CN115572287A - 一种手性氨基酸c-糖苷及其合成方法 - Google Patents
一种手性氨基酸c-糖苷及其合成方法 Download PDFInfo
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- CN115572287A CN115572287A CN202211216395.XA CN202211216395A CN115572287A CN 115572287 A CN115572287 A CN 115572287A CN 202211216395 A CN202211216395 A CN 202211216395A CN 115572287 A CN115572287 A CN 115572287A
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- nmr
- phenyl
- amino acid
- acetone
- chiral amino
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- 150000001413 amino acids Chemical class 0.000 title abstract description 12
- 238000001308 synthesis method Methods 0.000 title abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 8
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 claims abstract description 7
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 6
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims abstract description 4
- JOCBASBOOFNAJA-UHFFFAOYSA-N N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid Chemical compound OCC(CO)(CO)NCCS(O)(=O)=O JOCBASBOOFNAJA-UHFFFAOYSA-N 0.000 claims abstract description 4
- HFMDLUQUEXNBOP-UHFFFAOYSA-N n-[4-amino-1-[[1-[[4-amino-1-oxo-1-[[6,9,18-tris(2-aminoethyl)-15-benzyl-3-(1-hydroxyethyl)-12-(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl] Chemical compound OS(O)(=O)=O.N1C(=O)C(CCN)NC(=O)C(NC(=O)C(CCN)NC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)CCCCC(C)CC)CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C1CC1=CC=CC=C1 HFMDLUQUEXNBOP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000005037 alkyl phenyl group Chemical group 0.000 claims abstract description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 31
- -1 amino acid C-glycoside Chemical class 0.000 claims description 31
- 229930182476 C-glycoside Natural products 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 12
- 239000003446 ligand Substances 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- 229910052763 palladium Inorganic materials 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 229940125904 compound 1 Drugs 0.000 claims description 8
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- 238000000034 method Methods 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 125000004799 bromophenyl group Chemical group 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 3
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 3
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- 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 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 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
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 abstract description 6
- 239000000758 substrate Substances 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000000348 glycosyl donor Substances 0.000 abstract description 3
- 239000002243 precursor Substances 0.000 abstract description 3
- 125000001424 substituent group Chemical group 0.000 abstract description 3
- 229930182478 glucoside Natural products 0.000 abstract description 2
- 150000008131 glucosides Chemical class 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 101
- CSCPPACGZOOCGX-MICDWDOJSA-N 1-deuteriopropan-2-one Chemical compound [2H]CC(C)=O CSCPPACGZOOCGX-MICDWDOJSA-N 0.000 description 80
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- 229910004161 SiNa Inorganic materials 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 238000006206 glycosylation reaction Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 150000000700 C-glycosides Chemical class 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 150000001720 carbohydrates Chemical class 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000012973 diazabicyclooctane Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
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- 238000012746 preparative thin layer chromatography Methods 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 125000002306 tributylsilyl group Chemical group C(CCC)[Si](CCCC)(CCCC)* 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- IGRCWJPBLWGNPX-UHFFFAOYSA-N 3-(2-chlorophenyl)-n-(4-chlorophenyl)-n,5-dimethyl-1,2-oxazole-4-carboxamide Chemical compound C=1C=C(Cl)C=CC=1N(C)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl IGRCWJPBLWGNPX-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000000370 acceptor Substances 0.000 description 2
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
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- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- RUHJZSZTSCSTCC-UHFFFAOYSA-N 2-(bromomethyl)naphthalene Chemical compound C1=CC=CC2=CC(CBr)=CC=C21 RUHJZSZTSCSTCC-UHFFFAOYSA-N 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- UPULOMQHYQDNNT-UHFFFAOYSA-N 5h-1,3-oxazol-2-one Chemical class O=C1OCC=N1 UPULOMQHYQDNNT-UHFFFAOYSA-N 0.000 description 1
