CN115626929B - 一类氮原子作为桥头碳的手性桥环化合物及其合成方法 - Google Patents
一类氮原子作为桥头碳的手性桥环化合物及其合成方法 Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 32
- 229910052757 nitrogen Inorganic materials 0.000 title claims abstract description 30
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 229910052799 carbon Inorganic materials 0.000 title claims abstract description 15
- 125000004433 nitrogen atom Chemical group N* 0.000 title claims abstract description 14
- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- 239000002585 base Substances 0.000 claims abstract description 27
- 239000003446 ligand Substances 0.000 claims abstract description 26
- -1 dihydroQuinolinone compound Chemical class 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 10
- 238000006254 arylation reaction Methods 0.000 claims abstract description 6
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 5
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 58
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 37
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 35
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 26
- 229910052763 palladium Inorganic materials 0.000 claims description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000000460 chlorine Substances 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 239000012298 atmosphere Substances 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- TZOYXRMEFDYWDQ-UHFFFAOYSA-N 3,4-dihydro-1h-quinolin-2-one Chemical class C1=CC=C2NC(=O)CCC2=C1 TZOYXRMEFDYWDQ-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims description 2
- CUDYYMUUJHLCGZ-UHFFFAOYSA-N 2-(2-methoxypropoxy)propan-1-ol Chemical compound COC(C)COC(C)CO CUDYYMUUJHLCGZ-UHFFFAOYSA-N 0.000 claims description 2
- FAFGMAGIYHHRKN-UHFFFAOYSA-N 2-diphenylphosphanylethyl(diphenyl)phosphane;palladium Chemical compound [Pd].C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1.C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 FAFGMAGIYHHRKN-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- 101150003085 Pdcl gene Proteins 0.000 claims description 2
- 239000004280 Sodium formate Substances 0.000 claims description 2
- ZOAIGCHJWKDIPJ-UHFFFAOYSA-M caesium acetate Chemical compound [Cs+].CC([O-])=O ZOAIGCHJWKDIPJ-UHFFFAOYSA-M 0.000 claims description 2
- JCWIWBWXCVGEAN-UHFFFAOYSA-L cyclopentyl(diphenyl)phosphane;dichloropalladium;iron Chemical compound [Fe].Cl[Pd]Cl.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1 JCWIWBWXCVGEAN-UHFFFAOYSA-L 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 2
