CN113248480B - 一种呋喃卡宾化学选择性和对映选择性插入2-吡啶酮或3-哒嗪酮n-h键的方法 - Google Patents
一种呋喃卡宾化学选择性和对映选择性插入2-吡啶酮或3-哒嗪酮n-h键的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 title abstract description 15
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 title abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 89
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 63
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 38
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 36
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 20
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- 239000010948 rhodium Substances 0.000 claims description 9
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- 238000005804 alkylation reaction Methods 0.000 claims description 7
- 229910052703 rhodium Inorganic materials 0.000 claims description 7
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 7
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- C—CHEMISTRY; METALLURGY
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- 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
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- Y02P20/584—Recycling of catalysts
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Abstract
本发明属于不对称催化合成领域，具体公开了一种呋喃卡宾化学选择性和对映选择性插入2‑吡啶酮或3‑哒嗪酮N‑H键的方法，采用手性铑做催化剂、烯炔酮做呋喃卡宾前体与2‑吡啶酮(或3‑哒嗪酮)的化学选择性和对映选择性N‑H键插入反应，以高对映选择性合成N‑(呋喃烷基)‑2‑吡啶酮或N‑(呋喃烷基)‑3‑哒嗪酮衍生物。本发明方法的优点有：反应操作简单、条件温和、原料简单易得、底物适用范围广、产率高、化学和对映选择性好。
Description
技术领域
本发明属于不对称催化有机合成领域，具体涉及一种呋喃卡宾化学选择性和对映选择性插入2-吡啶酮或3-哒嗪酮N-H键的方法。
背景技术
手性N-烷基取代2-吡啶酮或者或3-哒嗪酮衍生物是天然产物和医药分子中重要的结构片段，含有该结构的化合物能作为鼻病毒蛋白酶抑制剂中间体(Tetrahedron 2004,60,759.)、葡萄糖激酶激活剂(Bioorg.Med.Chem.Lett.2009,19,3247.)、中性粒细胞弹性蛋白酶抑制剂(WO2005026123A1,2005)、丝氨酸蛋白酶抑制剂(WO2016044662A1,2016)、APJ受体激动剂(WO2018097944A1,2018)、磷酸二酯酶4(PDE4)抑制剂(WO2004058729A1,2004)、Met激酶抑制剂(WO2009006959A1,2009)、抗丙型肝炎病毒的抗病毒药(WO2007058392A1,2007)等。
通常合成该类化合物最直接的方法是通过2-吡啶酮或者或3-哒嗪酮的直接烷基化反应，然而2-吡啶酮(或3-哒嗪酮)存在2-羟基吡啶(或3-羟基哒嗪)的互变异构使得反应存在N-烷基化和O-烷基化的选择性问题，因此化学选择性和对映选择性的对2-吡啶酮进行不对称N-烷基化具有更大的挑战性。呋喃母核结构同样广泛存在于天然产物、药物分子中，如雷尼替丁作为强效组胺H2受体拮抗剂被用于胃酸过多、烧心的治疗，此外呋喃衍生物在农药及香料市场也有巨大的潜力。
金属卡宾是一类活泼的有机物种，可以作为烷基化试剂通过X-H键插入反应进行直接烷基化。2-羟基吡啶衍生物基于卡宾转移的不对称烷基化反应主要有：(1)手性金催化2-吡啶酮的不对称O-H键插入反应(Chem.Commun.,2017,53,3197.)；(2)手性铑催化O-取代的2-羟基吡啶衍生物通过酰基重排去芳构化获得手性N-烷基化2-吡啶酮化合物(Angew.Chem.Int.Ed.2019,58,1980)，该方法中需要使用给电子-吸电子类型的卡宾前体以实现其对映选择性。烯炔酮化合物作为常用的2-呋喃卡宾(给电子-给电子类型)前体被广泛研究，然而2-羟基吡啶基于给电子-给电子类型金属卡宾的不对称烷基化因具有更大的难度而鲜有报道。
