED-UHFFFAOYSA-N 0.000 claims description 3
- SXHNGJPCKLTEDF-UHFFFAOYSA-N N-bromo-2-chloroacetamide Chemical compound ClCC(=O)NBr SXHNGJPCKLTEDF-UHFFFAOYSA-N 0.000 claims description 3
- XYHPNDIYSSCQKA-UHFFFAOYSA-N N-bromo-2-iodoacetamide Chemical compound BrNC(=O)CI XYHPNDIYSSCQKA-UHFFFAOYSA-N 0.000 claims description 3
- YXUHKXOYEGLXCP-UHFFFAOYSA-N N-bromo-2-methoxyacetamide Chemical compound COCC(=O)NBr YXUHKXOYEGLXCP-UHFFFAOYSA-N 0.000 claims description 3
- UYKPFQRPPLZHDD-UHFFFAOYSA-N N-chloro-2-methoxyacetamide Chemical compound COCC(=O)NCl UYKPFQRPPLZHDD-UHFFFAOYSA-N 0.000 claims description 3
- HSPSCWZIJWKZKD-UHFFFAOYSA-N N-chloroacetamide Chemical compound CC(=O)NCl HSPSCWZIJWKZKD-UHFFFAOYSA-N 0.000 claims description 3
- WMSQJZHVGMMPQT-UHFFFAOYSA-N N-chlorobenzamide Chemical compound ClNC(=O)C1=CC=CC=C1 WMSQJZHVGMMPQT-UHFFFAOYSA-N 0.000 claims description 3
- WHAABULHPVZUNE-UHFFFAOYSA-N N-fluoro-2-iodoacetamide Chemical compound FNC(=O)CI WHAABULHPVZUNE-UHFFFAOYSA-N 0.000 claims description 3
- ZKVWRRMURBJYKL-UHFFFAOYSA-N N-iodo-2-methoxyacetamide Chemical compound COCC(=O)NI ZKVWRRMURBJYKL-UHFFFAOYSA-N 0.000 claims description 3
- GILWQKXNOCKBMH-UHFFFAOYSA-N O.O.[Os](=O)=O Chemical compound O.O.[Os](=O)=O GILWQKXNOCKBMH-UHFFFAOYSA-N 0.000 claims description 3
- FVSKHRXBFJPNKK-UHFFFAOYSA-N Propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Inorganic materials [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 claims description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- UAIHPMFLFVHDIN-UHFFFAOYSA-K trichloroosmium Chemical compound Cl[Os](Cl)Cl UAIHPMFLFVHDIN-UHFFFAOYSA-K 0.000 claims description 3
- 239000008241 heterogeneous mixture Substances 0.000 claims description 2
- 239000008240 homogeneous mixture Substances 0.000 claims description 2
- OTTSIBOPBONYJO-UHFFFAOYSA-N [NH-]C(O)=O Chemical compound [NH-]C(O)=O OTTSIBOPBONYJO-UHFFFAOYSA-N 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 30
- 239000007800 oxidant agent Substances 0.000 abstract description 21
- 239000000203 mixture Substances 0.000 abstract description 18
- 230000001590 oxidative Effects 0.000 abstract description 18
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 15
- 239000003960 organic solvent Substances 0.000 abstract description 9
- 238000007294 asymmetric addition reaction Methods 0.000 abstract description 3
- 239000006184 cosolvent Substances 0.000 abstract description 3
- 238000007259 addition reaction Methods 0.000 abstract 2
- 239000003426 co-catalyst Substances 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 238000000034 method Methods 0.000 description 56
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
- 238000006399 aminohydroxylation reaction Methods 0.000 description 20
- 239000008079 hexane Substances 0.000 description 20
- 239000000047 product Substances 0.000 description 19
- LJOQGZACKSYWCH-LHHVKLHASA-N (S)-[(2R,4S,5R)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol Chemical class C1=C(OC)C=C2C([C@H](O)[C@H]3C[C@@H]4CCN3C[C@@H]4CC)=CC=NC2=C1 LJOQGZACKSYWCH-LHHVKLHASA-N 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 16
- 239000011780 sodium chloride Substances 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 230000002194 synthesizing Effects 0.000 description 14
- 239000002585 base Substances 0.000 description 13
- 239000003444 phase transfer catalyst Substances 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- SQGYOTSLMSWVJD-UHFFFAOYSA-N Silver nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 239000001819 propan-2-yl (E)-3-phenylprop-2-enoate Substances 0.000 description 11
- RGACABDFLVLVCT-UHFFFAOYSA-N propan-2-yl 3-phenylprop-2-enoate Chemical compound CC(C)OC(=O)C=CC1=CC=CC=C1 RGACABDFLVLVCT-UHFFFAOYSA-N 0.000 description 11
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 9
- 229930013930 alkaloids Natural products 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- YUCBLVFHJWOYDN-PPIALRKJSA-N 4-[(R)-[(2R,4S,5R)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]-1-[(R)-[(2R,4R,5S)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]phthalazine Chemical compound C1=C(OC)C=C2C([C@@H](OC=3C4=CC=CC=C4C(O[C@@H]([C@@H]4N5CC[C@@H]([C@@H](C5)CC)C4)C=4C5=CC(OC)=CC=C5N=CC=4)=NN=3)[C@H]3C[C@@H]4CCN3C[C@@H]4CC)=CC=NC2=C1 YUCBLVFHJWOYDN-PPIALRKJSA-N 0.000 description 8
- 150000001414 amino alcohols Chemical class 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- LFSXCDWNBUNEEM-UHFFFAOYSA-N Phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 7
- IIACRCGMVDHOTQ-UHFFFAOYSA-N Sulfamic acid Chemical class NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 7
- 150000003797 alkaloid derivatives Chemical class 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 150000002009 diols Chemical group 0.000 description 7
- 239000011521 glass Substances 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 241000894007 species Species 0.000 description 7
- VDQQXEISLMTGAB-UHFFFAOYSA-N Chloramine-T Chemical compound [Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 VDQQXEISLMTGAB-UHFFFAOYSA-N 0.000 description 6
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 6
- 238000004896 high resolution mass spectrometry Methods 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 150000003456 sulfonamides Chemical class 0.000 description 6
- 229940093912 Gynecological Sulfonamides Drugs 0.000 description 5
- DRAJWRKLRBNJRQ-UHFFFAOYSA-M ONC([O-])=O Chemical class ONC([O-])=O DRAJWRKLRBNJRQ-UHFFFAOYSA-M 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 150000004056 anthraquinones Chemical class 0.000 description 5
- 238000006555 catalytic reaction Methods 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000006184 hydroxyamination reaction Methods 0.000 description 5
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 5
- 229940079867 intestinal antiinfectives Sulfonamides Drugs 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 229940005938 ophthalmologic antiinfectives Sulfonamides Drugs 0.000 description 5
- 229940026752 topical Sulfonamides Drugs 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- RZVHIXYEVGDQDX-UHFFFAOYSA-N Anthraquinone Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3C(=O)C2=C1 RZVHIXYEVGDQDX-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- CSCPPACGZOOCGX-WFGJKAKNSA-N Deuterated acetone Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L Sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 4
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical class [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 4
- ORMNPSYMZOGSSV-UHFFFAOYSA-N mercury(II) nitrate Inorganic materials [Hg+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ORMNPSYMZOGSSV-UHFFFAOYSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 229910001961 silver nitrate Inorganic materials 0.000 description 4
- 150000003440 styrenes Chemical class 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- WBYWAXJHAXSJNI-VOTSOKGWSA-N (2E)-3-phenylprop-2-enoic acid Chemical class OC(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-N 0.000 description 3
- 241000157855 Cinchona Species 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N Intaxel Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- 229960001592 Paclitaxel Drugs 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- ZXKINMCYCKHYFR-UHFFFAOYSA-N aminooxidanide Chemical compound [O-]N ZXKINMCYCKHYFR-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229940044727 chloramine-T trihydrate Drugs 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 125000006575 electron-withdrawing group Chemical group 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- 238000007654 immersion Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical class ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- PQGDTXWUDGZKJK-QWHCGFSZSA-N propan-2-yl (2R,3S)-3-acetamido-2-hydroxy-3-phenylpropanoate Chemical compound CC(C)OC(=O)[C@H](O)[C@@H](NC(C)=O)C1=CC=CC=C1 PQGDTXWUDGZKJK-QWHCGFSZSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 230000002441 reversible Effects 0.000 description 3
- 229910001220 stainless steel Inorganic materials 0.000 description 3
- 239000010935 stainless steel Substances 0.000 description 3
- 229930003347 taxol Natural products 0.000 description 3
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical group C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 2
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-(1R,3R,4S)-menthol Chemical group CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 2
- OTJZSGZNPDLQAJ-KZYPOYLOSA-N (2R,3S)-3-amino-2-hydroxy-3-phenylpropanoic acid;hydrochloride Chemical compound Cl.OC(=O)[C@H](O)[C@@H](N)C1=CC=CC=C1 OTJZSGZNPDLQAJ-KZYPOYLOSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- ARCFYUDCVYJQRN-ZPCQJLRDSA-N 1,4-bis[(S)-[(2R,4S,5S)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]anthracene-9,10-dione Chemical compound C1=C(OC)C=C2C([C@H](OC=3C=4C(=O)C5=CC=CC=C5C(=O)C=4C(O[C@H]([C@@H]4N5CC[C@H]([C@@H](C5)CC)C4)C=4C5=CC(OC)=CC=C5N=CC=4)=CC=3)[C@H]3C[C@@H]4CCN3C[C@H]4CC)=CC=NC2=C1 ARCFYUDCVYJQRN-ZPCQJLRDSA-N 0.000 description 2
- WGLLSSPDPJPLOR-UHFFFAOYSA-N 2,3-dimethylbut-2-ene Chemical group CC(C)=C(C)C WGLLSSPDPJPLOR-UHFFFAOYSA-N 0.000 description 2
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical class NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N 4-Anisaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M Caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N Chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- FWFSEYBSWVRWGL-UHFFFAOYSA-N Cyclohexenone Chemical compound O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 description 2
- 238000007167 Hofmann rearrangement reaction Methods 0.000 description 2
- LJOQGZACKSYWCH-AFHBHXEDSA-N Hydroquinidine Natural products C1=C(OC)C=C2C([C@@H](O)[C@H]3C[C@@H]4CCN3C[C@@H]4CC)=CC=NC2=C1 LJOQGZACKSYWCH-AFHBHXEDSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 229940040692 Lithium Hydroxide Monohydrate Drugs 0.000 description 2
- DWTRNJWJQAVZDE-JTQLQIEISA-N N-[(1R)-2-hydroxy-1-(2-methoxyphenyl)ethyl]acetamide Chemical compound COC1=CC=CC=C1[C@H](CO)NC(C)=O DWTRNJWJQAVZDE-JTQLQIEISA-N 0.000 description 2
- LCPNGNMOXMGETA-JTQLQIEISA-N N-[(1R)-2-hydroxy-1-(3-nitrophenyl)ethyl]acetamide Chemical compound CC(=O)N[C@@H](CO)C1=CC=CC([N+]([O-])=O)=C1 LCPNGNMOXMGETA-JTQLQIEISA-N 0.000 description 2
- HXGLDTKWORPRLC-JTQLQIEISA-N N-[(2R)-2-hydroxy-2-(2-methoxyphenyl)ethyl]acetamide Chemical compound COC1=CC=CC=C1[C@@H](O)CNC(C)=O HXGLDTKWORPRLC-JTQLQIEISA-N 0.000 description 2
- XCTLBNGPEQKUJT-JTQLQIEISA-N N-[(2R)-2-hydroxy-2-(3-nitrophenyl)ethyl]acetamide Chemical compound CC(=O)NC[C@H](O)C1=CC=CC([N+]([O-])=O)=C1 XCTLBNGPEQKUJT-JTQLQIEISA-N 0.000 description 2
- KJCJYQYRPOJUKJ-JTQLQIEISA-N N-[(2R)-2-hydroxy-2-phenylethyl]acetamide Chemical compound CC(=O)NC[C@H](O)C1=CC=CC=C1 KJCJYQYRPOJUKJ-JTQLQIEISA-N 0.000 description 2
- NFFSTVSAHCVTMU-UHFFFAOYSA-N N-chloroformamide Chemical class ClNC=O NFFSTVSAHCVTMU-UHFFFAOYSA-N 0.000 description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N Sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 2
- FDDDEECHVMSUSB-UHFFFAOYSA-N Sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 2
- VDZOOKBUILJEDG-UHFFFAOYSA-M Tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000002479 acid--base titration Methods 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 2
- 230000002051 biphasic Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 230000001419 dependent Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- IEPRKVQEAMIZSS-AATRIKPKSA-N diethyl fumarate Chemical compound CCOC(=O)\C=C\C(=O)OCC IEPRKVQEAMIZSS-AATRIKPKSA-N 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000011068 load Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- VPUIJHRNBVHUKJ-UHFFFAOYSA-N oxido(trioxo)osmium Chemical class [O-][Os](=O)(=O)=O VPUIJHRNBVHUKJ-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229920000915 polyvinyl chloride Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 229960001663 sulfanilamide Drugs 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- GTCDARUMAMVCRO-UHFFFAOYSA-M tetraethylazanium;acetate Chemical compound CC([O-])=O.CC[N+](CC)(CC)CC GTCDARUMAMVCRO-UHFFFAOYSA-M 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- 230000001131 transforming Effects 0.000 description 2
- RZARFIRJROUVLM-JGVFFNPUSA-N (2R,3S)-3-azaniumyl-2-hydroxy-3-phenylpropanoate Chemical compound [O-]C(=O)[C@H](O)[C@@H]([NH3+])C1=CC=CC=C1 RZARFIRJROUVLM-JGVFFNPUSA-N 0.000 description 1
- LJOQGZACKSYWCH-WZBLMQSHSA-N (R)-[(2S,4S,5R)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol Chemical compound C1=C(OC)C=C2C([C@@H](O)[C@@H]3C[C@@H]4CCN3C[C@@H]4CC)=CC=NC2=C1 LJOQGZACKSYWCH-WZBLMQSHSA-N 0.000 description 1
- ARCFYUDCVYJQRN-KGHNJIHGSA-N 1,4-bis[(R)-[(2R,4S,5S)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]anthracene-9,10-dione Chemical compound C1=C(OC)C=C2C([C@@H](OC=3C=4C(=O)C5=CC=CC=C5C(=O)C=4C(O[C@@H]([C@@H]4N5CC[C@H]([C@@H](C5)CC)C4)C=4C5=CC(OC)=CC=C5N=CC=4)=CC=3)[C@H]3C[C@@H]4CCN3C[C@H]4CC)=CC=NC2=C1 ARCFYUDCVYJQRN-KGHNJIHGSA-N 0.000 description 1
- ZFMOZNIUEPVNCV-UHFFFAOYSA-N 2,3-dimethyloct-2-ene Chemical compound CCCCCC(C)=C(C)C ZFMOZNIUEPVNCV-UHFFFAOYSA-N 0.000 description 1
- MTEZLAATISORQK-UHFFFAOYSA-N 2-methoxyacetamide Chemical compound COCC(N)=O MTEZLAATISORQK-UHFFFAOYSA-N 0.000 description 1
- RZARFIRJROUVLM-UHFFFAOYSA-N 3-azaniumyl-2-hydroxy-3-phenylpropanoate Chemical compound OC(=O)C(O)C(N)C1=CC=CC=C1 RZARFIRJROUVLM-UHFFFAOYSA-N 0.000 description 1
- GUCPYIYFQVTFSI-UHFFFAOYSA-N 4-methoxybenzamide Chemical compound COC1=CC=C(C(N)=O)C=C1 GUCPYIYFQVTFSI-UHFFFAOYSA-N 0.000 description 1
- 229940054066 Benzamide antipsychotics Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- DNSISZSEWVHGLH-UHFFFAOYSA-N Butyramide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 1
- BYHTXLVGJCGODN-VHSXEESVSA-M C(C)(=O)N[C@H]([C@H](C(=O)[O-])O)C1=CC=CC=C1 Chemical compound C(C)(=O)N[C@H]([C@H](C(=O)[O-])O)C1=CC=CC=C1 BYHTXLVGJCGODN-VHSXEESVSA-M 0.000 description 1
- 229940010415 CALCIUM HYDRIDE Drugs 0.000 description 1