- 235000019254 sodium formate Nutrition 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 3
- 125000001153 fluoro group Chemical group F* 0.000 claims 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 238000003756 stirring Methods 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract description 14
- 229910052751 metal Inorganic materials 0.000 abstract description 8
- 239000002184 metal Substances 0.000 abstract description 8
- 238000000926 separation method Methods 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- 150000004696 coordination complex Chemical class 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 19
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 125000001424 substituent group Chemical group 0.000 description 12
- 238000012512 characterization method Methods 0.000 description 11
- BGHCVCJVXZWKCC-UHFFFAOYSA-N tetradecane Chemical compound CCCCCCCCCCCCCC BGHCVCJVXZWKCC-UHFFFAOYSA-N 0.000 description 8
- 239000011734 sodium Substances 0.000 description 5
- 230000005587 bubbling Effects 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- YCOZIPAWZNQLMR-UHFFFAOYSA-N heptane - octane Natural products CCCCCCCCCCCCCCC YCOZIPAWZNQLMR-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000011914 asymmetric synthesis Methods 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
- 238000007664 blowing Methods 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 125000006575 electron-withdrawing group Chemical group 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 239000002879 Lewis base Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 150000007527 lewis bases Chemical class 0.000 description 1
- 238000001465 metallisation Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 150000003512 tertiary amines Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一类氮原子作为桥头碳的手性桥环化合物及其合成方法,属于有机化学技术领域。本发明以N‑苄基取代的二氢喹啉酮类化合物为原料,利用金属与手性配体配位形成手性金属络合物为催化剂,在碱的促进下,通过分子内羰基α位的芳基化反应合成含氮立体中心的手性Base类似物。本发明优势在于反应原料合成简单,反应产率高,反应的化学选择性和对映选择性好,底物的适用范围广,便于分离提纯。本发明制备的手性Base类似物官能团兼容性好,转化容易,同时该骨架也是制备手性药物中间体和手性配体的重要手性砌块,具有重要的应用价值和广阔的应用前景。
Description
技术领域
本发明属于有机化学技术领域,尤其是指一类氮原子作为桥头碳的手性桥环化合物及其合成方法。
背景技术