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 description 1
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
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- 150000003624 transition metals Chemical class 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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Abstract
本发明属于糖苷合成领域，公开了一种手性氨基酸C‑糖苷及其合成方法，其具有通式Ⅰ的结构或通式Ⅰ的对映异构体、非对映异构体：
其中，P选自TBDPS、TBS、TIPS、Ac、Piv、Bz、Boc、Bn、萘甲基、TMS、TES、TBDMS、甲基、PMB、Tr、MMT、DMT、MOM、BOM、MTM、THP、MEM、PMBOM、Cbz、Fmoc，R选自烷基、苯基、Bn、PMB、‑CH2CH2SMe，Ar选自苯基、烷基苯基、卤代苯基。本发明用保护基保护的3,4‑环碳酸酯‑半乳烯糖作为糖基供体，以氨基酸前体噁唑啉‑5‑酮作为受体，二者反应得到了一类骨架新颖的C‑糖苷化合物，反应具有优异的β‑选择性，而且产率高、对映选择性好，反应条件温和，适用于各种取代基、保护基的底物。
Description
技术领域
本发明属于糖苷合成领域，具体是一种手性氨基酸C-糖苷及其合成方法。
背景技术
糖化学与生物化学关系密切，一直是碳水化合物化学研究的焦点。在这个领域，随着对生物化学途径中的碳水化合物及其共轭物的研究日益深入，人们对形成糖苷键的糖基化反应越来越关注。研究表明，与O型或N型糖苷连接相比，C-糖苷具有更高的代谢稳定性，从而具有良好的物理化学和药理学特性。很多C型糖苷天然产物，包括C型糖基氨基酸类似物以及衍生的糖肽，具有药物治疗用途。
另一方面，在糖基化反应中，由于缺乏异头碳效应和分子内的糖苷配基传递，C-糖苷键的立体控制是一个难以解决的问题。通过碳正离子中间体发生的不饱和糖基供体的Ferrier重排是构建异头碳手性中心的经典方法，通常可以实现α-选择性。过渡金属催化可以用于生成C-糖基连接，特别是糖类的Heck型糖基化。
钯催化的糖类与烯丙基碳酸酯的脱羧反应为选择性糖基化获得O-、N-或C-糖苷开辟了一条实用的途径，反应通常不需要使用强碱，可以增加底物的兼容性。对于C-糖苷的合成，邹坤团队将芳基硼酸作为亲核试剂，与3,4-O-环碳酸酯烯糖反应，立体效应引导α-选择性地引入了芳基。
综上所述，β-选择性的C-糖苷化仍然缺乏有效的方法，需要加以发展。
发明内容
本发明的目的是提供一类结构新颖的手性氨基酸C-糖苷化合物。
本发明的另一目的是提供该类化合物的合成方法。
为达到上述目的之一，本发明采用以下技术方案：
一种手性氨基酸C-糖苷，其具有通式Ⅰ的结构或通式Ⅰ的对映异构体、非对映异构体：
其中，P选自TBDPS、TBS、TIPS、Ac、Piv、Bz、Boc、Bn、萘甲基、TMS、TES、TBDMS、甲基、PMB、Tr、MMT、DMT、MOM、BOM、MTM、THP、MEM、PMBOM、Cbz、Fmoc，
R选自烷基、苯基、Bn、PMB、-CH2CH2SMe，
Ar选自苯基、烷基苯基、卤代苯基。
进一步地，所述P选自TBDPS、TBS、TIPS、Ac、Piv、Bz、Boc、Bn、萘甲基、TMS、TES、TBDMS、PMB、MOM。
进一步地，所述P选自TBDPS、TBS、TIPS、Ac、Piv、Bz、Boc、Bn、萘甲基。
进一步地，所述R选自(C1～C4)烷基、苯基、Bn、PMB、-CH2CH2SMe。
进一步地，所述R选自甲基、异丙基、仲丁基、异丁基、苯基、Bn、PMB、-CH2CH2SMe。
进一步地，所述Ar选自苯基、(C1～C4)烷基取代的苯基、氟代苯基、氯代苯基、溴代苯基。
进一步地，所述Ar选自苯基、甲基苯基、乙基苯基、氟代苯基、氯代苯基、溴代苯基。
进一步地，所述Ar选自苯基、甲基苯基、溴代苯基。
进一步地，所述Ar选自苯基、对甲基苯基、间甲基苯基、对溴苯基。
进一步地，手性氨基酸C-糖苷选自以下化合物或它们的对映异构体、非对映异构体：
一种手性氨基酸C-糖苷的合成方法，包括以下步骤：在钯催化剂存在下，化合物1和化合物2反应如下：
进一步地，所述钯催化剂选自Pd(OAc)2、Pd(PPh3)4、Pd(acac)2、Pd2(dba)3、[Pd(allyl)Cl]2。
进一步地，反应加入配体，所述配体选自以下化合物：
进一步地，所述钯催化剂的用量至少是1mol％。
进一步地，所述配体的用量至少是2mol％。
钯催化剂、配体的用量的基准是相对于化合物1的用量，比如，钯催化剂的用量写成5mol％的形式，指每1mol化合物1使用0.05mol钯催化剂；配体的用量写成7.5mol％的形式，指每1mol化合物1使用0.075mol配体。
进一步地，所述化合物1和化合物2的摩尔比为1：(1～3)。
进一步地，所述反应以二氯甲烷、二氯乙烷、氯仿、四氢呋喃或乙腈为溶剂。
进一步地，所述反应的温度为25℃以上。
进一步地，所述反应的时间在0.5h以上。
进一步地，所述反应加入DABCO，DABCO的用量是120mol％。
TMS指三甲基硅基；TES指三乙基硅基；TBDMS指叔丁基二甲基硅基；TBDPS指叔丁基二苯基硅基；TBS指叔丁基二甲基硅基；TIPS指三异丙基硅基。
Bn指苄基；PMB指对甲氧基苄基；Tr指三苯甲基；MMT指对甲氧基三苯甲基；DMT指二甲氧基三苯甲基；MOM指甲氧基甲基；BOM指苄氧基甲基；MTM指甲硫基甲基；THP指四氢吡喃基；MEM指2-甲氧基乙氧基甲基；PMBOM指对甲氧基苄氧基甲基。
Ac指乙酰基；Piv指特戊酰基；Bz指苯甲酰基；Boc指叔丁氧基羰基；Cbz指苄氧基羰基；Fmoc指9-芴基甲氧基羰基；萘甲基指
DABCO指1,4-二氮杂二环[2.2.2]辛烷；TBAF指四正丁基氟化铵；EDCI指1-乙基-3-(3-二甲基氨基丙基)碳二亚胺。
本文所用的“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。烷基基团的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、2-戊基、异戊基、新戊基、己基、2-己基、3-己基、3-甲基戊基。
本发明具有以下有益效果：
本发明用保护基保护的3,4-环碳酸酯-半乳烯糖作为糖基供体，以氨基酸前体噁唑啉-5-酮作为受体，二者反应得到了一类骨架新颖的C-糖苷化合物，反应具有优异的β-选择性，而且产率高、对映选择性好，反应条件温和，适用于各种取代基、保护基的底物。
具体实施方式
除非另有说明，所有溶剂和试剂均购自商业化产品并且无需进一步纯化。薄层色谱分析(TLC)使用60GF254硅胶板；硅胶柱层析使用青岛海洋硅胶(60，粒径0.040-0.063mm)；TLC显色采用紫外光(254,365nm)。1H和13C核磁共振谱使用Bruker DPX 400兆或Bruker DPX500兆核磁共振仪表征，溶剂为DMSO-d6、CDCl3或丙酮-d6，以四甲基硅烷(TMS)为内标；化学位移的单位是ppm，耦合常数的单位是Hz。在1HNMR中，δ表示化学位移，s表示单峰，d表示双峰，t表示三重峰，q表示四重峰，p表示五重峰，m表示多重峰，br表示宽峰。13C核磁共振的数据以化学位移δ(ppm)为单位报告。用Q-Exactive(Thermo Scientific)进行高分辨率质谱(HRMS)分析。
实施例1
底物的合成
化合物1a-1h是根据文献【(a)Dai,Y.；Tian,B.；Chen,H.；Zhang,Q.ACS Catalysis2019,9,2909-2915；(b)Dai,Y.；Zheng,J.；Zhang,Q.Organic Letters 2018,20,3923-3927；(c)Meng,S.；Zhong,W.；Yao,W.；Li,Z.Organic Letters 2020,22,2981-2986.】制备。
化合物1i是按以下方法制备：
根据文献【Dai,Y.；Zheng,J.；Zhang,Q.Organic Letters 2018,20,3923-3927】制备s-1i。
在0℃(冰浴)、无水DMF(2mL)溶液中，用氢化钠(78mg,1.95mmol)缓慢处理碳酸酯衍生物s-1i(226mg,1.3mmol)。10分钟后，加入2-(溴甲基)-萘(431mg,1.95mmol)，所得混合物在室温下搅拌过夜。通过TLC色谱法检测起始材料被完全消耗。将反应混合物冷却到0℃，用NH4Cl水溶液淬灭，然后用EtOAc(10mL×2)萃取，合并的有机相用水(15mL)和食盐水(15mL)洗涤。分离的有机相经Na2SO4干燥并浓缩，得到粗品，经硅胶柱色谱法(EtOAc/石油醚＝1/3)纯化，得到白色粉末状的半乳糖供体1i(收率62％)。
1H NMR(400MHz,CDCl3)δ7.86–7.83(m,3H),7.78(s,1H),7.51–7.44(m,3H),6.68(d,J＝6.3Hz,1H),5.15(ddd,J＝7.7,3.1,1.1Hz,1H),4.96–4.91(m,2H),4.75(t,J＝12.4Hz,2H),4.10(td,J＝6.7,1.6Hz,1H),3.88–3.78(m,2H)；13C NMR(100MHz,CDCl3)δ154.0,149.2,134.6,133.2,133.1,128.4,127.9,127.7,126.8,126.3,126.1,125.6,98.0,73.9,73.2,72.5,68.8,68.0；HRMS(ESI)m/z:[M+Na]精确质量计算C18H16O5Na,335.0895；实测值,335.0891。
根据文献方法制备噁唑啉酮衍生物2【(a)Badiola,E.；Fiser,B.；Gómez-Bengoa,E.；Mielgo,A.；Olaizola,I.；Urruzuno,I.；García,J.M.；Odriozola,J.M.；Razkin,J.；Oiarbide,M.；Palomo,C.Journal of the American Chemical Society 2014,136,17869-17881；(b)Gerwick,W.H.；Fenical,W.The Journal of Organic Chemistry 1983,48,3325-3329；de Mello,A.C.；Momo,P.B.；Burtoloso,A.C.B.；Amarante,G.W.The Journalof Organic Chemistry 2018,83,11399-11406】。
