WO2003066614A1 - Epoxydation asymetrique d'olefines deficientes en electrons - Google Patents
Epoxydation asymetrique d'olefines deficientes en electrons Download PDFInfo
- Publication number
- WO2003066614A1 WO2003066614A1 PCT/US2003/003147 US0303147W WO03066614A1 WO 2003066614 A1 WO2003066614 A1 WO 2003066614A1 US 0303147 W US0303147 W US 0303147W WO 03066614 A1 WO03066614 A1 WO 03066614A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- olefin
- protecting group
- ketone
- epoxide
- Prior art date
Links
- 150000001336 alkenes Chemical class 0.000 title claims abstract description 53
- 230000002950 deficient Effects 0.000 title claims abstract description 17
- 238000006735 epoxidation reaction Methods 0.000 title description 13
- 150000002576 ketones Chemical class 0.000 claims abstract description 58
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000007800 oxidant agent Substances 0.000 claims abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 33
- 150000002148 esters Chemical class 0.000 claims abstract description 22
- 150000002118 epoxides Chemical class 0.000 claims abstract 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 125000006239 protecting group Chemical group 0.000 claims description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 125000004122 cyclic group Chemical group 0.000 claims description 13
- 150000004820 halides Chemical group 0.000 claims description 13
- -1 vinyl sulfone compound Chemical class 0.000 claims description 13
- 150000002009 diols Chemical group 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 8
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical group NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 6
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical group [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 6
- 239000004593 Epoxy Substances 0.000 claims description 6
- 150000004703 alkoxides Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000005587 carbonate group Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 229920002554 vinyl polymer Polymers 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- FHHJDRFHHWUPDG-UHFFFAOYSA-L peroxysulfate(2-) Chemical group [O-]OS([O-])(=O)=O FHHJDRFHHWUPDG-UHFFFAOYSA-L 0.000 claims 1
- 150000002924 oxiranes Chemical class 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- ASQQEOXYFGEFKQ-UHFFFAOYSA-N dioxirane Chemical compound C1OO1 ASQQEOXYFGEFKQ-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 235000014633 carbohydrates Nutrition 0.000 description 8
- 125000006575 electron-withdrawing group Chemical group 0.000 description 8
- 150000001720 carbohydrates Chemical class 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000009257 reactivity Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 229930091371 Fructose Natural products 0.000 description 4
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 4
- 239000005715 Fructose Substances 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- 230000007306 turnover Effects 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000002723 alicyclic group Chemical group 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- WBYWAXJHAXSJNI-UHFFFAOYSA-N cinnamic acid Chemical class OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 3
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LKDRXBCSQODPBY-AMVSKUEXSA-N L-(-)-Sorbose Chemical compound OCC1(O)OC[C@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-AMVSKUEXSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910021538 borax Inorganic materials 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000004844 dioxiranes Chemical class 0.000 description 2
- JZBWUTVDIDNCMW-UHFFFAOYSA-L dipotassium;oxido sulfate Chemical compound [K+].[K+].[O-]OS([O-])(=O)=O JZBWUTVDIDNCMW-UHFFFAOYSA-L 0.000 description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 150000004965 peroxy acids Chemical class 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 235000011008 sodium phosphates Nutrition 0.000 description 2
- 235000010339 sodium tetraborate Nutrition 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 0 CC(*)(COC(CO*)(C1=O)O*)*1O* Chemical compound CC(*)(COC(CO*)(C1=O)O*)*1O* 0.000 description 1
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical group CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- PYMYPHUHKUWMLA-VAYJURFESA-N aldehydo-L-arabinose Chemical compound OC[C@H](O)[C@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-VAYJURFESA-N 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- BJHIKXHVCXFQLS-UYFOZJQFSA-N keto-D-fructose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 description 1
- BJHIKXHVCXFQLS-FUTKDDECSA-N keto-L-fructose Chemical compound OC[C@H](O)[C@H](O)[C@@H](O)C(=O)CO BJHIKXHVCXFQLS-FUTKDDECSA-N 0.000 description 1
- BJHIKXHVCXFQLS-OTWZMJIISA-N keto-L-sorbose Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-OTWZMJIISA-N 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 229960001922 sodium perborate Drugs 0.000 description 1
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
- C07D301/14—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with organic peracids, or salts, anhydrides or esters thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
Definitions
- the present invention is directed to a method for enantioselectively epoxidizing olefms having at least one electron withdrawing group attached to the olefmic moiety.