发明内容
本发明公开了一种使用手性铑做催化剂、烯炔酮做2-呋喃卡宾前体与2-吡啶酮或3-哒嗪酮的化学选择性和对映选择性N-H键插入反应，高对映选择性合成2-吡啶酮或3-哒嗪酮的N-呋喃烷基化衍生物。本发明具体的反应通式如下：
一种呋喃卡宾化学选择性和对映选择性插入2-吡啶酮或3-哒嗪酮N-H键的方法，具体为：向干燥的反应管中加入手性铑催化剂、2-吡啶酮或3-哒嗪酮(1)和烯炔酮(2)，在氩气保护下加入溶剂，之后反应在-20～40℃搅拌12-72小时得到手性2-吡啶酮或3-哒嗪酮的N-呋喃烷基化衍生物(3)。
使用的手性铑催化剂为如下所示：
其中，最优催化剂为Rh2(S-TFPTTL)4。
手性N-(呋喃烷基)-2-吡啶酮或N-(呋喃烷基)-3-哒嗪酮衍生物(3)结构如下图：
其中：R1为Ph，4-MeC6H4，4-MeOC6H4，4-ClC6H4，4-FC6H4，4-EtO2CC6H4，3-FC6H4，3-MeC6H4，3-MeOC6H4，2-FC6H4，3,4-Me2C6H3，3,5-Me2C6H3，2-萘基，3-噻吩基，甲基，环丙基；
R2为乙酰基，丙酰基，异丁酰基，苯甲酰基，CO2Me，CO2Et；
R3为Me，Et，iPr，Ph，环丙基；
R为3-Cl，3-Me，4-Me，4-Br，4-MeO2C，4-BnO，5-Me，5-F，5-Br，5-I，5-CF3，5-MeO2C，5-CHO；X＝CH或N；
反应的溶剂为：乙醚，二氯甲烷，二氯乙烷，氯仿，四氯化碳，甲苯，三氟甲苯，氯苯，甲基环己烷，环己烷，环戊烷，正己烷，甲基叔丁基醚，环戊烷与乙醚混合溶剂，环戊烷与甲基叔丁基醚混合溶剂等。
其中，最优的溶剂为环戊烷与乙醚混合溶剂(体积比为1:1)。
反应中手性铑催化剂、2-吡啶酮(1)、烯炔酮(2)的摩尔比为：0.005～0.025:1:1～1.5，最优的摩尔比为：0.01:1:1.1。
反应液浓度为：0.01～0.10mol/L,最佳浓度为0.05mol/L。
反应的最佳温度为0℃。
反应过程中还可以加入添加剂，使用的添加剂为：分子筛、分子筛、分子筛，其中分子筛最好，其添加量为20mg/0.1mmol。
有益效果和优点
本发明公开的一种呋喃卡宾化学选择性和对映选择性插入2-吡啶酮或3-哒嗪酮N-H键的方法，解决了2-羟基吡啶或3-羟基哒嗪与给电子-给电子类型卡宾的N-选择性和对映选择性烷基化难题，同时为药物开发中快速构建该类含呋喃杂环母核的手性吡啶酮或哒嗪酮衍生物化合物库提供直接有效的方法。
本发明方法的优点有：反应操作简单、条件温和、原料简单易得、底物适用范围广、产率高、化学和对映选择性好。
附图说明
图1为实施例1得到的3aa的1H-NMR(核磁氢谱)；
图2为实施例1得到的3aa的13C-NMR(核磁碳谱)；
图3为实施例1得到的3aa的HRMS(高分辨质谱)；
图4为实施例1得到的3aa的HPLC(高效液相色谱)。
具体实施方式
下面将通过具体实施例对本发明做进一步说明，本发明并不局限于以下的实施例。
实施例1
向干燥的反应管中加入Rh2(S-TFPTTL)4(1.6mg,0.001mmol)，1a(9.5mg,0.1mmol)，2a(23.3mg,0.11mmol)和分子筛(20.0mg)，之后反应管抽真空后充氩气(该操作重复三次)，反应管冷却到0℃，加入环戊烷和乙醚混合溶剂(1:1,2mL)，反应在0℃搅拌48h。反应液减压蒸干，残余物使用柱色谱纯化(硅胶，淋洗剂：EtOAc/PE＝1:10-1:2)得到淡黄色固体产物(28.9mg,94％yield)，熔点：108-110℃；HPLC检测：96％ee；HPLC条件：Daicel ChiralpakIE column,n-hexane/i-PrOH＝60/40,flow rate 1.0mL/min,λ＝254nm,tR＝17.28min(major)and 19.65min(minor).[α]D 28:-53.0(c＝0.1,CHCl3；96％ee).1H NMR(400MHz,CDCl3)δ7.44(s,1H),7.40-7.32(m,4H),7.30-7.25(m,1H),7.19(d,J＝7.3Hz,2H),6.63(d,J＝9.2Hz,1H),6.46(s,1H),6.18(t,J＝6.7Hz,1H),2.58(s,3H),2.37(s,3H).13C NMR(100MHz,CDCl3)δ193.9,162.2,159.6,149.3,139.6,136.7,135.4,129.1,128.6,128.0,122.3,121.1,112.1,106.3,55.6,29.3,14.7.IRνmax(film,cm-1)2924,1663,1592,1535,1400,1229,1141,955,765,700,635.HRMS(ESI)calcd.for C19H17NNaO3[M+Na]+:330.1101,found:330.1097.