步骤1，合成N-苯甲酰氨基酸。在0℃下将相应的天然氨基酸(40mmol,1equiv)缓慢溶解于2N NaOH(50mL,100mmol,2.5equiv)，在此温度下滴加苯甲酰氯(1.05equiv)。添加完成后，在0℃下将该混合物再搅拌30分钟。随后，让该混合物升温至室温或75℃，再搅拌两小时。用冰浴冷却到0℃后，用6N HCl酸化反应混合物，得到白色沉淀物。混合物在0℃保持一小时，之后收集固体，用冷水洗涤，并风干，无需进一步提纯，粗品用于下一步。
步骤2，合成噁唑啉酮衍生物2。在室温下，向N-苯甲酰基氨基酸(10mmol)的无水CH2Cl2(30mL)悬浮液中加入EDCI-HCl(2.5g，13mmol，1.3equiv)。反应混合物用水(20mL)和盐水(20mL)洗涤，然后用Na2SO4干燥。在减压下除去溶剂，得到粗品，通过硅胶柱色谱法纯化，得到产物。化合物2a-2g的图谱与文献报道一致。
化合物2h：1H NMR(400MHz,CDCl3)δ7.92(d,J＝7.9Hz,2H),7.31(d,J＝8.0Hz,2H),4.30(d,J＝4.4Hz,1H),2.45(s,3H),2.45–2.36(m,1H),1.16(d,J＝6.9Hz,3H),1.04(d,J＝6.9Hz,3H)；13C NMR(100MHz,CDCl3)δ178.0,161.7,143.4,129.5,127.8,123.1,70.6,31.2,21.7,18.7,17.5；HRMS(ESI)m/z:[M+H]精确质量计算C13H16NO2,218.1181；实测值,218.1177。
化合物2i：1H NMR(400MHz,CDCl3)δ7.91–7.88(m,2H),7.29(d,J＝8.4Hz,2H),4.40(dz,J＝3.9Hz,0.54H),4.35(d,J＝4.3Hz,0.46H),2.43(s,3H),2.18–2.08(m,1H),1.74–1.33(m,2H),1.17–0.90(m,6H)；13C NMR(100MHz,CDCl3)δ178.7,177.9,161.7,161.6,143.3,129.5,129.5,127.8,127.8,123.1,69.7,69.1,37.7,26.2,25.0,21.7,15.4,14.4,11.8,11.7；HRMS(ESI)m/z:[M+H]精确质量计算C14H18NO2,232.1338；实测值,232.1332。
化合物2j：1H NMR(400MHz,CDCl3)δ7.88(d,J＝8.3Hz,2H),7.28(d,J＝8.0Hz,2H),4.40(dd,J＝8.9,5.7Hz,1H),2.43(s,3H),2.11–2.01(m,1H),1.83(ddd,J＝13.6,7.8,5.7Hz,1H),1.71–1.64(m,1H),1.03(d,J＝6.7Hz,3H),1.01(d,J＝6.7Hz,3H)；13C NMR(100MHz,CDCl3)δ179.2,161.4,143.3,129.5,127.8,123.2,63.9,40.8,25.2,22.7,22.0,21.7；HRMS(ESI)m/z:[M+H]精确质量计算C14H18NO2,232.1338；实测值,232.1333。
化合物2k：1H NMR(400MHz,CDCl3)δ7.88(d,J＝8.0Hz,2H),7.29(d,J＝8.0Hz,2H),4.58(dd,J＝7.2,5.8Hz,1H),2.73(t,J＝7.1Hz,2H),2.43(s,3H),2.30(dtd,J＝14.1,7.0,5.8Hz,1H),2.18–2.09(m,4H)；13C NMR(100MHz,CDCl3)δ178.6,162.1,143.5,129.5,127.9,123.0,63.6,30.5,30.0,21.7,15.1；HRMS(ESI)m/z:[M+H]精确质量计算C13H16NO2S,250.0902；实测值,250.0897。
实施例2
发明人考虑使用氨基酸作为烯糖受体，与现有技术使用的C-糖基受体相比，由于氨基酸可能发生O-或N-糖基化，反应控制更为复杂。发明人以6-O-TBDPS-3,4-环碳酸酯-半乳烯糖1a作为糖基供体，以4-苄基-2-对甲基苯基噁唑啉-5-酮2a作为氨基酸前体进行反应条件优化。
a：反应条件：1a(0.1mmol)、2a(1.2equiv)、[Pd]催化剂(5mol％)、配体(7.5mol％)和溶剂(2mL)室温下反应12小时，产率通过1H NMR确定，使用Ph3CH作为内标。b：反应时间为2小时。c：反应时间为0.5小时。
筛选膦配体，L1以36:64的比例形成非对映体b-(R)-3a和b-(S)-3a，总收率为91％，具有良好的b-选择性。筛选钯催化剂，Pd(acac)2可以将dr提高到31：69，总收率为96％，如果只用Pd(PPh3)4而不使用配体，总收率下降到48％。筛选溶剂，在CH2Cl2相比，其他溶剂没有带来明显的改善。当反应时间缩短到2小时，b-3a的dr为31.5:68.5，总收率为92％。
1H NMR(400MHz,acetone-d6)δ7.76–7.70(m,6H),7.45–7.37(m,6H),7.27(d,J＝7.9Hz,2H),7.20–7.12(m,5H),6.26(ddd,J＝10.4,5.7,2.0Hz,1H),6.08(dd,J＝10.3,1.5Hz,1H),4.60(d,J＝2.0Hz,1H),4.00–3.93(m,2H),3.87–3.79(m,2H),3.42(d,J＝13.5Hz,1H),3.31(d,J＝13.5Hz,1H),3.22(d,J＝9.5Hz,1H),2.36(s,3H),0.99(s,9H)；13CNMR(100MHz,acetone-d6)δ177.5,161.4,144.3,136.3,136.3,135.4,134.4,134.2,131.9,131.2,130.5,130.2,128.8,128.6,128.5,127.8,123.7,79.6,78.0,77.6,64.5,62.4,39.5,27.1,21.5,19.7；HRMS(ESI)m/z:[M+Na]精确质量计算C39H41NO5SiNa,654.2652；实测值,654.2662。
1H NMR(400MHz,acetone-d6)δ7.76–7.71(m,6H),7.46–7.38(m,6H),7.30–7.27(m,2H),7.21–7.11(m,5H),6.30(ddd,J＝10.2,5.8,2.0Hz,1H),6.14(dd,J＝10.3,1.8Hz,1H),4.70(d,J＝1.9Hz,1H),3.96(ddt,J＝7.5,5.7,1.7Hz,1H),3.90–3.79(m,3H),3.40(d,J＝13.3Hz,1H),3.31(d,J＝13.3Hz,1H),2.84(d,J＝9.9Hz,1H),2.37(s,3H),1.04(s,9H)；13CNMR(100MHz,acetone-d6)δ177.9,162.0,144.4,136.3,136.2,135.1,134.3,134.1,131.8,131.8,131.2,130.5,130.3,128.8,128.6,128.5,128.5,127.9,127.8,123.7,79.3,78.0,77.8,64.5,62.4,39.5,27.1,21.5,19.7.；HRMS(ESI)m/z:[M+Na]精确质量计算C39H41NO5SiNa,654.2652；实测值,654.2660。
通用合成方法：
在氩气环境下，在装有磁力搅拌棒的密封Schlenk管中加入Pd(acac)2(1.5mg,5mol％)、配体L1(4.1mg,7.5mol％)和化合物1(0.1mmol)、化合物2(0.12mmol)。然后加入无水CH2Cl2(2mL)，将得到的混合物脱气并填充-脱气三次。反应混合物在室温下搅拌，用TLC监测，直到化合物1在两小时内完全消耗。减压除去溶剂，得到粗品，通过制备TLC(EtOAc/石油醚)纯化，得到产物β-(R)-3和β-(S)-3。对于底物2g、2h、2i，额外加入1.2当量DABCO。
接下来进行底物的拓展，化合物2的C2位上苯基的甲基在邻位，对产率没有影响，将甲基换成溴，产率有所下降。苯环上没有取代基，对产率和dr值没有明显影响。化合物2的C4位上的苄基换成对甲氧基苄基，dr比(31:69)没有变化，产率很高(93％)，换成甲基、异丙基、仲丁基，以良好的产率(77～88％)和中等的dr值(36：64至26：74)得到产物；换成异丁基和-CH2CH2SMe，非对映选择性下降。这些糖苷化反应都表现出绝对的β-选择性。发明人继续研究半乳烯糖1中6位羟基的保护基对反应的影响。除了TBDPS基团，其他的硅基类似物TBS、TIPS，对反应没有任何影响，在具有类似非对映选择性的情况下，产率得到了提高。Ac和Piv保护的半乳糖，产率高(94％和98％)，dr值相同(36：64)。苯甲酰基和Boc保护基同样被容忍，对非对映选择性有细微的不利影响(42：58和44：56)，苄基保护的半乳烯糖为底物时也得到了C-糖苷产物，产率非常好(89％)，中等的dr值(35:65)，用较大的萘基代替苯环时，反应结果基本保持不变。
实施例3
1H NMR(400MHz,acetone-d6)δ7.75(dd,J＝7.4,1.8Hz,2H),7.71–7.69(m,2H),7.65–7.62(m,2H),7.45–7.31(m,8H),7.22–7.11(m,5H),6.28(ddd,J＝10.3,5.7,2.0Hz,1H),6.14(dd,J＝10.3,1.6Hz,1H),4.61(d,J＝2.2Hz,1H),4.00–3.92(m,2H),3.87–3.78(m,2H),3.41(d,J＝13.5Hz,1H),3.34(d,J＝13.5Hz,1H),3.08(d,J＝9.2Hz,1H),2.33(s,3H),0.98(s,9H)；13C NMR(100MHz,acetone-d6)δ177.5,161.4,139.4,136.3,136.3,135.4,134.4,134.2,134.1,131.9,131.2,130.5,130.5,129.5,128.9,128.8,128.6,127.9,126.5,125.7,79.6,78.1,77.7,64.5,62.4,39.5,27.0,21.1,19.6；HRMS(ESI)m/z:[M+Na]精确质量计算C39H41NO5SiNa,654.2652；实测值,654.2658。
1H NMR(400MHz,acetone-d6)δ7.76–7.73(m,4H),7.65–7.63(m,2H),7.44–7.34(m,8H),7.22–7.14(m,5H),6.30(ddd,J＝10.3,5.8,1.9Hz,1H),6.15(dd,J＝10.3,1.6Hz,1H),4.70(d,J＝2.0Hz,1H),3.99–3.95(m,1H),3.91–3.79(m,3H),3.41(d,J＝13.3Hz,1H),3.32(d,J＝13.3Hz,1H),2.81(d,J＝9.9Hz,1H),2.35(s,3H),1.04(s,9H)；13C NMR(100MHz,acetone-d6)δ177.9,162.0,139.5,136.3,136.3,135.1,134.4,134.3,134.2,131.8,131.2,130.5,130.5,129.6,128.9,128.8,128.6,128.6,127.9,127.8,126.5,125.7,79.4,78.1,77.9,64.6,62.4,39.5,27.1,21.1,19.7；HRMS(ESI)m/z:[M+Na]精确质量计算C39H41NO5SiNa,654.2652；实测值,654.2657。