开发高效和高选择性的策略来获得对映体富集的立体中心是现代合成研究的关键目标。其中,碳立体中心以及杂原子立体中心的构建已经发展了多种策略,相比之下,氮立体中心的对映选择性合成非常具有挑战性,因为氮上的孤对电子在室温下便可以自由翻转,从而导致氮手性快速消旋化。而手性氮立体中心化合物的对映选择性合成策略通常涉及氮氧化物、氮中心金属配位和季铵盐。[(a)Toda,F.;Mori,K.;Stein,Z.;Goldberg,I.Tetrahedron Lett.1989,30,1841-1844;(b)Tayama,E.;Tanaka,H.TetrahedronLett.2007,48,4183-4185;(c)Wu,H.-F.;Lin,W.-B.;Xia,L.-Z.;Luo,Y.-G.;Chen,X.-Z.;Li,G.-Y.;Zhang,G.-L.;Pan,X.-F.Helv.Chim.Acta 2009,92,677-688;(d)Iwamoto,T.;Mizuhata,Y.;Tokitoh,N.;Nakamura,M.Organometallics 2020,39,1672-1677;(e)Walsh,M.P.;Phelps,J.M.;Lennon,M.E.;Yufit,D.S.;Kitching,M.O.Nature 2021,597,70-76.]除了以上这些骨架,另一种代表性骨架则是刚性的叔胺骨架,通过抑制氮上孤对电子的翻转,使得氮手性更加稳定。这些结构通常存在于许多生物碱[(a)Gan,C.-Y.;Robinson,W.T.;Etoh,T.;Hayashi,M.;Komiyama,K.;Kam,T.-S.Org.Lett.2009,11,3962-3965;(b)Reimann,C.E.;Ngamnithiporn,A.;Hayashida,K.;Saito,D.;Korch,K.M.;Stoltz,B.M.Angew.Chem.Int.Ed.2021,60,17957-17962.]、药物(Beckerbauer,L.;Tepe,J.J.;Cullison,J.;Reeves,R.;Williams,R.M.Chemistry&Biology 2000,7,805-812.)和手性路易斯碱催化剂中。[(a)Harmata,M.;Kahraman,M.Tetrahedron Asymmetry 2000,11,2875-2879;(b)Shen,Y.-M.;Zhao,M.-X.;Xu,J.;Shi,Y.Angew.Chem.Int.Ed.2006,45,8005-8008;(c)Sigman,M.S.;Jensen,D.R.Acc.Chem.Res.2006,39,221-229.]
在这些刚性手性叔胺化合物中,一个特别引人注目的结构是 Base。它具有两个彼此垂直的芳香环,其与中心双环[3.3.1]框架融合,能够形成具有两个氮立体中心的刚性裂隙状V形支架。鉴于/> Base特殊的结构特点,其在自组装研究、分子识别、DNA相互作用探针以及Lewis碱催化剂中有着广泛的应用。[(a)Harmata,M.;Kahraman,M.Tetrahedron Asymmetry 2000,11,2875-2879;(b)Shen,Y.-M.;Zhao,M.-X.;Xu,J.;Shi,Y.Angew.Chem.Int.Ed.2006,45,8005-8008;(c)Sigman,M.S.;Jensen,D.R.Acc.Chem.Res.2006,39,221-229;(d)Koichiro,N.;Rinko,F.;Masanori,K.;Masatoshi,Y.;Hiroaki,C.Bull.Chem.Soc.Jpn.1989,62,83-88;(e)/>A.;Demeunynck,M.;Andraud,C.;Collet,A.;Lhomme,J.Chem.Commun.1999,161-162;(f)Kimber,M.C.;Try,A.C.;Painter,L.;Harding,M.M.;Turner,P.J.Org.Chem.2000,65,3042-3046;(g)Yuan,C.;Xin,Q.;Liu,H.;Wang,L.;Jiang,M.;Tao,X.Sci.China Chem2011,54,587-595;(h)Kazem-Rostami,M.New J.Chem.2019,43,7751-7755;(i)Antonangelo,A.R.;Hawkins,N.;Tocci,E.;Muzzi,C.;Fuoco,A.;Carta,M.J.Am.Chem.Soc.2022,144,15581-15594.]然而,由于/> Base在酸性条件下易开环,导致构型不稳定,所以其对映选择性合成很少被开发,[(a)Greenberg,A.;Molinaro,N.;Lang,M.J.Org.Chem.1984,49,1127-1130;(b)D.A.Lenev,K.A.Lyssenko,D.G.Golovanov,V.Buss,R.G.Kostyanovsky,Chem.Eur.J.2006,12,6412-6418;(c)Jameson,D.L.;Field,T.;Schmidt,M.R.;DeStefano,A.K.;Stiteler,C.J.;Venditto,V.J.;Krovic,B.;Hoffman,C.M.;Ondisco,M.T.;Belowich,M.E.J.Org.Chem.2013,78,11590-11596.],极大的限制了其广泛应用。
发明内容
为解决上述技术问题,本发明提供了一类氮原子作为桥头碳的手性桥环化合物及其合成方法。在此,本发明通过钯催化分子内羰基α位的芳基化反应来实现含氮立体中心的手性 Base类似物的催化不对称合成。通过钯源催化剂和手性配体的结合,实现N-苄基取代的二氢喹啉酮类化合物分子内的羰基α位的芳基化反应,实现含氮立体中心的手性/> Base类似物的催化不对称合成,从而丰富氮手性化学。(本发明所述氮原子作为桥头碳的桥环化合物即含氮立体中心的手性/> Base类似物)。
本发明的实施方案如下:
本发明的第一个目的在于提供一类氮原子作为桥头碳的手性桥环化合物,所述手性桥环化合物的结构式为:
R为吸电子取代基或给电子取代基;
其中,所述吸电子取代基为含有氟、氯或三氟甲基的取代基团;
所述给电子取代基为C1~C10烷基或烷氧基、C1~C7保护的氨基基团;
Ar为吸电子或给电子取代的芳基;
其中,所述吸电子的基团为含有氟、氯或三氟甲基的取代基团;
给电子的基团为C1~C10的烷基或烷氧基。
本发明的第二个目的在于提供所述的氮原子作为桥头碳的手性桥环化合物的合成方法,包括以下步骤:
