CN115340441A - 一种手性环丁醇化合物的合成方法、手性环丁醇及用途 - Google Patents
一种手性环丁醇化合物的合成方法、手性环丁醇及用途 Download PDFInfo
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- CN115340441A CN115340441A CN202110519867.8A CN202110519867A CN115340441A CN 115340441 A CN115340441 A CN 115340441A CN 202110519867 A CN202110519867 A CN 202110519867A CN 115340441 A CN115340441 A CN 115340441A
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- Prior art keywords
- cyclobutanol
- chiral
- dosage
- cdcl
- nmr
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- KTHXBEHDVMTNOH-UHFFFAOYSA-N cyclobutanol Chemical compound OC1CCC1 KTHXBEHDVMTNOH-UHFFFAOYSA-N 0.000 title claims abstract description 68
- -1 cyclobutanol compound Chemical class 0.000 title claims description 43
- 238000001308 synthesis method Methods 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 58
- SHQSVMDWKBRBGB-UHFFFAOYSA-N cyclobutanone Chemical compound O=C1CCC1 SHQSVMDWKBRBGB-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 21
- 239000003054 catalyst Substances 0.000 claims abstract description 18
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052741 iridium Inorganic materials 0.000 claims abstract description 11
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003446 ligand Substances 0.000 claims abstract description 11
- 238000006459 hydrosilylation reaction Methods 0.000 claims abstract description 10
- 239000012004 corey–bakshi–shibata catalyst Substances 0.000 claims abstract description 8
- 125000001424 substituent group Chemical group 0.000 claims abstract description 7
- 230000009471 action Effects 0.000 claims abstract description 5
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 20
- UCXUKTLCVSGCNR-UHFFFAOYSA-N diethylsilane Chemical compound CC[SiH2]CC UCXUKTLCVSGCNR-UHFFFAOYSA-N 0.000 claims description 20
- WIWBLJMBLGWSIN-UHFFFAOYSA-L dichlorotris(triphenylphosphine)ruthenium(ii) Chemical group [Cl-].[Cl-].[Ru+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 WIWBLJMBLGWSIN-UHFFFAOYSA-L 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 8
- 125000002524 organometallic group Chemical group 0.000 claims description 8
- 229910052707 ruthenium Inorganic materials 0.000 claims description 8
- 230000002194 synthesizing effect Effects 0.000 claims description 8
- 239000012298 atmosphere Substances 0.000 claims description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 150000002978 peroxides Chemical class 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 4
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 claims description 3
- 239000004912 1,5-cyclooctadiene Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- FYGUSUBEMUKACF-UHFFFAOYSA-N bicyclo[2.2.1]hept-2-ene-5-carboxylic acid Chemical compound C1C2C(C(=O)O)CC1C=C2 FYGUSUBEMUKACF-UHFFFAOYSA-N 0.000 claims description 3
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 150000004673 fluoride salts Chemical class 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- JFNLZVQOOSMTJK-KNVOCYPGSA-N norbornene Chemical compound C1[C@@H]2CC[C@H]1C=C2 JFNLZVQOOSMTJK-KNVOCYPGSA-N 0.000 claims description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
- RRKODOZNUZCUBN-CCAGOZQPSA-N (1z,3z)-cycloocta-1,3-diene Chemical compound C1CC\C=C/C=C\C1 RRKODOZNUZCUBN-CCAGOZQPSA-N 0.000 claims description 2
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- TVRHDFJMHSSQCP-UHFFFAOYSA-M [Ir]Cl.C1CC=CCCC=C1 Chemical class [Ir]Cl.C1CC=CCCC=C1 TVRHDFJMHSSQCP-UHFFFAOYSA-M 0.000 claims description 2
- ZJZVENPDGLOUHW-UHFFFAOYSA-M [Ir]Cl.C1CCCC=CCC1.C1CCCC=CCC1 Chemical class [Ir]Cl.C1CCCC=CCC1.C1CCCC=CCC1 ZJZVENPDGLOUHW-UHFFFAOYSA-M 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- BZBMBZJUNPMEBD-UHFFFAOYSA-N tert-butyl bicyclo[2.2.1]hept-2-ene-5-carboxylate Chemical compound C1C2C(C(=O)OC(C)(C)C)CC1C=C2 BZBMBZJUNPMEBD-UHFFFAOYSA-N 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000006657 (C1-C10) hydrocarbyl group Chemical group 0.000 claims 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- 150000002367 halogens Chemical class 0.000 claims 2
- 125000002252 acyl group Chemical group 0.000 claims 1
- 125000004442 acylamino group Chemical group 0.000 claims 1
- 125000004423 acyloxy group Chemical group 0.000 claims 1
- OYGJCQBQTZZCQO-UHFFFAOYSA-N benzyl bicyclo[2.2.1]hept-2-ene-5-carboxylate Chemical compound C1C(C=C2)CC2C1C(=O)OCC1=CC=CC=C1 OYGJCQBQTZZCQO-UHFFFAOYSA-N 0.000 claims 1
- 235000010290 biphenyl Nutrition 0.000 claims 1
- 239000004305 biphenyl Substances 0.000 claims 1
- 125000006267 biphenyl group Chemical group 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 125000001891 dimethoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 125000004185 ester group Chemical group 0.000 claims 1
- FCCGTJAGEHZPBF-UHFFFAOYSA-N ethyl bicyclo[2.2.1]hept-2-ene-5-carboxylate Chemical compound C1C2C(C(=O)OCC)CC1C=C2 FCCGTJAGEHZPBF-UHFFFAOYSA-N 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 229910001512 metal fluoride Inorganic materials 0.000 claims 1
- RMAZRAQKPTXZNL-UHFFFAOYSA-N methyl bicyclo[2.2.1]hept-2-ene-5-carboxylate Chemical compound C1C2C(C(=O)OC)CC1C=C2 RMAZRAQKPTXZNL-UHFFFAOYSA-N 0.000 claims 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 1
- 238000006722 reduction reaction Methods 0.000 claims 1
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 claims 1
- 230000000707 stereoselective effect Effects 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 20
- 238000002360 preparation method Methods 0.000 abstract description 16
- 125000000524 functional group Chemical group 0.000 abstract description 7
- 230000009467 reduction Effects 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 182
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 74
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 69
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 56
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 239000000543 intermediate Substances 0.000 description 45
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 39
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 34
- 238000001514 detection method Methods 0.000 description 32
- 239000012300 argon atmosphere Substances 0.000 description 31
- 229910052786 argon Inorganic materials 0.000 description 24
- 238000000375 direct analysis in real time Methods 0.000 description 24
- 238000012063 dual-affinity re-targeting Methods 0.000 description 24
- 239000000243 solution Substances 0.000 description 23
- 239000007788 liquid Substances 0.000 description 21