实施例4
1H NMR(400MHz,acetone-d6)δ7.76–7.64(m,8H),7.45–7.36(m,6H),7.21–7.11(m,5H),6.27(ddd,J＝10.4,5.6,2.0Hz,1H),6.16(dd,J＝10.3,1.5Hz,1H),4.62(d,J＝2.2Hz,1H),4.00–3.91(m,2H),3.88–3.75(m,2H),3.42(d,J＝13.5Hz,1H),3.35(d,J＝13.5Hz,1H),3.13(d,J＝9.0Hz,1H),0.97(s,9H)；13C NMR(100MHz,acetone-d6)δ177.1,160.6,136.3,136.3,135.2,134.3,134.1,132.9,131.9,131.1,130.5,130.5,130.2,128.8,128.5,127.9,127.7,127.7,125.7,79.7,77.9,77.8,64.6,62.4,39.4,27.0,19.6；HRMS(ESI)m/z:[M+Na]精确质量计算C38H38BrNO5SiNa,718.1600；实测值,718.1602。
1H NMR(400MHz,acetone-d6)δ7.77–7.68(m,8H),7.46–7.38(m,6H),7.20–7.12(m,5H),6.29(ddd,J＝10.4,5.7,1.9Hz,1H),6.18(dd,J＝10.2,1.6Hz,1H),4.70(d,J＝2.0Hz,1H),3.98–3.95(m,1H),3.89–3.77(m,3H),3.43(d,J＝13.4Hz,1H),3.31(d,J＝13.4Hz,1H),2.87(d,J＝8.8Hz,1H),1.03(s,9H)；13C NMR(100MHz,acetone-d6)δ177.5,161.2,136.3,136.3,135.0,134.3,134.1,133.0,131.8,131.2,130.5,130.3,128.8,128.6,128.6,128.0,127.9,127.7,125.7,79.5,78.3,77.9,64.6,62.4,39.5,27.1,19.7；HRMS(ESI)m/z:[M+Na]精确质量计算C38H38BrNO5SiNa,718.1600；实测值,718.1602。
实施例5
1H NMR(400MHz,acetone-d6)δ7.85–7.82(m,2H),7.76–7.69(m,4H),7.59–7.55(m,1H),7.48–7.36(m,8H),7.22–7.10(m,5H),6.27(ddd,J＝10.3,5.7,2.1Hz,1H),6.13(dd,J＝10.3,1.7Hz,1H),4.62(d,J＝1.9Hz,1H),4.00–3.92(m,2H),3.88–3.79(m,2H),3.43(d,J＝13.5Hz,1H),3.34(d,J＝13.5Hz,1H),3.17(d,J＝9.3Hz,1H),0.98(s,9H)；13C NMR(100MHz,acetone-d6)δ178.0,162.0,159.7,144.4,136.3,136.3,134.3,134.2,132.3,131.8,130.5,130.3,128.6,128.6,128.5,127.8,126.8,123.8,114.1,79.3,78.2,77.8,64.5,62.4,55.3,38.7,27.1,21.5,19.7；HRMS(ESI)m/z:[M+Na]精确质量计算C38H39NO5SiNa,640.2495；实测值,640.2502。
1H NMR(400MHz,acetone-d6)δ7.84(dd,J＝8.0,1.4Hz,2H),7.76–7.73(m,4H),7.62–7.58(m,1H),7.50–7.38(m,8H),7.22–7.13(m,5H),6.30(ddd,J＝10.3,5.7,2.0Hz,1H),6.16(dd,J＝10.2,1.6Hz,1H),4.70(d,J＝1.9Hz,1H),3.97(ddd,J＝9.8,5.7,1.7Hz,1H),3.91–3.80(m,3H),3.43(d,J＝13.3Hz,1H),3.32(d,J＝13.3Hz,1H),2.85(d,J＝9.8Hz,1H),1.04(s,9H)；13C NMR(100MHz,acetone-d6)δ177.8,161.9,136.3,136.3,135.1,134.3,134.1,133.6,131.8,131.2,130.5,130.5,129.6,128.8,128.6,128.5,128.5,127.9,127.8,126.6,79.4,78.1,77.8,64.6,62.4,39.5,27.1,19.7；HRMS(ESI)m/z:[M+Na]精确质量计算C38H39NO5SiNa,640.2495；实测值,640.2499。
实施例6
1H NMR(400MHz,acetone-d6)δ7.76–7.70(m,6H),7.47–7.37(m,6H),7.27(d,J＝8.0Hz,2H),7.11(d,J＝8.3Hz,2H),6.72(d,J＝8.5Hz,2H),6.26(ddd,J＝10.3,5.7,2.0Hz,1H),6.07(dd,J＝10.3,1.6Hz,1H),4.58(d,J＝2.2Hz,1H),3.99–3.93(m,2H),3.89–3.75(m,2H),3.66(s,3H),3.35(d,J＝13.7Hz,1H),3.25(d,J＝13.7Hz,1H),3.18(d,J＝9.5Hz,1H),2.36(s,3H),1.00(s,9H)；13C NMR(100MHz,acetone-d6)δ177.6,161.4,159.7,144.3,136.3,136.3,134.4,134.1,132.2,131.8,130.5,130.5,130.2,128.6,128.5,127.9,127.0,123.8,114.1,79.5,78.0,77.8,64.5,62.4,55.3,38.7,27.1,21.5,19.7；HRMS(ESI)m/z:[M+Na]精确质量计算C40H43NO6SiNa,684.2757；实测值,684.2765。
1H NMR(400MHz,acetone-d6)δ7.76–7.72(m,6H),7.46–7.38(m,6H),7.30–7.28(m,2H),7.11–7.09(m,2H),6.71(d,J＝8.3Hz,2H),6.30(ddd,J＝10.5,5.9,2.0Hz,1H),6.13(dd,J＝10.4,1.6Hz,1H),4.67(s,1H),3.98–3.94(m,1H),3.90–3.79(m,3H),3.66(s,3H),3.33(d,J＝13.5Hz,1H),3.25(d,J＝13.5Hz,1H),2.83(d,J＝10.1Hz,1H),2.37(s,3H),1.05(s,9H)；13C NMR(100MHz,acetone-d6)δ178.0,162.0,159.7,144.4,136.3,136.3,134.3,134.2,132.3,131.8,130.5,130.3,128.6,128.6,128.5,127.8,126.8,123.8,114.1,79.3,78.2,77.8,64.5,62.4,55.3,38.7,27.1,21.5,19.7；HRMS(ESI)m/z:[M+Na]精确质量计算C40H43NO6SiNa,684.2757；实测值,684.2761。
实施例7
1H NMR(400MHz,acetone-d6)δ7.92(d,J＝8.1Hz,2H),7.78–7.75(m,2H),7.70–7.68(m,2H),7.63–7.61(m,2H),7.49–7.33(m,11H),6.19(ddd,J＝10.3,5.8,2.2Hz,1H),5.63(dd,J＝10.3,1.6Hz,1H),4.83(d,J＝2.0Hz,1H),3.93(ddt,J＝7.5,5.8,1.8Hz,1H),3.85(dd,J＝8.9,4.1Hz,1H),3.78–3.71(m,2H),2.68(d,J＝9.4Hz,1H),2.39(s,3H),0.93(s,9H)；13C NMR(100MHz,acetone-d6)δ176.2,161.7,144.5,136.3,136.3,135.4,134.3,134.0,131.9,130.5,130.3,129.6,129.5,128.8,128.6,128.5,127.7,127.2,123.9,79.9,79.4,78.4,64.3,62.2,27.0,21.6,19.6；HRMS(ESI)m/z:[M+Na]精确质量计算C38H39NO5SiNa,640.2495；实测值,640.2505。
1H NMR(400MHz,acetone-d6)δ7.97(d,J＝8.0Hz,2H),7.80–7.78(m,2H),7.72–7.68(m,4H),7.49–7.37(m,11H),6.19(ddd,J＝10.2,5.8,1.9Hz,1H),5.60(dd,J＝10.4,1.7Hz,1H),5.01(d,J＝2.0Hz,1H),3.95–3.90(m,1H),3.87–3.80(m,2H),3.74–3.70(m,1H),2.81(d,J＝9.4Hz,1H),2.43(s,3H),1.02(s,9H)；13C NMR(100MHz,acetone-d6)δ177.6,162.4,144.7,136.2,136.2,135.8,134.3,134.0,131.3,130.5,130.4,130.4,129.6,129.6,128.8,128.6,128.5,127.2,127.1,123.9,80.7,79.4,77.3,64.5,62.1,27.1,21.6,19.6；HRMS(ESI)m/z:[M+Na]精确质量计算C38H39NO5SiNa,640.2495；实测值,640.2498。
实施例8
1H NMR(400MHz,acetone-d6)δ7.85(d,J＝8.0Hz,2H),7.73–7.70(m,2H),7.67–7.65(m,2H),7.46–7.32(m,8H),6.24(ddd,J＝10.3,5.7,2.1Hz,1H),6.05(dd,J＝10.3,1.6Hz,1H),4.45(d,J＝2.0Hz,1H),3.97–3.93(m,1H),3.90–3.85(m,1H),3.77–3.72(m,2H),2.89(d,J＝9.4Hz,1H),2.39(s,3H),1.56(s,3H),0.96(s,9H)；13C NMR(100MHz,acetone-d6)δ178.7,161.3,144.2,136.3,136.3,134.3,134.1,131.6,130.5,130.5,130.2,128.6,128.5,127.8,124.2,79.3,78.6,72.8,64.3,62.3,27.0,21.5,19.8,19.6；HRMS(ESI)m/z:[M+Na]精确质量计算C33H37NO5SiNa,578.2339；实测值,578.2342。