- Chiral epoxides having at least an electron withdrawing group attached to the epoxide carbon are useful intermediates for the synthesis of a variety of enantiomerically enriched or enantiomerically pure complex molecules, including therapeutically useful compounds.
- asymmetric epoxidation of electron deficient olefins presents an attractive strategy for the synthesis of optically active corresponding epoxides, for example, producing glycidic esters from , ⁇ -unsaturated esters.
- One aspect of the present invention provides a method for producing an enantiomerically enriched epoxide from an electron deficient olefin, said method comprising admixing the olefin, an enantiomerically enriched chiral ketone, and an oxidizing agent under conditions sufficient to produce the enantiomeric enriched epoxide, wherein the yield and the enantiomeric excess of the epoxide is at least about 50% and at least about 80%, respectively.
- the electron deficient olefin is selected from the group consisting of an ⁇ , ⁇ -unsaturated ester, an ⁇ , ⁇ -unsaturated ketone, a vinyl sulfone compound, a vinyl nitrile compound, and a vinyl nitro compound. More preferably, the electron deficient olefin is an ⁇ , ⁇ -unsaturated ester.
- the chiral ketone is a cyclic chiral ketone of the formula:
- bonds a, b and c are any combination of cis- or trans-configuration relative to one another;
- X is hydrogen, halide, or alkoxide
- Y is -OR 1 , hydrogen, or halide
- R 1 is selected from the group consisting of a carboxyl group, carbamate, carbonate, alkyl, and other hydroxy protecting group
- R 2 is selected from the group consisting of a carboxyl group, carbamate group and a carbonate group
- each of R 3 and R 4 is independently a hydroxy protecting group or R 3 and R 4 together form a diol protecting group.
- Another aspect of the present invention provides, a method for producing an enantiomerically enriched ⁇ , ⁇ -epoxy ester comprising admixing an ⁇ , ⁇ -unsaturated ester, an enantiomerically enriched cyclic chiral ketone, and an oxidizing agent under conditions sufficient to produce the ⁇ , ⁇ -epoxy ester at a yield of at least 50%.
- the enantiomeric excess of the cyclic chiral ketone is at least about
- bonds a, b and c are any combination of cis- or trans-configuration relative to one another;
- X is hydrogen, halide, or alkoxide;
- Y is -OR 1 , hydrogen, or halide;
- R 1 is selected from the group consisting of a carboxyl group, carbamate, carbonate, alkyl, and other hydroxy protecting group;
- R 2 is selected from the group consisting of a carboxyl group, carbamate group and a carbonate group; and each of R 3 and R 4 is independently a hydroxy protecting group or R 3 and R 4 together form a diol protecting group.
- compound of Formula II is of the formula:
- R 1 , R 2 , R 3 , R 4 , a, b, and c are those defined herein.
- R 1 and R 2 are independently a carboxyl group.
- R 3 and R 4 together form a diol protecting group.
- chiral ketone of Formula II is of the formula:
- electron withdrawing group refers to a moiety whose electronegativity increases the nucleophilic attack of the olefinic moiety to which it is attached to.
- the electron withdrawing group comprises an unsaturation which is conjugated with the olefinic moiety.
- Exemplary preferred electron withdrawing groups include esters, ketone, sulfone, nitrile, and nitro. More preferably, the electron withdrawing group is an ester.
- esters and “ester group” are used interchangeably herein and refer to a moiety of the formula -CO 2 R, where R is optionally substituted alicyclic, cyclic, aliphatic, aromatic hydrocarbon moiety or a combination thereof comprising at least one carbon atom.
- the present invention provides a method for producing an enantiomerically enriched epoxide from an electron deficient olefin.
- Methods of the present invention can also be used for kinetic resolution of the electron deficient olefins.
- the method generally involves converting one of the stereoisomer of the electron deficient olefin to an epoxide at a higher rate than the other isomer, which results in a relative enrichment of the other stereoisomer.
- enrichment and “relative enrichment” are used herein interchangeably to describe an increase of one stereoisomer relative to the other. It should be appreciated that enrichment of an electron deficient olefin is a result of a decrease in the amount of one stereoisomer by conversion to an epoxide. Olefin
- an "electron deficient olefin” refers to an olefin having at least one electron withdrawing group bonded directly to the olefinic moiety.