- 229920001971 elastomer Polymers 0.000 description 18
- 238000003818 flash chromatography Methods 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000003480 eluent Substances 0.000 description 15
- DBYQHFPBWKKZAT-UHFFFAOYSA-N lithium;benzene Chemical group [Li+].C1=CC=[C-]C=C1 DBYQHFPBWKKZAT-UHFFFAOYSA-N 0.000 description 15
- 239000003208 petroleum Substances 0.000 description 14
- RRRQFPCYRFHXBX-UHFFFAOYSA-M [Ir]Cl.C1=CCCCCCC1 Chemical class [Ir]Cl.C1=CCCCCCC1 RRRQFPCYRFHXBX-UHFFFAOYSA-M 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 239000003960 organic solvent Substances 0.000 description 9
- 239000007789 gas Substances 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 6
- BFAKENXZKHGIGE-UHFFFAOYSA-N bis(2,3,5,6-tetrafluoro-4-iodophenyl)diazene Chemical compound FC1=C(C(=C(C(=C1F)I)F)F)N=NC1=C(C(=C(C(=C1F)F)I)F)F BFAKENXZKHGIGE-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 4
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 150000001336 alkenes Chemical class 0.000 description 4
- 239000000539 dimer Substances 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 238000004262 preparative liquid chromatography Methods 0.000 description 4
- 238000007789 sealing Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000007106 1,2-cycloaddition reaction Methods 0.000 description 3
- 238000010499 C–H functionalization reaction Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 150000001361 allenes Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- XXUNFCYRICIBKD-UHFFFAOYSA-K C1=CCCCCCC1.[Ir](Cl)(Cl)Cl Chemical compound C1=CCCCCCC1.[Ir](Cl)(Cl)Cl XXUNFCYRICIBKD-UHFFFAOYSA-K 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- BZJQMDXGDLFSKE-UHFFFAOYSA-N naphthalen-1-ol Chemical compound C1=CC=C[C]2C(O)=C=CC=C21 BZJQMDXGDLFSKE-UHFFFAOYSA-N 0.000 description 2
- 239000003504 photosensitizing agent Substances 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000006516 2-(benzyloxy)ethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- IJJWOSAXNHWBPR-HUBLWGQQSA-N 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-n-(6-hydrazinyl-6-oxohexyl)pentanamide Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)NCCCCCC(=O)NN)SC[C@@H]21 IJJWOSAXNHWBPR-HUBLWGQQSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 1
- SJKPJXGGNKMRPD-UHFFFAOYSA-N Fragnanol Natural products CC(=C)C1CCC1(C)CCO SJKPJXGGNKMRPD-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- OLIWQDQTJVIVPA-UHFFFAOYSA-K [Ir](Cl)(Cl)Cl.C1=CCCCCCC1.C1=CCCCCCC1 Chemical compound [Ir](Cl)(Cl)Cl.C1=CCCCCCC1.C1=CCCCCCC1 OLIWQDQTJVIVPA-UHFFFAOYSA-K 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- DFLRGCFWSRELEL-UHFFFAOYSA-N cyclobut-2-en-1-one Chemical compound O=C1CC=C1 DFLRGCFWSRELEL-UHFFFAOYSA-N 0.000 description 1
- FOTDHUVOUZZTTB-UHFFFAOYSA-N cyclobuten-1-ol Chemical compound OC1=CCC1 FOTDHUVOUZZTTB-UHFFFAOYSA-N 0.000 description 1
- VYFJKDKXCBMBNL-UHFFFAOYSA-N cyclobutyloxysilane Chemical class C1(CCC1)O[SiH3] VYFJKDKXCBMBNL-UHFFFAOYSA-N 0.000 description 1
- ORBBTCHHNMWMCP-UHFFFAOYSA-K cycloocta-1,5-diene trichloroiridium Chemical compound [Ir](Cl)(Cl)Cl.C1=CCCC=CCC1 ORBBTCHHNMWMCP-UHFFFAOYSA-K 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000004386 diacrylate group Chemical group 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- SJKPJXGGNKMRPD-VHSXEESVSA-N grandisol Chemical compound CC(=C)[C@@H]1CC[C@]1(C)CCO SJKPJXGGNKMRPD-VHSXEESVSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000009878 intermolecular interaction Effects 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229930003658 monoterpene Natural products 0.000 description 1
- 150000002773 monoterpene derivatives Chemical class 0.000 description 1
- 235000002577 monoterpenes Nutrition 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QAZLUNIWYYOJPC-UHFFFAOYSA-M sulfenamide Chemical compound [Cl-].COC1=C(C)C=[N+]2C3=NC4=CC=C(OC)C=C4N3SCC2=C1C QAZLUNIWYYOJPC-UHFFFAOYSA-M 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- PTMFUWGXPRYYMC-UHFFFAOYSA-N triethylazanium;formate Chemical compound OC=O.CCN(CC)CC PTMFUWGXPRYYMC-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
- C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/42—Separation; Purification; Stabilisation; Use of additives
- C07C303/44—Separation; Purification
-
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Abstract
本发明公开了一种手性环丁醇化合物的合成方法、手性环丁醇及用途,该合成方法是在CBS催化剂,还原剂作用下,带有不同取代基的环丁酮在发生不对称还原,生成具有手性中心的环丁醇化合物;手性环丁醇在铱催化剂,硅氢试剂,菲啰啉配体,氢受体存在下发生甲基C‑H键活化,生成具有季碳手性中心的环丁醇衍生物。本发明原料和试剂简单易得,制备方便;反应条件温和,操作简单;底物普适性广;官能团兼容性好;产物具有高对映选择性(90%ee~>99%ee),易分离纯化。
Description
技术领域
本发明属于化学合成领域,涉及一种手性环丁醇化合物的合成方法及该手性环丁醇化合物及用途。
背景技术
具有手性中心的环丁烷结构广泛存在于药物分子和天然产物中。对映选择性[2+2]环加成反应是一类重要的构建手性环丁烷骨架的方法,Toste在2011年报道了过渡金属金催化分子内的联烯与烯烃的不对称[2+2]环加成反应,反应底物需要有联烯存在(J.Am.Chem.Soc.2011,133,5500.)。Brown报道了利用手性路易斯酸催化联烯酸酯与简单烯烃的不对称分子间
[2+2]环加成反应,类似的联烯底物是必要的,并且简单的烯烃底物仅有单取代烯烃或者环状烯烃,因此底物存在局限性(J.Am.Chem.Soc.2015,137,3482.)。Bach在2009年报道了利用手性光敏剂在光照条件下将能量传递给底物,但是这类方法需要底物与光敏剂通过氢键形式结合,也因此底物需要特定的官能团(Angew.Chem.Int.Ed.2009,48,6640)。基于此,为获得高对映选择性的简单的环丁烷结构分子目前现有的方法都存在一些局限性。环丁酮的制备简单易操作,通过手性还原试剂或者催化剂还原环丁酮获得手性环丁醇的方法暂时没有报道,只有Toshio Honda在1993年首次利用不对称还原策略将环丁烯酮还原成手性环丁烯醇中间体并应用在具有手性环丁烷骨架的单萜grandisol的合成(Tetrahedron:Asymmetry 1993,4,1537.)。通过醇导向实现醇γ位甲基的碳氢键功能化已经在2012年被Hartwig报道(Nature 2012,483,70.),因此通过不对称还原易得的环丁酮底物得到高对映立体选择性的环丁醇底物,然后发生醇导向的碳氢键功能化反应便能实现多手性中心的环丁烷骨架,并且能够得到含有季碳手性中心的环丁烷骨架。手性环丁烷骨架结构是一类重要的合成砌块,可以转化为多种多样的分子结构。因此,进一步发展高效的方法合成手性环丁烷中间体具有重要的理论与现实意义。
发明内容
本发明的目的是提供一类手性环丁醇的合成方法。即首先通过手性CBS催化剂将环丁酮还原成手性环丁醇,然后在铱催化下利用醇导向策略实现醇γ位甲基碳氢键选择性硅化反应,直接构建含有季碳手性中心的环丁醇化合物。
为了达到上述目的,本发明提供了构建手性中心的手性环丁醇2的方法,包括:在CBS催化剂和还原剂作用下,带有不同取代基的环丁酮1在发生不对称还原,生成具有手性中心的环丁醇化合物。
本发明中,合成手性环丁醇的操作步骤如下:
1)方法一:在惰性气体氛围下,加入有机溶剂,CBS溶液,和一定BH3·SMe2的溶液,加入底物环丁酮;其中,CBS如下:
优选地,带有取代基的环丁酮1与CBS催化剂的用量的摩尔比为1:(0.01~0.50),带有取代基的环丁酮1与BH3·SMe2的用量的摩尔比为1:(0.1~5.0)。
方法二:加入有机溶剂和(-)-(Ipc)2BCl溶液,在-20℃下加入底物环丁酮溶液,在-20℃下反应;。
2)待步骤1)反应完全后,淬灭反应,浓缩,快速柱层析得具有手性的环丁醇。
合成手性环丁醇的操作步骤如反应式(I)所示:
进行硅化反应,构建含有季碳手性中心的环丁醇化合物,步骤如下:
3)在惰性气体氛围下,使用钌催化剂,使得手性环丁醇2与硅氢试剂在室温下反应得到环丁醇硅醚衍生物;
4)环丁醇硅醚衍生物在铱催化剂、菲啰啉配体和氢受体的作用下在20~150℃反应2~48h;
5)方法一:在-78℃下冷却并向步骤4)的反应物中加入一定量有机金属试剂反应,得到具有季碳手性中心的环丁醇衍生物3。
方法二:或者向步骤4)的反应物中加入一定量的KHCO3,氟化盐,过氧化物,MeOH,并在50℃下加热反应得到具有季碳手性中心的环丁醇衍生物4。优选地,氟化盐为KF,过氧化物为H2O2。
手性环丁醇在铱催化剂硅氢试剂(反应式以二乙基硅烷为例),菲啰啉配体,氢受体存在下发生甲基C-H键活化。反应过程如反应式(II)所示:
其中,R1为烃基,带有官能团的烃基,苯基,芳基或杂环基;R2为烃基,带有官能团的烃基,苯基,芳基或者杂环基。
优选地,反应式(I)中,R1为末端取代或非取代的C1-C20烃基,苯基,芳基或者杂环基;反应式(II)中,R2为末端取代或非取代的C1-C10烃基,苯基,芳基或者杂环基。
进一步地,反应式(I)中,R1为末端取代或非取代的C1-C10烃基,苯基,芳基或者杂环基;反应式(II)中,R2为末端取代或非取代的C1-C10烃基,苯基,芳基或者杂环基。