在惰性氛围、有机溶剂中,利用N-苄基取代的二氢喹啉酮类化合物为原料,在钯源和手性配体的催化下,在碱的促进下,发生分子内羰基α位的芳基化反应,得到所述氮原子作为桥头碳的手性桥环化合物;
R为吸电子取代基或给电子取代基;
其中,所述吸电子取代基为含有氟、氯或三氟甲基的取代基团;
所述给电子取代基为C1~C10烷基或烷氧基、C1~C7保护的氨基基团;
Ar为吸电子或给电子取代的芳基;
其中,所述吸电子的基团为含有氟、氯或三氟甲基的取代基团;
给电子的基团为C1~C10的烷基或烷氧基。
在本发明的一个实施例中,所述芳基化反应的条件为:反应温度为30℃-120℃,反应时间为2h-36h。
在本发明的一个实施例中,所述手性配体为如下结构的手性膦配体的一种或多种:
其中,
Ar1选自Ph或3,5-tBu2-4-MeOC6H2;
Ar2选自3,5-tBu2-4-MeOC6H2;
R选自H或Me,
R1选自Ph或Cy;
R2选自Ad、tBu、4-MeOC6H4、4-PhC6H4、4-MeC6H4、2,5-Me2C6H3或3,5-tBu2-4-MeOC6H2。
在本发明的一个实施例中,所述碱选自三乙胺、三正丙胺、二乙胺、二环己基胺、N,N-二异丙基乙胺、三乙烯二胺、1,8-二氮杂二环十一碳-7-烯、碳酸钾、碳酸铯、乙酸铯、乙酸钠、叔丁醇钠、叔丁醇钾、氢氧化钾、磷酸钾、碳酸氢钾、碳酸氢钠、氢氧化钠和甲酸钠中的一种或多种。
在本发明的一个实施例中,所述钯源选自Pd2(dba)3、Pd(dba)2、Pd2(dba)3·CHCl3、Pd(OAc)2、Pd(OPiv)2、Pd(acac)2、PdI2、PdCl2、PdBr2、Pd(TFA)2、[Pd(allyl)Cl]2、Pd(dppf)2Cl2、Pd(CH3CN)2Cl2和Pd(dppe)2Cl2中的一种或多种。
在本发明的一个实施例中,所述有机溶剂选自正戊烷、正己烷、环己烷、四氢呋喃、1,4-二氧六环、乙醚、甲基叔丁基醚、环戊己甲基醚、二甲基亚砜,甲苯、1,2-二氯乙烷、三氯甲烷、乙酸乙酯、乙腈、丙酮、甲醇、乙醇、异丙醇、叔丁醇、叔戊醇、二丙二醇甲醚和二甲基甲酰胺中的一种或多种。
在本发明的一个实施例中,所述惰性氛围中气体为氮气和/或惰性气体。进一步的,所述惰性氛围中气体为氮气。
在本发明的一个实施例中,所述N-苄基取代的二氢喹啉酮类化合物、钯源、手性配体与碱的摩尔比为1:(0.005~0.075):(0.02~0.3):(0~10)。
在本发明的一个实施例中,所述合成方法具体步骤:
将N-苄基取代的二氢喹啉酮类化合物、钯源催化剂、手性配体和碱混合,在惰性氛围以及干燥条件下,加入有机溶剂,反应温度设置为30-120℃,进行反应,待反应完全,分离提纯得到所述氮原子作为桥头碳的手性桥环化合物。
进一步的,合成方法具体如下:
(1)在室温下,向干燥的封管中加入0.30mmol-6mmol的N-苄基取代的二氢喹啉酮类化合物,0.015mmol-0.3mmol的金属催化剂,0.033mmol-0.66mmol手性配体和0.6mmol-1.2mmol碱,然后将封管用氮气进行抽换气,并置于高纯氮气中,使体系处于无水无氧条件,最后在鼓气下,加入3mL-60mL干燥的有机溶剂,移至30℃-120℃且转速为800转-1500转的油浴中进行反应,直至完全反应为止;
(2)用TLC监测至反应结束后,将反应液过滤,滤液旋干,并采用石油醚和乙酸乙酯的混合液作为流动相进行柱层析分离,即得到相应的含氮立体中心的手性 Base类似物,反应收率为3-99%,对映选择性为1-97%ee。
在本发明的一个实施例中,所述反应温度30℃-120℃通过油浴方式实现。
在本发明的一个实施例中,分离提纯过程利用柱层析分离方法进行纯化。进一步的,柱层析分离中流动相使用石油醚和乙酸乙酯的混合溶剂。
本发明提供的含氮立体中心的手性 Base类似物的制备方法,是利用N-苄基取代的二氢喹啉酮类化合物,在钯源和手性配体的催化下,在碱的促进下,在氮气氛围下,30℃-120℃且转速为800转-1500转的油浴下,发生分子内羰基α位的芳基化反应,高效合成含氮立体中心的手性/> Base类手性化合物。而该反应的具体历程为,首先钯源与手性配体配位形成的手性钯物种与N-苄基取代的二氢喹啉酮类化合物先发生氧化加成,得到二价钯物种,然后在碱的作用下,发生转金属化,再发生还原消除便可以得到含氮立体中心的手性/> Base类似物,同时释放零价钯,完成其催化循环。
本发明的上述技术方案相比现有技术具有以下优点:
1.本发明通过钯催化剂或钯络合物和手性配体的催化,制备含氮立体中心的手性 Base类似物,高效且环境友好,其优势在于反应原料合成简单,反应产率高,反应的化学选择性和对映选择性好,底物的适用范围广,便于分离提纯。
2.本发明为这类化合物的催化不对称合成提供了一种简洁高效的途径。本发明合成的一系列含氮立体中心的手性 Base类似物是一类多官能团的刚性化合物,其官能团兼容性好,转化容易,该骨架是制备手性药物中间体和手性配体的重要手性砌块,具有重要的应用价值和广阔的应用前景。
附图说明
为了使本发明的内容更容易被清楚的理解,下面根据本发明的具体实施例并结合附图,对本发明作进一步详细的说明,其中
图1是本发明实施例1的反应式以及利用不同手性配体进行制备的结果。
图2是本发明实施例2的反应式以及利用不同碱进行制备的结果。
图3是本发明实施例3的反应式以及利用不同钯源进行制备的结果。
图4是本发明实施例4的反应式以及利用不同溶剂进行制备的结果。
具体实施方式
下面结合附图和具体实施例对本发明作进一步说明,以使本领域的技术人员可以更好地理解本发明并能予以实施,但所举实施例不作为对本发明的限定。
实施例1
含氮立体中心的手性 Base类似物IIa的制备,其中给出了利用不同手性配体进行制备的结果。