- the olefin is an ⁇ , ⁇ -unsaturated ester, i.e., where at least one of R a , R b , R c and R d
- the initial concentration of the olefin is from about 0.001 mole/liter
- Methods of the present invention generally comprises admixing the olefin, an enantiomerically enriched chiral ketone, and an oxidizing agent under conditions sufficient to produce the enantiomeric enriched epoxide.
- asymmetric epoxidation of the present invention can be performed in a variety of different sequences.
- the addition sequences of the olefin, the chiral ketone, and the oxidizing agent can be interchanged.
- the oxidizing agent is added to a reaction mixture comprising the chiral ketone and the olefin.
- a reverse-addition technique can also be used depending upon the reactivity of each component.
- contacting an oxidizing agent with a chiral ketone produces a chiral dioxirane, which is believed to be the active species in generating the epoxide from the olefin.
- the chiral dioxirane is generated and used in situ by contacting (i.e., reacting) a chiral ketone with an oxidizing agent in the presence of the olefin.
- the actual epoxidizing agent e.g., dioxirane
- the chiral ketone and the olefin may be generated in a separate reaction prior to contacting with an olefin, it is more advantageous to combine the chiral ketone and the olefin in a single reaction mixture and generate the dioxirane in situ by adding an oxidizing agent to the reaction mixture.
- the present invention is described in reference to dioxirane as being the actual epoxidizing agent, the scope of the present invention is not limited to such. Generally, any reactive species which stereoselectively generates the epoxide from the reaction mixture provided herein is within the scope of the present invention. However, for brevity and consistancy throughout this disclosure, the reactive species is described as being a dioxirane of the chiral ketone.
- the ketones of the present invention have a turn-over number of at least about 3, more preferably at least about 50 and most preferably at least about 100. Moreover, since the ketones have such a high turn-over number, the amount of the ketones required to epoxidize a given amount of olefin can be less than the stoichiometric amount, i.e., one equivalent, of the olefin. Preferably no more than about 0.3 equivalents of ketone is used to epoxidize olefins, more preferably no more than about 0.05 equivalents, and most preferably no more than about 0.01 equivalents.
- the chiral ketone is a cyclic chiral ketone.
- the cyclic chiral ketone is of the formula:
- bonds a, b and c are any combination of cis- or trans-configuration relative to one another;
- X is hydrogen, halide, or alkoxide;
- Y is -OR 1 , hydrogen, or halide;
- R 1 is selected from the group consisting of a carboxyl group, carbamate, carbonate, alkyl, and other hydroxy protecting group;
- R 2 is selected from the group consisting of a carboxyl group, carbamate group and a carbonate group; and each of R 3 and R 4 is independently a hydroxy protecting group or R 3 and R 4 together form a diol protecting group.
- Suitable hydroxy protecting groups are well known to one skilled in the art.
- R 3 and R 4 together form a dial protecting group.
- diol protection groups are well l ⁇ iown to one skilled in the art. See, for example, Protective Groups in Organic Synthesis, 3rd edition, T.W. Greene and P.G.M. Wuts, John Wiley & Sons, New York, 1999, pp.
- bonds a, b, and c can be any combination of cis- or trans-configuration relative to one another.
- bonds a and b are of cis-configuration relative to each other.
- bonds a, b and c are of cis-configuration relative to each other.
- One of the advantages of the present invention is availability of relatively inexpensive starting materials for producing chiral ketones.
- chiral ketones of Formula I can be synthesized in high overall yield from readily available carbohydrates, such as fructose and sorbose.
- Formula I is derived from a carbohydrate.
- the chiral ketone is derived from an oxidation of an unprotected hydroxy group of a carbohydrate compound having at least one protected hydroxy group.
- the protecting groups for protected hydroxy groups are selected from the group consisting of silyl ethers, ethers, acetals, ketals, esters, ortho esters, sulfonates, phosphates and mixtures thereof.
- the protecting groups for two or more hydroxy groups of the carbohydrate or its derivative can be interconnected. For example, an acetonide group protecting 4,5-hydroxy groups of fructose can be considered to be "two interconnected acetal protecting groups" since they protect two hydroxy groups on the fructose.
- oxidation of a hydroxy group of a carbohydrate to form a carbonyl group is well known to one skilled in the art. See Mio et al. Tetrahedron 1991, 47, 2133-2144.
- pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Swern oxidation condition or other oxidizing conditions can be used to oxidize a hydroxy group of a carbohydrate or its derivative to a ketone compound of the present invention.