- ULTBYROMHFVMAX-LURJTMIESA-N CCOC(=O)[C@@H](O)CNC(C)=O Chemical compound CCOC(=O)[C@@H](O)CNC(C)=O ULTBYROMHFVMAX-LURJTMIESA-N 0.000 description 1
- UUGAXJGDKREHIO-UHFFFAOYSA-N Calcium hydride Chemical compound [H-].[H-].[Ca+2] UUGAXJGDKREHIO-UHFFFAOYSA-N 0.000 description 1
- 229940107161 Cholesterol Drugs 0.000 description 1
- 241000744472 Cinna Species 0.000 description 1
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 description 1
- LDCRTTXIJACKKU-ONEGZZNKSA-N Dimethyl fumarate Chemical compound COC(=O)\C=C\C(=O)OC LDCRTTXIJACKKU-ONEGZZNKSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N Docetaxel Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 229920000126 Latex Polymers 0.000 description 1
- LWJROJCJINYWOX-UHFFFAOYSA-L Mercury(II) chloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 description 1
- QPBLBBVSBIWJJZ-HZPDHXFCSA-N N-[(1R,2R)-2-hydroxy-1,2-diphenylethyl]acetamide Chemical compound C1([C@@H](O)[C@H](NC(=O)C)C=2C=CC=CC=2)=CC=CC=C1 QPBLBBVSBIWJJZ-HZPDHXFCSA-N 0.000 description 1
- 241000382928 Oxya Species 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N Quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 150000003869 acetamides Chemical class 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000004421 aryl sulphonamide group Chemical group 0.000 description 1
- 238000006256 asymmetric dihydroxylation reaction Methods 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- 150000003936 benzamides Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 125000004432 carbon atoms Chemical group C* 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940099111 chloramine-T Drugs 0.000 description 1
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000002939 deleterious Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- DRXGWTUAIWQOKN-UHFFFAOYSA-L dihydroxy(dioxo)molybdenum;phosphonic acid Chemical compound OP(O)=O.O[Mo](O)(=O)=O DRXGWTUAIWQOKN-UHFFFAOYSA-L 0.000 description 1
- 229960004419 dimethyl fumarate Drugs 0.000 description 1
- AASUFOVSZUIILF-UHFFFAOYSA-N diphenylmethanone;sodium Chemical compound [Na].C=1C=CC=CC=1C(=O)C1=CC=CC=C1 AASUFOVSZUIILF-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- QZEPRSLOWNHADS-VOTSOKGWSA-N ethyl (E)-3-(3-nitrophenyl)prop-2-enoate Chemical compound CCOC(=O)\C=C\C1=CC=CC([N+]([O-])=O)=C1 QZEPRSLOWNHADS-VOTSOKGWSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000001815 facial Effects 0.000 description 1
- 238000010265 fast atom bombardment Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminium hydride Substances [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 description 1
- OCZDCIYGECBNKL-UHFFFAOYSA-N lithium;alumanuide Chemical compound [Li+].[AlH4-] OCZDCIYGECBNKL-UHFFFAOYSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 229960002523 mercuric chloride Drugs 0.000 description 1
- 150000002730 mercury Chemical class 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- YQWIWXOIMLZUJQ-UHFFFAOYSA-N methyl 3-(4-fluoro-3-nitrophenyl)prop-2-enoate Chemical compound COC(=O)C=CC1=CC=C(F)C([N+]([O-])=O)=C1 YQWIWXOIMLZUJQ-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000001343 mnemonic Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 239000005445 natural product Substances 0.000 description 1
- 229930014626 natural products Natural products 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 150000002907 osmium Chemical class 0.000 description 1
- BDEWURIQTAKHIF-UHFFFAOYSA-N osmium(8+) Chemical compound [Os+8] BDEWURIQTAKHIF-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 238000003408 phase transfer catalysis Methods 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000006894 reductive elimination reaction Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- MMRQKDZHQWWYJC-UHFFFAOYSA-M sodium;chloroazanidylformate Chemical class [O-]C(=O)N([Na])Cl MMRQKDZHQWWYJC-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective Effects 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000002480 thymidyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 229960001479 tosylchloramide sodium Drugs 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Definitions
- the invention relates to the regio-selective and enantio- selective conversion of olefins to ⁇ -hydroxyamides. More particularly, the invention relates to catalytic asymmetric additions or amidohydroxylations of olefins and other unsaturated substrates using an N-halo carboxamide as an oxidizing agent in the presence of an osmium catalyst and a chiral ligand.
- the ⁇ -aminoalcohol moiety is one of the most abundant structural units in biologically active compounds.
- Recent developments by us Li et al. Angew . Chem. 1996, 208, 449-452; Angew. Chem. Int. Ed. Engl. 1996, 35, 451-454; Li et al. Acta Chem. Scand. 1996, 50, 649-651) and others (Larrow et al. J. Am. Chem. Soc. 1996, 118, 7420-7421; Shibasaki et al. Pure Appl. Chem. 1996, 68, 523-530) have led to viable metal catalyzed routes for its asymmetric synthesis.
- Each oxyamination procedure has unique reaction conditions and includes variations in solvents, auxiliary salts, nucleophiles, temperature, stoichiometric v. catalytic amounts of osmium species and stoichiometric v. catalytic amounts of ligand.
- Each procedure is highly dependent on the nature of the substrate and possesses unique properties which afford different yields, chemoselectivities, stereoselectivities, regioselectivities and enantioselectivitive outcomes.
- the first reported oxyamination procedure (Sharpless et al. J. Am . Chem . Soc . 1975, 97 , 2305) generated aminoalcohols from mono and di substituted olefins, using stoichiometric quantities of a tri-oxo(tert-butylimido) osmium species.
- the procedure required reductive cleavage of the osmate ester which was performed with lithium aluminum hydride and afforded tertiary vicinal aminoalcohols. Yields were good to excellent, but in some cases, the side product vicinal diol was formed as an undesired by-product.
- the first procedure used phase transfer catalysis conditions at 55-60 °C with 1% Os0 4 , 1:1 v/v, 0.20 Molar CHC1 3 /H 2 0, and benzyltriethylammonium chloride as the phase transfer catalyst.
- the chloramine T-trihydrate (TsS0 2 NClNa"3H 2 0) was either added directly or formed in situ in water; this solution was then directly used in the phase transfer mixture.
- the in situ procedure for generating the chloramine salts, involved stirring a suspension of the arylsulfonamide with an equivalent of sodium hypochlorite (Clorox) until a homogenous solution was obtained.
- the yields were comparable with those obtained with isolated chloramine salts and the procedure was found most effective for monosubstituted and 1,2 disubstituted olefins.
- the phase transfer method gave poor results with trisubstituted and 1, 1-disubstituted olefins and the procedure did not succeed with diethyl fumarate and 2- cyclohexen-1-one. Sharpless et al. J. Org. Chem .1978, 43, 2544.
- phase transfer catalyst or tert-butyl alcohol procedures succeeded with tetramethyl ethylene, 2 , 3-dimethyl-2- octene, diethyl fumarate, or 2-cyclohexen-l-one. Negative results were also obtained with most hindered tri- and tetrasubstituted olefins. Herranz E. , MIT Ph.D. Thesis, 1979, 33.
- Solvent conditions for the synthesis of the hydroxysulfonamides included organic solvents such as acetonitrile, tert-butyl alcohol, isopropyl alcohol and chloroform which was in contact with the aqueous phase in the phase transfer catalyst procedure.
- Preferred ligands for use with sulfonamides have included the use of monovalent cinchona alkaloids or the bivalent phthalazine based, commercially available (DHQ) 2 PHAL and (DHQD) 2 PHAL alkaloids. Sharpless et al. Angew. Chemie Intl Ed . 1996, 35 , 451.
- Temperature conditions for the hydroxysulfonamide asymmetric a inohydroxylations have varied from 60 °C to 25 °C for reactions including sulfonamides, auxiliary salts, ligands, phase transfer catalysts and stoichiometric or catalytic osmium species, primarily in organic solvents with small amounts of water. Recently, it has been shown that temperature can been lowered to 0 °C while running the reaction, to obtain product by filtration; many hydroxysulfonamides tend to be highly crystalline Sharpless et al. Acta Chemica Scandinavica 1996 in press.
- nucleophiles such as tetraethylammonium acetate were also proven to be beneficial to the reaction in the procedures using the silver and mercury salts of the chloramines from carbonates.
- the reactivity and yields were enhanced by addition of excess AgN0 3 and Hg(N0 3 ) 2 (over that needed to react with the NaClNCOOR salt) Sharpless et al. J. Org Chem . 1980, 45 , 2710.
- Preferred conditions included employment of ROCONClNa + Hg(N0 3 ) 2 + Et 4 NOAc with N-chloro-N-sodiocarbamates; these conditions were recommended as the best procedure for mono, di and tri substituted olefins even including some olefins unreactive in all of the various chloramine T based processes. (Sharpless et al. Org. Syn . 1981, 61 , 93).
- Sharpless disclosed the use of stoiciometric amounts of a first generation monovalent alkaloid ligand with a tert-butyl derived N-chloro-N-argentocarbamate for hydroxyamination in a series of patent applications directed to ligand accelerated catalytic asymmetric dihydroxylation.
- the invention is directed to a method for converting olefinic substrates to asymmetric ⁇ -hydroxyamide products.
- the method of the invention employs an asymmetric addition reaction involving the addition of a carboxamide radical and a hydroxyl radical to the olefinic substrate.
- Enhanced yields, regioselectivity, and enantioselectivity may be achieved according to the method of the invention.
- the asymmetric addition reaction is carried out in a reaction solution which includes the olefinic substrate, an osmium catalyst, a chiral ligand for enantiomerically and regioselectively directing the asymmetric addition, an N-halo carboxamide, a base, and a solvent in homogeneous or heterogeneous conditions.
- the N-halo carboxamide serves as a source for the carboxamide radical.
- the olefinic substrate and N-halo carboxamide are present and soluble within the solvent or cosolvent in approximately stoichiometric amounts as defined below.
- the osmium is present within the solvent or co-solvent in catalytic amounts.
- One aspect of the invention is directed to a method for converting an olefinic substrate to an asymmetric amidoalcohol product by means of a one step osmium-catalyzed asymmetric addition.
- a carboxamide radical and a hydroxyl radical are added to the olefinic substrate.
- the reaction mixture employs a solvent having both an organic component and an aqueous component.
- the aqueous component of the solvent serves as the source of the hydroxyl radical.
- An N- halo carboxamide serves as the source of the carboxamide radical.
- the reaction mixture also includes the olefinic substrate, the N-halo carboxamide, an osmium-containing catalyst, a chiral ligand for enantiomerically directing said asymmetric addition, and a base.
- N-halo carboxamides include N-fluoro- (Ci- C 15 (alkyl) ) -amide, N-chloro- (C 1 -C 15 (alkyl) ) -amide, N-bromo-(C !
- N-halo carboxamides are N-bromoacetamide, N-chloroacetamide, N- bromobenzamide, N-chlorobenzamide, N-fluoro-2-chloro-acetamide, N-fluoro-2-bromo-acetamide, N-fluoro-2-iodo-acetamide, N-bromo- 2-chloro-acetamide, N-bromo-2-bromo-acetamide, N-bromo-2-iodo- acetamide, N-iodo-2-chloro-acetamide, N-iodo-2-bromo-acetamide, N-iodo-2-iodo-acetamide, N-chloro-p-methoxy benzamide, N-chloro- 2-methoxy acetamide, N-bromo-p-methoxy acetamide, N-bromo-2- methoxy acetamide, N-iododo
- Preferred osmium containing catalysts include potassium osmate dihydrate, osmium tetroxide, osmium(IV) oxide, osmium(IV) oxide dihydrate, osmium(III) chloride, and osmium hexachlorooxmate(IV) .
- the catalytic concentration of the osmium is within a range of 0.50 - 20 mole%.
- Preferred chiral ligands include p-phenylbenzoyl dihydroquinidine; acetyl dihydroquinine; dimethylcarbamoyl dihydroquinine; benzoyl dihydroquinine; 4-methoxybenzoyl dihydroquinine; 4-chlorobenzoyl dihydroquinine; 2-chlorobenzoyl dihydroquinine; 4-nitrobenzoyl dihydroquinine; 3-chlorobenzoyl dihydroquinine; 2-methoxybenzo ⁇ l dihydroquinine; 3- methoxybenzoyl dihydroquinine; 2-naphthoyl dihydroquinine; cyclohexanoyl dihydraquinine; p-phenylbenzoyl dihydroquinine; methoxydihydroquinidine; acetyl dihydroquinidine; dimethylcarbamoyl dihydroquinidine
- R x is radical selected from a group consisting of a group represented by one of the following structures:
- the chiral ligand is present and soluble within the reaction solution at a catalytic concentration within a range of substantially 0.50 mole % to 10 mole %.
- the catalytic concentration of the osmium is within a range of 0.50 - 20 mole% and the chiral ligand has a catalytic concentration of approximately 5 mole%.
- Preferred bases include LiOH, NaOH, KOH, NH 4 OH, Na 2 C0 3 , K 2 C0 3 , CaC0 3 , and BaC0 3 .
- preferred organic compounds include methanol, ethanol, n-butanol, n- pentanol, n-propanol, 2-propanol, 2-butanol, tert-butanol, ethylene glycol; acetonitrile, propionitrile; tetrahydrofuran, diethyl ether, tert-butyl methyl ether, dimethoxyethane, 1,4- dioxane; dimethyl formamide, acetone, benzene, toluene, chloroform, and methylene chloride.
- the aqueous/organic solvent system may be either a homogenous or heterogeneous mixture.
- the aqueous component is water wherein the aqueous component of the solvent has a range between 10% and 90% on a volume basis.
- the aqueous and organic components of the solvent are each approximately 50% on a volume basis.
- Exemplary olefins include cis stilbene, trans stilbene, ethyl acrylate, styrene and C 1 -C 6 (alkyl) -cinnamate ester.
- a preferred reaction temperature is within a range between -5.0 and 5.0 °C.
- Figure 1 illustrates preffered cinchona alkaloid ligand derivatives.
- Figure 2 shows a generic scheme indicating that a variety of olefins, as defined below, can be reacted smoothly with 1.1 equivalents of the oxidant/nitrogen donor to give the vicinal aminoalcohols in good yield and with high enantiomeric excess.