向干燥的封管中加入0.1mmol的N-苄基取代的二氢喹啉酮类化合物Ia、0.005mmol(5mol%)金属催化剂Pd2(dba)3,0.011mmol(11mol%)手性配体和0.2mmol碳酸铯,然后用氮气将封管进行置换气,使得体系处于无水无氧条件,再在鼓气下,加入1.0mL干燥的甲苯,置于100℃且转速为1000转的油浴中进行反应,TLC监测反应,待反应结束后,加入10微升正十四烷进行定标,利用GC测得产率,利用HPLC测定ee值。
本实施例的反应式以及利用不同手性配体进行制备的结果如图1所示。
实施例2
含氮立体中心的手性 Base类似物IIa的制备,其中给出了利用不同碱进行制备的结果。
向干燥的封管中加入0.1mmol的N-苄基取代的二氢喹啉酮类化合物Ia、0.005mmol(5mol%)金属催化剂Pd2(dba)3,0.011mmol(11mol%)手性配体PC-Phos和0.2mmol碱,然后用氮气将封管进行置换气,使得体系处于无水无氧条件,再在鼓气下,加入1.0mL干燥的甲苯,置于100℃且转速为1000转的油浴中进行反应,TLC监测反应,待反应结束后,加入10微升正十四烷进行定标,利用GC测得产率,利用HPLC测定ee值。
本实施例的反应式以及利用不同碱进行制备的方法如图2所示,相应的结果如下表1所示:
表1
实施例3
含氮立体中心的手性 Base类似物IIa的制备,其中给出了利用不同钯源进行制备的结果。
向干燥的封管中加入0.1mmol的N-苄基取代的二氢喹啉酮类化合物Ia、0.01mmol(10mol%)金属催化剂,0.011mmol(11mol%)手性配体PC-Phos和0.2mmol碳酸铯,然后用氮气将封管进行置换气,使得体系处于无水无氧条件,再在鼓气下,加入1.0mL干燥的甲苯,置于100℃且转速为1000转的油浴中进行反应,TLC监测反应,待反应结束后,加入10微升正十四烷进行定标,利用GC测得产率,利用HPLC测定ee值。
本实施例的反应式以及利用不同钯源进行制备的方法如图3所示,相应的结果如下表2所示:
表2
实施例4
含氮立体中心的手性 Base类似物IIa的制备,其中给出了利用不同溶剂进行制备的结果。
向干燥的封管中加入0.1mmol的N-苄基取代的二氢喹啉酮类化合物Ia、0.005mmol(5mol%)金属催化剂Pd2(dba)3,0.011mmol(11mol%)手性配体GF-Phos和0.2mmol碳酸铯,然后用氮气将封管进行置换气,使得体系处于无水无氧条件,再在鼓气下,加入1.0ml干燥的溶剂,置于100℃且转速为1000转的油浴中进行反应,TLC监测反应,待反应结束后,加入10微升正十四烷进行定标,利用GC测得产率,利用HPLC测定ee值。
本实施例的反应式以及利用不同溶剂进行制备,其中制备方法如图4所示,相应的结果如下表3所示:
表3
实施例5
含氮立体中心的手性 Base类似物IIa的制备
向干燥的封管中加入0.3mmol的N-苄基取代的二氢喹啉酮类化合物Ia、0.015mmol(5mol%)金属催化剂Pd2(dba)3,0.033mmol(11mol%)手性配体GF-Phos和0.6mmol碳酸铯,然后用氮气将封管进行置换气,使得体系处于无水无氧条件,再在鼓气下,加入3.0mL干燥的乙腈,置于100℃且转速为1000转的油浴中进行反应,TLC监测反应,待反应结束后,过滤,旋干滤液,通过柱层析得到相应的产物,利用HPLC测定ee值。
以下是不同的含氮立体中心的手性 Base类似物的1H NMR、13C NMR的谱图数据,所有化合物可以利用实施例1~4的任意方法制备,相应的产率和对映选择性有一定的差异。
化合物例IIa的结构表征:1H NMR(400MHz,CDCl3)δ7.86(d,J=7.7Hz,1H),7.49–7.41(m,1H),7.30(d,J=7.3Hz,1H),7.23–7.12(m,3H),7.10–7.02(m,1H),6.94(d,J=7.2Hz,1H),4.80(d,J=16.9Hz,1H),4.29(d,J=17.0Hz,1H),4.04(d,J=13.5Hz,1H),3.69–3.64(m,1H),3.48(s,1H).13C NMR(100MHz,CDCl3)δ195.2,154.3,134.9,132.5,131.9,129.4,128.4,127.5,127.1,126.8,125.2,125.0,124.1,57.5,50.3,45.0.HRMS(ESI):m/z:Calcd for(C16H13NO+H)+236.1070,found 236.1073.HPLC conditions:DaicelChiralpak OD-H column(己烷/异丙醇=90/10,flow rate 1.0mL/min,254nm);tR=11.604(major),tR=12.400(minor),96%ee.
化合物例IIb的结构表征:1H NMR(400MHz,CDCl3)δ8.16(s,1H),7.66(d,J=8.3Hz,1H),7.35–7.28(m,2H),7.24–7.18(m,2H),6.96(d,J=7.3Hz,1H),4.84(d,J=16.9Hz,1H),4.33(d,J=16.9Hz,1H),4.04(d,J=13.6Hz,1H),3.71(d,J=13.6Hz,1H),3.55(s,1H).13CNMR(100MHz,CDCl3)δ193.8,157.2,132.2,131.3,131.0(dd,J=6.6,3.2Hz),129.5,128.7,127.5,126.8,125.7,125.2,125.11(overlap),125.0,57.5,50.0,44.6.19F NMR(377MHz,CDCl3)δ-62.5.HRMS(ESI):m/z:Calcd for(C17H12F3NO+H)+304.0944,found 304.0936.HPLCconditions:Daicel Chiralpak OD-H column(己烷/异丙醇=90/10,flow rate 1.0mL/min,254nm);tR=7.710(major),tR=11.166(minor),93%ee.