进一步地,反应式(I)中,R1选自C1-C10直链烷基,C1-C10环烷基,末端带有官能团的C1-C10烷基,苯基,芳基或者杂环基;反应式(II)中R2选自C1-C10直链烷基,C1-C10环烷基,末端带有官能团的C1-C10烷基,苯基,芳基或者杂环基;进一步优选地,反应式(I)中,R1选自甲基,乙基,正丙基,异丙基,正丁基,正戊基,正己基,正庚基,正辛基,苯乙基,4-氯丁基,3-甲基丁基,3-氰基丙基,烯丙基;反应式(II)中R2选自甲基,乙基,正丙基,叔丁基,苯基,邻甲基苯基,间甲基苯基,对甲基苯基,间甲氧基苯基,对氯苯基,对溴苯基,对酯基苯基,2-萘基,3-噻吩基。
优选地,手性环丁醇2与硅氢试剂用量的摩尔比为1∶(0.1~5),手性环丁醇2与钌催化剂的用量的摩尔比为1∶(0.0001~0.5)。
优选地,手性环丁醇2与铱催化剂的用量的摩尔比为1∶(0.0001~0.5),手性环丁醇2与菲啰啉配体用量的摩尔比为1∶(0.05~1),优选地,手性环丁醇2与有机金属的摩尔比为1∶(1~5)。
优选地,本发明所述的钌催化剂为三(三苯基膦)二氯化钌(II)。优选三(三苯基膦)二氯化钌(II)。
优选地,本发明所述的铱催化剂为二(1,5-环辛二烯)二-M-甲氧基二铱(I),(1,5-环辛二烯)氯化铱(I)二聚体,二(环辛烯)氯化铱(I)二聚体中的任意一种或多种。优选地,为二(1,5-环辛二烯)二-M-甲氧基二铱(I),(1,5-环辛二烯)氯化铱(I)二聚体。
优选地,本发明所述的菲啰啉配体为L1,L2,L3,L4中的任意一种或多种。进一步地,为L1。
优选地,本发明所述的氢受体为降冰片烯,环辛二烯,双环[2.2.1]-5-庚烯-2-甲酸酯中的任意一种或多种。优选地,为双环[2.2.1]-5-庚烯-2-甲酸叔丁酯和降冰片烯。
优选地,本发明所述的有机金属试剂选自有机金属锂试剂,有机金属镁试剂中的任意一种或多种,所述的有机金属锂试剂的结构通式为R-Li,所述的有机金属镁试剂的结构通式为R-MgX,其中,R为C1~C6的烃基、苯基或芳基,所述芳基是邻、间、对位有C1~C6烃基取代的苯基。进一步地,所述的有机金属锂试剂为苯基锂。
本发明的创新点在于,本发明通过以简单易得的官能化环丁酮为起始原料,在钌催化剂,甲酸三乙胺共沸物5:2的作用下,首次实现了一步合成具有高光学活性的环丁醇化合物。并且通过手性环丁醇在铱催化下实现碳氢键活化,实现了季碳手性环丁醇合成。
本发明的有益效果还包括:原料和试剂简单易得,制备方便;反应条件温和,操作简单;底物普适性广;官能团兼容性好;产物具有高对映选择性(90%ee~>99%ee);产物易分离纯化等。
具体实施方式
下面将对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
具体实施方式如下:
方法一:将干燥的反应管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气,依次加入一定体积的有机溶剂四氢呋喃,一定体积的1N的CBS的四氢呋喃溶液,和一定体积2N的BH3·SMe2的四氢呋喃溶液,室温下在一定时间内将一定体积的底物环丁酮的四氢呋喃溶液滴加到上述体系中,滴加完毕后室温搅拌1.0小时;其中,所述有机溶剂四氢呋喃的用量为1.0-5.0mL/mmol是以官能化环丁酮的用量为基准。优选地,为2.0mL/mmol。所述一定体积的IN的CBS的四氢呋喃溶液的用量为0.1-1.0mL/mmol是以官能化环丁酮的用量为基准。优选地,为0.1mL/mmol。所述一定体积的2N的BH3·SMe2的四氢呋喃溶液指官能化环丁酮底物的用量为基准,所述的用量为0.1-1.0mL/mmol。优选地,为0.3mL/mmol。
方法二:将干燥的反应管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气,依次加入一定体积的有机溶剂四氢呋喃,一定体积的1.7N的(-)-(Ipc)2BCl的庚烷溶液,和,在-20℃下在逐滴加入一定体积的底物环丁酮的四氢呋喃溶液,滴加完毕后-20℃搅拌1.0小时;其中,所述一定体积的四氢呋喃指以官能化环丁酮底物用量为基准,所述有机溶剂的用量为1.0-5.0mL/mmol。优选地,为0.1mL/mmol。所述一定体积的1.7N的(-)-(Ipc)2BCl的庚烷溶液指官能化环丁酮底物的用量为基准,所述的用量为0.1-1.0mL/mmol。优选地,为0.7mL/mmol。
2)待步骤1)反应完全后,加入一定体积的甲醇淬灭反应,浓缩,快速柱层析得具有手性的环丁醇化合物;其中,所述一定体积的甲醇指以官能化环丁酮底物用量为基准,所述有机溶剂的用量为1.0-5.0mL/mmol。优选地,为1.0mL/mmol。
3)待步骤2)得到手性环丁醇后。向一个干燥的反应管中加入钌催化剂,连接真空泵,在氩气氛围下置换氩气,依次加入一定体积的手性环丁醇的四氢呋喃溶液,和一定体积的二乙基硅烷,然后室温反应12小时,真空1小时抽干多余的四氢呋喃和二乙基硅烷得到环丁醇硅醚衍生物。所述一定体积的四氢呋喃溶液指官能化环丁酮底物的用量为基准,所述的用量为1.0-5.0mL/mmol。
4)待步骤3)真空除去低沸点物质后。在另一个干燥的反应管中加入铱催化剂,菲啰啉配体,连接真空泵,在氩气氛围下置换氩气,以此加入环丁醇硅醚衍生物,四氢呋喃,氢受体。将反应管置于室温下搅拌2小时,再放入100℃油浴下反应24小时。
5)方法一:待步骤4)反应完成后,将反应管置于78℃下冷却并加入一定量有机金属试剂,在78℃下反应3小时。其中,所述一定量的有机溶剂是指以步骤3)中手性环丁醇的用量为基准,所述一定量有机金属试剂用量为1.0-5.0mmol/mmol。
方法二:待步骤4)反应完成后,将反应管冷却至室温,依次加入一定量的KHCO3,KF,H2O2,MeOH,在50℃下反应10小时。其中,所述一定量的有机溶剂是指以步骤3)中手性环丁醇的用量为基准,所述一定量KHCO3,KF,H2O2用量都为1.0-20mmol/mmol。一定量MeOH用量为1.0-5.0mL/mmol。
结合以下具体实施例,对本发明作进一步的详细说明。实施本发明的过程、条件、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。所有实施例中所涉及的CBS催化剂,氢受体,菲啰啉配体的具体结构式和对应编号如下所示:
实施例1
其中,THF表示四氢呋喃,mmol表示毫摩尔,mL表示毫升,M表示摩尔每升,ee表示对映异构体过量百分数。
往一个干燥的封管中依次加四氢呋喃(1mL),(S)-B-Me(0.100mmol,0.10mL,1.0Min THF),BH3·SMe2(0.600mmol,0.30mL,2.0M in THF),使用注射泵滴加1a(0.250g,1.00mmol)的THF(1.0mL)溶液,滴加速度为1mL/h。滴加完毕后,室温搅拌1h,加入甲醇(1mL)室温搅拌5分钟,浓缩,快速柱层析(淋洗剂:石油醚(60~90℃)/乙酸乙酯=10/1)得到手性环丁醇产物(R)-2a(0.139g,94%):固体;Ee:91%(AD-H;5%i-PrOH inhexanes;flow rate=1.0mL/min;detection at 210nm;t1=8.8min(minor);t2=9.4min(major).178.93(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.42-7.38(m,2H),7.31-7.22(m,4H),7.20-7.09(m,4H),4.12(dd,J=9.5,7.1Hz,1H),3.44(dd,J=11.7,7.2Hz,1H),2.49(dd,J=11.7,9.5Hz,1H),1.61(brs,1H),1.13(s,3H),0.94(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):147.26,143.80,128.00,127.97,127.84,127.74,125.69,125.60,70.80,50.86,49.07,39.75,26.40,20.43.HRMS-DART(m/z):[M+NH4]+calcd.for C18H24ON,270.1851;found,270.1852。
往一个干燥的封管中依次加入手性环丁醇2a(0.126g,0.500mmol)。将封管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,加入新鲜制备的三(三苯基膦)二氯化钌(II)(0.958mg,1.00μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(66.2mg,0.750mmol),四氢呋喃溶液(0.4mL)。将封管密闭好置于35℃反应12小时。将封管连接真空系统,真空下将多余的四氢呋喃与二乙基硅烷抽去得到硅醚中间体。在另一个封管中加入二(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol),将封管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入上述硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL)。将封管密闭好置于室温反应2小时,再放入100℃油浴下反应24小时。恢复室温,置于-78℃下并加入PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol),在-78℃下反应3小时,加入饱和氯化铵溶液(1.0mL)淬灭反应,恢复室温加入水(5.0mL),分别用二氯甲烷(10mL),二氯甲烷(10mL),二氯甲烷(5.0mL)萃取,干燥,浓缩,快速柱层析(淋洗剂:石油醚(60~90℃)/二氯甲烷=3/1)得到手性环丁醇产物3a(56.1mg,27%):无色液体;Ee:92%(AD-H;2%i-PrOH in hexanes;flow rate=0.5mL/min;detection at 210nm;t1=17.1min(minor);t2=26.6min(major).32.07(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.56-7.49(m,2H),7.37-7.30(m,5H),7.31-7.16(m,6H),7.17-7.04(m,2H),3.77(dt,J=7.0,5.4Hz,1H),3.09(dd,J=12.6,7.0Hz,1H),2.67(dd,J=12.5,5.6Hz,1H),1.21(d,J=14.8Hz,1H),1.13-1.06(m,s,3H+OH,1H),1.04-0.87(m,9H),0.87-0.79(m,2H).13C NMR(101MHz,CDCl3)δ(ppm):146.24,146.01,138.17,134.33,129.07,128.65,128.07,127.82,127.78,127.59,125.47,125.39,72.93,54.80,51.75,37.31,27.67,20.25,7.64,7.48,5.20,4.79.HRMS-DART(m/z):[M+NH4]+calcd.for C28H38ONSi,432.2712;found,432.2717。
实施例2
操作同实施例1。(S)-B-Me(0.200mmol,0.20mL,1.0M in THF),BH3·SMe2(1.20mmol,0.60mL,2.0M in THF),四氢呋喃(4.0mL),1b(0.252g,2.00mmol)。快速柱层析(淋洗剂:石油醚(60~90℃)/乙酸乙酯=10/1)得到手性环丁醇产物(R)-2b(0.239g,93%):白色固体;Ee:95%(OD-H;0%i-PrOH in hexanes;flow rate=2.0mL/min;detection at 210nm;t1=4.6min(major);t2=5.7min(minor)通过苯甲酸酯衍生物测定.-40.59(c1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):3.93(virt,q,J=7.6Hz,1H),2.03(dd,J=11.1,7.6Hz,1H),1.63(dd,J=11.1,8.2Hz,1H),1.41(d,J=7.4Hz,1H),0.99(s,3H),0.98(s,3H),0.95(s,3H),0.92(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):44.18,42.50,32.53,25.62,24.02,22.45,17.96.HRMS-EI(m/z):[M-H2O]+calcd.for C8H14,110.1092;found,110.1090.
操作同实施例1。硅醚中间体的制备使用(R)-2b(64.0mg,0.500mmol),三(三苯基膦)二氯化钌(II)(0.958mg,1.00μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(66.2mg,0.750mmol),四氢呋喃溶液(0.4mL)。将封管密闭好置于35℃反应12小时抽干。(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol),将封管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入上述硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL)与硅醚中间体100℃油浴下反应24小时。PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol)在-78℃下反应3小时。柱层析得3b(0.110g,68%):无色液体;Ee:97%(OJ-H;2%i-PrOH in hexanes;flow rate=1.0mL/min;detectionat 210nm;t1=4.1min(major);t2=7.2min(minor).7.73(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.60-7.55(m,2H),7.42-7.30(m,3H),3.54(dt,J=7.3,3.8Hz,1H),1.97(dd,J=12.1,7.0Hz,1H),1.41(dd,J=12.1,3.7Hz,1H),1.17(d,J=14.7Hz,1H),1.07-0.97(m,10H),0.97-0.86(m,2H),0.84-0.79(m,s,3H+d,J=14.7Hz,1H).13C NMR(101MHz,CDCl3)δ(ppm):138.29,134.27,129.03,128.03,74.11,45.61,40.70,36.97,26.42,24.68,23.95,15.77,7.58,7.54,5.05,4.79.HRMS-DART(m/z):[M+NH4]+calcd.forC18H34ONSi,308.2402;found,308.2404.