- the carbohydrate is selected from the group consisting of fructose, sorbose, arabinose, mannose, and glucose.
- the carbohydrate is selected from the group consisting of (D)-fructose, (L)- fructose, (L)-sorbose, (L)-arabinose, and (D)-arabinose.
- the oxidizing agent is added as a solution or a solid to the reaction mixture comprising the chiral ketone and the olefin.
- the chiral ketone can be used in an amount less than the stoichiometric amount relative to the amount of the olefin. It should be appreciated that in situ generation of dioxirane from a ketone generally requires the oxidizing agent to be more reactive towards the ketone than the olefin to avoid competing oxidation of olefin by the oxidizing agent.
- the amount of ketone used is at least about 3 times more than the amount olefin, more preferably at least about 5 times, and most preferably at least about 10 times.
- the initial concentration of the oxidizing agent is from about 0.1 M to about 1 M, more preferably from about 0.2 M to about 0.5 M.
- the rate of addition of the oxidizing agent to the reaction mixture will vary depending on a various factors, such as the reaction temperature, the size of the reaction, and the olefin substrates.
- any oxidizing agent capable of providing dioxiranes from a corresponding ketone can be used in the present invention.
- a relatively inexpensive oxidizing agents such as peracids, hydrogen peroxide, sodium hypochlorite, peroxomonosulfate (e.g., potassium peroxomonosulfate), sodium perborate and hypofluoride (HOF) are preferred.
- Non-organic oxidizing agents i.e., a compound that does not contain any carbon atom
- the amount of oxidizing agent used in the present invention depends on a variety of factors including the reactivity of the ketone, olefin, and the decomposition rate of ⁇ the oxidizing agent. Typically, the amount of an oxidizing agent used is at least about 1 times the amount of the ketone, preferably at least about 9 times, and more preferably at least about 100 times. In another embodiment of the present invention, the amount of an oxidizing agent used is less than about 10 times the amount of the olefin, and more preferably less than about 3 times. However, it should be appreciated that the present invention is not limited to these particular amounts of the oxidizing agent.
- the oxidizing agent is potassium peroxomonosulfate.
- oxidizing agent any suitable oxidizing agents known to one skilled in the art can be used.
- suitable oxidizing agents include, but are not limited to, peracids (e.g., mCPBA), hydrogen peroxide and a mixture of hydrogen peroxide and a nitrile compound.
- a longer reaction period generally provides higher yield of the epoxide.
- reaction time is from about 5 h to about 48 h, preferably from about 10 h to about 36 h, and more preferably from about 20 h to about 30 h.
- the present invention is not limited to these particular reaction times.
- methods of the present invention can also comprise adjusting the pH of the reaction mixture.
- the useful pH range is broad. Typically, however, the pH is preferably at least about pH 5. Because the pH can fluctuate during the course of reaction, the reaction pH referred to herein refers to an apparent pH.
- the pH of the reaction is from about pH 5 to about pH 14, more preferably from about pH 5 to about pH 10, and most preferably from about pH 7 to about pH 9.
- the pH of the reaction solution can be conveniently achieved by adding sufficient amount of base to maintain the pH at the desired level. The base can be added separately, it can be added to the solution containing the ketone, or it can be added to the solution containing the oxidizing agent.
- a solid mixture of the base and oxidizing agent can be added to the reaction mixture.
- a base is used to control the reaction pH, preferably the base is selected from the group consisting of hydroxides, carbonates, bicarbonates, borates and phosphates.
- the base is selected from the group consisting of potassium carbonate, potassium bicarbonate, lithium carbonate, lithium bicarbonate, sodium carbonate, sodium bicarbonate, calcium carbonate, sodium borate, sodium phosphate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide and calcium hydroxide, most preferably the base is selected from the group consisting of potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate, sodium hydroxide, sodium borate, sodium phosphate, potassium phosphate and potassium hydroxide.
- the desire pH of the reaction can be more easily maintained by using a buffer solution.
- solvent system Another factor that can determine the yield of the epoxide and/or enantioselectivity of the reaction is the solvent system used.
- any relatively inert organic solvent can be used for the present invention.
- Exemplary solvents include, nitriles such as acetonitrile and propionitrile, dimethoxymethane (DMM), dimethoxyethane (DME), ethers such as tetrahydrofuran (THF), dichloromethane, chloroform, ethyl acetate, hexane, benzene, toluene, xylenes, dioxane, dimethyl formamide (DMF), pentane, alcohols including, but not limited to, methanol, ethanol and t-propyl alcohol, and mixtures thereof.