- Figure 3 illustrates Table 1: Acetamide based asymmetric aminohydroxylation of various olefins wherein the indicated notations are defined as follows [a] Conditions: see experimental procedure, [b] From reaction catalyzed by (DHQ) 2 - PHAL. [c] Determined by ⁇ -NMR. [d] Determined by chiral HPLC (entry 1-4) or GC (entry 5) . [e] Negative values indicate the formation of the opposite enantiomer (product from reaction catalyzed by (DHQD) 2 -PHAL) . [f] Isolated yields of the pure products 1-5 after chromatography on silica gel. [g] tButanol/water 1:1 was employed, [h] KOH as base and 1-
- Figure 4 illustrates a large scale synthesis based on acetamide as the oxidant for the amidohydroxylation.
- Figure 5 illustrates regioselectivity preferences using AQN ligands and N-bromobenzamide.
- Figure 6 illustrates the reversal of the regioselectivity with styrene derivatives wherein the indicated notations are defined as follows: [a] Conditions: see experimental procedure, [b] The DHQD-derivative was used, [c] Determined by ⁇ -N R. [d] Determined by chiral HPLC. [e] Yields refer to the mixtures of isomers after chromatography on silica gel. [f] Not determined.
- Figure 7 illustrates the effects on regio and stereochemistry using acetamide base amidohydroxylation using (DHQD) 2 PHAL (entries 1-3) or the (DHQD) 2 AQN (entries 4-6) ligands on the respective olefins (substrate olefins not shown) .
- Figure 8 illustrates heterogenous conditions with a phase transfer catalyst wherein the stereochemistry is reversed using the indicated AQN ligand.
- the ⁇ -aminoalcohol moiety is a widespread structural motif in natural products and synthetic drugs. Its generation in an enantioselective manner via metal catalysis represents a major challenge for synthetic organic chemists.
- the catalytic asymmetric aminohydroxylation (AA) represents an even more elegant approach. Alkenes are therein converted into protected ⁇ -amino alcohols in a single step via a syn-cycloaddition catalyzed by osmium salts and chiral quinuclidine-type ligands derived from cinchona alkaloids.
- Three major aspects are to be addressed in this reaction: namely, chemo-, regio-, and enantioselection.
- the most important variable is the ultimate oxidant/nitrogen source for the generation of the active osmium(VIII) imido species responsible for aminohydroxylation.
- the akali metal salts of (1) N-halosulfonamides (for the synthesis of ⁇ -hydroxysulfonamides) and the 2) N-halocarbamates (for the synthesis of ⁇ -hydroxycarbamates) .
- N-halosulfonamides for the synthesis of ⁇ -hydroxysulfonamides
- N-halocarbamates for the synthesis of ⁇ -hydroxycarbamates
- the invention is therefore directed to a novel method for the regio-selective and enantio-selective conversion of olefins to ⁇ -hydroxyamides using an ⁇ -halo carboxamide as the oxidizing agent in the presence of an osmium catalyst and a chiral ligand.
- a major advantage of this system is that only a stoichiometric amount of oxidant is needed, rather than an excess of oxidant, which greatly simplifies isolation and purification of the product. In fact, use of excess of oxidant does not improve the reaction in any way.
- cinnamates are among the best substrates (Table 3, entries 1-3; the use of isopropyl cinnamates instead of the methyl esters is preferable in terms of greater stability towards hydrolysis and enhanced regioselectivity under the reaction conditions.
- compounds 1 and 2 which are quite soluble in the reaction medium, the use of more than 50 % (v/v) water may result in slightly increased regioselectivities) .
- the benzylic amides were formed with higher asymmetric induction (8, 85-96 % ee) than the benzylic alcohols (7, 62-94 % ee) , but poor regioselectivity was observed when phthalazine ligands were used.
- our recently introduced anthraquinone (AQN) ligands Becker et al. Angew. Chem.
- the phenyl glycinols (8) arise using the carbamate 7 ⁇ A/phthalazine ligand combination and the adrenaline-type regioisomers (7) are preferentially derived using the acetamide AA/anthraquinone ligand combination.
- Experiments with other substrates indicate that a reversal of regiochemistry occurs when anthraquinone derived ligands instead of phthalazines are used.
- DHQ class dihydroquinine derived ligands
- DHQD diastereomeric dihydroquinidine
- the AA product was isolated by crystallization of the crude reaction mixture from ethyl acetate/hexane, and a second crop from diethyl ether. Subsequent hydrolysis furnished the enantiomerically pure aminoalcohol as the hydrochloride salt (9) in 68 % yield over two steps ( Figure 4) .
- amidohydroxylation employing the use of N- bromoacetamide as the nitrogen source with styrenes as the olefin shows that the regiochemistry of aminoalcohol formation is reversed from that delivered by the carbamate version of the AA.
- An efficient large scale synthesis of enantiomerically pure 3-phenylisoserine highlights the prodical potential of this latest advance in the osmium-catalyzed asymmetric aminohydroxylation process.
- alkali metal salts of N-chloro carboxamides are unstable and readily undergo Hofmann rearrangement.
- the N- bromo derivatives are preferred oxidants for amidohydroxylation reactions run at 4 °C.
- the standard substrates are smoothly converted into protected amidoalcohols with N-bromo alkali (K + or Li + ) salts of acetamide.
- K + or Li + N-bromo alkali
- AQ ⁇ ligands an anthraquinone spacer
- the regiochemistry is reversed compared to the carbamate procedure with phthalazine (PHAL) ligands, see Figure 7.
- PHAL phthalazine
- anthraquinone-type (AON) ligands such as (DHQ) 2 AQN or (DHQD) 2 AQN and acetamide
- the major product is formed in high ee bearing the nitrogen substituent in the terminal position (adrenaline type products) .
- the carbamate recipe gives similar regioselectivities in those cases but the ee's are low.
- electron poor cinnamates e.g. ethyl 3-nitrocinnamate
- the carbamate recipe gives low regioselectivities (typically 1:1) in those cases.
- the amide-based nitrogen oxidant source is generally used in near stoichiometric amounts (eg. 0.90 - 1.2 equivalents; defined herein as near stoichiometric amounts) but can operate efficiently in the range of 0.50 equivalents (less for difficult purification conditions and inexpensive olefins) to 10 equivalents (for less reactive olefins) wherein the N-halo carboxamide can be commercially purchased or synthesized according to standard procedures well known in the art as disclosed vida supra.
- the addition of an alkali metal in situ forms the alkali metal salt of the N-halo carboxamide.
- N-halo carboxamide in a basic solution containing the alkali metal (eg. LiOH, NaOH, etc.).
- alkali metal eg. LiOH, NaOH, etc.
- the genus of amide-based nitrogen sources which are preferred with the invention include the following N-halo carboxyamides : N-fluoro- (C ! -C 15 (alkyl) ) -amide, N-chloro- (C x - C 15 (alkyl) ) -amide, N-bromo- (C !
- N-halo carboxyamides work optimally well with the procedure: N- bromoacetamide, N-chloroacetamide, N-bromobenzamide, N- chlorobenzamide, N-fluoro-2-chloro-acetamide, N-fluoro-2-bromo- acetamide, N-fluoro-2-iodo-acetamide, N-bromo-2-chloro- acetamide, N-bromo-2-bromo-acetamide, N-bromo-2-iodo-acetamide, N-iodo-2-chloro-acetamide, N-iodo-2-bromo-acetamide, N-iodo-2- iodo-acetamide, N-chloro-p-methoxy benzamide, N-chloro-2-methoxy acetamide, N-bromo-p-methoxy acetamide, N-bromo-p-methoxy benzamide,
- AA asymmetric amidohydroxylation
- three olefin classes 1) monosubstituted; 2) cis-disubstituted, and 3) trans-disubstituted olefins.
- the 1,1 disubstituted and trisubstituted types of olefins give only racemic or low ee's while the tetrasusbstituted class, does not provide any signs of turnover; / ⁇ unsaturated esters, ⁇ / ⁇ unsaturated amides, aromatic olefins and heteroaromatic olefins work particularly well with the invention.
- High regioselectivity is one of the more useful features of the amidohydroxylation.
- the chemistry exhibits a strong preference for nitrogen attachment to the olefinic carbon bearing an aromatic substituent or, in the case of olefins conjugated with a strong electron withdrawing group (EWG) , the nitrogen is strongly directed to the olefinic carbon distal to the EWG.
- EWG electron withdrawing group
- the alkaloid ligand is responsible for high regioselectivity. When the ligand is omitted, there is little preference for either regioisomer. Beyond probable contributions from "binding pocket" effects, the strong regioselection phenomenon requires the operation of powerful electronic determinants.
- Preferred solvents include acetonitrile, n-propanol, tert- butanol and suitable solvents include methanol, ethanol, n- butanol, n-pentanol, n-propanol, 2-propanol, 2-butanol, tert- butanol, ethylene glycol; nitriles: acetonitrile, propionitrile; ethers: tetrahydrofurane, diethyl ether, tert. butyl methyl ether, dimethoxyethane, 1,4-dioxane; miscellaneous: dimethyl formamide, acetone, benzene, toluene, chloroform, methylene chloride.
- Preferred ligands are shown in Figure 1 and are commercially available or synthesized by procedures well known in the art. Additional preferred ligands, which can be equally used with the invention with the specified concentrations as described herein, are as follows: p-phenylbenzoyl dihydroquinidine; acetyl dihydroquinine; dimethylcarbamoyl dihydroquinine; benzoyl dihydroquinine; 4-methoxybenzoyl dihydroquinine; 4- chlorobenzoyl dihydroquinine; 2-chlorobenzoyl dihydroquinine; 4- nitrobenzoyl dihydroquinine; 3-chlorobenzoyl dihydroquinine; 2- methoxybenzoyl dihydroquinine; 3-methoxybenzoyl dihydroquinine; 2-naphthoyl dihydroquinine; cyclohexanoyl dihydraquinine; p- phenyl
- the ligand can range from ca. 0.5 to 10 mol % (less is appropriate for lower temperatures; eg. 0.5 % might be enough at O °C and 10 % would probably be needed to keep the % ee at reasonable levels if the temperature reaches 35 or 40 °C.
- the osmium containing catalyst can be selected from any one of the various commercially available osmium sources including, but not restricted to potassium osmate dihydrate, osmium tetroxide, osmium(IV) oxide, osmium(IV) oxide dihydrate, osmium(III) chloride, and osmium hexachlorooxmate (IV) .
- the amount of Os catalyst can range from 0.5% (probably even less in the very best cases, and in any case the number will drop as the process if further improved) to 10 or even 20%.
- the general procedure conditions uses 4% to have fast reaction times, but 2% is good for most cases.
- the high loadings of 20%, for example, is needed to achieve reasonable rates with very poor substrates (this conclusion follows from the extensive experience by us and others with the AD, where in desparate situations 20 or more % Os catalyst is needed.
- the following table contains data on the amount of osmium and ligand one can use for the isopropyl cinnamate AA with N-bromo acetamide.
- Heterogeneous Condition Variation For most cases, the hydroxyamide AA process is run in homogeneous conditions, however, applying heterogeneous phase transfer conditions as illustrated in Figure 8, enhanced chemoselectivity was found for some olefins (see synthesis for: methyl (2S, 3R) -2- (benzamido) -3-hydroxy-3- (4-fluoro-3- nitrophenyDpropanoate 16, vida infra). In particular, we found that the AQN ligands furnished a complete reversal of the regioselectivity with cinnamates as olefins.
- Phase Transfer Catalysts For heterogeneous conditions, a commercially available phase transfer catalyst such as tetra-n-butylammonium hydroxide is preferred, however other standard phase transfer catalysts (eg. tetra-alkyl ammonium or phosphonium salts) work well equally with the invention when heterogeneous conditions are required.
- phase transfer catalyst such as tetra-n-butylammonium hydroxide
- other standard phase transfer catalysts eg. tetra-alkyl ammonium or phosphonium salts
- the hydroxyamide AA process is run in LiOH or KOH, however other alkali earth bases such as NaOH and CsOH are acceptable using the conditions and concentrations as indicated vida infra.
- Preferred bases are LiOH, NaOH, KOH, NH 4 OH, alkyl or arylammonium hydroxides, and alkali or earth alkali salts of carbonates and bicarbonates (eg. Na 2 C0 3 , K 2 C0 3 , CaC0 3 , BaC0 3 et.)
- NMR spectra were recorded on Bruker AMX-500, AM-300, or AM- 250 instruments. The following abbreviations were used to explain the multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; apt, apparent; b, broad; obs, obscured.
- IR spectra were recorded on Nicolet 205, Perkin Elmer 1600 or Galaxy 2020 series FT-IR spectrophotometers . Optical rotations were recorded using a Perkin Elmer 241 polarimeter. High-resolution mass spectra (HRMS) were recorded on a VG ZAB- ZSE mass spectrometer under Fast Atom Bombardment (FAB) conditions, at the Scripps Research Institute.
- the combined crystalline, white solid, 260 g is of 99 %ee as determined by HPLC on Chiralcel OD-H, Daicel, i-PrOH/hexane 40:60 v/v, 0.5 mL/min, 254 nm; retention times: 8.2 min ( 2S, 3R) , 12.7 min ( 2R, 3S) .
- the crude product was taken up in 500 mL ethyl acetate and passed through a 4.5-inch sintered glass funnel covered with a one inch layer of silica gel.
- Product purification was accomplished by recrystallization from ethyl acetate/hexane 1:2 (4 mL/g) .
- a second crop of material was obtained by trituration of the previously evaporated mother liquor with 100 mL Et 2 0 and subsequent filtration. Yield 119.5 g (71 % yield, 99 % ee) .
Abstract
β-Hydroxyamides are synthesized from olefin substrates by means of a catalyzed asymmetric addition reaction. N-halo carboxamides are employed as the oxidant nitrogen source for the production of the β-hydroxysulfonamides. The addition reaction is catalyzed by osmium and is co-catalyzed by chiral ligands. The chiral ligands, in addition to being co-catalysts with the osmium, also serve to direct the addition reaction regioselectively and enantio-selectively. Divalent ligands are preferred over monovalent ligands because of their enhanced regio- and enantio-selectivity. Excellent yields and enantiomeric efficiencies are achieved with both organic solvents (homogeneous conditions) and co-solvent conditions (heterogenous conditions), generally containing a 50/50 (v/v) mixtures of water and organic solvent.
Description
CATALYTIC ASYMMETRIC AMIDOHYDROXYLATION OF OLEFINS WITH N-HALO CARBOXAMIDES
Description
Field of Invention:
The invention relates to the regio-selective and enantio- selective conversion of olefins to β-hydroxyamides. More particularly, the invention relates to catalytic asymmetric additions or amidohydroxylations of olefins and other unsaturated substrates using an N-halo carboxamide as an oxidizing agent in the presence of an osmium catalyst and a chiral ligand.
Background;
The β-aminoalcohol moiety is one of the most abundant structural units in biologically active compounds. Recent developments by us (Li et al. Angew . Chem. 1996, 208, 449-452; Angew. Chem. Int. Ed. Engl. 1996, 35, 451-454; Li et al. Acta Chem. Scand. 1996, 50, 649-651) and others (Larrow et al. J. Am. Chem. Soc. 1996, 118, 7420-7421; Shibasaki et al. Pure Appl. Chem. 1996, 68, 523-530) have led to viable metal catalyzed routes for its asymmetric synthesis.