化合物例IIc的结构表征:1H NMR(400MHz,CDCl3)δ7.92–7.72(m,1H),7.41–7.37(m,1H),7.31–7.26(m,1H),7.25–7.20(m,1H),7.20–7.15(m,2H),6.95(d,J=7.3Hz,1H),4.79(d,J=17.0Hz,1H),4.24(d,J=16.9Hz,1H),4.01(dt,J=13.6,1.5Hz,1H),3.67(dd,J=13.5,2.5Hz,1H),3.49(s,1H).13C NMR(100MHz,CDCl3)δ194.0,152.7,134.8,132.2,131.5,129.8,129.5,128.7,127.41,127.1,126.9,126.6,126.4,57.5,50.2,44.5.HRMS(ESI):m/z:Calcd for(C16H12ClNO+H)+270.0680,found 270.0684.HPLC conditions:Daicel Chiralpak IC column(己烷/异丙醇=90/10,流速1.0mL/min,254nm);tR=7.012(minor),tR=7.410(major),95%ee.
化合物例IId的结构表征:1H NMR(400MHz,CDCl3)δ7.94–7.81(m,1H),7.56–7.48(m,1H),7.31(d,J=7.3Hz,1H),7.23–7.13(m,3H),6.95(d,J=7.1Hz,1H),4.79(d,J=17.0Hz,1H),4.27(d,J=17.0Hz,1H),4.04(d,J=13.4Hz,1H),3.65(d,J=13.4Hz,1H),3.48(s,1H),1.27(s,9H).13C NMR(100MHz,CDCl3)δ195.6,151.9,147.1,132.7,132.6,132.2,129.4,128.3,127.1,126.8,124.7,124.6,123.6,57.4,50.5,45.1,34.4,31.1.HRMS(ESI):m/z:Calcd for(C20H21NO+H)+292.1696,found 292.1703.HPLC conditions:DaicelChiralpak IG column(己烷/异丙醇=90/10,流速1.0mL/min,254nm);tR=8.233(minor),tR=9.329(major),94%ee.
化合物例IIe的结构表征:1H NMR(400MHz,CDCl3)δ7.36–7.26(m,2H),7.22–7.12(m,3H),7.07–7.01(m,1H),6.93(d,J=7.2Hz,1H),4.75(d,J=17.0Hz,1H),4.20(d,J=17.0Hz,1H),4.02(d,J=13.4Hz,1H),3.73(s,3H),3.64(d,J=13.4Hz,1H),3.46(s,1H).13CNMR(100MHz,CDCl3)δ195.3,156.2,147.8,132.4,131.9,129.2,128.4,127.1,126.8,126.3,125.6,123.7,108.5,57.3,55.5,50.6,44.8.HRMS(ESI):m/z:Calcd for(C17H15NO2+Na)+288.0995,found 288.1003.HPLC conditions:Daicel Chiralpak IC column(己烷/异丙醇=90/10,流速1.0mL/min,254nm);tR=10.558(minor),tR=14.867(major),93%ee.
化合物例IIf的结构表征:1H NMR(400MHz,CDCl3)δ7.30(d,J=7.2Hz,1H),7.21–7.08(m,4H),6.98–6.87(m,2H),4.74(d,J=17.0Hz,1H),4.18(d,J=17.0Hz,1H),4.02(d,J=13.3Hz,1H),3.62(dd,J=13.3,1.5Hz,1H),3.45(s,1H),2.86(s,6H).13C NMR(100MHz,CDCl3)δ195.9,147.6,144.2,132.6,132.1,129.2,128.2,126.9,126.8,125.6,125.4,120.5,109.2,57.3,50.7,45.1,40.7.HRMS(ESI):m/z:Calcd for(C18H18N2O+H)+279.1492,found 279.1496.HPLC conditions:Daicel Chiralpak AD-H column(己烷/异丙醇=90/10,流速1.0mL/min,254nm);tR=11.968(minor),tR=13.600(major),94%ee.