1H NMR(400MHz,acetone-d6)δ7.85(d,J＝7.9Hz,2H),7.72–7.69(m,4H),7.45–7.34(m,8H),6.27(ddd,J＝10.4,5.8,1.9Hz,1H),6.13(dd,J＝10.2,1.7Hz,1H),4.53(d,J＝2.0Hz,1H),3.96–3.91(m,1H),3.83–3.76(m,2H),3.73–3.67(m,1H),2.73(d,J＝9.8Hz,1H),2.41(s,3H),1.56(s,3H),1.01(s,9H)；13C NMR(100MHz,acetone-d6)δ179.5,161.8,144.3,136.3,136.2,134.3,134.1,131.4,130.5,130.3,128.6,128.6,128.5,127.6,124.2,79.1,78.5,72.8,64.4,62.3,27.1,21.6,19.7,19.6；HRMS(ESI)m/z:[M+H]精确质量计算C33H38NO5Si,556.2519；实测值,556.2519。
实施例9
1H NMR(400MHz,acetone-d6)δ7.87(d,J＝8.0Hz,2H),7.70–7.68(m,2H),7.65–7.63(m,2H),7.45–7.32(m,8H),6.24(ddd,J＝10.4,5.7,2.1Hz,1H),6.03(dd,J＝10.3,1.5Hz,1H),4.66(d,J＝2.0Hz,1H),3.94–3.90(m,1H),3.86–3.79(m,1H),3.76–3.70(m,2H),2.75(d,J＝9.6Hz,1H),2.49(hept,J＝7.1Hz,1H),2.39(s,3H),1.09(d,J＝6.8Hz,3H),0.94(s,9H),0.90(d,J＝6.7Hz,3H)；13C NMR(100MHz,acetone-d6)δ178.5,161.8,144.3,136.3,134.3,134.0,131.9,130.5,130.3,128.7,128.5,127.2,123.9,80.2,79.4,76.5,64.4,62.4,32.1,27.0,21.5,19.6,17.3,17.0；HRMS(ESI)m/z:[M+Na]精确质量计算C35H41NO5SiNa,606.2652；实测值,606.2658。
1H NMR(400MHz,acetone-d6)δ7.89(d,J＝8.0Hz,2H),7.76–7.73(m,4H),7.48–7.38(m,8H),6.25(ddd,J＝10.2,5.9,1.9Hz,1H),5.85(dd,J＝10.2,1.7Hz,1H),4.74(d,J＝1.9Hz,1H),3.94–3.78(m,4H),2.61(hept,J＝7.1Hz,1H),2.57(d,J＝10.4Hz,1H),2.43(s,3H),1.07–1.04(m,12H),0.96(d,J＝6.8Hz,3H)；13C NMR(100MHz,acetone-d6)δ178.7,162.4,144.6,136.3,136.3,134.3,134.2,132.2,130.5,130.5,128.7,128.6,127.7,123.7,79.7,79.2,75.3,64.5,62.3,31.7,27.1,21.6,19.7,17.1,16.7；HRMS(ESI)m/z:[M+Na]精确质量计算C35H41NO5SiNa,606.2652；实测值,606.2656。
实施例10
1H NMR(400MHz,acetone-d6)δ7.87(d,J＝7.9Hz,2H),7.69–7.67(m,2H),7.63–7.60(m,2H),7.43–7.31(m,8H),6.26(ddd,J＝10.4,5.8,2.0Hz,1H),6.09(d,J＝10.4Hz,1H),4.68(d,J＝2.0Hz,1H),3.91(dd,J＝9.1,6.3Hz,1H),3.84–3.77(m,1H),3.73–3.67(m,2H),2.59(d,J＝9.7Hz,1H),2.38(s,3H),2.18(ddt,J＝10.4,7.0,3.5Hz,1H),1.12–1.00(m,5H),0.92–0.86(m,12H)；13C NMR(100MHz,acetone-d6)δ178.9,161.6,144.2,136.2,134.3,134.0,131.9,130.5,130.3,128.6,128.5,128.5,127.1,124.0,80.9,79.3,76.5,64.3,62.4,38.9,27.0,24.9,21.5,19.6,13.2,11.9；HRMS(ESI)m/z:[M+Na]精确质量计算C36H43NO5SiNa,620.2808；实测值,620.2814。
1H NMR(400MHz,acetone-d6)δ7.88(d,J＝8.0Hz,2H),7.74–7.72(m,4H),7.45–7.37(m,8H),6.26(ddd,J＝10.2,5.9,1.9Hz,1H),5.90(dd,J＝10.2,1.7Hz,1H),4.81(d,J＝2.0Hz,1H),3.91(dd,J＝10.4,6.0Hz,1H),3.86–3.80(m,3H),2.57(d,J＝10.5Hz,1H),2.43(s,3H),2.33(dqd,J＝10.1,7.0,3.1Hz,1H),1.68(dqd,J＝15.0,7.4,2.9Hz,1H),1.19(ddd,J＝13.4,10.4,7.1Hz,1H),1.03(s,9H),0.99(d,J＝6.9Hz,3H),0.89(t,J＝7.4Hz,3H)；13C NMR(100MHz,acetone-d6)δ178.6,162.4,144.6,136.3,136.3,134.2,134.1,132.1,130.5,130.4,128.6,128.6,128.6,127.7,123.7,79.8,79.1,75.3,64.5,62.3,38.0,27.1,23.8,21.6,19.6,12.7,11.9；HRMS(ESI)m/z:[M+Na]精确质量计算C36H43NO5SiNa,620.2808；实测值,620.2812。
实施例11
1H NMR(400MHz,acetone-d6)δ7.88(d,J＝8.0Hz,2H),7.72–7.69(m,2H),7.66–7.64(m,2H),7.46–7.32(m,8H),6.23(ddd,J＝10.3,5.7,2.1Hz,1H),6.03(dd,J＝10.4,1.1Hz,1H),4.46(d,J＝2.3Hz,1H),3.93(dd,J＝8.9,6.1Hz,1H),3.85(dt,J＝9.9,5.0Hz,1H),3.76–3.70(m,2H),2.83(d,J＝9.4Hz,1H),2.39(s,3H),2.14(dd,J＝14.0,4.9Hz,1H),1.83(dd,J＝14.0,8.0Hz,1H),1.68–1.59(m,1H),0.95(s,9H),0.91(d,J＝6.7Hz,3H),0.82(d,J＝6.6Hz,3H)；13C NMR(100MHz,acetone-d6)δ179.1,161.3,144.3,136.3,136.3,134.3,134.0,131.8,130.5,130.5,130.3,128.6,128.5,127.6,124.1,79.3,78.9,76.2,64.3,62.3,42.1,27.0,25.4,24.4,23.0,21.5,19.6；HRMS(ESI)m/z:[M+Na]精确质量计算C36H43NO5SiNa,620.2808；实测值,620.2808。
1H NMR(400MHz,acetone-d6)δ7.87(d,J＝8.0Hz,2H),7.73–7.71(m,4H),7.45–7.36(m,8H),6.24(ddd,J＝10.4,5.8,1.9Hz,1H),6.06(dd,J＝10.3,1.6Hz,1H),4.50(d,J＝2.0Hz,1H),3.93–3.89(m,1H),3.83–3.71(m,3H),2.68(d,J＝9.8Hz,1H),2.42(s,3H),2.08(dd,J＝14.1,6.0Hz,1H),1.92(dd,J＝14.1,6.6Hz,1H),1.64–1.55(m,1H),1.02(s,9H),0.88(d,J＝6.6Hz,3H),0.85(d,J＝6.6Hz,3H)；13C NMR(100MHz,acetone-d6)δ179.4,161.9,144.5,136.3,136.3,134.3,134.1,131.6,130.5,130.4,128.6,128.6,128.5,127.9,124.0,79.2,78.7,76.6,64.4,62.3,42.0,27.1,25.5,24.2,23.6,21.6,19.6；HRMS(ESI)m/z:[M+Na]精确质量计算C36H43NO5SiNa,620.2808；实测值,620.2814。
实施例12
1H NMR(400MHz,acetone-d6)δ7.88(d,J＝8.0Hz,2H),7.73–7.71(m,2H),7.68–7.66(m,2H),7.46–7.32(m,8H),6.24(ddd,J＝10.3,5.8,2.1Hz,1H),6.02(dd,J＝10.7,1.7Hz,1H),4.50(d,J＝2.0Hz,1H),3.96–3.92(m,1H),3.90–3.85(m,1H)3.79–3.71(m,2H),2.97(d,J＝9.3Hz,1H),2.58–2.51(m,1H),2.46–2.28(m,6H),2.00(s,3H),0.97(s,9H)；13CNMR(100MHz,acetone-d6)δ178.4,162.3,144.4,136.3,136.3,134.3,134.1,131.9,130.5,130.5,130.3,128.7,128.5,127.5,124.1,79.4,78.3,75.5,64.3,62.3,32.4,29.2,27.0,21.6,19.6,14.8；HRMS(ESI)m/z:[M+Na]精确质量计算C35H41NO5SSiNa,638.2372；实测值,638.2374。
1H NMR(400MHz,acetone-d6)7.87(d,J＝8.0Hz,2H),7.74–7.72(m,4H),7.46–7.35(m,8H),6.25(ddd,J＝10.4,5.7,1.9Hz,1H),6.06(dd,J＝10.3,1.6Hz,1H),4.57(d,J＝2.0Hz,1H),3.95–3.91(m,1H),3.86–3.73(m,3H),2.75(d,J＝9.7Hz,1H),2.55–2.48(m,1H),2.44–2.31(m,6H),2.01(s,3H),1.03(s,9H)；13C NMR(100MHz,acetone-d6)δ178.8,162.7,144.5,136.3,136.3,134.3,134.1,131.8,130.5,130.4,128.7,128.6,128.5,127.7,124.0,79.3,78.1,76.0,64.4,62.3,32.7,28.9,27.1,21.6,19.6,14.9；HRMS(ESI)m/z:[M+Na]精确质量计算C35H41NO5SSiNa,638.2372；实测值,638.2377。