Separate and distinct synthetic methodologies have been developed by Sharpless et al. for the vicinal hydroxya ination of olefins to form the β-aminoalcohol moiety. There are three major groups of oxyamination procedures which produce aminoalcohols (Sharpless et al. J. Am. Chem. Soc. 1975, 97,
2305; Sharpless et al. J. Org. Chem. 1978, 43, 2628; Sharpless et al. J. Org. Chem. 1980, 45, 2257) , hydroxysulfona ides (Sharpless et al. J. Org. Chem. 1976, 41, 177; Sharpless et al. J. Org. Chem. 1978, 43, 2544; Sharpless et al. J. Org. Chem. 1979, 44, 1953; Sharpless et al. Org. Syn. 1980, 61, 85) or hydroxycarbamates (Sharpless et al. J. Am. Chem. Soc. 1978, 100, 3596; Sharpless et al. J. Org. Chem. 1980, 45, 2710; Sharpless et al. U.S. Patent No. 's 4,871,855; 4,965,364; 5,126,494; EP 0 395 729) . Each oxyamination procedure has unique reaction conditions and includes variations in solvents, auxiliary salts,
nucleophiles, temperature, stoichiometric v. catalytic amounts of osmium species and stoichiometric v. catalytic amounts of ligand. Each procedure is highly dependent on the nature of the substrate and possesses unique properties which afford different yields, chemoselectivities, stereoselectivities, regioselectivities and enantioselectivitive outcomes.
l. Ajninoalco Qls
The first reported oxyamination procedure (Sharpless et al. J. Am . Chem . Soc . 1975, 97 , 2305) generated aminoalcohols from mono and di substituted olefins, using stoichiometric quantities of a tri-oxo(tert-butylimido) osmium species. The procedure required reductive cleavage of the osmate ester which was performed with lithium aluminum hydride and afforded tertiary vicinal aminoalcohols. Yields were good to excellent, but in some cases, the side product vicinal diol was formed as an undesired by-product. The stereochemistry of addition, in methylene chloride or pyridine, was exclusively cis (Sharpless et al. J. Org . Chem . 1978, 43 , 2628). In addition, the carbon- nitrogen bond formed was, in every case, at the least substituted olefinic carbon atom. Di and tri-substituted olefins reacted much slower with the generated i ido reagent than with monosubstituted alkenes; tetrasubstituted alkenes yielded only the corresponding diol. However, by using a coordinating solvent such as pyridine, higher yields and higher ratios of aminoalcohol to diol were reported. Sharpless et al. J. Org . Chem . 1980, 45 , 2257; Sharpless et al. J . Org . Chem . 1976, 41 , 177; Sharpless et al. J. Org. Chem . 1978, 43 , 2544.
2. Hydroxγsulfonamides
Sharpless et al. first demonstrated that hydroxysulfonamides could be obtained using either stoichiometric or catalytic amounts of 1% osmium tetraoxide in the presence of 1.5 - 5 equivalents of Chloramine-T trihydrate (TsS02NClNa'3H20, Ts = tosylate; commercially obtained) to effect cis addition of a hydroxyl (OH) and an arylsulfona ide moiety (Ar-S02NH) across a mono or disubstituted olefinic linkages (Sharpless et. al. J. Org. Chemistry 1976, 41 , 177).
Two procedures were developed to effect hydroxyamination of olefins using sulfonamides . (Sharpless et al. Org. Syn . 1980, 61 , 85). The first procedure used phase transfer catalysis conditions at 55-60 °C with 1% Os04, 1:1 v/v, 0.20 Molar CHC13/H20, and benzyltriethylammonium chloride as the phase transfer catalyst. The chloramine T-trihydrate (TsS02NClNa"3H20) was either added directly or formed in situ in water; this solution was then directly used in the phase transfer mixture. The in situ procedure, for generating the chloramine salts, involved stirring a suspension of the arylsulfonamide with an equivalent of sodium hypochlorite (Clorox) until a homogenous solution was obtained. The yields were comparable with those obtained with isolated chloramine salts and the procedure was found most effective for monosubstituted and 1,2 disubstituted olefins. The phase transfer method, however, gave poor results with trisubstituted and 1, 1-disubstituted olefins and the procedure did not succeed with diethyl fumarate and 2- cyclohexen-1-one. Sharpless et al. J. Org. Chem .1978, 43, 2544. A second procedure was carried out in tert-butyl alcohol at 55- 60 °C with 1% Os04, silver nitrate (with or without) and commercially obtained chloramine T-trihydrate (TsS02NClNa"3H20) which provided the only source of water. The procedure did not succeed with tetramethylethylene and cholesterol, and negative results were found with most hindered tri- and tetrasubstituted olefins. Sharpless et. al. J. Org. Chemistry 1976, 41 , 177; Sharpless et al. Org. Syn . 1980, 61 , 85. The addition of divalent metal salts such as AgN03 and Hg(N03)2 improved some reactions, however, other reactions suffered deleterious effects from the addition of the metal salts. Sharpless et al. J . Org Chem . 1978, 43 , 2544; Sharpless et. al. J. Org. Chemistry 1976, 41 , 177.
Further elaboration on either procedure showed that other sulfonamide derivatives (ArS02NClNa) could be successfully employed in addition to chloramine T, where Ar = phenyl, o- tolyl, p-chlorophenyl, p-nitrophenyl, and o-carboalkoxyphenyl. Sharpless et al. J. Org. Chem .1978, 43, 2546.
Neither the phase transfer catalyst or tert-butyl alcohol procedures succeeded with tetramethyl ethylene, 2 , 3-dimethyl-2-
octene, diethyl fumarate, or 2-cyclohexen-l-one. Negative results were also obtained with most hindered tri- and tetrasubstituted olefins. Herranz E. , MIT Ph.D. Thesis, 1979, 33. Solvent conditions for the synthesis of the hydroxysulfonamides included organic solvents such as acetonitrile, tert-butyl alcohol, isopropyl alcohol and chloroform which was in contact with the aqueous phase in the phase transfer catalyst procedure. The tert-butyl alcohol procedure (including other solvents used) was not run with added water; the phase transfer catalyst (PTC) procedure required a biphasic mixture of 1:1 v/v chloroform/water. Recently, however, an improvement was reported which used a 1:1 ratio of organic solvent to water in a homogeneous, rather than a biphasic solution or organic solvent with small amounts of water. These conditions were found to provide optimum enantioselectivity, regioselectivity and improved yields from either the previously described t-butyl alcohol or PTC conditions. Sharpless et al. Angew . Chemie Intl Ed . 1996, 35 , 451.
The use of chiral ligands with sulfonamides provides enantioselectivity and has been observed to both accelerate and decelerate the rate of catalysis. The hydroxysulfonamide process is a stereoselective cis process. The presence of ligands also has a dramatic effect on the regioselectivity. In a study with no ligand present with methyl cinna ate, the two regioisomers were present in a 2:1 ratio. With the addition of ligand, the ratio was improved to 5:1 or greater. Another positive effect of the ligand was its ability to suppress formation of diol by-product. Angew. Chemie Intl Ed . 1996, 35 , 451.
Preferred ligands for use with sulfonamides have included the use of monovalent cinchona alkaloids or the bivalent phthalazine based, commercially available (DHQ)2PHAL and (DHQD)2PHAL alkaloids. Sharpless et al. Angew. Chemie Intl Ed . 1996, 35 , 451.
Temperature conditions for the hydroxysulfonamide asymmetric a inohydroxylations have varied from 60 °C to 25 °C
for reactions including sulfonamides, auxiliary salts, ligands, phase transfer catalysts and stoichiometric or catalytic osmium species, primarily in organic solvents with small amounts of water. Recently, it has been shown that temperature can been lowered to 0 °C while running the reaction, to obtain product by filtration; many hydroxysulfonamides tend to be highly crystalline Sharpless et al. Acta Chemica Scandinavica 1996 in press.
Cleavage of the sulfonamides, to free aminoalcohols, have been accomplished via standard deprotection conditions including dissolving metals (Na, NH3; Sharpless et al J. Org. Chem 1976, 41 , 177) and HBr, acetic acid and phenol (Fukuyama et al. Tetrahedron Lett , in press) .
.Hydroxycarbamates
A drawback with the hydroxysulfonamide procedure was that cleavage conditions were too strong for some substrates. The use of carbamates to protect the nitrogen, however, provided a methodology which avoided the use of harsh acids or reducing deprotection problems found with hydroxysulfonamides (Sharpless et al. J. Am . Chem . Soc . 1978, 200, 3596; Sharpless et al. J. Org. Chem . 1980, 45 , 2710; Sharpless et al. Org. Syn . 1981, 61 , 93; Sharpless et al. U.S. Patent No.'s 4,871,855; 4,965,364; 5,126,494; EP 0 395 729). Sharpless first demonstrated the synthesis of hydroxycarbamates with the use of N-chloro-N-argentocarbamates (Sharpless et al J. Am . Chem . Soc . 1978 200, 3596). The N- chloro-N-argentocarbamates were generated in situ via the addition of W-chlorosodiocarbamates and silver nitrate to a solution of the olefin in acetonitrile or tert-butanol with trace amounts of water (4.5 molar equivalents based on olefin) and 1% of osmium tetroxide catalyst to generate vicinal hydroxycarbamates in generally good yields. The methodology was reported to be more effective with electron deficient olefins such as dimethyl fumarate and trisubstituted olefins were reported to be less readily oxya inated with N-chloro-N- argentocarbamates than with the chloramine-T procedures (Sharpless et. al. J . Org. Chem . 1976, 41 , 177).
Sodio-N-chlorocarbamates were always first converted to either argento or mercurio salt analogs. The addition of the AgN03 or Hg(N03)2 salts, to make N-chloro-N-argentocarbamates or mercurio salt analogs, was crucial for the reaction to retain its desired properties. (Sharpless et al J. Org. Chem . , 1980, 45 , 2711) . This was in contrast to the sulfonamide conditions, where the sodio-N-chloro-sulfonamide salts could be used directly with either the t-butanol or chloroform/water - phase transfer catalyst procedures (Sharpless et al. J . Org. Chem . 1978, 43 , 2544).
The addition of nucleophiles such as tetraethylammonium acetate were also proven to be beneficial to the reaction in the procedures using the silver and mercury salts of the chloramines from carbonates. Alternatively, the reactivity and yields were enhanced by addition of excess AgN03 and Hg(N03)2 (over that needed to react with the NaClNCOOR salt) Sharpless et al. J. Org Chem . 1980, 45 , 2710.
Preferred conditions included employment of ROCONClNa + Hg(N03)2 + Et4NOAc with N-chloro-N-sodiocarbamates; these conditions were recommended as the best procedure for mono, di and tri substituted olefins even including some olefins unreactive in all of the various chloramine T based processes. (Sharpless et al. Org. Syn . 1981, 61 , 93).
Among the carbamates tried, it was found that both benzyl W-chloro-W-argentocarbamate and tert-butyl N-chloro-N- argentocarbamates (or mercurio analogs) were among the most effective oxidants, especially with addition of nucleophiles such as tetraethylammonium acetate. Other carbamates such as isopropyl, ethyl, menthyl and bornyl derivatives were also used, however, chemo, regio and stereoselectivities were lower. Virtually no asymmetric induction was observed when chiral menthyl or bornyl derived carbamates were employed for hydroxyaminations. (Sharpless et al J. Am . Chem . Soc . 1978 200, 3596) . Sharpless disclosed the use of stoiciometric amounts of a first generation monovalent alkaloid ligand with a tert-butyl derived N-chloro-N-argentocarbamate for hydroxyamination in a series of patent applications directed to ligand accelerated
catalytic asymmetric dihydroxylation. These disclosures illustrated an hydroxyamination on trans-stilbene with the use of 1.0 equivalent (stoichiometric to olefin) of monovalent DHQD- p-chlorobenzoate (DHQD= hydroquinidine) ligand, 1 mol % osmium tetroxide, silver nitrate (figure) or mercuric chloride (.80 equivalents; in protocal), 0.09 Molar acetonitrile (93.11 volume % acetonitrile) / water mix (6.89 volume % water) and tertbutyl derived N-chloro-N-argentocarbamate (1.45 equivalents) at 20 °C (figure) or 60 °C (protocal) for 1 hour. The disclosure reported a 51% ee with a 93% yield of aminoalcohol. (Sharpless et al. U.S. Patent No.'s 4,871,855; 4,965,364; 5,126,494; EP 0 395 729) .
In a review on ligand accelerated catalysis , Sharpless et al. noted that a 92% ee had been achieved in a stoichiometric reaction of trioxo-(tert-butylimido) osmium with stilbene in the presence of DHQD-CLB at ambient temperatures (Sharpless et al. Angew . Chem . Int . Ed . Engl . 1995, 34 , 1059, ref. 80 "unpublished results") ; this mention did not disclose reaction conditions.
Recently, an oxyamination reaction for the hemisynthesis of taxol and analogs was reported using a tertbutyl derived N- chloro-N-argentocarbamate, excess silver nitrate or other metallic salts, with the use of either catalytic or stoichiometric amounts of osmium and the addition of stoichiometric amounts of monovalent DHQD (hydroquinidine) , DHQ (hydroquinine) ligands in an unsuccessful attempt to influence the diastereoselectivity and the regioselectivity of the aminohydroxylation process. Solvent conditions varied from acetonitrile, toluene or pyridine, and the reactions were carried out at 4 °C to room temperature, in the dark. The study reported that quinuclidine ligands had no effect on the amino alcohol yields but found that the addition of chiral tertiary amines had some beneficial effect on the yields of the various amino alcohol isomers formed. (Mangatal et al. Tetrahedron 1989 45 , 4177) . However, the two pseudoenantioraeric alkaloid ligands (i.e. DHQ-OAc and DHQD-OAc; OAc = acetate) gave a mixture of stereo and regioisomeric products. The result indicates that this particular hydroxyamination process (be it stoichiometric or catalytic was unclear) had exhibited no "asymmetric" effects.
The procedure can therefore not be regarded as an asymmetric aminohydroxylation.
As a whole, the prior art uses hydroxycarbamates which always run at room temperature with either argento or mercurio salt analogs, monovalent ligands, stoichiometric or catalytic osmium species and organic solvents with trace amounts of water. (Sharpless et al. J. Am . Chem . Soc. 1978, 200, 3596; Sharpless et al. J. Org. Chem . 1980, 45 , 2710; Sharpless et al. U.S. Patent No.'s 4,871,855; 4,965,364; 5,126,494; EP 0 395 729). Cleavages of the hydroxycarbamates, to free aminoalcohols, are well known in the art and include mild acid or base hydrolysis and catalytic hydrogenolysis, depending on the attached functionality to the carbamate. (Greene, Protective Groups in Organic Synthesis , 1981, Wiley, 1st edn. pp. 223-249) . Currently, there is nothing in the art which directly converts achiral olefinic substrates to asymmetric β- hydroxyamides. What is needed, then, is a method for catalyzing the asymmetric amidohydroxylation of olefin substrates using a cost efficient oxidant which supplies both a carboxamide radical and a hydroxyl radical directly achieving asymmetric β- hydroxyamides in enhanced yields, enantiomeric efficiency, and regio-selectivity while reducing material and labor costs.
Summary of Invention The invention is directed to a method for converting olefinic substrates to asymmetric β-hydroxyamide products. The method of the invention employs an asymmetric addition reaction involving the addition of a carboxamide radical and a hydroxyl radical to the olefinic substrate. Enhanced yields, regioselectivity, and enantioselectivity may be achieved according to the method of the invention.