化合物例IIg的结构表征:1H NMR(400MHz,CDCl3)δ9.43(d,J=8.7Hz,1H),7.87(d,J=8.8Hz,1H),7.69(d,J=8.0Hz,1H),7.63–7.54(m,1H),7.44–7.34(m,2H),7.31(d,J=8.8Hz,1H),7.22–7.12(m,2H),6.95(d,J=7.2Hz,1H),4.85(d,J=16.8Hz,1H),4.52(d,J=16.8Hz,1H),4.22(d,J=13.2Hz,1H),3.73(d,J=13.2Hz,1H),3.52(s,1H).13C NMR(100MHz,CDCl3)δ197.1,156.3,136.1,133.0,132.2,132.0,131.0,129.4,129.3,128.4,128.3,127.3,126.7,126.5,125.2,124.0,117.2,56.9,50.1,47.0.HRMS(ESI):m/z:Calcdfor(C20H15NO+Na)+308.1046,found 308.1042.HPLC conditions:Daicel Chiralpak OD-Hcolumn(己烷/异丙醇=90/10,流速1.0mL/min,254nm);tR=9.345(major),tR=11.803(minor),92%ee.
化合物例IIh的结构表征:1H NMR(400MHz,CDCl3)δ7.86(dd,J=7.8,1.4Hz,1H),7.51–7.45(m,1H),7.42(s,2H),7.25–7.19(m,2H),7.11–7.06(m,1H),4.81(d,J=17.1Hz,1H),4.34(d,J=17.1Hz,1H),4.07(d,J=13.6Hz,1H),3.67(dd,J=13.6,2.3Hz,1H),3.55(s,1H).13C NMR(100MHz,CDCl3)δ194.3,154.1,136.0,135.3,133.4,130.7,130.4,129.9,127.6,125.1,125.0,124.5,123.9(dd,J=7.5,3.6Hz),123.8(dd,J=7.8,3.9Hz),57.3,50.0,45.0.19F NMR(377MHz,CDCl3)δ-62.8.HRMS(ESI):m/z:Calcd for(C17H12F3NO+Na)+326.0763,found 326.0758.HPLC conditions:Daicel Chiralpak OD-H column(己烷/异丙醇=90/10,流速1.0mL/min,254nm);tR=8.026(major),tR=8.580(minor),94%ee.
化合物例IIi的结构表征:1H NMR(400MHz,CDCl3)δ7.36–7.28(m,1H),7.28–7.23(m,1H),7.13(d,J=8.8Hz,1H),7.05(dd,J=8.8,2.8Hz,1H),6.91–6.81(m,1H),6.65(d,J=8.6Hz,1H),4.71(d,J=17.1Hz,1H),4.17(d,J=17.1Hz,1H),4.01(d,J=13.5Hz,1H),3.74(s,3H),3.59(d,J=13.4Hz,1H),3.43(s,1H).13C NMR(100MHz,CDCl3)δ195.0,162.7(d,J=246.2Hz),156.3,147.5,134.5(d,J=6.5Hz),130.8(d,J=7.9Hz),127.6(d,J=2.9Hz),126.3,125.5,123.8,114.3(d,J=21.4Hz),113.4(d,J=21.1Hz),108.5,57.3,55.5,50.6,44.0.19F NMR(377MHz,CDCl3)δ-112.9.HRMS(ESI):m/z:Calcd for(C17H14FNO2+H)+284.1081,found 284.1079.HPLC conditions:Daicel Chiralpak OD-H column(己烷/异丙醇=90/10,流速1.0mL/min,254nm);tR=9.688(major),tR=11.403(minor),96%ee.
化合物例IIj的结构表征:1H NMR(400MHz,CDCl3)δ7.86(d,J=7.7Hz,1H),7.49–7.41(m,1H),7.18(d,J=8.1Hz,1H),7.10-7.04(m,1H),6.74(s,1H),6.36(s,1H),5.87(s,1H),5.80(s,1H),4.69(d,J=16.7Hz,1H),4.14(d,J=16.8Hz,1H),3.96(d,J=13.4Hz,1H),3.59(dd,J=13.4,1.6Hz,1H),3.32(s,1H).13C NMR(100MHz,CDCl3)δ195.2,154.2,148.0,146.7,134.8,127.4,125.3,125.2,125.0,124.8,124.2,108.9,106.5,100.9,57.7,50.3,44.8.HRMS(ESI):m/z:Calcd for(C17H13NO3+Na)+302.0788,found 302.0785.HPLCconditions:Daicel Chiralpak AD-H column(己烷/异丙醇=90/10,流速1.0mL/min,254nm);tR=12.653(minor),tR=17.745(major),96%ee.