实施例3
操作同实施例1。(S)-B-Me(0.200mmol,0.20mL,1.0M in THF),BH3·SMe2(1.20mmol,0.60mL,2.0M in THF),四氢呋喃(2+2mL),1c(0.348g,2.00mmol)。快速柱层析(淋洗剂∶石油醚(60~90℃)/乙酸乙酯=10/1)得到一对非对映异构体手性环丁醇产物(R)-2c(0.326g,93%;cis-2c:trans-2c=1∶0.93):无色液体;两个非对映异构可以通过半制备液相色谱分离(YMC-Pack SIL,40%MTBE in hexanes,10.0mL/min).Ee:cis-2o92%,trans-2o 98%(AD-H;2%i-PrOH in hexanes;flow rate=1.0mL/min;detection at 210nm;cis-2o t1=14.9min(minor);t2=17.3min(major),trans-2o t1=20.4min(minor);t2=21.5min(major).(1R,3R)-2,2-Dimethyl-3-phenylcyclobutan-1-ol(cis-2c).-40.94(c 1.21,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.37-7.26(m,2H),7.25-7.16(m,1H),7.16-7.08(m,2H),3.96(t,J=7.9Hz,1H),2.81(dd,J=11.2,7.5Hz,1H),2.52(dt,J=10.9,7.3Hz,1H),2.15(td,J=11.0,8.6Hz,1H),1.69(brs,1H),1.26(s,3H),0.67(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):139.80,128.04,127.42,125.96,71.90,47.02,41.66,31.81,28.32,15.66.HRMS-EI(m/z):[M]+calcd.for C12H16O,176.1201;found,176.1196.(1R,3S)-2,2-Dimethyl-3-phenylcyclobutan-1-ol(trans-2c).5.88(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.34-7.25(m,2H),7.22-7.11(m,3H),4.08(t,J=6.4Hz,1H),3.25(dd,J=9.7,6.1Hz,1H),2.63(ddd,J=12.6,7.4,6.1Hz,1H),2.21(ddd,J=12.6,9.7,5.6Hz,1H),1.72(brs,1H),1.24(s,3H),0.65(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):141.73,128.08,127.68,125.86,73.35,44.99,44.66,31.66,23.30,22.95.HRMS-EI(m/z):[M]+calcd.for C12H16O,176.1200;found,176.1196.
操作同实施例1。硅醚中间体的制备使用cis-2c(88.1mg,0.500mmol),三(三苯基膦)二氯化钌(II)(0.958mg,1.00μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(66.2mg,0.750mmol),四氢呋喃溶液(0.4mL)。将封管密闭好置于35℃反应12小时抽干。(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol),将封管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入上述硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL)与硅醚中间体100℃油浴下反应24小时。PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol)在-78℃下反应3小时。柱层析得cis-3c(79.3mg,47%):无色液体;Ee:92%(OD-H;2%i-PrOH in hexanes;flow rate=0.5mL/min;detection at 210nm;t1=14.2min(major);t2=15.3min(minor).-24.15(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.51-7.44(m,2H),7.37-7.26(m,5H),7.24-7.16(m,1H),7.14-7.07(m,3H),3.79(td,J=7.5,4.4Hz,1H),2.74(dd,J=10.9,7.6Hz,1H),2.40(dt,J=11.1,7.3Hz,1H),2.06(td,J=11.0,8.0Hz,1H),1.17(d,J=4.9Hz,1H),0.94-0.81(m,8H),0.81-0.64(m,3H),0.33(d,J=15.0Hz,1H).13C NMR(101MHz,CDCl3)δ(ppm):140.06,138.30,134.36,128.83,128.03,127.98,127.90,126.00,72.64,49.83,44.83,30.64,29.48,13.90,7.55,7.45,5.02,4.83.HRMS-DART(m/z):[M+NH4]+calcd.forC22H34ONSi,356.2399;found,356.2404.
操作同实施例1。硅醚中间体的制备使用trans-2c(88.1mg,0.500mmol),三(三苯基膦)二氯化钌(II)(0.958mg,1.00μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(66.2mg,0.750mmol),四氢呋喃溶液(0.4mL)。将封管密闭好置于35℃反应12小时抽干。(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol),将封管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL)与硅醚中间体100℃油浴下反应24小时。PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol)在-78℃下反应3小时。柱层析得trans-3c(0.110g,64%):无色液体;Ee:98%(OD-H;3%i-PrOH in hexanes;flow rate=0.5mL/min;detection at210nm;t1=17.8min(minor);t2=23.8min(major).-12.47(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.63-7.55(m,2H),7.43-7.34(m,3H),7.24(t,J=7.4Hz,2H),7.15(t,J=7.3Hz,1H),7.00-6.92(m,2H),3.70(dt,J=6.8,3.1Hz,1H),3.29(t,J=8.5Hz,1H),2.45(dt,J=12.3,7.3Hz,1H),2.00(ddd,J=12.8,9.2,3.9Hz,1H),1.43-1.34(m,brs,1H+d,1H),1.17(d,J=14.6Hz,1H),1.08-0.95(m,6H),0.98-0.86(m,4H),0.69(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):141.37,137.72,134.23,129.26,128.20,127.90,127.54,125.76,74.31,47.82,47.16,30.49,22.81,21.56,7.43,7.41,4.82,4.38.HRMS-DART(m/z):[M+NH4]+calcd.for C22H34ONSi,356.2401;found,356.2404.
实施例4
操作同实施例1。(S)-B-Me(0.500mmol,0.50mL,1.0M in THF),BH3·SMe2(3.00mmol,1.5mL,2.0M in THF),四氢呋喃(5+5mL),1d(0.945g,5.00mmol)。快速柱层析(淋洗剂:石油醚(60~90℃)/乙酸乙酯=10/1)得到一对非对映异构体手性环丁醇产物(R)-2d(0.933g,98%;cis-2d:trans-2d=1∶0.95):无色液体;两个非对映异构可以通过半制备液相色谱分离(YMC-Pack SIL,40%MTBE in hexanes,10.0mL/min).(1R,3R)-2,2-Dimethyl-3-(p-tolyl)cyclobutan-1-ol(cis-2d).Ee:91%(AD-H;2%i-PrOHin hexanes;flow rate=0.5mL/min;detection at 210 nm;t1=24.9min(minor);t2=32.2min(major).-33.60(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.12(d,J=7.8Hz,2H),7.01(d,J=7.9Hz,2H),3.95(dd,J=8.6,7.1Hz,1H),2.77(dd,J=11.1,7.5Hz,1H),2.51(dt,J=10.8,7.3Hz,1H),2.34(s,1H),2.13(td,J=11.0,8.6Hz,1H),1.73(brs,1H),1.25(s,3H),0.67(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):136.66,135.40,128.74,127.31,71.90,46.87,41.29,31.91,28.29,20.98,15.65.HRMS-EI(m/z):[M]+calcd.forC13H18O,190.1350;found,190.1352.(1R,3S)-2,2-Dimethyl-3-(p-tolyl)cyclobutan-1-ol(trans-2d)Ee:98%(AD-H;2%i-PrOH in hexanes;flow rate=0.5mL/min;detection at 210nm;t1=29.1min(major);t2=30.5min(minor).2.13(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.12(d,J=7.9Hz,2H),7.03(d,J=8.1Hz,2H),4.08(ddd,J=7.0,5.7,1.1Hz,1H),3.20(dd,J=9.8,6.0Hz,1H),2.60(ddd,J=12.5,7.4,6.0Hz,1H),2.33(s,3H),2.21(ddd,J=12.6,9.7,5.6Hz,1H),1.76(brs,1H),1.24(s,3H),0.66(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):138.62,135.28,128.77,127.58,73.35,44.57,44.51,31.79,23.30,22.91,20.97.HRMS-EI(m/z):[M]+calcd.for C13H18O,190.1355;found,190.1352.
操作同实施例1。硅醚中间体的制备使用(R)-2d(0.206g,1.08mmol),三(三苯基膦)二氯化钌(II)(1.9mg,2.00μmol)的四氢呋喃溶液(0.2mL),二乙基硅烷(0.132g,1.50mmol),四氢呋喃溶液(0.8mL)。将封管密闭好置于35℃反应12小时抽干。(环辛烯)氯化铱(I)二聚体(16.8mg,25.0μmol),L1(14.2mg,60.0μmol),将封管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入上述硅醚中间体,NBE(0.113g,1.20mmol),四氢呋喃(4.0mL)与硅醚中间体100℃油浴下反应24小时。PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol)在-78℃下反应3小时。快速柱层析(淋洗剂∶石油醚(60~90℃)/乙酸乙酯=20/1)得3d(0.233g,61%;cis-3d:trans-3d=1:1.08):无色液体;两个非对映异构可以通过快速柱层析(淋洗剂∶石油醚(60~90℃)/二氯甲烷=3/1)得到一部分的纯品用于表征。(1R,2S,3R)-2-((Diethyl(phenyl)silyl)methyl)-2-methyl-3-(p-tolyl)cyclobutan-1-ol(cis-3d).Ee:93%(AD-H;2%i-PrOH in hexanes;flow rate=0.5mL/min;detection at 210nm;t1=13.6min(minor);t2=15.2min(major).-26.42(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.53-7.46(m,2H),7.38-7.30(m,3H),7.12(d,J=7.8Hz,2H),7.00(d,J=7.8Hz,2H),3.80(td,J=7.6,5.2Hz,1H),2.71(dd,J=10.9,7.6Hz,1H),2.40(dt,J=11.2,7.4Hz,1H),2.35(s,3H),2.04(td,J=11.0,8.0Hz,1H),1.30(s,3H),1.12(d,J=5.3Hz,1H),0.94-0.82(m,8H),0.84-0.69(m,3H),0.35(d,J=15.0Hz,1H).13C NMR(101MHz,CDCl3)δ(ppm):138.35,136.94,135.41,134.40,128.84,128.76,127.91,127.88,72.71,49.72,44.48,30.81,29.51,21.02,13.93,7.58,7.49,5.07,4.87.HRMS-DART(m/z):[M+NH4]+calcd.for C23H36ONSi,370.2561;found,370.2561.(1R,2S,3R)-2-((Diethyl(phenyl)silyl)methyl)-2-methyl-3-(p-tolyl)cyclobutan-1-ol(trans-3d).Ee:97%(IA;2%i-PrOH in hexanes;flow rate=0.5mL/min;detection at 210nm;t1=18.3min(major);t2=22.8min(minor).-15.00(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.65-7.55(m,2H),7.40(dd,J=4.2,2.2Hz,3H),7.06(d,J=7.8Hz,2H),6.86(d,J=7.8Hz,2H),3.78-3.63(m,1H),3.26(t,J=8.5Hz,1H),2.44(dt,J=12.5,7.3Hz,1H),2.31(s,3H),2.00(ddd,J=12.9,9.3,4.0Hz,1H),1.45-1.32(m,2H),1.17(d,J=14.6Hz,1H),1.06-0.98(m,6H),0.97-0.91(m,4H),0.71(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):138.27,137.76,135.22,134.24,129.25,128.63,128.20,127.47,47.47,47.03,30.67,22.82,21.51,20.96,7.44,7.42,4.83,4.40.HRMS-DART(m/z):[M+NH4]+calcd.for C23H36ONSi,370.2559;found,370.2561.