The asymmetric addition reaction is carried out in a reaction solution which includes the olefinic substrate, an osmium catalyst, a chiral ligand for enantiomerically and regioselectively directing the asymmetric addition, an N-halo carboxamide, a base, and a solvent in homogeneous or heterogeneous conditions. The N-halo carboxamide serves as a source for the carboxamide radical. The olefinic substrate and
N-halo carboxamide are present and soluble within the solvent or cosolvent in approximately stoichiometric amounts as defined below. The osmium is present within the solvent or co-solvent in catalytic amounts. One aspect of the invention is directed to a method for converting an olefinic substrate to an asymmetric amidoalcohol product by means of a one step osmium-catalyzed asymmetric addition. During the conversion, a carboxamide radical and a hydroxyl radical are added to the olefinic substrate. The reaction mixture employs a solvent having both an organic component and an aqueous component. The aqueous component of the solvent serves as the source of the hydroxyl radical. An N- halo carboxamide serves as the source of the carboxamide radical. The reaction mixture also includes the olefinic substrate, the N-halo carboxamide, an osmium-containing catalyst, a chiral ligand for enantiomerically directing said asymmetric addition, and a base.
Preferred N-halo carboxamides include N-fluoro- (Ci- C15(alkyl) ) -amide, N-chloro- (C1-C15(alkyl) ) -amide, N-bromo-(C!- C15(alkyl) ) -amide, N-iodo-(C1-C15(alkyl) ) -amide, N-fluoro- (aryl) - amide, N-chloro- (aryl) -amide, N-bromo- (aryl) -amide, N-iodo- (aryl) -amide, N-fluoro-2-chloro-(C1-C15(alkyl) ) amide, N-fluoro-2- bromo-(Cx-C15(alkyl) )amide, N-fluoro-2-iodo-(Cα-C15(alkyl) )amide, N-bromo-2-chloro-(C1-C15(alkyl) ) amide, N-bromo-2-bromo-(C!- C15(alkyl) ) amide, N-bromo-2-iodo-(Cη-C15(alkyl) ) amide, N-iodo-2- chloro-(C1-C15(alkyl) ) amide, N-iodo-2-bromo-(C1-C15(alkyl) ) amide, N-iodo-2-iodo-(C1-C15(alkyl) )amide, N-fluoro-alkoxybenzamide, N- chloro-alkoxybenzamide, N-bromo-alkoxybenzamide, N-iodo- alkoxybenzamide, N-fluoro-2-alkoxyacetamide, N-chloro-2- alkoxyacetamide, N-bromo-2-alkoxyacetamide, and N-iodo-2- alkoxyaceta ide. More particularly, preferred N-halo carboxamides are N-bromoacetamide, N-chloroacetamide, N- bromobenzamide, N-chlorobenzamide, N-fluoro-2-chloro-acetamide, N-fluoro-2-bromo-acetamide, N-fluoro-2-iodo-acetamide, N-bromo- 2-chloro-acetamide, N-bromo-2-bromo-acetamide, N-bromo-2-iodo- acetamide, N-iodo-2-chloro-acetamide, N-iodo-2-bromo-acetamide, N-iodo-2-iodo-acetamide, N-chloro-p-methoxy benzamide, N-chloro- 2-methoxy acetamide, N-bromo-p-methoxy benzamide, N-bromo-2-
methoxy acetamide, N-iodo-p-methoxy benzamide, and N-iodo-2- methoxy acetamide. The preferred concentration of the N-halo carboxamides is within a range of 0.50 to 10 equivalents. In a preferred mode, the N-halo carboxamide is present in near stoichiometric amounts.
Preferred osmium containing catalysts include potassium osmate dihydrate, osmium tetroxide, osmium(IV) oxide, osmium(IV) oxide dihydrate, osmium(III) chloride, and osmium hexachlorooxmate(IV) . In a preferred mode, the catalytic concentration of the osmium is within a range of 0.50 - 20 mole%.
Preferred chiral ligands include p-phenylbenzoyl dihydroquinidine; acetyl dihydroquinine; dimethylcarbamoyl dihydroquinine; benzoyl dihydroquinine; 4-methoxybenzoyl dihydroquinine; 4-chlorobenzoyl dihydroquinine; 2-chlorobenzoyl dihydroquinine; 4-nitrobenzoyl dihydroquinine; 3-chlorobenzoyl dihydroquinine; 2-methoxybenzoγl dihydroquinine; 3- methoxybenzoyl dihydroquinine; 2-naphthoyl dihydroquinine; cyclohexanoyl dihydraquinine; p-phenylbenzoyl dihydroquinine; methoxydihydroquinidine; acetyl dihydroquinidine; dimethylcarbamoyl dihydroquinidine; benzoyl dihydroquinidine; 4- methoxybenzoyl dihydroquinidine; 4-chlorobenzoyl dihydroquinidine: 2-chlorobenzoyl dihydroquinidine; 4- nitrobenzoyl dihydroquinidine; 3-chlorobenzoyl dihydroquinidine; 2-methoxybenzoyl dihydroquinidine; 3-methoxybenzoyl dihydroquinidine; 2-naphthoyl dihydroquinidine; cyclohexanoyl dihydroquinidine; and ligands represented by the following structures:
wherein Rx is radical selected from a group consisting of a group represented by one of the following structures:
In a preferred mode, the chiral ligand is present and soluble within the reaction solution at a catalytic concentration within a range of substantially 0.50 mole % to 10 mole %. In a preferred example, the catalytic concentration of the osmium is within a range of 0.50 - 20 mole% and the chiral ligand has a catalytic concentration of approximately 5 mole%.
Preferred bases include LiOH, NaOH, KOH, NH4OH, Na2C03, K2C03, CaC03, and BaC03.
In the preferred aqueous/organic solvent system, preferred organic compounds include methanol, ethanol, n-butanol, n- pentanol, n-propanol, 2-propanol, 2-butanol, tert-butanol, ethylene glycol; acetonitrile, propionitrile; tetrahydrofuran, diethyl ether, tert-butyl methyl ether, dimethoxyethane, 1,4- dioxane; dimethyl formamide, acetone, benzene, toluene, chloroform, and methylene chloride. The aqueous/organic solvent system may be either a homogenous or heterogeneous mixture. The aqueous component is water wherein the aqueous component of the solvent has a range between 10% and 90% on a volume basis. In a preferred mode, the aqueous and organic components of the solvent are each approximately 50% on a volume basis. Exemplary olefins include cis stilbene, trans stilbene, ethyl acrylate, styrene and C1-C6(alkyl) -cinnamate ester. A preferred reaction temperature is within a range between -5.0 and 5.0 °C.
Brief Description of Figures
Figure 1 illustrates preffered cinchona alkaloid ligand derivatives.
Figure 2 shows a generic scheme indicating that a variety of olefins, as defined below, can be reacted smoothly with 1.1 equivalents of the oxidant/nitrogen donor to give the vicinal aminoalcohols in good yield and with high enantiomeric excess.
Figure 3 illustrates Table 1: Acetamide based asymmetric aminohydroxylation of various olefins wherein the indicated notations are defined as follows [a] Conditions: see experimental procedure, [b] From reaction catalyzed by (DHQ)2- PHAL. [c] Determined by ^-NMR. [d] Determined by chiral HPLC (entry 1-4) or GC (entry 5) . [e] Negative values indicate the formation of the opposite enantiomer (product from reaction catalyzed by (DHQD)2-PHAL) . [f] Isolated yields of the pure products 1-5 after chromatography on silica gel. [g] tButanol/water 1:1 was employed, [h] KOH as base and 1-
Propanol/water 1:1 as the solvent was used, [i] CH3CN/water 1:1 was used as a solvent.
Figure 4 illustrates a large scale synthesis based on acetamide as the oxidant for the amidohydroxylation.
Figure 5 illustrates regioselectivity preferences using AQN ligands and N-bromobenzamide.
Figure 6 illustrates the reversal of the regioselectivity with styrene derivatives wherein the indicated notations are defined as follows: [a] Conditions: see experimental procedure, [b] The DHQD-derivative was used, [c] Determined by ^-N R. [d] Determined by chiral HPLC. [e] Yields refer to the mixtures of isomers after chromatography on silica gel. [f] Not determined.
Figure 7 illustrates the effects on regio and stereochemistry using acetamide base amidohydroxylation using (DHQD)2PHAL (entries 1-3) or the (DHQD)2AQN (entries 4-6) ligands on the respective olefins (substrate olefins not shown) .
Figure 8 illustrates heterogenous conditions with a phase transfer catalyst wherein the stereochemistry is reversed using the indicated AQN ligand.
Detailed Description:
The β-aminoalcohol moiety is a widespread structural motif in natural products and synthetic drugs. Its generation in an enantioselective manner via metal catalysis represents a major challenge for synthetic organic chemists. The catalytic asymmetric aminohydroxylation (AA) represents an even more elegant approach. Alkenes are therein converted into protected β-amino alcohols in a single step via a syn-cycloaddition catalyzed by osmium salts and chiral quinuclidine-type ligands derived from cinchona alkaloids. Three major aspects are to be addressed in this reaction: namely, chemo-, regio-, and enantioselection. The most important variable is the ultimate oxidant/nitrogen source for the generation of the active osmium(VIII) imido species responsible for aminohydroxylation. As described in the background, several different reactants have been introduced in the literature thus far: the akali metal salts of (1) N-halosulfonamides (for the synthesis of β-hydroxysulfonamides) , and the 2) N-halocarbamates (for the synthesis of β-hydroxycarbamates) . What is needed, however, is a direct method to synthesize β-hydroxycarboxamides, the amide form of β-aminoalcohols, which are important chemical moieties found in such important targets as the anticancer taxol.
The invention is therefore directed to a novel method for the regio-selective and enantio-selective conversion of olefins to β-hydroxyamides using an Ν-halo carboxamide as the oxidizing
agent in the presence of an osmium catalyst and a chiral ligand.
Alkali metal salts of N-chloro carboxamides have been well- known for their proclivity to undergo Hofmann rearrangement (Hofmann et al. Ber. 1881, 14, 2725; Wallis et al . Org. React . 1967, 3, 267-306) . For the invention, however, were pleased to find that this undesirable competing reaction could be completely supressed by operating at 4 °C while also using the more stable N-bromo derivative (the acetamide derivative, N- bromoacetamide is commercially available from Lancaster, but it should be recrystallized in a mixture of chloroform/hexane 1:1 before use. We recommend preparation via the published procedure by Oliveto et al. Org. Synth . , Coll . Vol . IV 104-105. The purity of this oxidant was checked via acid-base titration using the procedure of Bachand et al. J. Org. Chem . 1974, 39, 3136-3138 and Virgil et al. (N-Bromoacetamide) in Encyclopedia of Reagents for Organi c Synthesis, Vol . 1 (Ed.: L. A. Paquette) , John Wiley & Sons, 1995, p. 691) . By suppressing the competing Hof an rearrangement, therefore, we were able to obtain the direct conversion of olefins to β-hydroxyamides using the Ν-halo carboxamide as oxidizing agent in the presence of an osmium catalyst.
In particular, in the presence of 4 mol-% of potassium osmate dihydrate and 5 mol-% of the second generation alkaloid ligands (Kolb et al. Chem. Rev. 1994, 94, 2483-2547) olefins reacted smoothly with 1.1 equivalents of the oxidant/nitrogen donor to give the vicinal aminoalcohols in good yield and with high enantiomeric excess as generally shown in Figure 2.
For each olefin class given in Figure 3, the reaction parameters were optimized in terms of ligand, solvent, base and base/oxidant ratio; since the base/oxidant ratio should not exceed 1:1, the amount of hydroxide resulting from the initial K20s02 (OH) 4-oxidation to OsVIII, releasing two equivalents of base, was taken into account. Both product enantiomers can be obtained by using either 'pseudoenantiomers ' of the alkaloid
ligands (Kolb et al. Chem. Rev. 1994, 94, 2483-2547) . A major advantage of this system is that only a stoichiometric amount of oxidant is needed, rather than an excess of oxidant, which greatly simplifies isolation and purification of the product. In fact, use of excess of oxidant does not improve the reaction in any way.
As in the sulfonamide and carbamate based transformations, cinnamates are among the best substrates (Figure 3, entries 1-3; the use of isopropyl cinnamates instead of the methyl esters is preferable in terms of greater stability towards hydrolysis and enhanced regioselectivity under the reaction conditions. As in the case of compounds 1 and 2, which are quite soluble in the reaction medium, the use of more than 50 % (v/v) water may result in slightly increased regioselectivities) . While cis- stilbene gave mostly diol, trans-stilbene afforded the threo- aminoalcohol 4 in 50 % yield (together with 10 % diol) and high enantiomeric excess (Figure 3, entry 4) . Ethyl acrylate gave rise to the isoserine derivative as the major regioisomer detected by Η-NMR (isoserine/serine" >20 : 1, Figure 3, entry 5). It is important to note that, with styrenes as substrates (Figure 5) , the regioselectivity is highly dependent on the choice of solvent and ligand. For example, alcoholic solvents resulted in a slight preference (8/7 = 1.1-2.5:1) for introduction of the nitrogen substituent at the benzylic position (regioisomer 8, Figure 6) , whereas acetonitrile significantly favored the other regioisomer (7) (7/8 = 2-13:1). In most cases, the benzylic amides were formed with higher asymmetric induction (8, 85-96 % ee) than the benzylic alcohols (7, 62-94 % ee) , but poor regioselectivity was observed when phthalazine ligands were used. However, our recently introduced anthraquinone (AQN) ligands (Becker et al. Angew. Chem. 1996, 108, 447-449; Angew. Chem . Int . Ed. Engl . 1996, 35, 448-451). Both (DHQ)2-AQN and (DHQD)2-AQN were more effective, leading to good regioselectivities with this olefin class (Figure 6, entry 3,6,9). The AA protocols now enable selective synthesis of
either of the regioisomeric 3-aminoalcohols derived from styryl olefins. The phenyl glycinols (8) arise using the carbamate 7ΛA/phthalazine ligand combination and the adrenaline-type regioisomers (7) are preferentially derived using the acetamide AA/anthraquinone ligand combination. Experiments with other substrates indicate that a reversal of regiochemistry occurs when anthraquinone derived ligands instead of phthalazines are used.
Irrespective of the regiochemical outcome, the facial selectivity of these acetamide AA reactions agrees with the face selectivity rule for the AD (so far, only a few exceptions to our mnemonic device for the AD have been reported: Hale et al . Tetrahedron Lett . 1994, 35, 425-428; Krysan et al . , Tetrahedron Lett . 1996, 37, 1375-1376; Boger et al. J. Am. Chem . Soc . 1996, 118, 2301-2302; Salvadori et al . J. Org. Chem. 1996, 61 , 4190- 4191; Vanhessche et al. J. Org. Chem. 1996, 61 , 7987-7979) . Thus, dihydroquinine derived ligands (DHQ class) give rise to oxidation from the -face of the olefin, whereas the diastereomeric dihydroquinidine (DHQD) ligands effect attack on the β-face of the double bond.
With this efficient new process in hand, we focused on its application for a large scale synthesis of ( 2R, 3S) -3- phenylisoserine (the yield might be further increased (5-10 %) by optimizing the isolation procedure; we believe that this new amide-AA-based protocol is superior to our earlier AA- or AD- based approaches: Wang et al. J. Org. Chem . 1994, 59, 5104- 5105) a precursor for the side chains of the anti-cancer drugs Taxol and Taxotere®.