化合物例IIk的结构表征:1H NMR(400MHz,CDCl3)δ9.40(d,J=8.7Hz,1H),7.87(d,J=8.8Hz,1H),7.69(d,J=8.0Hz,1H),7.61–7.56(m,1H),7.42–7.37(m,1H),7.28(d,J=8.8Hz,1H),6.81(s,1H),6.38(s,1H),5.87(s,1H),5.77(s,1H),4.76(d,J=16.6Hz,1H),4.38(d,J=16.6Hz,1H),4.14(d,J=13.1Hz,1H),3.66(d,J=13.0Hz,1H),3.36(s,1H).13CNMR(100MHz,CDCl3)δ197.3,156.1,147.9,146.7,136.0,131.9,131.0,129.2,128.2,126.4,126.0,125.2,124.9,123.8,117.1,109.0,106.4,100.9,56.9,50.1,46.8.HRMS(ESI):m/z:Calcd for(C21H15NO3+Na)+352.0944,found 352.0935.HPLC conditions:Daicel Chiralpak OD-H column(己烷/异丙醇=90/10,流速1.0mL/min,254nm);tR=14.213(major),tR=16.509(minor),87%ee.
显然,上述实施例仅仅是为清楚地说明所作的举例,并非对实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引申出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (7)
1.一类氮原子作为桥头碳的手性桥环化合物,其特征在于,所述手性桥环化合物的结构式为:
R为H、氟、氯、三氟甲基、C1~C10烷基、C1~C10烷氧基、C1~C7保护的氨基基团;
Ar为氟、氯、三氟甲基、C1~C10的烷基或C1~C10的烷氧基取代的芳基。
2.权利要求1所述的氮原子作为桥头碳的手性桥环化合物的合成方法,其特征在于,包括以下步骤:
在惰性氛围、有机溶剂中,利用N-苄基取代的二氢喹啉酮类化合物为原料,在钯源和手性配体的催化下,在碱的促进下,发生分子内羰基α位的芳基化反应,得到所述氮原子作为桥头碳的手性桥环化合物;
R为H、氟、氯、三氟甲基、C1~C10烷基、C1~C10烷氧基、C1~C7保护的氨基基团;
Ar为氟、氯、三氟甲基、C1~C10的烷基或C1~C10的烷氧基取代的芳基;
所述手性配体为如下结构的手性膦配体的一种或多种:
其中,
Ar1选自Ph或3,5-tBu2-4-MeOC6H2;
Ar2选自3,5-tBu2-4-MeOC6H2;
R选自H或Me;
R1选自Ph或环己基;
R2选自金刚烷基、tBu、4-MeOC6H4、4-PhC6H4、4-MeC6H4、2,5-Me2C6H3或3,5-tBu2-4-MeOC6H2;
所述钯源选自Pd2(dba)3、Pd(dba)2、Pd2(dba)3·CHCl3、Pd(OAc)2、Pd(OPiv)2、Pd(acac)2、PdI2、PdCl2、PdBr2、Pd(TFA)2、[Pd(allyl)Cl]2、Pd(dppf)2Cl2、Pd(CH3CN)2Cl2和Pd(dppe)2Cl2中的一种或多种;
所述N-苄基取代的二氢喹啉酮类化合物、钯源、手性配体与碱的摩尔比为1:(0.005~0.075):(0.02~0.3):(0~10)。
3.根据权利要求2所述的合成方法,其特征在于,所述芳基化反应的条件为:反应温度为30-120℃,搅拌速度为800-1500转。
4.根据权利要求2所述的合成方法,其特征在于,所述碱选自三乙胺、三正丙胺、二乙胺、二环己基胺、N,N-二异丙基乙胺、三乙烯二胺、1,8-二氮杂二环十一碳-7-烯、碳酸钾、碳酸铯、乙酸铯、乙酸钠、叔丁醇钠、叔丁醇钾、氢氧化钾、磷酸钾、碳酸氢钾、碳酸氢钠、氢氧化钠和甲酸钠中的一种或多种。
5.根据权利要求2所述的合成方法,其特征在于,所述有机溶剂选自正戊烷、正己烷、环己烷、四氢呋喃、1,4-二氧六环、乙醚、甲基叔丁基醚、环戊己甲基醚、二甲基亚砜,甲苯、1,2-二氯乙烷、三氯甲烷、乙酸乙酯、乙腈、丙酮、甲醇、乙醇、异丙醇、叔丁醇、叔戊醇、二丙二醇甲醚和二甲基甲酰胺中的一种或多种。
6.根据权利要求2所述的合成方法,其特征在于,所述惰性氛围中气体为氮气和/或惰性气体。
7.根据权利要求2所述的合成方法,其特征在于,所述合成方法具体步骤:
将N-苄基取代的二氢喹啉酮类化合物、钯源催化剂、手性配体和碱混合,在惰性氛围以及干燥条件下,加入有机溶剂,反应温度设置为30℃-120℃,进行反应,待反应完全,分离提纯得到所述氮原子作为桥头碳的手性桥环化合物。
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