实施例5
操作同实施例1。(S)-B-Me(0.200mmol,0.20mL,1.0M in THF),BH3·SMe2(1.20mmol,0.60mL,2.0M in THF),四氢呋喃(2+2mL),1e(0.417g,2.00mmol)。快速柱层析(淋洗剂∶石油醚(60~90℃)/乙酸乙酯=10/1)得到一对非对映异构体手性环丁醇产物(R)-2e(0.326g,93%;cis-2e:trans-2e=1∶0.94):无色液体;两个非对映异构可以通过半制备液相色谱分离(YMC-Pack SIL,40%MTBE in hexanes,10.0mL/min).(1R,3R)-3-(4-Chlorophenyl)-2,2-dimethylcyclobutan-1-ol(cis-2e).Ee:92%(OJ-H;3%i-PrOH in hexanes;flow rate=1.0mL/min;detection at 210nm;t1=10.5min(minor);t2=11.3min(major).-34.80(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.32-7.22(m,2H),7.07-7.00(m,2H),3.96(q,J=7.5Hz,1H),2.76(dd,J=11.1,7.4Hz,1H),2.52(dt,J=10.9,7.3Hz,1H),2.09(td,J=11.0,8.6Hz,1H),1.59(d,J=7.3Hz,1H),1.24(s,3H),0.65(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):138.32,131.68,128.68,128.16,71.67,47.02,41.15,31.79,28.24,15.67.HRMS-EI(m/z):[M]+ calcd.for C12H15OCl,210.0810;found,210.0806.(1R,3S)-3-(4-Chlorophenyl)-2,2-dimethylcyclobutan-1-ol(trans-2e).Ee:98%(OJ-H;3%i-PrOH in hexanes;flow rate=1.0mL/min;detection at 210nm;t1=10.2min(minor);t2=11.0min(major).5.77(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.34-7.20(m,2H),7.06(d,J=8.4Hz,2H),4.06(t,J=6.4Hz,1H),3.22(dd,J=9.7,6.2Hz,1H),2.57(ddd,J=13.2,7.3,6.2Hz,1H),2.21(ddd,J=12.6,9.7,5.5Hz,1H),1.76(brs,1H),1.23(s,3H),0.64(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):140.23,131.56,128.95,128.20,73.19,44.66,44.46,31.60,23.24,22.87.HRMS-EI(m/z):[M]+calcd.for C12H15OCl,210.0799;found,210.0806.
操作同实施例1。硅醚中间体的制备使用cis-2e(0.105g,0.500mmol),三(三苯基膦)二氯化钌(II)(0.958mg,1.00μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(66.2mg,0.750mmol),四氢呋喃溶液(0.4mL)。将封管密闭好置于35℃反应12小时抽干。(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol),将封管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入上述硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL)与硅醚中间体100℃油浴下反应24小时。PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol)在-78℃下反应3小时。柱层析得cis-3e(0.113g,61%):无色液体;Ee:92%(OD-H;2%i-PrOH in hexanes;flow rate=0.5mL/min;detection at 210nm;t1=14.9min(major);t2=16.7min(minor).-25.00(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.54-7.45(m,2H),7.40-7.31(m,3H),7.33-7.24(m,2H),7.10-6.96(m,2H),3.80(dt,J=10.9,5.3Hz,1H),2.72(dd,J=10.7,7.7Hz,1H),2.42(dt,J=11.2,7.4Hz,1H),2.01(td,J=10.9,7.8Hz,1H),1.30(s,3H),1.15(d,J=4.5Hz,1H),0.95-0.84(m,8H),0.86-0.71(m,3H),0.27(d,J=15.0Hz,1H).13C NMR(101MHz,CDCl3)δ(ppm):138.73,138.08,134.36,131.73,129.29,128.96,128.16,127.99,72.56,49.76,44.54,30.66,29.45,14.21,7.54,7.46,5.05,4.78.HRMS-DART(m/z):[M+NH4]+calcd.forC22H33ONClSi,390.2009;found,390.2014.
操作同实施例1。硅醚中间体的制备使用trans-2e(0.105g,0.500mmol),三(三苯基膦)二氯化钌(II)(0.958mg,1.00μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(66.2mg,0.750mmol),四氢呋喃溶液(0.4mL)。将封管密闭好置于35℃反应12小时抽干。(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol),将封管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入上述硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL)与硅醚中间体100℃油浴下反应24小时。PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol)在-78℃下反应3小时。柱层析得trans-3e(0.132g,71%):无色液体;Ee:98%(AD-H;2%i-PrOH in hexanes;flow rate=0.5mL/min;detection at 210nm;t1=19.7min(major);t2=28.6min(minor).-13.35(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.65-7.56(m,2H),7.41(dd,J=4.5,1.9Hz,3H),7.20(d,J=8.4Hz,2H),6.83(d,J=8.3Hz,2H),3.69(dd,J=6.9,3.9Hz,1H),3.24(t,J=8.4Hz,1H),2.41(dt,J=12.4,7.3Hz,1H),2.02(ddd,J=12.8,9.2,3.9Hz,1H),1.39(d,J=14.6Hz,1H+brs,1H),1.15(d,J=14.5Hz,1H),1.09-0.88(m,10H),0.69(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):139.87,137.56,134.25,131.45,129.33,128.81,128.25,128.00,74.18,47.25,47.19,30.58,22.77,21.48,7.40,7.38,4.82,4.33.HRMS-DART(m/z):[M+NH4]+calcd.for C22H33ONClSi,390.2014;found,390.2014.
实施例6
操作同实施例1。(S)-B-Me(0.200mmol,0.20mL,1.0M in THF),BH3·SMe2(1.20mmol,0.60mL,2.0M in THF),四氢呋喃(2+2mL),1f(0.465g,2.00mmol)。快速柱层析(淋洗剂∶石油醚(60~90℃)/乙酸乙酯=10/1)得到一对非对映异构体手性环丁醇产物(R)-2f(0.448g,93%;cis-2f:trans-2f=1∶0.95):无色液体;(1R,3S)3-(2-(Benzyloxy)ethyl)-2,2-dimethylcyclobutan-1-ol(cis-2f)+(1R,3R)-3-(2-(Benzyloxy)ethyl)-2,2-dimethylcyclobutan-1-ol(trans-2f).1H NMR(400MHz,CDCl3)δ(ppm):7.38-7.23(m,5H+5H),4.48(d,J=1.6Hz,2H),4.48(s,2H),3.89(dd,J=7.1,5.3Hz,1H),3.71(t,J=7.9Hz,1H),3.50-3.33(m,2H+2H),2.32(dt,J=10.8,7.0Hz,1H),1.99-1.78(m,4H),1.77-1.69(m,4H),1.63(d,J=15.1Hz,3H),1.60-1.48(m,3H),1.41(td,J=10.5,8.7Hz,1H),1.05(s,3H),1.04(s,3H),0.97(s,3H),0.93(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):138.47,128.33,128.32,127.59,127.49,73.26,72.96,72.94,72.26,69.10,69.04,43.83,42.02,35.22,34.74,33.84,33.22,31.27,30.12,28.02,22.27,22.10,14.98.(1R,3S)-3-(2-(Benzyloxy)ethyl)-2,2-dimethylcyclobutan-1-ol(cis-2f).cis-2fwas prepared byNaBH4 reduction of 1r.1H NMR(400MHz,CDCl3)δ(ppm):7.39-7.29(m,4H),7.32-7.24(m,1H),4.48(s,2H),3.71(t,J=7.9Hz,1H),3.40(t,J=6.5Hz,2H),2.32(dt,J=10.8,6.9Hz,1H),1.76(brs,1H),1.79-1.66(m,1H),1.64-1.48(m,1H),1.48-1.35(m,1H),1.05(s,3H),0.94(s,3H).13C NMR(101MHz,CDCl3)δ(PPm):138.45,128.30,127.57,127.47,72.91,72.21,69.02,43.80,34.68,33.81,30.10,28.01,14.98.HRMS-DART(m/z):[M+H]+calcd.for C15H23O2,235.1692;found,235.1693.