实施例13
1H NMR(400MHz,acetone-d6)δ7.73(d,J＝8.0Hz,2H),7.30(d,J＝8.0Hz,2H),7.21–7.10(m,5H),6.27(ddd,J＝10.4,5.8,2.0Hz,1H),6.11(dd,J＝10.2,1.6Hz,1H),4.59(d,J＝2.1Hz,1H),3.93–3.89(m,1H),3.85(dd,J＝10.5,5.6Hz,1H),3.72(dd,J＝10.5,6.3Hz,1H),3.61(ddd,J＝7.1,4.0,1.5Hz,1H),3.40(d,J＝13.4Hz,1H),3.33(d,J＝13.5Hz,1H),2.99(d,J＝9.4Hz,1H),2.38(s,3H),0.84(s,9H),0.00(s,6H)；13C NMR(100MHz,acetone-d6)δ177.6,161.3,144.3,135.3,132.0,131.2,130.2,128.8,128.5,127.8,127.7,123.8,79.6,78.0,77.7,63.7,62.2,39.6,26.2,21.5,18.8,-5.1,-5.4；HRMS(ESI)m/z:[M+Na]精确质量计算C29H37NO5SiNa,530.2339；实测值,530.2342。
1H NMR(400MHz,acetone-d6)δ7.73(d,J＝8.1Hz,2H),7.31(d,J＝8.0Hz,2H),7.21–7.12(m,5H),6.30(ddd,J＝10.3,5.9,1.9Hz,1H),6.13(dd,J＝10.2,1.7Hz,1H),4.66(d,J＝2.0Hz,1H),3.90–3.86(m,1H),3.77(dd,J＝10.1,5.6Hz,1H),3.71–3.62(m,2H),3.40(d,J＝13.3Hz,1H),3.28(d,J＝13.3Hz,1H),2.69(d,J＝10.0Hz,1H),2.39(s,3H),0.89(s,9H),0.06(s,3H),0.05(s,3H)；13C NMR(100MHz,acetone-d6)δ177.9,162.0,144.4,135.1,131.9,131.2,130.3,128.8,128.5,127.9,127.7,123.8,79.2,78.1,77.8,63.5,62.1,39.5,26.2,21.5,18.8,-5.2,-5.4；HRMS(ESI)m/z:[M+H]精确质量计算C29H38NO5Si,508.2519；实测值,508.2517。
实施例14
1H NMR(400MHz,acetone-d6)δ7.72(d,J＝8.0Hz,2H),7.30(d,J＝8.0Hz,2H),7.21–7.10(m,5H),6.28(ddd,J＝10.4,5.8,2.0Hz,1H),6.08(dd,J＝10.3,1.6Hz,1H),4.61(d,J＝2.0Hz,1H),3.98–3.93(m,2H),3.83(dd,J＝10.2,6.2Hz,1H),3.66(td,J＝6.0,1.7Hz,1H),3.42(d,J＝13.4Hz,1H),3.32(d,J＝13.5Hz,1H),3.02(d,J＝9.5Hz,1H),2.38(s,3H),1.11–0.97(m,21H)；13C NMR(100MHz,acetone-d6)δ177.6,161.3,144.3,135.3,132.0,131.2,130.2,128.8,128.5,127.8,127.7,123.8,79.7,78.1,77.8,64.0,62.3,39.6,21.5,18.3,12.6；HRMS(ESI)m/z:[M+Na]精确质量计算C32H43NO5SiNa,572.2808；实测值,572.2813。
1H NMR(400MHz,acetone-d6)δ7.73(d,J＝8.1Hz,2H),7.31(d,J＝7.9Hz,2H),7.21–7.12(m,5H),6.31(ddd,J＝10.3,5.9,1.9Hz,1H),6.13(dd,J＝10.2,1.7Hz,1H),4.68(d,J＝2.0Hz,1H),3.94–3.85(m,2H),3.79(dd,J＝10.1,6.2Hz,1H),3.69(td,J＝6.1,1.6Hz,1H),3.40(d,J＝13.3Hz,1H),3.29(d,J＝13.3Hz,1H),2.73(d,J＝10.1Hz,1H),2.39(s,3H),1.15–1.01(m,21H)；13C NMR(100MHz,acetone-d6)δ177.9,162.0,144.4,135.2,132.0,131.2,130.3,128.8,128.5,127.9,127.7,123.8,79.3,78.1,77.8,63.9,62.2,39.5,21.5,18.3,18.3,12.6；HRMS(ESI)m/z:[M+H]精确质量计算C32H44NO5Si,550.2989；实测值,550.2993。
实施例15
1H NMR(400MHz,acetone-d6)δ7.74(d,J＝8.3Hz,2H),7.31(d,J＝7.8Hz,2H),7.22–7.11(m,5H),6.24(ddd,J＝10.3,5.6,2.1Hz,1H),6.12(dd,J＝10.3,1.7Hz,1H),4.54(d,J＝2.0Hz,1H),4.30(dd,J＝11.6,7.6Hz,1H),4.16(dd,J＝11.6,4.7Hz,1H),3.93(ddt,J＝7.7,5.7,2.1Hz,1H),3.80(ddd,J＝7.2,4.7,2.2Hz,1H),3.51(d,J＝9.2Hz,1H),3.39(d,J＝13.5Hz,1H),3.34(d,J＝13.5Hz,1H),2.39(s,3H),1.89(s,3H)；13C NMR(100MHz,acetone-d6)δ177.3,170.8,161.5,144.3,135.3,131.4,131.2,130.2,128.8,128.5,127.8,127.8,123.8,77.7,77.4,76.7,64.3,62.3,39.2,21.5,20.6；HRMS(ESI)m/z:[M+H]精确质量计算C25H26NO6,436.1760；实测值,436.1763。
1H NMR(400MHz,acetone-d6)δ7.74(d,J＝8.0Hz,2H),7.31(d,J＝7.9Hz,2H),7.23–7.13(m,5H),6.26(ddd,J＝10.3,5.7,1.9Hz,1H),6.14(dd,J＝10.3,1.6Hz,1H),4.63(d,J＝2.2Hz,1H),4.21–4.12(m,2H),3.92–3.88(m,1H),3.82(ddd,J＝7.0,4.8,1.8Hz,1H),3.42(d,J＝13.3Hz,1H),3.27(d,J＝13.3Hz,1H),3.08(d,J＝9.6Hz,1H),2.39(s,3H),2.01(s,3H)；13C NMR(100MHz,acetone-d6)δ177.1,170.0,161.2,143.6,134.3,130.5,130.4,129.5,128.0,127.7,127.1,127.0,123.0,77.1,76.7,75.7,63.6,61.5,38.7,20.7,19.9；HRMS(ESI)m/z:[M+H]精确质量计算C25H26NO6,436.1760；实测值,436.1757。
实施例16
1H NMR(400MHz,acetone-d6)δ7.73(d,J＝8.0Hz,2H),7.30(d,J＝7.9Hz,2H),7.29–7.11(m,5H),6.25(ddd,J＝10.4,5.5,2.0Hz,1H),6.14(dd,J＝10.3,1.5Hz,1H),4.55(d,J＝2.1Hz,1H),4.28(dd,J＝11.3,7.7Hz,1H),4.18(dd,J＝11.6,4.5Hz,1H),3.96–3.92(m,1H),3.82(ddd,J＝7.2,4.5,2.0Hz,1H),3.46(d,J＝9.2Hz,1H),3.40(d,J＝13.5Hz,1H),3.33(d,J＝13.5Hz,1H),2.38(s,3H),1.08(s,9H)；13C NMR(100MHz,acetone-d6)δ177.3,176.5,160.6,143.4,134.5,130.6,130.3,129.4,128.0,127.7,127.0,123.0,77.1,76.7,76.0,63.6,61.6,38.5,38.3,26.4,20.7；HRMS(ESI)m/z:[M+Na]精确质量计算C28H31NO6Na,500.2049；实测值,500.2053。
1H NMR(400MHz,acetone-d6)δ7.72(d,J＝8.0Hz,2H),7.30(d,J＝7.9Hz,2H),7.21–7.12(m,5H),6.27(ddd,J＝10.4,5.6,1.9Hz,1H),6.18(dd,J＝10.3,1.5Hz,1H),4.65(d,J＝2.1Hz,1H),4.21(dd,J＝11.5,7.5Hz,1H),4.14(dd,J＝11.5,4.7Hz,1H),3.91(ddd,J＝9.5,5.3,2.2Hz,1H),3.85(ddd,J＝7.1,4.7,1.8Hz,1H),3.41(d,J＝13.3Hz,1H),3.28(d,J＝13.3Hz,1H),3.10(d,J＝9.6Hz,1H),2.38(s,3H),1.19(s,9H)；13C NMR(100MHz,acetone-d6)δ178.1,177.8,161.9,144.4,135.1,131.3,131.2,130.3,128.8,128.5,127.9,127.9,123.8,77.9,77.8,76.6,64.3,62.4,39.4,39.2,27.4,21.5；HRMS(ESI)m/z:[M+Na]精确质量计算C28H31NO6Na,500.2049；实测值,500.2050。
实施例17
1H NMR(400MHz,acetone-d6)δ7.91(d,J＝7.5Hz,2H),7.71(d,J＝8.0Hz,2H),7.63–7.59(m,1H),7.45(t,J＝7.7Hz,2H),7.26(d,J＝8.0Hz,2H),7.21–7.10(m,5H),6.28(ddd,J＝10.5,5.5,2.0Hz,1H),6.19(dd,J＝10.4,1.4Hz,1H),4.59(d,J＝2.0Hz,1H),4.55–4.47(m,2H),4.06(ddd,J＝9.4,5.1,2.4Hz,1H),3.99(ddd,J＝7.3,4.9,2.1Hz,1H),3.57(d,J＝9.0Hz,1H),3.37(t,J＝13.9Hz,2H),2.38(s,3H)；13C NMR(100MHz,acetone-d6)δ177.3,166.5,161.5,144.2,135.3,133.7,131.4,131.2,131.1,130.2,130.1,129.2,128.8,128.4,127.9,127.8,123.8,77.8,77.4,76.8,65.0,62.4,39.2,21.5；HRMS(ESI)m/z:[M+H]精确质量计算C30H28NO6,498.1917；实测值,498.1921。