A 630-fold scale-up of our standard one mmol recipe was undertaken with a somewhat lower catalyst loading (1.5% osmate salt and 1% (DHQ)2PHAL), which did not affect the outcome of the catalysis. The fact that less ligand than osmium can be used, demonstrates once again the great advantages of a ligand accelerated catalysis (LAC) ; for a review see D. J. Berrisford, C. Bolm, K. B. Sharpless, Angew. Chem. 1995, 107, 1159-1171;
Angew. Chem. Int . Ed. Engl . 1995, 34, 1059-1070. The AA product was isolated by crystallization of the crude reaction mixture from ethyl acetate/hexane, and a second crop from diethyl ether. Subsequent hydrolysis furnished the enantiomerically pure aminoalcohol as the hydrochloride salt (9) in 68 % yield over two steps (Figure 4) .
The amidohydroxylation employing the use of N- bromoacetamide as the nitrogen source with styrenes as the olefin shows that the regiochemistry of aminoalcohol formation is reversed from that delivered by the carbamate version of the AA. An efficient large scale synthesis of enantiomerically pure 3-phenylisoserine highlights the prodical potential of this latest advance in the osmium-catalyzed asymmetric aminohydroxylation process. Generally, alkali metal salts of N-chloro carboxamides are unstable and readily undergo Hofmann rearrangement. Thus the N- bromo derivatives are preferred oxidants for amidohydroxylation reactions run at 4 °C. The standard substrates are smoothly converted into protected amidoalcohols with N-bromo alkali (K+ or Li+) salts of acetamide. When working with styrene derivatives and alkaloid ligands that contain an anthraquinone spacer (AQΝ ligands) , the regiochemistry is reversed compared to the carbamate procedure with phthalazine (PHAL) ligands, see Figure 7. 1.1 equivalents of the oxidant/nitrogen source suffice for complete conversion, and for isopropyl cinnamate as the olefin, the catalyst loading can be significantly lowered without affecting yield or enantioselecitvity.
Lowering the amount of catalyst and/or ligand does not influence yield, regioselectivity or ee of the amidohydroxylation (example: acetamide amidohydroxylation of isopropyl cinnamate on a large scale) . This is in contrast to the carbamate procedures.
Only stoichiometric amounts of nitrogen sources are
necessary, in contrast to the carbamate recipes where 2-3 equivalents with respect to the olefinic substrate are needed for complete conversion and high ee/regioselectivity.
Electronic tuning of the nitrogen source by using amides of different pKa's is possible (and thus the reactivity can be varied) , in contrast to the carbamate nitrogen sources where the acidity of the carbamate nitrogen protons stays more or less the same no matter which carbamate is used.
When using anthraquinone-type (AON) ligands such as (DHQ)2AQN or (DHQD)2AQN and acetamide, the major product is formed in high ee bearing the nitrogen substituent in the terminal position (adrenaline type products) . The carbamate recipe gives similar regioselectivities in those cases but the ee's are low. Under biphasic conditions with benzamides as nitrogen sources, electron poor cinnamates (e.g. ethyl 3-nitrocinnamate) can also be converted to the products bearing the nitrogen substituent to the ester group in high regioselectivity. The carbamate recipe gives low regioselectivities (typically 1:1) in those cases.
Nitrogen Sources (Oxidant)
The amide-based nitrogen oxidant source, the N-halo carboxamide, is generally used in near stoichiometric amounts (eg. 0.90 - 1.2 equivalents; defined herein as near stoichiometric amounts) but can operate efficiently in the range of 0.50 equivalents (less for difficult purification conditions and inexpensive olefins) to 10 equivalents (for less reactive olefins) wherein the N-halo carboxamide can be commercially purchased or synthesized according to standard procedures well known in the art as disclosed vida supra. The addition of an alkali metal in situ, forms the alkali metal salt of the N-halo carboxamide. One can generate beforehand this salt, if desired by premixing the N-halo carboxamide in a basic solution containing the alkali metal (eg. LiOH, NaOH, etc.).
The genus of amide-based nitrogen sources which are preferred with the invention include the following N-halo carboxyamides : N-fluoro- (C!-C15 (alkyl) ) -amide, N-chloro- (Cx- C15 (alkyl) ) -amide, N-bromo- (C!-C15 (alkyl) ) -amide, N-iodo- (Cx- C15 (alkyl) ) -amide, N-fluoro- (aryl) -amide, N-chloro- (aryl) -amide, N-bromo- (aryl) -amide, N-iodo- (aryl) -amide, N-fluoro-2-chloro- (Cx- C15 (alkyl) ) amide, N-fluoro-2-bromo- (C1-C15 (alkyl) ) amide, N-fluoro- 2-iodo- (Ci-Cis (alkyl) ) amide, N-bromo-2-chloro- (Cx-C15 (alkyl) ) amide, N-bromo-2-bromo- (C^C-^ (alkyl) ) amide, N-bromo-2-iodo- (Cx- C15 (alkyl) ) amide, N-iodo-2-chloro- (Cx-C^ (alkyl) ) amide, N-iodo-2- bromo- (C^C^ (alkyl) ) amide, N-iodo-2-iodo- (C^C^ (alkyl) ) amide, N- fluoro-alkoxybenzamide, N-chloro-alkoxybenzamide, N-bromo- alkoxybenzamide, N-iodo-alkoxybenzamide, N-fluoro-2- alkoxyacetamide, N-chloro-2-alkoxyacetamide, N-bromo-2- alkoxyacetamide, and N-iodo-2-alkoxyacetamide wherein aryl is defined as any substituted or unsubstituted aromatic containing amides and alkyl is defined as any C1-C15 aliphatic containing amides .
In particular, the following species of N-halo carboxyamides work optimally well with the procedure: N- bromoacetamide, N-chloroacetamide, N-bromobenzamide, N- chlorobenzamide, N-fluoro-2-chloro-acetamide, N-fluoro-2-bromo- acetamide, N-fluoro-2-iodo-acetamide, N-bromo-2-chloro- acetamide, N-bromo-2-bromo-acetamide, N-bromo-2-iodo-acetamide, N-iodo-2-chloro-acetamide, N-iodo-2-bromo-acetamide, N-iodo-2- iodo-acetamide, N-chloro-p-methoxy benzamide, N-chloro-2-methoxy acetamide, N-bromo-p-methoxy benzamide, N-bromo-2-methoxy acetamide, N-iodo-p-methoxy benzamide, and N-iodo-2-methoxy acetamide. The following table contains additional data on N-bromo-N- lithio amide nitrogen sources other than from acetamide (isopropyl cinnamate as olefin, standard conditions as described in the paper attached to the claim, solvent tbutanol/water 1:1, no ee's determined. A= major regioisomer, B= minor regioisomer, C= diol byproduct) :
Amide Convrsn/% A/B (A+B)/ n-butyramide 99 25:1 13:1 benzamide 94 1.8:1 1:1.6 p-methoxy benzamide 75 2:1 3:1
2-methoxy acetamide 55 15:1 3:1
Olefin Classes
The asymmetric amidohydroxylation (AA) works well with three olefin classes: 1) monosubstituted; 2) cis-disubstituted, and 3) trans-disubstituted olefins. The 1,1 disubstituted and trisubstituted types of olefins give only racemic or low ee's while the tetrasusbstituted class, does not provide any signs of turnover; /β unsaturated esters, α/β unsaturated amides, aromatic olefins and heteroaromatic olefins work particularly well with the invention.
Regioselectivity
High regioselectivity is one of the more useful features of the amidohydroxylation. The chemistry exhibits a strong preference for nitrogen attachment to the olefinic carbon bearing an aromatic substituent or, in the case of olefins conjugated with a strong electron withdrawing group (EWG) , the nitrogen is strongly directed to the olefinic carbon distal to the EWG. The alkaloid ligand is responsible for high regioselectivity. When the ligand is omitted, there is little preference for either regioisomer. Beyond probable contributions from "binding pocket" effects, the strong regioselection phenomenon requires the operation of powerful electronic determinants.
Solvent Variations:
Preferred solvents include acetonitrile, n-propanol, tert- butanol and suitable solvents include methanol, ethanol, n- butanol, n-pentanol, n-propanol, 2-propanol, 2-butanol, tert- butanol, ethylene glycol; nitriles: acetonitrile, propionitrile;
ethers: tetrahydrofurane, diethyl ether, tert. butyl methyl ether, dimethoxyethane, 1,4-dioxane; miscellaneous: dimethyl formamide, acetone, benzene, toluene, chloroform, methylene chloride.
Solvent Concentration Varations:
In its present form the process starts to give lower selectivities for some substrates when the concentration of olefin (which of course prescribes the standard concentration of all the other species) gets much above 0.1 molar.
Ligand Variations;
Preferred ligands are shown in Figure 1 and are commercially available or synthesized by procedures well known in the art. Additional preferred ligands, which can be equally used with the invention with the specified concentrations as described herein, are as follows: p-phenylbenzoyl dihydroquinidine; acetyl dihydroquinine; dimethylcarbamoyl dihydroquinine; benzoyl dihydroquinine; 4-methoxybenzoyl dihydroquinine; 4- chlorobenzoyl dihydroquinine; 2-chlorobenzoyl dihydroquinine; 4- nitrobenzoyl dihydroquinine; 3-chlorobenzoyl dihydroquinine; 2- methoxybenzoyl dihydroquinine; 3-methoxybenzoyl dihydroquinine; 2-naphthoyl dihydroquinine; cyclohexanoyl dihydraquinine; p- phenylbenzoyl dihydroquinine; methoxydihydroquinidine; acetyl dihydroquinidine; dimethylcarbamoyl dihydroquinidine; benzoyl dihydroquinidine; 4-methoxybenzoyl dihydroquinidine; 4- chlorobenzoyl dihydroquinidine: 2-chlorobenzoyl dihydroquinidine; 4-nitrobenzoyl dihydroquinidine; 3- chlorobenzoyl dihydroquinidine; 2-methoxybenzoyl dihydroquinidine; 3-methoxybenzoyl dihydroquinidine; 2-naphthoyl dihydroquinidine; and cyclohexanoyl dihydroquinidine.
The ligand can range from ca. 0.5 to 10 mol % (less is appropriate for lower temperatures; eg. 0.5 % might be enough at O °C and 10 % would probably be needed to keep the % ee at
reasonable levels if the temperature reaches 35 or 40 °C. In practice, the molarity of the ligand matters and the amount of ligand needed to realize the "ceiling ee" scales directly with the reaction concentration (ie if twice the volume of solvent is used, then the mol% of ligand added must also double to keep its molarity constant and correspondingly if the reaction is run twice as concentrated as usual (see general recipe below) then half of the usual mol % ligand gives the needed ligand molarity) . Because the crucial binding of the ligand is an extremely rapid bimolecular process, the equilibrium constant is highly sensitive to temperature which is why the molarity of ligand needed, increases rapidly with temperature.
Osmium Variations: The osmium containing catalyst can be selected from any one of the various commercially available osmium sources including, but not restricted to potassium osmate dihydrate, osmium tetroxide, osmium(IV) oxide, osmium(IV) oxide dihydrate, osmium(III) chloride, and osmium hexachlorooxmate (IV) . The amount of Os catalyst can range from 0.5% (probably even less in the very best cases, and in any case the number will drop as the process if further improved) to 10 or even 20%. The general procedure conditions uses 4% to have fast reaction times, but 2% is good for most cases. The high loadings of 20%, for example, is needed to achieve reasonable rates with very poor substrates (this conclusion follows from the extensive experience by us and others with the AD, where in desparate situations 20 or more % Os catalyst is needed.
As a typical example of the ranges that are preferred, the following table contains data on the amount of osmium and ligand one can use for the isopropyl cinnamate AA with N-bromo acetamide.
Mol-% Mol-% Conversion A/B (A+B) /C ee/s
K2[Os02(OH) J (DHQ)2PHAL /%
4 5 99 25:1 25:1 99
1.5 1 99 25:1 25:1 99
0.9 0.6 99 20:1 11:1 99
0.4 0.5 89 15:1 2.4:1 n. d
0.2 0.25 36 2:1 1.4:1 n. d
Temperature Variations: For most cases, the hydroxyamide AA process is run between -5.0 and +5.0 degrees Celcius. There may be cases where up to 35 to 40 degrees may be advantageous depending on substrate.
Heterogeneous Condition Variation: For most cases, the hydroxyamide AA process is run in homogeneous conditions, however, applying heterogeneous phase transfer conditions as illustrated in Figure 8, enhanced chemoselectivity was found for some olefins (see synthesis for: methyl (2S, 3R) -2- (benzamido) -3-hydroxy-3- (4-fluoro-3- nitrophenyDpropanoate 16, vida infra). In particular, we found that the AQN ligands furnished a complete reversal of the regioselectivity with cinnamates as olefins.
Phase Transfer Catalysts: For heterogeneous conditions, a commercially available phase transfer catalyst such as tetra-n-butylammonium hydroxide is preferred, however other standard phase transfer catalysts (eg. tetra-alkyl ammonium or phosphonium salts) work well equally with the invention when heterogeneous conditions are required.
Base variations;
For most cases, the hydroxyamide AA process is run in LiOH or KOH, however other alkali earth bases such as NaOH and CsOH are acceptable using the conditions and concentrations as indicated
vida infra. Preferred bases are LiOH, NaOH, KOH, NH4OH, alkyl or arylammonium hydroxides, and alkali or earth alkali salts of carbonates and bicarbonates (eg. Na2C03, K2C03, CaC03, BaC03 et.)
General Conditions:
While a preferred form of the invention has been shown in the description, drawings and synthetic protocals, variations in the preferred form will be apparent to those skilled in the art using the disclosed variety of substrates and reagents with the range of conditions indicated herein. The invention should not be construed as limited to the specific form shown and described, but instead is as set forth in the following claims.
Synthetic Protocals
NMR spectra were recorded on Bruker AMX-500, AM-300, or AM- 250 instruments. The following abbreviations were used to explain the multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; apt, apparent; b, broad; obs, obscured. IR spectra were recorded on Nicolet 205, Perkin Elmer 1600 or Galaxy 2020 series FT-IR spectrophotometers . Optical rotations were recorded using a Perkin Elmer 241 polarimeter. High-resolution mass spectra (HRMS) were recorded on a VG ZAB- ZSE mass spectrometer under Fast Atom Bombardment (FAB) conditions, at the Scripps Research Institute.
All reactions were monitored by color change, HPLC, GC or thin-layer chromatography carried out on 0.25 mm Whatman silica gel plates (K6F-60 A) using UV light, p - anisaldehyde, or 7% ethanolic phosphomolybdic acid and heat as developing agent. E. Merck silica gel (60, particle size 0.040-0.063 mm) was used for flash column chromatography. Tetrahydrofuran (THF) and ethyl ether were distilled from sodium-benzophenone and methylene chloride, benzene and toluene were distilled from calcium hydride. All reagents were obtained from Aldrich Chemical Co. Inc. unless otherwise noted. Solvents used for workup, chromatography, and recrystallizations were reagent grade from Fisher Scientific and were used as received. General Procedure using homogenous condtions:
Carry out all procedures in a well-ventilated laboratory, an wear disposable vinyl or latex gloves.