操作同实施例1。硅醚中间体的制备使用(R)-2f(0.234g,1.00mmol),三(三苯基膦)二氯化钌(II)(1.9mg,2.00μmol)的四氢呋喃溶液(0.2mL),二乙基硅烷(0.132g,1.50mmol),四氢呋喃溶液(0.8mL)。将封管密闭好置于35℃反应12小时抽干。(环辛烯)氯化铱(I)二聚体(16.8mg,25.0μmol),L1(14.2mg,60.0μmol),将封管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入上述硅醚中间体,A(0.194g,1.00mmol),四氢呋喃(4.0mL)与硅醚中间体100℃油浴下反应24小时。PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol)在-78℃下反应3小时。快速柱层析(淋洗剂:石油醚(60~90℃)/乙酸乙酯=10/1)得cis-3f(0.117g,58%);trans-3f(0.104g,54%):无色液体;(1R,2S,3S)-3-(2-(Benzyloxy)ethyl)-2-((diethyl(phenyl)silyl)methyl)-2-methylcyclobutan-1-ol(cis-3f).Ee:94%(OD-H;2%i-PrOH in hexanes;flow rate=0.5mL/min;detection at 210nm;t1=18.4min(major);t2=22.4min(minor).18.30(c1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.60-7.51(m,2H),7.36-7.30(m,7H),7.30-7.22(m,1H),4.46(s,2H),3.56(t,J=7.1Hz,1H),3.36(ddt,J=9.2,7.0,3.1Hz,2H),2.24(dt,J=11.3,7.1Hz,1H),1.81-1.65(m,1H),1.64-1.45(m,2H),1.30(ddd,J=11.2,8.7,7.2Hz,1H),1.14(d,J=14.9Hz,1H),1.11(s,3H),1.04-0.83(m,10H),0.79(d,J=14.6Hz,1H).13C NMR(101MHz,CDCl3)δ(ppm):138.51,138.27,134.38,128.93,128.30,127.97,127.59,127.46,73.37,72.90,68.87,46.11,36.95,33.11,30.97,29.07,13.66,7.62,7.56,5.17,4.96.HRMS-DART(m/z):[M+H]+calcd.for C25H37O2Si,397.2553;found,397.2557.(1R,2S,3R)-3-(2-(Benzyloxy)ethyl)-2-((diethyl(phenyl)silyl)methyl)-2-methylc yclobutan-1-ol(trans-3f).Ee:98%(AS-H;2%i-PrOH inhexanes;flow rate=0.5mL/min;detection at 210nm;t1=12.6min(minor);t2=13.9min(major).-22.16(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.59-7.46(m,2H),7.38-7.20(m,8H),4.42(d,J=2.7Hz,2H),3.63(t,J=5.7Hz,1H),3.25(td,J=8.7,5.4Hz,1H),3.17(dt,J=8.9,7.0Hz,1H),1.96-1.74(m,3H),1.62-1.52(m,1H),1.47(brs,1H),1.41(ddd,J=10.5,6.5,3.8Hz,1H),1.06(d,J=14.5Hz,1H),1.05-0.94(m,10H),0.94-0.82(m,4H).13C NMR(101MHz,CDCl3)δ(ppm):138.54,137.80,134.16,128.93,128.27,127.88,127.51,127.41,74.75,72.84,69.15,44.20,37.61,32.84,30.93,22.13,19.88,7.44,7.43,4.80,4.60.HRMS-DART(m/z):[M+NH4]+calcd.for C25H40O2NSi,414.2818;found,414.2823.
实施例7
操作同实施例1。(S)-B-Me(0.500mmol,0.50mL,1.0M in THF),BH3·SMe2(3.00mmol,1.5mL,2.0M in THF),四氢呋喃(5+5mL),1g(0.942g,5.00mmol)。快速柱层析(淋洗剂∶石油醚(60~90℃)/乙酸乙酯=10/1)得到一对非对映异构体手性环丁醇产物(R)-cis-2g(0.475g,50%);(R)-trans-2g(0.473g,49%):无色液体;(1R,3R)-2,2,3-Trimethyl-3-phenylcyclobutan-1-ol(cis-2g).Ee:97%(OJ-H;3%i-PrOH inhexanes;flow rate=0.5mL/min;detection at 210nm;t1=17.8min(minor);t2=23.7min(major).-65.32(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.34-7.25(m,2H),7.22-7.12(m,1H),7.11-7.03(m,2H),4.12(q,J=8.0Hz,1H),2.39-2.22(m,2H),1.48(d,J=8.1Hz,1H),1.33(s,3H),1.24(s,3H),0.71(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):147.90,128.01,125.95,125.50,71.26,46.40,41.29,39.43,27.54,23.21,19.37.HRMS-EI(m/z):[M-H2O]+calcd.for C13H16,172.1246;found,172.1247.(1R,3S)-2,2,3-Trimethyl-3-phenylcyclobutan-1-ol(trans-2g).Ee:93%(OJ-H;3%i-PrOH inhexanes;flow rate=0.5mL/min;detection at 210nm;t1=22.6min(major);t2=30.1min(minor).27.24(c 1.21,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.35-7.25(m,2H),7.20-7.14(m,3H),3.91(dt,J=7.0,4.2Hz,1H),2.96(dd,J=12.6,7.1Hz,1H),1.84(dd,J=12.5,4.3Hz,1H),1.67(d,J=4.3Hz,1H),1.48(s,3H),1.20(s,3H),0.68(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):147.90,127.91,126.22,125.38,72.90,45.22,44.03,38.59,27.57,26.41,18.13.HRMS-EI(m/z):[M-H2O]+calcd.for C13H16,172.1253;found,172.1247.
操作同实施例1。硅醚中间体的制备使用cis-2g(95.2mg,0.500mmol),三(三苯基膦)二氯化钌(II)(0.958mg,1.00μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(66.2mg,0.750mmol),四氢呋喃溶液(0.4mL)。将封管密闭好置于35℃反应12小时抽干。(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol),将封管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入上述硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL)与硅醚中间体100℃油浴下反应24小时。PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol)在-78℃下反应3小时。柱层析得cis-3g(48.8mg,28%):无色液体;Ee:97%(AD-H;2%i-PrOH in hexanes;flow rate=0.5mL/min;detection at 210nm;t1=12.2min(minor);t2=16.8min(major).-34.68(c 1.21,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.54-7.46(m,2H),7.38-7.27(m,5H),7.23-7.14(m,1H),7.11-7.03(m,2H),4.00(dd,J=8.4,7.5Hz,1H),2.29(dd,J=10.8,8.4Hz,1H),2.18(dd,J=10.8,7.4Hz,1H),1.30(s,3H),1.29(s,3H),0.98-0.81(m,8H),0.82-0.74(m,2H),0.70(d,J=14.7Hz,1H),0.62(d,J=15.2Hz,1H).13C NMR(101MHz,CDCl3)δ(ppm):147.90,138.59,134.45,128.78,128.03,127.87,126.22,125.43,71.62,49.68,42.78,38.13,28.07,23.54,18.23,7.62,7.45,5.32,5.09.HRMS-DART(m/z):[M+NH4]+calcd.forC22H36ONSi,370.2557;found,370.2561.
操作同实施例1。硅醚中间体的制备使用trans-2g(95.2mg,0.500mmol),三(三苯基膦)二氯化钌(II)(0.958mg,1.00μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(66.2mg,0.750mmol),四氢呋喃溶液(0.4mL)。将封管密闭好置于35℃反应12小时抽干。(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol),将封管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入上述硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL)与硅醚中间体100℃油浴下反应24小时。PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol)在-78℃下反应3小时。柱层析得trans-3g(96.1mg,55%):无色液体;(1R,2S,3S)-2-((Diethyl(phenyl)silyl)methyl)-2,3-dimethyl-3-phenylcyclobutan-1-ol(trans-3s).Ee:94%(OJ-H;2%i-PrOH in hexanes;flow rate=0.5mL/min;detection at 210nm;t1=12.5min(major);t2=18.6min(minor).54.75(c 1.20,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.66-7.55(m,2H),7.40(dt,J=4.6,1.6Hz,3H),7.31-7.22(m,2H),7.18-7.09(m,1H),7.08-7.01(m,2H),3.39(dd,J=6.8,1.1Hz,1H),2.72(dd,J=12.7,6.8Hz,1H),1.68(dd,J=14.5,1.1Hz,1H),1.60(dd,J=12.7,1.1Hz,1H),1.48(s,3H),1.11-0.91(m,11H),0.80(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):149.29,137.94,134.08,129.47,128.39,127.90,125.77,125.16,74.16,48.02,46.89,36.46,28.76,26.58,16.98,7.48,4.83,4.34.HRMS-DART(m/z):[M+NH4]+calcd.forC22H36ONSi,370.2557;found,370.2561.
实施例8
操作同实施例1。(S)-B-Me(0.200mmol,0.20mL,1.0M in THF),BH3·SMe2(1.20mmol,0.60mL,2.0M in THF),四氢呋喃(2+2mL),1h(0.619g,2.00mmol)。快速柱层析(淋洗剂∶石油醚(60~90℃)/乙酸乙酯=20/1)得到一对非对映异构体手性环丁醇产物(R)-2h(0.326g,93%;cis-2h:trans-2h=0.96∶1):无色液体;两个非对映异构可以通过半制备液相色谱分离(YMC-Pack SIL,15%i-PrOH in hexanes,10.0mL/min).N-(((1S,3R)-3-Hydroxy-1,2,2=trimethylcyclobutyl)methyl)-N,4=dimethylbenzenesulfonamide(cis-2h).Ee:98%(OD-H;5%i-PrOH in hexanes;flow rate=1.0mL/min;detection at 210nm;t1=20.4min(major);t2=24.2min(minor).9.28(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.63(d,J=8.2Hz,2H),7.31(d,J=8.0Hz,2H),3.97(t,J=7.9Hz,1H),3.13(d,J=13.3Hz,1H),2.73(d,J=13.3Hz,1H),2.61(s,3H),2.42(s,3H),2.07(dd,J=11.0,7.5Hz,1H),1.77(dd,J=11.1,8.4Hz,1H),1.70(brs,1H),1.12(s,3H),1.00(s,3H),0.95(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):143.18,134.65,129.63,127.27,71.79,55.80,45.35,41.46,35.97,35.32,22.44,21.46,20.61,17.11.HRMS-DART(m/z):[M+H]+calcd.for C16H26O3NS,312.1624;found,312.1628.
N-(((1S,3S)-3-Hydroxy-1,2,2-trimethylcyclobutyl)methyl)-N,4-dimethylbenzenesulfonamide(trans-2h).Ee:92%(OD-H;5%i-PrOH inhexanes;flow rate=1.0mL/min;derection at 210nm;t1=20.1min(minor);t2=22.7min(major).-17.10(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.64(d,J=8.3Hz,2H),7.31(d,J=8.0Hz,2H),3.88(t,J=7.0Hz,1H),3.05(d,J=13.4Hz,1H),2.93(d,J=13.5Hz,1H),2.69(s,3H),2.48(dd,J=12.1,7.4Hz,1H),2.42(s,3H),1.73(brs,1H),1.59(dd,J=12.1,6.6Hz,1H),1.11(s,3H),1.00(s,3H),0.95(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):143.22,134.67,129.64,127.35,72.20,56.41,45.06,39.39,37.50,37.24,22.14,21.46,20.16,18.16.HRMS-DART(m/z):[M+H]+calcd.for C16H26O3NS,312.1625;found,312.1628.