1H NMR(400MHz,acetone-d6)δ8.06(d,J＝8.3Hz,2H),7.74(d,J＝8.0Hz,2H),7.65(t,J＝7.4Hz,1H),7.52(t,J＝7.7Hz,2H),7.30(d,J＝7.9Hz,2H),7.22–7.12(m,5H),6.30(ddd,J＝10.5,5.5,1.9Hz,1H),6.18(dd,J＝10.3,1.6Hz,1H),4.68(d,J＝2.0Hz,1H),4.49(dd,J＝11.6,4.6Hz,1H),4.42(dd,J＝11.5,7.4Hz,1H),4.04–4.01(m,2H),3.44(d,J＝13.3Hz,1H),3.27(d,J＝13.4Hz,1H),3.22(d,J＝9.6Hz,1H),2.38(s,3H)；13C NMR(100MHz,acetone-d6)δ177.9,166.6,162.0,144.4,135.1,133.9,131.3,131.3,131.1,130.3,130.2,129.3,128.7,128.5,127.9,127.9,123.8,77.9,77.6,76.6,65.1,62.5,39.5,21.5；HRMS(ESI)m/z:[M+H]精确质量计算C30H28NO6,498.1917；实测值,498.1919。
实施例18
1H NMR(400MHz,acetone-d6)δ7.73(d,J＝7.9Hz,2H),7.31(d,J＝7.9Hz,2H),7.22–7.11(m,5H),6.25(ddd,J＝10.5,5.6,2.0Hz,1H),6.10(dd,J＝10.3,1.5Hz,1H),4.58(d,J＝2.2Hz 1H),4.28(dd,J＝11.5,7.5Hz,1H),4.20(dd,J＝11.5,4.2Hz,1H),3.94(ddd,J＝8.8,5.5,2.5Hz,1H),3.82(ddd,J＝7.0,4.1,1.9Hz,1H),3.46(d,J＝9.2Hz,1H),3.40(d,J＝13.5Hz,1H),3.33(d,J＝13.5Hz,1H),2.38(s,3H),1.38(s,9H)；13C NMR(100MHz,acetone-d6)δ177.4,161.4,154.2,144.3,135.3,131.4,131.2,130.3,128.8,128.5,127.9,127.8,123.8,81.9,77.7,77.5,76.7,67.3,62.4,39.4,27.8,21.5；HRMS(ESI)m/z:[M+H]精确质量计算C28H32NO7,494.2179；实测值,494.2182。
1H NMR(400MHz,acetone-d6)δ7.74(d,J＝7.9Hz,2H),7.31(d,J＝7.9Hz,2H),7.25–7.10(m,5H),6.27(ddd,J＝9.9,5.5,1.6Hz,1H),6.13(dd,J＝10.3,1.2Hz,1H),4.64(d,J＝2.1Hz,1H),4.21(dd,J＝11.6,7.4Hz,1H),4.15(dd,J＝11.5,4.3Hz,1H),3.92–3.88(m,1H),3.85–3.81(m,1H),3.41(d,J＝13.3Hz,1H),3.28(d,J＝13.3Hz,1H),3.03(d,J＝9.8Hz,1H),2.39(s,3H),1.45(s,9H)；13C NMR(100MHz,acetone-d6)δ177.9,162.1,154.2,144.4,135.1,131.3,131.3,130.3,128.8,128.5,127.9,127.8,123.8,82.0,77.9,77.4,76.5,67.2,62.4,39.5,27.8,21.5；HRMS(ESI)m/z:[M+H]精确质量计算C28H32NO7,494.2179；实测值,494.2182。
实施例19
1H NMR(400MHz,acetone-d6)δ7.77–7.74(m,2H),7.30(d,J＝8.0Hz,2H),7.27–7.11(m,10H),6.25(ddd,J＝10.3,5.6,2.1Hz,1H),6.16(dd,J＝10.4,1.6Hz,1H),4.58(q,J＝1.9Hz,1H),4.53(d,J＝12.4Hz,1H),4.46(d,J＝12.3Hz,1H),3.91(d,J＝6.6Hz,1H),3.79(ddd,J＝6.7,4.5,2.1Hz,1H),3.74(dd,J＝10.6,4.5Hz,1H),3.60(dd,J＝10.6,6.9Hz,1H),3.39(q,J＝13.4Hz,1H),3.35(q,J＝13.5Hz,1H),3.16(d,J＝9.1Hz,1H),2.39(s,3H)；13C NMR(100MHz,acetone-d6)δ177.5,161.3,144.3,139.9,135.4,131.7,131.2,130.3,128.9,128.8,128.5,128.0,127.9,127.8,127.7,123.9,78.7,77.9,77.6,73.7,70.9,62.7,39.3,21.5；HRMS(ESI)m/z:[M+H]精确质量计算C30H30NO5,484.2124；实测值,484.2127。
1H NMR(400MHz,acetone-d6)δ7.73(d,J＝8.3Hz,2H),7.37–7.12(m,12H),6.27(ddd,J＝10.3,5.8,2.0Hz,1H),6.14(dd,J＝10.3,1.7Hz,1H),4.67(q,J＝1.9Hz,1H),4.55(s,2H),3.88(ddt,J＝9.6,5.8,1.9Hz,1H),3.82(ddd,J＝6.8,4.8,1.9Hz,1H),3.66(dd,J＝10.4,4.9Hz,1H),3.56(dd,J＝10.4,6.8Hz,1H),3.42(d,J＝13.3Hz,1H),3.28(d,J＝13.3Hz,1H),2.82(d,J＝9.8Hz,1H),2.38(s,3H)；13C NMR(100MHz,acetone-d6)δ178.1,161.9,144.4,139.8,135.2,131.7,131.2,130.3,129.0,128.8,128.5,128.2,128.0,127.9,127.7,123.8,78.1,78.0,77.7,73.5,70.6,62.6,39.5,21.5；HRMS(ESI)m/z:[M+H]精确质量计算C30H30NO5,484.2124；实测值,484.2127。
实施例20
1H NMR(400MHz,acetone-d6)δ7.86–7.81(m,2H),7.77–7.74(m,3H),7.70(s,1H),7.50–7.44(m,2H),7.33(dd,J＝8.5,1.7Hz,1H),7.28(d,J＝8.0Hz,2H),7.23–7.11(m,5H),6.26(ddd,J＝10.3,5.6,2.1Hz,1H),6.18(dd,J＝10.3,1.6Hz,1H),4.71(dd,J＝12.6,0.9Hz,1H),4.63(dd,J＝12.6,0.9Hz,1H),4.59(q,J＝1.9Hz,1H),3.94(ddt,J＝9.2,5.5,1.9Hz,1H),3.85–3.79(m,2H),3.70–3.64(m,1H),3.38(s,2H),3.19(d,J＝9.1Hz,1H),2.36(s,3H)；13C NMR(100MHz,acetone-d6)δ177.5,161.3,144.3,137.6,135.4,134.2,133.7,131.7,131.2,130.3,128.8,128.6,128.5,128.5,128.4,127.8,127.7,126.7,126.4,126.4,126.4,123.9,78.8,77.9,77.6,73.9,71.0,62.7,39.3,21.5；HRMS(ESI)m/z:[M+H]精确质量计算C34H32NO5,534.2280；实测值,534.2286。
1H NMR(400MHz,acetone-d6)δ7.89–7.84(m,4H),7.70(d,J＝8.3Hz,2H),7.52–7.45(m,3H),7.27–7.11(m,7H),6.27(ddd,J＝10.3,5.7,2.0Hz,1H),6.15(dd,J＝10.3,1.6Hz,1H),4.75–4.71(m,2H),4.69(q,J＝1.8Hz,1H),3.92–3.84(m,2H),3.70(dd,J＝10.5,4.6Hz,1H),3.60(dd,J＝10.5,6.8Hz,1H),3.42(d,J＝13.3Hz,1H),3.29(d,J＝13.3Hz,1H),2.84(d,J＝9.8Hz,1H),2.35(s,3H)；13C NMR(100MHz,acetone-d6)δ178.1,161.9,144.4,137.4,135.2,134.2,133.8,131.7,131.2,130.3,128.8,128.7,128.6,128.5,128.4,127.9,127.7,126.8,126.7,126.5,126.5,123.8,78.1,78.0,77.8,73.5,70.7,62.7,39.5,21.5；HRMS(ESI)m/z:[M+H]精确质量计算C34H32NO5,534.2280；实测值,534.2281。
实施例20
为了证明所获得的β-C-糖苷的用途，对β-(R)-3a进行醇解和脱保护，产率分别为85％和82％，得到β-(R)-5a。对β-(S)-3a进行的同样反应，得到相应的C-糖苷β-(S)-5a，它含有一个与β-(R)-5a手性相反的季碳立体中心。
在氩气环境下，在装有磁性搅拌棒、干燥、密封的Schlenk管中加入β-(R)-3a或β-(S)-3a(63mg,0.1mmol)和无水的MeOH(1mL)。然后，加入MeONa(27μL，0.15mmol，30％在MeOH中)，反应混合物在室温下搅拌20分钟。反应完成后(通过TLC监测)，用H2O(15mL)稀释混合物，并用EtOAc(10mL×2)萃取。合并的有机相用食盐水洗涤，Na2SO4干燥，然后减压浓缩。残留物经硅胶柱色谱法纯化，分别得到β-(R)-4a(85％产率)或β-(S)-4a(79％产率)。