Equipment
* Stainless steel reaction vessel (40 L) * Mechanical stirrer w. stainless steel stirring shaft (1 m) and four blade rotor (6 cm)
* Immersion cooler w. cold finger probe
* Low temperature thermometer
* Erlenmeyer flask (2 L)
* Teflon-coated magnetic stirbar (4 cm)
* Erlenmeyer flask (1 L)
* PVC tubing (1 m x 10 mm) * 2 Erlenmeyer flasks (4 L)
* Glass filter (15 cm) with folded filter paper
* Single-necked round bottomed flask (2 L)
* Sintered glass filter funnel (2 L, medium porosity)
* Recovery flask (4 L) * High vacuum pump
* Oil bath (0.5 L)
* Single-necked round bottomed flask (1 L)
* Reflux condensor
* Sintered glass filter funnel (1 L, medium porosity)
Materials
Hydroquinine 1, 4-phthalazinediyl diether, (DHQ)2PHAL, 9.738 g, 12.5 mmol
* t-Butanol, 7.5 L * Lithium hydroxide monohydrate 56.12 g, 1.337 mol
* Water, 11.25 L
* 'Potassium osmate dihydrate' (K2 [0s02 (OH) 4] ) , 6.909 g, 18.75 mmol
* Isopropyl cinnamate 237.8 g (96 % pure by GC) , c. 1.250 mol
* N-Bromoacetamide 195.6 g (97 % pure by titration) 1.375 mol
* Sodium sulfite, 150 g
* Sodium chloride, 1.5 kg * Ethyl acetate, 22.55 L
k Anhydrous sodium sulfate, 1.3 kg
* Chloroform, 0.4 L
* Silica gel for filtration
* Hexane, 0.3 L
* Diethyl ether, 0.6 L
* t-Butyl methyl ether, 0.1 L
* 10 % Hydrochloric acid, 1.5 L
Synthetic steps :
1. In a stainless steel reaction vessel (40 L) equipped with a mechanical stirrer, a thermometer and an immersion cooler with a temperature controller set to 4 °C, dissolve hydroquinine 1,4- phthalazinediyl diether, (DHQ)2PHAL, (9.738 g, 12.5 mmol), in t- butanol (7 L) with stirring (150 rpm) .
2. Add water (10 L) and start cooling.
3. In an Erlenmeyer flask (2 L) , dissolve lithium hydroxide monohydrate (56.12 g, 1.337 mmol) in water (1.25 L) with stirring. Add K2 [Os02 (OH) 4] (6.909 g, 18.75 mmol) and continue stirring until you obtain a pink solution.
4. Pour the osmate solution into the reaction vessel.
5. Add isopropyl cinnamate (273.8 g, c. 1.25 mol). Rinse the residual olefin with t-butanol (0.5 L) . Add N-bromoacetamide (195.6 g, c. 1.375 mol) quickly in a single portion at 4 °C. Continue stirring of the green reaction mixture at this temperature for 3.5 hours .
6. At this point, a thin layer chromatogram shows the absence of starting material (Rf = 0.85) and the mixture is red. Add sodium sulfite (150 g) , remove the immersion cooler and stir for 12 hours.
7. Add 1.5 kg ΝaCl and stir for 15 min. Stop stirring and allow phase separation. Siphon the upper organic layer through a PVC tubing (1 m, 10 mm diameter) into two Erlenmeyer flasks (4 L)
which contain anhydrous sodium sulfate (300 g each) .
8. Filter the dried solution into a single-necked, round- bottomed flask (2 L) and concentrate the mixture on a rotary evaporator set to 60 °C. 9. Extract the remaining aqueous layer with ethyl acetate (1 x 6 L and 3 x 4 L) . Decant the organic extract into the Erlenmeyer flasks.
10. Concentrate the organic extracts until you obtain a dark, red oil. Add a mixture of warm ethyl acetate-chloroform (1.6 L, 3:1 v/v). Filter through a sintered glass filter funnel containing a 5-cm layer of Si02, covered with a 1-cm layer of Na2S04. Wash with ethyl acetate (3 L) . Evaporate the filtrate in a round-bottomed single-necked flask (2 L) to a volume of c. 0.8 L, add hexane (250 L) and a magnetic stirbar. Cool with stirring to 4 °C with an ice-water bath.
11. After 1 h, filter the suspension through a sintered glass filter funnel (1 L) and wash with ethyl acetate/hexane (250 mL, 3:2 v/v) . Dry the filter cake under high vacuum for 4 h to yield 233 g of the AA product. 12. Concentrate the mother liquor and triturate with diethyl ether/t-butyl methyl ether (200 mL, 1:1 v/v). Filtration after 2 h and drying yields another 27 g of product. The combined crystalline, white solid, 260 g is of 99 %ee as determined by HPLC on Chiralcel OD-H, Daicel, i-PrOH/hexane 40:60 v/v, 0.5 mL/min, 254 nm; retention times: 8.2 min ( 2S, 3R) , 12.7 min ( 2R, 3S) .
13. Heat the combined material in a 2 L round-bottomed flask immersed in an oil bath and equipped with a reflux condenser and a magnetic stirbar in 10 % HCl (1.5 L, 4 h, 100 °C) . 14. Concentrate the mixture to c. 20 % of the initial volume on a rotary evaporator set to 60 °C.
15. Filter the product through a sintered glass funnel (1 L) , wash with cold diethyl ether (0.5 L) , and dry the white crystals of hydrochloride ( 2R, 3S) for 12 h under high vacuum at 40 °C;
m.p. 224-6 °C, [a]o(25,D) = -14.8 (c = 0.55, 6 M HC1) , 209.5 g, 77 % (based on 96 % GC-pure cinnamate) .
2nd example of homogeneous procedure: (example using isopropyl cinnamate)
In 3 mL of an aqueous solution of LiOH.H20 (42.8 mg, 1.02 mmol), K2Os02(OH)4 (14.7 mg, 0.04 mmol, 4 mol %) was dissolved with stirring. After addition of tBuOH (0.17 Molar; 6 mL) , (DHQ)2-PHAL (39 mg, 0.05 mmol, 5 mol %) was added and the mixture was stirred for ten minutes to give a clear solution. Water
(0.17 Molar; 6 mL) was added subsequently, and the mixture was immersed in a cooling bath set to 4 °C. After addition of isopropyl cinnamate (190 mg, 1 mmol), N-bromoacetamide (151.8 mg, 1.1 mmol; N-bromoacetamide is commercially available (e.g. from Lancaster), but.it should be recrystallized (CHCl3/hexane 1:1) before use. We recommend preparation via a published procedure: E. P. Oliveto, C. Gerold, Org. Synth . , Coll . Vol . IV 104-105. The purity of this oxidant was checked via acid-base titration: Bachand et al. J. Org. Chem. 1974, 39, 3136-3138. (b) S.C. Virgil ( N-Bromoacetamide ) in Encyclopedia of Reagents for Organic Synthesis, Vol . 1 (Ed.: L. A. Paquette) , John Wiley & Sons, 1995, p. 691) was added in one portion (which resulted in an immediate color change to green) and the mixture was vigorously stirred at the same temperature. The reaction was monitored by tic and pH control (full conversion is indicated when the mixture reaches pH 7) . After 20 h, the reaction mixture was treated with Νa2S03 (0.5 g) and, after stirring at room temperature for 30 min, ethyl acetate (5 mL) was added. The organic layer was separated, and the water layer was extracted with ethyl acetate (3 x 10 mL) . The combined organic extracts were washed with brine (5 mL) , and dried over MgS04. After evaporation of the solvent, the crude product was purified by chromatography on silica gel (hexanes/ethyl acetate 1:1) to give 215 mg (81 % yield, 99 % ee) of isopropyl ( 2R, 3S) -3-
(acetylamino) -2-hydroxy-3-phenylpropanoate (1) .
Homogeneous procedure with modifications of the above procedure: see Figure 3. For styryl olefins (Figure 6), 1.0 eq. KOH and a 1:1 solvent/water ratio (15 mL) was employed. For reactions with anthraquinone based ligands, (DHQD)2-AQN (42.8 mg, 0.05 mmol, 5 mol %) instead of the PHAL ligand were used.
Homogeneous procedure for large scale synthesis using the example of (2R,3S) -3-phenylisoserine hydrochloride (9) :
The above procedure was followed with 120.0 g isopropyl cinnamate (0.631 mol, not corrected for purity, 96 %, Lancaster), tBuOH (3.79 L) , water (5.68 L) , 99.71 g (0.694 mol, 96 % pure upon titration) N-bromoacetamide, 28.32 g (1.07 eq., 0.675 mol) LiOH.H20, [6] 4.914 g (DHQ)2-PHAL (6.31 mmol, 1 mol %) and 3.486 g (9.08 mmol, 1.5 mol %) K2Os02(OH)4. Reaction time: 4 h. To separate the ligand after completion of the reaction, the crude product was taken up in 500 mL ethyl acetate and passed through a 4.5-inch sintered glass funnel covered with a one inch layer of silica gel. Product purification was accomplished by recrystallization from ethyl acetate/hexane 1:2 (4 mL/g) . A second crop of material was obtained by trituration of the previously evaporated mother liquor with 100 mL Et20 and subsequent filtration. Yield 119.5 g (71 % yield, 99 % ee) . Hydrolysis of this material (10 % HC1, reflux, 4 h, followed by concentration and filtration) provided 92.5 g (68 % over two steps) enantiomerically pure ( 2R, 3S) 9 (m.p. 224-226 °C, [α]\o(25,D) = -14.9 (c = 0.55 in 6N HC1, lit. -14.8); correct elemental analysis.
Heterogeneous Example: Synthesis of methyl (2S, 3R)-2- (benzamido) -3-hydroxy-3- (4- luoro-3-nitrophenyl)propanoate (16) wherein ligand used is (DHQD)≥-PHAL) as shown in Figure 8.
In 2 ml of an aqueous solution of phase transfer reagent tetra- n-butylammonium hydroxide (170.3 mg of a 40 % aqueous solution, 0.2625 mmol; commercially available - see above for other available phase transfer catalysts), K2Os02OH4 (3.68 mg, 0.01 mmol, 4 mol-%) was dissolved with stirring. After addition of chlorobenzene (2 ml), (DHQD)2-AQN (10.72 mg, O.OX mmol, 5 mol-%) was added with stirring, and the mixture was immersed in a cooling bath set -to 4 °C. After addition of methyl 4-fluoro-3- nitrocinnamate (56.3 mg, 0.25 mmol), N-bromobenzamide (55.0 mg, 0.275 mmol) was added in one portion, (color change to green) and the mixture was vigorously stirred at the same temperature. After 16 h, the reaction mixture was treated with 0.2 g Na2S03 and after stirring at room temperature for 30 min, ethyl acetate (5 ml) was added. The organic layer was separated, and the water layer was extracted with ethyl acetate (3 x 10 rnL) . The combined organic extracts were washed with brine (5 mL) , and dried over MgS04. After evaporation of the solvent, the crude product was purified by chromatography on silica gel (hexanes/ethyl acetate 1:2) to give 46.4 mg (53 %) methyl (2S,3R)-N- (benzamido)-2amino-3-hydro -3- (4-fluoro-3-nitro- phenyl)propanoate (16) .
Experimental Data for selected compounds :
sopropyl (2R,3S) -3- (acetylamino) -2-hydroxy-3-phenylpropanoate (1)
M.p. 112-113 °C; [α]o(", = +20.0 (c = 1.16 in 95 % EtOH) ; *H NMR
(400 MHz, CDC13) δ = 1.21 (d, J = 6.3 Hz, 3H) , 1.29 (d, J = 6.3 Hz, 3H) , 1.97 (s, 3H) , 4.46 (d, J = 2.3 Hz, IH) , 5.09 (septet, J = 6.3 Hz, 1 H) , 5.54 (dd, J = 9.3, 2.3 Hz, IH) , 6.46 (d, 9.3 Hz, IH) , 7.26-7.40 ( , 5 H) ; 13C NMR (100 MHz, CDC13) δ = 21.4, 21.6, 23.0, 54.4 (2C) , 70.6, 73.3, 126.8, 127.7, 128.5, 138.8, 169.5, 172.3; FT-IR (neat): o(~,v) = 3344, 1732, 1656, 1103 cm"1; HR-MS (NBA/Nal) : m/z: exp. 288.1216 [M+Na]\ calc. 288.1212 for C14H19N04Na; HPLC: Chiralcel OD-H, 40 % iPrOH/hexane, 0.5 mL min"1, 254 nm, 8.2 min (25, 3R) , 12.7 min (2R,3S) . The absolute configuration was established, after hydrolysis, by comparison to the known (2R,3S) aminoalcohol hydrochloride, I1<" [ ]o(25,D) = - 14.9 (c = 0.55 in 6N HC1) .
Isopropyl (2S,3R) -3- (acetylamino) -2-hydroxy-3- (2- methoxyphenyl) propanoate (enfc-2) (ligand = (DHQD)Z-PHAL)
M.p. 161-162 °C; [ ]o(25,D) = -16.9 (c = 1.41 in 95 % EtOH) ; Η ΝMR (400 MHz, CDC13) δ = 1.12 (d, J = 6.3 Hz, 3H) , 1.24 (d, J = 6.3 Hz, 3H) , 1.98 (s, 3H) , 3.43 (d, J = 5.4 Hz, IH) , 4.53 (dd, J = 5.4, 4.1 Hz, IH) , 5.00 (septet; 6.3 Hz, IH) , 5.70 (dd, J = 8.8, 4.1 Hz, IH) , 6.87 (br d, J = 8.8 Hz, IH) , 6.84-6.95 (m, 2H) ,
7.17-7.28 (m, 2H) ; 13C ΝMR (100 MHz, CDC13) δ = 21.3, 21.6, 23.2, 52.0, 52.1, 55.4, 69.9, 72.5, 110.6, 120.6, 126.0, 128.1, 129.0, 156.6, 169.6, 172.6; FT-IR (neat) : o(-,v) = 3326, 1727, 1643, 1242 cm-1; HR-MS (ΝBA/Νal) : m/z: exp. 318.1323 [M+Νa]+, calc. 318.1317 for C15H21Ν06Νa; HPLC: Chiralcel OG, 15 % iPrOH/hexane, 1 mL min-1, 254 n , 12.6 min (2S,3R), 16.7 min (2R,3S) . The absolute
configuration is assumed to be ( 2S, 3R) in analogy to the AA product from isopropyl cinnamate.
Isopropyl (2i?,3S) -3- (acetylamino) -2-hydroxy-3- (4- methoxyphenyl) propanoate (3)
M.p. 159-160 °C; [α]θ(",D) = +38.9 (c = 1.00 in 95 % EtOH) ; Η NMR (400 MHz, CDC13) δ = 1.27 (2 d, J = 7.0, 7.0 Hz, 6H) , 1.97 (s, 3H) , 3.31 (d, J = 3.9 Hz, IH) , 3.78 (s, 3H) , 4.43 (dd, J = 3.4, 2.4 Hz, IH) , 5.11 (septet, J = 6.3 Hz, IH) , 5.48 (dd, J = 9.3, 2.1 Hz, IH) , 6.22 (d, 9.3 Hz, IH) , 6.84-6.91 (m, 2H) , 6.22-6.33 (m, 2H) ; 13C NMR (100 MHz, CDC13) δ = 21.5, 21.6, 23.2, 53.8, 55.3, 70.7, 73.3, 113.9, 128.1, 131.0, 159.1, 169.2, 172.4; FT- IR (neat): o(~,v) = 3324, 1711, 1650, 1247 cm-1; HR-MS (NBA/Nal): m/ z : exp. 318.1324 [M+Na]+, calc. 318.1317 for C15H21N05Na; HPLC: Chiralcel OG, 20 % iPrOH/hexane, 1 mL min"1, 224 nm, 10.4 min
(2R, 3S) , 14.6 min (25, 3R) . The absolute configuration is assumed to be (2R, 35) in analogy to the AA product from isopropyl cinnamate .