操作同实施例1。硅醚中间体的制备使用(R)-2h(0.311g,1.00mmol),三(三苯基膦)二氯化钌(II)(1.9mg,2.00μmol)的四氢呋喃溶液(0.2mL),二乙基硅烷(0.132g,1.50mmol),四氢呋喃溶液(0.8mL)。将封管密闭好置于35℃反应12小时抽干。(环辛烯)氯化铱(I)二聚体(16.8mg,25.0μmol),L1(14.2mg,60.0μmol),将封管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入上述硅醚中间体,A(0.194g,1.00mmol),四氢呋喃(4.0mL)与硅醚中间体100℃油浴下反应24小时。反应液回到室温,依次加入KHCO3(0.250g,2.50mmol),KF(95.0mg,2.50mmol),H2O2(1.13g,10.0mmol,30%in H2O),MeOH(4.0mL)。将封管密闭好置于50℃反应12小时,回到室温,加入饱和硫代硫酸钠溶液(10mL)淬灭反应,加入水(10mL),分别用乙酸乙酯(10mL),乙酸乙酯(10mL),乙酸乙酯(5.0mL)萃取,干燥,浓缩,快速柱层析(淋洗剂∶二氯甲烷/乙酸乙酯=4/1)得到cis-3h(0.102g,63%);trans-3h(94.0mg,56%):无色液体;N-(((1S,2R,3R)-3-Hydroxy-2-(hydroxymethyl)-1,2-dimethylcyclobutyl)methyl)-N,4-dimethylbenzenesulfonamide(cis-3h).Ee:97%(IC;20%i-PrOH in hexanes;flow rate=1.0mL/min;detection at 210nm;t1=20.9min(minor);t2=23.3min(major).2.20(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(PPm):7.62(d,J=8.3Hz,2H),7.30(d,J=8.0Hz,2H),4.12(t,J=8.0Hz,1H),3.94(d,J=11.3Hz,1H),3.59(d,J=11.4Hz,1H),3.19(d,J=13.3Hz,1H),2.95(d,J=13-3Hz,1H),2.87(brs,1H),2.63(s,3H),2.42(s,3H),2.09(d,J=8.0Hz,1H),1.13(s,3H),1.01(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):143.31,134.46,129.67,127.24,72.86,72.84,65.29,54.87,49.33,42.37,36.27,35.37,21.86,21.45,17.32.HRMS-DART(m/z):[M+H]+calcd.for C16H26O4NS,328.1573;found,328.1577.N-(((1S,2R,3S)-3-Hydroxy-2-(hydroxymethyl)-1,2-dimethylcyclobutyl)methyl)-N,4-dimethylbenzenesulfonamide(trans-3h).Ee:93%(IC;20%i-PrOH inhexanes;flow rate=1.0mL/min;detection at 210 nm;t1=21.6min(major);t2=27.5min(minor).-14.33(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.67(d,J=8.2Hz,2H),7.35(d,J=8.0Hz,2H),4.17(d,J=11.1Hz,1H),4.10(t,J=7.4Hz,1H),3.54(d,J=11.0Hz,1H),3.07(d,J=13.6Hz,0H),2.99(d,J=13.6Hz,1H),2.74(s,3H),2.60(dd,J=12.0,7.6Hz,1H),2.46(s,3H),1.83(ddd,J=12.0,7.2,1.2Hz,1H),1.70(brs,1H),1.16(s,3H),1.07(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):143.39,134.57,129.72,127.39,72.42,65.58,56.85,48.32,39.27,37.76,36.41,21.49,19.14,16.56.HRMS-DART(m/z):[M+H]+calcd.for C16H26O4NS,328.1574;found,328.1577.
实施例9
操作同实施例1。(S)-B-Me(0.200mmol,0.20mL,1.0M in THF),BH3·SMe2(1.00mmol,0.5mL,2.0M in THF),四氢呋喃(2+2mL),1i(0.283g,1.00mmol)。快速柱层析(淋洗剂∶石油醚(60~90℃)/乙酸乙酯=4/1)得到一对非对映异构体手性环丁醇产物(R)-cis-2i(0.165g,56%);(R)-trans-2i(86.0mg,29%):白色固体;(1S,5S,6R)-7,7-dimethyl-3-tosyl-3-azabicyclo[3.2.0]heptan-6-ol(cis-2i).Ee:44%(OJ-H;15%i-PrOH in hexanes;flow rate=1.0mL/min;detection at 210nm;t1=19.6min(minor);t2=25.4min(major).-11.72(c1.20,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.72(d,J=8.3Hz,2H),7.35(d,J=8.0Hz,2H),3.79(ddd,J=12.1,7.5,1.7Hz,1H),3.71(d,J=9.9Hz,1H),3.50(d,J=10.2Hz,1H),2.99(q,J=7.2Hz,1H),2.48-2.37(m,6H),2.28(d,J=12.1Hz,1H),1.16(s,3H),0.98(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):143.96,130.85,129.57,128.29,73.99,49.61,47.05,44.12,40.62,38.67,30.07,21.52,14.93.HRMS-DART(m/z):[M+H]+calcd.for C15H22O3NS,296.1313;found,296.1315.(1R,5R,6R)=7,7-dimethyl-3-tosyl-3-azabicyclo[3.2.0]heptan-6-ol(trans-2i).Ee:98%(OJ-H;8%i-PrOH in hexanes;flow rate=1.0mL/min;detection at 210nm;t1=21.1min(minor);t2=31.0min(major).9.82(c 1.20,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.69(d,J=8.2Hz,2H),7.33(d,J=8.1Hz,2H),3.78(d,J=5.0Hz,1H),3.55-3.44(m,2H),2.59(dt,J=8.6,5.2Hz,1H),2.51-2.44(m,2H),2.43(s,3H),2.18(t,J=8.1Hz,1H),1.91(brs,1H),1.08(s,3H),1.01(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):143.64,131.79,129.52,128.05,76.89,51.61,48.29,44.03,42.25,39.38,22.93,21.78,21.52.HRMS-DART(m/z):[M+H]+calcd.forC15H22O3NS,296.1312;found,296.1315.
操作同实施例1。硅醚中间体的制备使用ent-cis-2i(0.145g,0.500mmol),三(三苯基膦)二氯化钌(II)(0.958mg,1.00μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(66.2mg,0.750mmol),四氢呋喃溶液(0.4mL)。将封管密闭好置于35℃反应12小时抽干。(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol),将封管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入上述硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL)与硅醚中间体100℃油浴下反应24小时。PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol)在-78℃下反应3小时。柱层析得ent-cis-3i(0.176g,77%):无色液体;Ee:69%(OD-H;5%i-PrOH in hexanes;flow rate=0.5mL/min;detection at 210nm;t1=21.2min(minor);t2=43.6min(major).19.60(c 1.20,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.69(d,J=8.0Hz,2H),7.59-7.50(m,2H),7.39-7.30(m,5H),3.64(d,J=10.0Hz,1H),3.63-3.55(m,1H),3.37(d,J=10.4Hz,1H),2.93(q,J=6.8Hz,1H),2.46-2.34(m,5H),2.27(dd,J=10.4,7.3Hz,1H),2.09-2.03(m,1H),1.15(s,3H),1.07-0.95(m,7H),0.95-0.77(m,5H).13C NMR(101MHz,CDCl3)δ(ppm):143.99,137.65,134.42,131.17,129.58,128.82,128.35,127.76,75.39,49.65,47.49,46.73,43.06,38.18,29.80,21.56,12.53,7.55,5.07,4.68.HRMS-DART(m/z):[M+H]+calcd.forC25H36O3NSSi,458.2174;found.458.2180.
操作同实施例1。硅醚中间体的制备使用ent-trans-2i(0.145g,0.500mmol),三(三苯基膦)二氯化钌(II)(0.958mg,1.00μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(66.2mg,0.750mmol),四氢呋喃溶液(0.4mL)。将封管密闭好置于35℃反应12小时抽干。(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol),将封管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入上述硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL)与硅醚中间体100℃油浴下反应24小时。PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol)在-78℃下反应3小时。柱层析得ent-trans-3i(0.181g,79%):无色液体;Ee:98%(AD-H;8%i-PrOH in hexanes;flow rate=1.0mL/min;detection at 210nm;t1=24.1min(minor);t2=39.8min(major).-18.22(c1.20,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.68-7.61(m,2H),7.52-7.44(m,2H),7.37-7.28(m,5H),3.65-3.56(m,1H),3.43(d,J=9.4Hz,1H),3.27(d,J=10.3Hz,1H),2.52-2.35(m,5H),2.20(dd,J=10.4,7.7Hz,1H),2.12-2.01(m,1H),1.71(d,J=6.4Hz,1H),1.10-1.02(m,s,3H+d,1H),1.02-0.94(m,7H),0.90-0.82(m,4H).13C NMR(101MHz,CDCl3)δ(ppm):143.58,137.34,134.22,131.84,129.49,128.95,128.03,127.86,78.90,51.64,48.20,43.81,42.71,41.50,22.01,21.52,19.59,7.45,4.90,4.72.HRMS-DART(m/z):[M+H]+calcd.for C25H36O3NSSi,458.2174;found,458.2180.
实施例10
操作同实施例1。(S)-B-Me(0.300mmol,0.30mL,1.0M in THF),BH3·SMe2(1.50mmol,0.75mL,2.0M in THF),四氢呋喃(3+3mL),1j(0.300g,1.50mmol)。快速柱层析(淋洗剂∶石油醚(60~90℃)/乙酸乙酯=10/1)得到一对非对映异构体手性环丁醇产物(R)-cis-2j(0.183g,61%):白色固体;(R)-trans-2j(0.117g,39%):白色固体;(1R,2aS,8aR)-2,2-Dimethyl-1,2,2a,3,8,8a-hexahydrocyclobuta[b]naphthalen-1-ol(cis-2j).Ee:54%(OD-H;2%i-PrOH in hexanes;flow rate=0.5mL/min;detectionat 210nm;t1=24.2min(major);t2=27.8min(minor).7.02(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.21-7.07(m,3H),3.96(d,J=7.4Hz,1H),3.00-2.79(m,2H),2.76-2.56(m,3H),2.14(dtd,J=8.8,6.9,1.6Hz,1H),1.43(brs,1H),1.18(s,3H),0.81(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):139.11,138.68,128.13,127.76,126.27,126.22,76.04,40.97,39.72,34.34,30.78,28.97,26.50,16.49.HRMS-EI(m/z):[M]+calcd.forC14H18O,202.1352;found,202.1353.(1R,2aR,8aS)-2,2-Dimethyl-1,2,2a,3,8,8a-hexahydrocyclobuta[b]naphthalen-1-ol(trans-2j).Ee:95%(OJ-H;2%i-PrOH in hexanes;flow rate=0.5mL/min;detection at 210nm;t1=25.3min(major);t2=32.5min(minor).22.28(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.20-7.05(m,4H),3.27(d,J=6.8Hz,1H),2.82-2.68(m,2H),2.69-2.58(m,3H),2.11(dt,J=10.5,5.6Hz,1H),1.66(brs,1H),1.12(s,3H),0.84(s,3H).13C NMR(101MHz,CDCla)δ(ppm):139.02,138.43,128.76,128.14,126.14,125.92,76.74,40.83,39.56,37.25,31.02,29.25,23.53,21.63.HRMS-EI(m/z):[M]+calcd.for C14H18O,202.1352;found,202.1359.