- the solvent is selected from the group consisting of acetonitrile,
- the temperature of the reaction can also affect the yield of the reaction and enantioselectivity of the epoxide. Generally, a lower reaction temperature requires a longer reaction time but results in higher enantioselectivity.
- the reaction temperature is about 50 °C or less, more preferably about 30 °C or less, and most preferably from about 0 °C to about room temperature.
- the scope of the present invention is not limited to these particular reaction temperatures.
- methods of the present invention results in the yield of the epoxide being at least about 50%, more preferably at least about 60% and most preferably at least about 70%.
- the enantiomeric excess of the resulting epoxide is at least about
- the enantiomeric excess of the resulting epoxide is at least about 80%, more preferably at least about 85%, and most preferably at least about 90%.
- combinations of the preferred embodiments of any particular characteristics or properties described herein form other preferred embodiments.
- methods of the present invention provides an enantiomerically enriched epoxide at a yield of at least about 50%) and enantiomeric excess of at least about 80%.
- epoxides were purified by flash chromatography and gave satisfactory spectroscopic characterization. c. 0.30 eq. Ketone used. d. 0.25 eq. ketone used. e. 0.20 eq. ketone used.
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AU2003219702A AU2003219702A1 (en) | 2002-02-04 | 2003-01-29 | Asymmetric epoxidation of electron deficient olefins |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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EP1770095A1 (fr) * | 2005-09-26 | 2007-04-04 | Institut Catala D'Investigacio Quimica | Catalyseurs efficaces pour l'epoxydation asymetrique d'olefines deficientes en electrons ainsi que d'olefines non deficientes en electrons |
EP1770094A1 (fr) * | 2005-09-26 | 2007-04-04 | Institut Catala D'Investigacio Quimica | Synthese efficace d'un cata lyseur d'epoxydation asymetrique |
WO2012167406A1 (fr) * | 2011-06-10 | 2012-12-13 | 中国科学院化学研究所 | Procédé de préparation d'ambrisentan (+)- et de darusentan (+)- optiquement purs |
Citations (1)
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WO1998015544A1 (fr) * | 1996-10-08 | 1998-04-16 | Colorado State University Research Foundation | Epoxydation asymetrique catalytique |
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- 2003-01-29 WO PCT/US2003/003147 patent/WO2003066614A1/fr not_active Application Discontinuation
- 2003-01-29 AU AU2003219702A patent/AU2003219702A1/en not_active Abandoned
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WO1998015544A1 (fr) * | 1996-10-08 | 1998-04-16 | Colorado State University Research Foundation | Epoxydation asymetrique catalytique |
Non-Patent Citations (2)
Title |
---|
DATABASE HCAPLUS [online] (COLUMBUS, OH, USA); YANG ET AL.: "Novel cyclic ketones for catalytis oxidation reactions", XP002965416, accession no. STN Database accession no. 1998-748088 * |
J. ORG. CHEM., vol. 63, no. 26, 1998, pages 9888 - 9894 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1770095A1 (fr) * | 2005-09-26 | 2007-04-04 | Institut Catala D'Investigacio Quimica | Catalyseurs efficaces pour l'epoxydation asymetrique d'olefines deficientes en electrons ainsi que d'olefines non deficientes en electrons |
EP1770094A1 (fr) * | 2005-09-26 | 2007-04-04 | Institut Catala D'Investigacio Quimica | Synthese efficace d'un cata lyseur d'epoxydation asymetrique |
WO2007039493A1 (fr) * | 2005-09-26 | 2007-04-12 | Intitut Català D'investigació Química (Iciq) | Catalyseur efficace destine a l'epoxydation asymetrique d'alcenes deficients ou non deficients en electrons |
WO2007039492A1 (fr) * | 2005-09-26 | 2007-04-12 | Institut Català D'investigació Química (Iciq) | Synthese efficace d'un catalyseur i d'epoxydation asymetrique |
WO2012167406A1 (fr) * | 2011-06-10 | 2012-12-13 | 中国科学院化学研究所 | Procédé de préparation d'ambrisentan (+)- et de darusentan (+)- optiquement purs |
US9040698B2 (en) | 2011-06-10 | 2015-05-26 | Institute Of Chemistry Chinese Academy Of Sciences | Method for preparing optically pure (+)-ambrisentan and (+)-darusentan |
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