(1R,2R) -2- (Acetylamino) -1,2-diphenylethanol (ent-4) (ligand = (DHQD)2-PHAL)
M.p. 158-159 °C; [α]o(25,D) = +3.1 (c = 0.713 in 95 % EtOH) (enantiomerically pure product, obtained by recrystallization from diethyl ether); Η NMR (400 MHz, CDC13) δ = 1.90 (s, 3H) , 3.14 (br s, IH) , 4.94 (d, J = 4.6 Hz, IH) , 5.16 (dd, J = 7.8,
4.6 Hz, IH) , 7.03-7.40 (m, 10 H) ; 13C NMR (100 MHz, CDC13) δ = 23.1, 59.6, 77.1, 126.0, 126.1, 126.9, 127.8, 128.3, 128.6, 139.4, 140.7, 170.6; HPLC: Chiralcel ODH, 15 % iPrOH/hexane, 0.5 mL min"1, 254 nm, 21.8 min ( 1R, 2R) , 31.7 min (15,25). The absolute configuration was established, after hydrolysis ( 3N HCl, reflux, 1 h, followed by evaporation) , by comparison to the known aminoalcohol hydrochloride.
Ethyl (S) -3- (acetylamino) -2-hydroxypropanoate (ent-5) (ligand = (DHQD)2-PHAL)
GC: Cyclodex B, J&W Scientific, initial time 5 min, initial temperature: 120 °C (5 min), rate: 0.5 °C/min, final temperature: 140 °C, 40.3 min (R) , 41.3 min (5); [α]o(25,D) = +17.8 (c = 0.5 in CHC13, 90 % ee) , lit.'161 for (R) [α]o(25, = - 18.7 (c = 3 in CHC13) .
(R) -2- (Acetylamino) -1-phenylethanol (7a)
HPLC: Chiralpak AD, 5 % iPrOH/hexane, 1.5 mL min"1, 254 nm, 12.7 min (R) , 16.2 min (5) .
(i?) -2- (Acetylamino) -2-phenylethanol (8a)
HPLC: Chiralpak AD, 5 % iPrOH/hexane, 1.5 L min"1, 254 nm, 11.6 min (R) , 10.1 min (5) .
(R) -2- (Acetylamino) -1- (3-nitrophenyl) ethanol (7b) :
M.p. 124-125 °C; [α]θ(25, = +6.1 (c = 0.655 in 95 % EtOH) ; lE NMR (400 MHz, DMSO-d6) δ = 1.76 (s, 3H) , 3.16-3.23 (m, IH) , 3.26-3.33 (m, IH) , 4.73-4.78 (m, IH) , 5.81 (d, J = 4.5 Hz, IH) , 7.62 (t, J = 7.9, 1 H) , 7.76 (d, J = 7.7 Hz, IH) , 7.97 (t, J = 5.6 Hz, IH) , 8.11 (dd, J = 8.1, 1.5 Hz, IH) , 8.16 - 8.18 (m, IH) ; 13C NMR (100 MHz, DMSO-d6) δ = 22.5, 46.4, 70.5, 120.6, 122.0, 129.6, 132.9, 146.1, 147.7, 169.6; FT-IR (neat) : o(-,v) = 3345, 3274, 1602, 1524, 1346 cm"1; HR-MS (NBA/Nal) : m/z: exp. 225.0871 [M+H]+, calc. 225.0875 for C10H13N2O4; HPLC: N, O-diacetate derivative: Chiralcel ODH, 7.5 % iPrOH/hexane, 1 mL min"1, 254 nm, 26.1 min (R) , 28.8 min (5) .
(R) -2- (Acetylamino) -2- (3-nitrophenyl) ethanol (8b) :
M.p. 152-153 °C; [α]o(25,D) = - 82.6 (c = 1.05 in 95 % EtOH) ; lH
ΝMR (400 MHz, acetone-d6) δ = 1.96 (s, 3H) , 3.82 (t, J = 5.6 Hz, 2H) , 4.19 (t, J = 5.6 Hz, IH) , 5.08 - 5.16 (m, IH) , 7.60 (t, J = 7.9, IH) , 7.71 (bs, IH) , 7.79 -7.83 (m, IH) , 8.08 - 8.12 (m, IH) , 8.24 (t, J = 1.9 Hz, IH) ; 13C ΝMR (100 MHz, acetone-d6) δ = 22.9, 55.6, 65.6, 122.6 (2C) , 130.2, 133.3, 134.7, 144.8, 170.1; FT-IR (neat) : o(~,v) = 3374, 3295, 1652, 1524, 1346 cm"1; HR-MS (ΝBA/Νal) : m/z: exp. 247.0690 [M+Νa]\ calc. 247.0695 for C10H12N2O4Na; HPLC: N, O-diacetate derivative: Chiralcel ODH, 7.5 % iPrOH/hexane, 1 mL min-1, 254 nm, 36.4 min (R) , 32.5 min (5) .
(R) -2- (Acetylamino) -1- ( -methoxyphenyl) ethanol (7c)
HPLC: N, O-diacetate derivative: Chiralcel ODH, 7.5 % iPrOH/hexane, 1 mL min-1, 254 nm, 19.1 min (R) , 23.6 min (5).
(R) -2- (Acetylamino) -2- ( -methoxyphenyl) ethanol (8c) :
M.p. 99-100 °C; [ ]o(25, = - 126.8 (c = 1.1 in 95 % EtOH) ; JH ΝMR (400 MHz, acetone-d6) δ = 1.92 (s, 3H) , 3.69 (d, J = 6.2 Hz, 2H) , 3.74 (s, 3H) , 4.38 (bs, IH) , 4.93 - 5.00 (m, IH) , 6.82 - 6.87 ( , 2H) , 7.24 -7.28 (m, 2H) , 8.08 - 8.12 ( , IH) , 8.24 (d, J = 7.4 Hz, IH) ; 13C ΝMR (100 MHz, acetone-d6) δ = 23.0, 55.4, 55.8, 66.3, 114.3, 128.9, 133.7, 159.6, 170.4; FT-IR (neat) : o(-,v) = 3374, 3288, 1645, 1546, 1246, 1026 cm"1; HR-MS (ΝBA/Νal) : m/z: exp. 232.0954 [M+Νa]+, calc. 232.0950 for CnH15N03Na; HPLC: N, O-diacetate derivative: Chiralcel ODH, 7.5 % iPrOH/hexane, 1 mL min-1, 254 nm, 26.2 min (R) , 21.6 min (5) .
Transformation of R-COOH to R-COOMe
Procedure as adapted from Chan et al. Synthesis 1983, 201
Claims
1. A method for converting an olefinic substrate to an asymmetric amidoalcohol product by osmium-catalyzed asymmetric addition of a carboxamide radical and a hydroxyl radical to the olefinic substrate comprising the step of combining the olefinic substrate, an N-halo carboxamide as the source of the carboxamide radical, an osmium-containing catalyst, a chiral ligand for enantiomerically directing said asymmetric addition, a base, and a solvent having an organic component and an aqueous component, the aqueous component being the source of the hydroxyl radical for producing the asymmetric amidoalcohol product.
2. A method for converting an olefinic substrate to an asymmetric amidoalcohol product as described in claim 1, wherein the N-halo carboxamide is selected from the group consisting of N-fluoro- (C^C^ (alkyl) ) -amide, N-chloro- (C^C^ (alkyl) ) -amide, N- bromo- (C1-C15(alkyl)) -amide, N-iodo- (C^C^ (alkyl) ) -amide, N- fluoro- (aryl) -amide, N-chloro- (aryl) -amide, N-bromo- (aryl) - amide, N-iodo- (aryl) -amide, N-fluoro-2-chloro- (C^ C15 (alkyl) ) amide, N-fluoro-2-bromo- (C-C^ (alkyl) ) amide, N-fluoro- 2-iodo- (Cx-Cis (alkyl) ) amide, N-bromo-2-chloro- (C^C^ (alkyl) ) amide, N-bromo-2-bromo- (C1-C15 (alkyl) ) amide, N-bromo-2-iodo- (C^ C15 (alkyl) ) amide, N-iodo-2-chloro- (alkyl) ) mide, N-iodo-2- bromo- (C^C^ (alkyl) ) amide, N-iodo-2-iodo- (C-C^ (alkyl) ) amide, N- fluoro-alkoxybenzamide, N-chloro-alkoxybenzamide, N-bromo- alkoxybenzamide, N-iodo-alkoxybenzamide, N-fluoro-2- alkoxyacetamide, N-chloro-2-alkoxyacetamide, N-bromo-2- alkoxyacetamide, and N-iodo-2-alkoxyacetamide.
3. A method for converting an olefinic substrate to an asymmetric amidoalcohol product as described in claim 2 wherein the N-halo carboxyamide is selected from the group consisting of N-bromoacetamide, N-chloroacetamide, N-bromobenzamide, N- chlorobenzamide, N-fluoro-2-chloro-acetamide, N-fluoro-2-bromo- acetamide, N-fluoro-2-iodo-acetamide, N-bromo-2-chloro- acetamide, N-bromo-2-bromo-acetamide, N-bromo-2-iodo-acetamide, N-iodo-2-chloro-acetamide, N-iodo-2-bromo-acetamide, N-iodo-2- iodo-acetamide, N-chloro-p-methoxy benzamide, N-chloro-2-methoxy acetamide, N-bromo-p-methoxy benzamide, N-bromo-2-methoxy acetamide, N-iodo-p-methoxy benzamide, and N-iodo-2-methoxy acetamide.
4. A method for converting an olefinic substrate to an asymmetric amidoalcohol product as described in claim 3, wherein wherein the osmium containing catalyst is selected from the group consisting of potassium osmate dihydrate, osmium tetroxide, osmium (IV) oxide, osmium (IV) oxide dihydrate, osmium(III) chloride, and osmium hexachlorooxmate (IV) .
5. A method for converting an olefinic substrate to an asymmetric amidoalcohol product as described in claim 4, wherein the chiral ligand is selected from a group consisting of p- phenylbenzoyl dihydroquinidine; acetyl dihydroquinine; dimethylcarbamoyl dihydroquinine; benzoyl dihydroquinine;
4-methoxybenzoyl dihydroquinine; 4-chlorobenzoyl dihydroquinine; 2-chlorobenzoyl dihydroquinine; 4-nitrobenzoyl dihydroquinine; 3-chlorobenzoyl dihydroquinine; 2-methoxybenzoyl dihydroquinine; 3-methoxybenzoyl dihydroquinine; 2-naphthoyl dihydroquinine; cyclohexanoyl dihydraquinine; p-phenylbenzoyl dihydroquinine; methoxydihydroquinidine; acetyl dihydroquinidine; dimethylcarbamoyl dihydroquinidine; benzoyl dihydroquinidine; 4- methoxybenzoyl dihydroquinidine; 4-chlorobenzoyl dihydroquinidine: 2-chlorobenzoyl dihydroquinidine; 4- nitrobenzoyl dihydroquinidine; 3-chlorobenzoyl dihydroquinidine; 2-methoxybenzoyl dihydroquinidine; 3-methoxybenzoyl dihydroquinidine; 2-naphthoyl dihydroquinidine; and cyclohexanoyl dihydroquinidine and a group represented by one of the following structures:
wherein R╬▒ is radical selected from a group consisting of a group represented by one of the following structures:
6. A method for converting an olefinic substrate to an asymmetric amidoalcohol product as described in claim 5, wherein the base is selected from the group consisting of LiOH, NaOH, KOH, NH4OH, Na2C03, K2C03, CaC03, and BaC03.
7. A method for converting an olefinic substrate to an asymmetric amidoalcohol product as described in claim 6, wherein: the organic component of the solvent is selected from the group consisting of methanol, ethanol, n-butanol, n- pentanol, n-propanol, 2-propanol, 2-butanol, tert-butanol, ethylene glycol; acetonitrile, propionitrile; tetrahydrofuran, diethyl ether, tert-butyl methyl ether, dimethoxyethane, 1,4- dioxane; dimethyl formamide, acetone, benzene, toluene, chloroform, and methylene chloride
8. A method for converting an olefinic substrate to an asymmetric amidoalcohol product as described in claim 7 wherein the solvent being present as a homogenous mixture.
9. A method for converting an olefinic substrate to an asymmetric amidoalcohol product as described in claim 7 wherein the solvent being present as a heterogeneous mixture.
10. A method for converting an olefinic substrate to an asymmetric amidoalcohol product as described in claim 7, wherein the N-halo carboxamide having a concentration within a range of 0.50 to 10 equivalents.
11. A method for converting an olefinic substrate to an asymmetric amidoalcohol product as described in claim 10, wherein the N-halo carboxamide being present in near stoichiometric amounts.
12. A method for converting an olefinic substrate to an asymmetric amidoalcohol product as described in claim 11, wherein the aqueous component is water.
13. A method for converting an olefinic substrate to an asymmetric amidoalcohol product as described in claim 12, wherein:
the aqueous component of the solvent has a range between 10% and 90% on a volume basis.
14. A method for converting an olefinic substrate to an asymmetric amidoalcohol product as described in claim 13, wherein:
the aqueous and organic components of the solvent are each approximately 50% on a volume basis.
15. A method for converting an olefinic substrate to an asymmetric amidoalcohol product as described in claim 14, wherein: the chiral ligand being present and soluble within the reaction solution at a catalytic concentration within a range of substantially 0.50 mole % to 10 mole %.
16. A method for converting an olefinic substrate and asymmetric amidoalcohol product as described in claim 15, wherein the catalytic concentration of the osmium is within a range of 0.50 - 20 mole %.
17. A method for converting an olefinic substrate an asymmetric amidoalcohol product as described in claim 16, wherein the catalytic concentration of the osmium is within a range of 0.50 - 20 mole %, and wherein the chiral ligand having a catalytic concentration of approximately 5 mole %.
18. A method for converting an olefinic substrate to an asymmetric amidoalcohol product as described in claim 14 wherein the reaction temperature is within a range of -5.0 to 5.0 ┬░C.
19. A method for converting an olefinic substrate to an asymmetric amidoalcohol product as described in claim 18, wherein the olefin is selected from the group consisting of cis stilbene, trans stilbene, ethyl acrylate, styrene and C2- C6 (alkyl) -cinnamate ester.
Priority Applications (1)
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AU57101/98A AU5710198A (en) | 1996-12-18 | 1997-12-18 | Catalytic asymmetric amidohydroxylation of olefins with n-halo carboxamides |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US3313196P | 1996-12-18 | 1996-12-18 | |
US60/033,131 | 1996-12-18 |
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WO1998027051A2 WO1998027051A2 (en) | 1998-06-25 |
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WO1998027051A9 true WO1998027051A9 (en) | 1998-11-12 |
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TWI239327B (en) | 2000-03-02 | 2005-09-11 | Upjohn Co | Aminohydroxylation of olefins in the presence of acetamide |
FR2810666B1 (en) * | 2000-06-22 | 2002-11-08 | Rhodia Chimie Sa | CHIRAL LIGANDS OF THE BETA-AMINOALKYL TYPE -PHOSPHIN, -PHOSPHITE, -PHOSPHONITE AND -PHOSPHINITE, CORRESPONDING METAL COMPLEXES AND THEIR USE IN ASYMMETRIC CATALYSIS |
WO2011159177A1 (en) | 2010-06-18 | 2011-12-22 | Industrial Research Limited | Improved aminohydroxylation of alkenes |
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WO1989006225A1 (en) * | 1988-01-11 | 1989-07-13 | Massachusetts Institute Of Technology | Ligand-accelerated catalytic asymmetric dihydroxylation |
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