操作同实施例1。硅醚中间体的制备使用cis-2j(0.101g,0.500mmol),三(三苯基膦)二氯化钌(II)(0.958mg,1.00μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(66.2mg,0.750mmol),四氢呋喃溶液(0.4mL)。将封管密闭好置于35℃反应12小时抽干。(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol),将封管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入上述硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL)与硅醚中间体100℃油浴下反应24小时。PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol)在-78℃下反应3小时。柱层析得cis-3j(0.126g,69%):无色液体;Ee:96%(OD-H;1%i-PrOH in hexanes;flow rate=0.5mL/min;detection at 210nm;t1=18.8min(minor);t2=21.6min(major).1.93(c 1.20,CHCl3).1H NMR(400MHz,CDCla)δ(ppm):7.59-7.51(m,2H),7.40-7.32(m,3H),7.15-7.08(m,3H),7.10-7.02(m,1H),3.67(td,J=6.4,2.6Hz,1H),2.91-2.74(m,2H),2.66(dd,J=14.2,9.0Hz,1H),2.59-2.44(m,2H),2.01-1.79(m,1H),1.25(s,3H),1.11(d,J=14.7Hz,1H),1.07(d,J=6.4Hz,1H),1.04-0.93(m,6H),0.96-0.84(m,4H),0.81(d,J=14.7Hz,1H).13CNMR(101MHz,CDCl3)δ(ppm):139.35,139.05,138.17,134.24,129.01,127.98,127.70,127.63,126.12,125.91,76.75,44.55,42.10,32.95,30.53,29.89,25.22,14.25,7.53,4.97,4.74.HRMS-DART(m/z):[M+NH4]+calcd.for C24H36ONSi,382.2555;found,382.2561.
操作同实施例1。硅醚中间体的制备使用trans-2j(0.145g,0.500mmol),三(三苯基膦)二氯化钌(II)(0.958mg,1.00μmol)的四氢呋喃溶液(0.1mL),二乙基硅烷(66.2mg,0.750mmol),四氢呋喃溶液(0.4mL)。将封管密闭好置于35℃反应12小时抽干。(环辛烯)氯化铱(I)二聚体(8.4mg,12.5μmol),L1(7.1mg,30.0μmol),将封管用橡皮塞塞好后,连接真空泵,在氩气氛围下置换氩气三次,在氩气保护氛围下,分别加入上述硅醚中间体,A(92.1mg,0.500mmol),四氢呋喃(2.0mL)与硅醚中间体100℃油浴下反应24小时。PhLi(1.2M的乙醚溶液,1.25mL,1.50mmol)在-78℃下反应3小时。柱层析得trans-3j(0.181g,79%):无色液体;Ee:92%(AD-H;2%i-PrOH in hexanes;flow rate=0.5mL/min;detection at 210nm;t1=38.1min(minor);t2=45.5min(major).-35.82(c 1.20,CHCl3).1H NMR(400MHz,CDCl3)δ(ppm):7.59-7.50(m,2H),7.40-7.32(m,3H),7.16-7.04(m,3H),7.07-6.99(m,1H),3.14(d,J=7.0Hz,1H),2.75-2.60(m,2H),2.54(dddd,J=10.9,7.0,5.4,4.1Hz,1H),2.45-2.29(m,2H),2.13-1.95(m,1H),1.09-0.96(m,8H),0.98-0.85(m,4H),0.80(s,3H).13C NMR(101MHz,CDCl3)δ(ppm):139.02,138.37,137.72,134.38,128.80,128.69,128.09,127.75,126.10,125.85,78.66,43.08,39.59,37.58,31.07,28.98,22.16,20.08,7.56,7.52,5.06,4.81.HRMS-DART(m/z):[M+NH4]+calcd.forC24H36ONSi,382.2557;found,382.2561.
上述实施例仅为了说明本发明的技术构思及特点,其目的在于让本领域技术人员能够了解本发明的内容并据以实施,并不能以此限制本发明的保护范围。凡是根据本发明内容的实质所作出的等效变化或修饰,都涵盖在本发明保护范围内。
尽管本发明的内容已经通过上述优选实施例作了详细介绍,但应当认识到上述的描述不应被认为是对本发明的限制。在本领域技术人员阅读了上述内容后,对于本发明的多种修改和替代都将是显而易见的。因此,本发明的保护范围应由所附的权利要求来限定。
Claims (10)
2.如权利要求1所述的手性环丁醇化合物的合成方法,其特征在于,R1为末端取代或未取代的C1-C10烃基;R2为末端取代或非取代的C1-C10烃基;其中,取代基选自碳-碳双键、碳-碳三键、酯基、羟基、酰基、酰氧基、酰胺基、卤素、羧基、氰基中的一种或两种以上。
3.如权利要求1所述的手性环丁醇化合物的合成方法,其特征在于:所述的还原剂为BH3·SMe2或(-)-(Ipc)2BCl。
4.如权利要求3所述的手性环丁醇化合物的合成方法,其特征在于:带有取代基的环丁酮(1)与CBS催化剂的用量的摩尔比为1∶(0.01~0.50),带有取代基的环丁酮(1)与BH3·SMe2的用量的摩尔比为1∶(0.1~5.0)。
6.一种根据权利要求5所述的手性环丁醇的用途,其特征在于,对其进行手性醇导向的立体选择性碳氢键硅化反应制备具有季碳手性中心的环丁醇衍生物,反应步骤如下:
步骤1:在惰性气体氛围下,使用钌催化剂,使得手性环丁醇(2)与硅氢试剂在室温下反应得到环丁醇硅醚衍生物;
步骤2:环丁醇硅醚衍生物在铱催化剂、菲啰啉配体和氢受体的作用下在20~150℃反应2~48h;
步骤3:制备具有季碳手性中心的环丁醇衍生物(3)或(4),结构通式如下:
R为苯基、芳基或C1~C6的烃基,所述芳基是邻、间、对位有C1~C6烃基取代的苯基,*代表手性中心;
其中,制备具有季碳手性中心的环丁醇衍生物(3)的方法为:在-78℃下冷却并向步骤2的反应物中加入一定量有机金属试剂反应,得到具有季碳手性中心的环丁醇衍生物(3);
制备具有季碳手性中心的环丁醇衍生物(4)的方法包含:向步骤2的反应物中加入一定量的KHCO3,金属氟盐,过氧化物,MeOH,并在50~80℃下加热反应得到具有季碳手性中心的环丁醇衍生物(4)。
7.如权利要求6所述的用途,其特征在于:手性环丁醇(2)与硅氢试剂用量的摩尔比为1∶(0.1~5),手性环丁醇(2)与钌催化剂的用量的摩尔比为1∶(0.0001~0.5),手性环丁醇(2)与铱催化剂的用量的摩尔比为1∶(0.0001~0.5),手性环丁醇(2)与菲啰啉配体用量的摩尔比为1∶(0.05~1),环丁醇化合物与有机金属的摩尔比为1∶(1~5),环丁醇与KHCO3、金属氟盐、过氧化物用量的摩尔比均为1∶(1~20)。
8.如权利要求6所述的用途,其特征在于,所述铱催化剂选自二(1,5-环辛二烯)二-M-甲氧基二铱(I),(1,5-环辛二烯)氯化铱(I)二聚体,二(环辛烯)氯化铱(I)二聚体中的任意一种或多种,所述菲啰啉配体选自L1,L2,L3,L4中的任意一种或多种,其中,L1~L4结构式如下:
所述的氢受体选自降冰片烯,环辛二烯,双环[2.2.1]-5-庚烯-2-甲酸酯中的任意一种或多种,所述的双环[2.2.1]-5-庚烯-2-甲酸酯包含双环[2.2.1]-5-庚烯-2-甲酸甲酯、双环[2.2.1]-5-庚烯-2-甲酸乙酯、双环[2.2.1]-5-庚烯-2-甲酸苄酯、双环[2.2.1]-5-庚烯-2-甲酸叔丁基酯中的任意一种或两种以上;所述钌催化剂为三(三苯基膦)二氯化钌(II),所述硅氢试剂包含二乙基硅烷、二甲基硅氢、二苯基硅氢、二乙氧基硅氢、二甲氧基硅氢中的任意一种或任意两种以上。
9.如权利要求6所述的用途,其特征在于,所述的有机金属锂试剂的结构通式为R-Li,所述的有机金属镁试剂的结构通式为R-MgX,X代表卤素,R为苯基、芳基或C1~C6的烃基,所述芳基是邻、间、对位有C1~C6烃基取代的苯基。
10.如权利要求6所述的用途,其特征在于:手性环丁醇(2)和具有季碳手性中心的环丁醇衍生物中,R1选自甲基,乙基,正丙基,异丙基,正丁基,正戊基,正己基,正庚基,正辛基,苯乙基,4-氯丁基,3-甲基丁基,3-氰基丙基,烯丙基中的任意一种;R2选自甲基,乙基,正丙基,叔丁基,苯基,邻甲基苯基,间甲基苯基,对甲基苯基,间甲氧基苯基,对氯苯基,对溴苯基,对酯基苯基,2-萘基,3-噻吩基中的任意一种。
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KR101632561B1 (ko) * | 2015-01-16 | 2016-06-22 | 순천향대학교 산학협력단 | 키랄 포스포네이트 유도체의 제조방법 |
JP2020015858A (ja) * | 2018-07-26 | 2020-01-30 | 味の素株式会社 | 樹脂組成物 |
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KR101632561B1 (ko) * | 2015-01-16 | 2016-06-22 | 순천향대학교 산학협력단 | 키랄 포스포네이트 유도체의 제조방법 |
JP2020015858A (ja) * | 2018-07-26 | 2020-01-30 | 味の素株式会社 | 樹脂組成物 |
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