1H NMR(400MHz,acetone-d6)δ7.79–7.77(m,4H),7.66(d,J＝8.3Hz,2H),7.51(s,1H),7.48–7.40(m,6H),7.30–7.27(m,2H),7.22–7.16(m,5H),6.35(dd,J＝10.5,1.5Hz,1H),6.02(ddd,J＝10.4,5.6,2.2Hz,1H),4.73(d,J＝1.9Hz,1H),3.98–3.97(m,2H),3.92(ddt,J＝7.7,5.7,1.9Hz,1H),3.82–3.74(m,5H),3.50(d,J＝13.0Hz,1H),3.14(d,J＝7.8Hz,1H),2.32(s,3H),1.04(s,9H)；13C NMR(100MHz,acetone-d6)δ171.2,167.3,142.2,136.6,136.3,134.3,134.2,133.0,131.2,130.7,130.5,130.5,129.6,129.2,128.9,128.6,128.0,127.6,79.7,76.3,67.1,65.2,62.6,52.2,39.0,27.2,21.3,19.6；HRMS(ESI)m/z:[M+H]精确质量计算C40H46NO6Si,664.3094；实测值,664.3093。
1H NMR(400MHz,acetone-d6)δ7.89–7.84(m,4H),7.71(d,J＝7.9Hz,2H),7.52–7.48(m,6H),7.41(s,1H),7.29–7.23(m,4H),7.18–7.14(m,3H),6.24(d,J＝10.4Hz,1H),6.04(ddd,J＝10.3,5.5,2.1Hz,1H),4.58(d,J＝2.2Hz,1H),4.11–3.92(m,4H),3.84–3.81(m,1H),3.72(s,3H),3.67(d,J＝13.6Hz,1H),3.20(d,J＝8.1Hz,1H),2.37(s,3H),1.12(s,9H)；13C NMR(100MHz,acetone-d6)δ171.4,167.3,142.5,137.7,136.3,136.3,134.3,134.2,132.9,131.6,130.6,130.5,130.1,129.7,128.8,128.7,128.0,127.2,80.4,76.0,66.8,65.4,62.7,52.4,35.9,27.2,21.3,19.7；HRMS(ESI)m/z:[M+H]精确质量计算C40H46NO6Si,664.3094；实测值,664.3091。
在室温下向β-(R)-4a(63mg)或β-(S)-4a(48mg)的THF溶液中加入TBAF(1.2eq.,0.5M在THF中)，然后将反应混合物搅拌15分钟。反应完成后(通过TLC监测)，减压浓缩混合物，得到粗品，通过制备TLC纯化，分别得到β-(R)-5a(82％产率)或β-(S)-5a(84％产率)。
1H NMR(400MHz,CDCl3)δ7.59(d,J＝8.2Hz,2H),7.22–7.19(m,5H),7.13(s,1H),7.10–7.08(m,2H),6.20(dd,J＝10.4,1.4Hz,1H),6.14(ddd,J＝10.3,5.5,2.0Hz,1H),4.98(d,J＝1.9Hz,1H),3.90(t,J＝7.1Hz,1H),3.82–3.70(m,6H),3.57–3.52(m,2H),2.64(s,1H),2.37(s,3H),2.36(s,1H)；13C NMR(100MHz,CDCl3)δ171.3,167.6,142.2,135.5,132.0,130.1,129.3,129.3,128.4,128.3,127.1,127.0,77.2,75.8,68.2,62.9,62.8,52.6,36.9,21.5；HRMS(ESI)m/z:[M+H]精确质量计算C24H28NO6,426.1917；实测值,426.1913。
1H NMR(400MHz,CDCl3)δ7.57(d,J＝8.1Hz,2H),7.26–7.18(m,5H),7.12–7.09(m,2H),7.01(s,1H),6.15(ddd,J＝10.3,5.7,2.1Hz,1H),6.05(dd,J＝10.2,1.5Hz,1H),5.15(d,J＝1.8Hz,1H),4.08(d,J＝13.8Hz,1H),3.93(dd,J＝11.3,6.4Hz,2H),3.83–3.82(m,4H),3.71(ddd,J＝6.7,4.7,1.6Hz,1H),3.57(d,J＝13.8Hz,1H),2.39(s,3H),2.16(s,1H),1.99(d,J＝9.7Hz,1H)；13C NMR(100MHz,CDCl3)δ171.8,167.1,142.4,135.9,131.9,130.0,129.4,129.1,129.0,128.3,127.0,126.9,77.6,76.1,68.3,62.8,53.1,35.4,21.5；HRMS(ESI)m/z:[M+H]精确质量计算C24H28NO6,426.1917；实测值,426.1913。
β-(R)-3a和β-(S)-3a烯烃双羟化时，C3位新形成的羟基可以对噁唑-5(4H)-酮环亲核开环，得到内酯并糖苷产物，可以保留立体化学结构(β-(R)-6a，β-(S)-6a)。β-(S)-6a经X-射线晶体衍射(CCDC 2201062)，确定其立体构型。
在室温下向β-(R)-3a(63mg,0.1mmol)或β-(S)-3a(63mg,0.1mmol)的丙酮/H2O(1mL/0.2mL,5:1)溶液加入K2OsO4·2H2O(1.8mg,5mol％)和NMO(35mg,0.3mmol)，然后将反应混合物搅拌24小时。反应完成后(通过TLC监测)，用EtOAc(5mL×2)提取混合物，合并的有机相用食盐水洗涤，Na2SO4干燥。在减压下除去溶剂，然后通过制备性TLC纯化，分别得到β-(R)-6a(92％产率)或β-(S)-6a(90％产率)。
1H NMR(400MHz,CDCl3)δ7.62–7.56(m,4H),7.49(d,J＝8.0Hz,2H),7.45–7.34(m,4H),7.29–7.22(m,7H),7.07(d,J＝7.9Hz,2H),6.30(s,1H),4.73(dd,J＝9.8,2.4Hz,1H),4.47(s,1H),4.31–4.28(m,2H),4.10(d,J＝3.7Hz,1H),3.95–3.86(m,3H),3.50(d,J＝13.9Hz,1H),3.30(d,J＝13.9Hz,1H),3.16(brs,1H),2.31(s,3H),0.94(s,9H)；13C NMR(100MHz,CDCl3)δ171.9,166.7,142.5,135.5,135.4,134.3,132.5,132.0,130.5,130.3,130.1,130.0,129.3,128.6,127.9,127.9,127.6,127.1,76.6,75.9,75.7,72.6,66.7,65.4,60.0,41.3,26.6,21.5,19.1；HRMS(ESI)m/z:[M+H]精确质量计算C39H44NO7Si,666.2887；实测值,666.2887。
1H NMR(400MHz,CDCl3)δ7.78–7.76(m,2H),7.71–7.68(m,2H),7.47–7.32(m,13H),7.14–7.12(m,2H),6.34(s,1H),5.28(d,J＝10.3Hz,1H),4.59(dd,J＝10.3,2.5Hz,1H),4.51–4.49(m,1H),4.23(d,J＝3.6Hz,1H),4.13(dd,J＝11.2,4.0Hz,1H),4.06–3.98(m,2H),3.83(s,1H),3.52(d,J＝14.1Hz,1H),3.30(d,J＝14.1Hz,1H),2.33(s,3H),2.04(s,1H),1.08(s,9H)；13C NMR(100MHz,CDCl3)δ172.7,166.8,142.5,135.7,135.5,133.1,132.3,132.2,130.9,130.3,130.0,130.0,129.2,128.9,128.0,127.9,127.9,126.9,75.7,74.2,72.8,67.3,65.6,62.0,34.2,26.7,21.4,19.1；HRMS(ESI)m/z:[M+H]精确质量计算C39H44NO7Si,666.2887；实测值,666.2884。
由X射线衍射分析确定化合物β-(S)-6a的绝对构型，相关数据可在剑桥晶体学数据中心(www.ccdc.cam.ac.uk/conts/retrieving.html)获取，存放编号为CCDC 2201062，详细信息如下表所示：
实施例21
放大实验，参照通用合成方法，6-O-TBDPS-3,4-环碳酸酯-半乳烯糖1a用量为10mmol，4-苄基-2-对甲基苯基噁唑啉-5-酮2a用量为12mmol，催化剂Pd(acac)2用量为1mol％，配体L1用量为2mol％，β-(R)-3a分离收率为27％，β-(S)-3a离收率为20％。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何属于本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应该以权利要求的保护范围为准。
Claims (10)
1.一种手性氨基酸C-糖苷，其特征在于，其具有通式Ⅰ的结构或通式Ⅰ的对映异构体、非对映异构体：
其中，P选自TBDPS、TBS、TIPS、Ac、Piv、Bz、Boc、Bn、萘甲基、TMS、TES、TBDMS、甲基、PMB、Tr、MMT、DMT、MOM、BOM、MTM、THP、MEM、PMBOM、Cbz、Fmoc，
R选自烷基、苯基、Bn、PMB、-CH2CH2SMe，
Ar选自苯基、烷基苯基、卤代苯基。
2.根据权利要求1所述的手性氨基酸C-糖苷，其特征在于，所述P选自TBDPS、TBS、TIPS、Ac、Piv、Bz、Boc、Bn、萘甲基。
3.根据权利要求1所述的手性氨基酸C-糖苷，其特征在于，所述R选自(C1～C4)烷基、苯基、Bn、PMB、-CH2CH2SMe。
4.根据权利要求3所述的手性氨基酸C-糖苷，其特征在于，所述R选自甲基、异丙基、仲丁基、异丁基、苯基、Bn、PMB、-CH2CH2SMe。
5.根据权利要求1所述的手性氨基酸C-糖苷，其特征在于，所述Ar选自苯基、(C1～C4)烷基取代的苯基、氟代苯基、氯代苯基、溴代苯基。
6.根据权利要求5所述的手性氨基酸C-糖苷，其特征在于，所述Ar选自苯基、对甲基苯基、间甲基苯基、对溴苯基。
7.根据权利要求1所述的手性氨基酸C-糖苷，其特征在于，其选自以下化合物或它们的对映异构体、非对映异构体：
8.一种权利要求1～7任意一项所述的手性氨基酸C-糖苷的合成方法，其特征在于，包括以下步骤：在钯催化剂存在下，化合物1和化合物2反应如下：
所述P、Ar、R如权利要求1～7任意一项所定义。
9.根据权利要求8所述的合法方法，其特征在于，加入配体，所述配体选自以下化合物：
10.根据权利要求8或9所述的合法方法，其特征在于，钯催化剂选自Pd(OAc)2、Pd(PPh3)4、Pd(acac)2、Pd2(dba)3、[Pd(allyl)Cl]2；所述钯催化剂的用量至少是1mol％；所述配体的用量至少是2mol％；所述化合物1和化合物2的摩尔比为1：(1～3)；所述反应以二氯甲烷、二氯乙烷、氯仿、四氢呋喃或乙腈为溶剂；所述反应的温度为25℃以上，所述反应的时间在0.5h以上。
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