实施例2：
向干燥的反应管中加入Rh2(S-TFPTTL)4(1.6mg,0.001mmol)，1a(9.5mg,0.1mmol)，2a(23.3mg,0.11mmol)，之后反应管抽真空后充氩气(该操作重复三次)，反应管冷却到0℃加入环戊烷和乙醚混合溶剂(1:1,2mL)，反应在0℃搅拌60h。反应液减压蒸干，残余物使用柱色谱纯化(硅胶，淋洗剂：EtOAc/PE＝1:10-1:2)得到淡黄色固体产物(28.2mg,92％yield)，HPLC检测：96％ee。
实施例3：
向干燥的反应管中加入Rh2(S-TFPTTL)4(1.6mg,0.001mmol)，1a(9.5mg,0.1mmol)，2a(23.3mg,0.11mmol)，之后反应管抽真空后充氩气(该操作重复三次)，室温下加入乙醚(2mL)，反应在25℃搅拌36h。反应液减压蒸干，残余物使用柱色谱纯化(硅胶，淋洗剂：EtOAc/PE＝1:10-1:2)得到淡黄色固体产物(25.8mg,84％yield)，HPLC检测：90％ee。
实施例4：
向干燥的反应管中加入Rh2(S-PTTL)4(1.3mg,0.001mmol)，1a(9.5mg,0.1mmol)，2a(23.3mg,0.11mmol)，之后反应管抽真空后充氩气(该操作重复三次)，室温下加入乙醚(2mL)，反应在25℃搅拌24h。反应液减压蒸干，残余物使用柱色谱纯化(硅胶，淋洗剂：EtOAc/PE＝1:10-1:2)得到淡黄色固体产物(26.4mg,86％yield)，HPLC检测：78％ee。
实施例5：
向干燥的反应管中加入Rh2(S-PTAD)4(1.6mg,0.001mmol)，1a(9.5mg,0.1mmol)，2a(23.3mg,0.11mmol)，之后反应管抽真空后充氩气(该操作重复三次)，室温下加入乙醚(2mL)，反应在25℃搅拌60h。反应液减压蒸干，残余物使用柱色谱纯化(硅胶，淋洗剂：EtOAc/PE＝1:10-1:2)得到淡黄色固体产物(19.3mg,63％yield)，HPLC检测：75％ee。
实施例6：
向干燥的反应管中加入Rh2(S-PTV)4(1.2mg,0.001mmol)，1a(9.5mg,0.1mmol)，2a(23.3mg,0.11mmol)，之后反应管抽真空后充氩气(该操作重复三次)，室温下加入乙醚(2mL)，反应在25℃搅拌24h。反应液减压蒸干，残余物使用柱色谱纯化(硅胶，淋洗剂：EtOAc/PE＝1:10-1:2)得到淡黄色固体产物(16.0mg,52％yield)，HPLC检测：82％ee。
实施例7：
向干燥的反应管中加入Rh2(S-TFPTTL)4(1.6mg,0.001mmol)，1a(9.5mg,0.1mmol)，2a(23.3mg,0.11mmol)和分子筛(20.0mg)，之后反应管抽真空后充氩气(该操作重复三次)，反应管冷却到0℃，加入环戊烷和乙醚混合溶剂(1:1,4mL)，反应在0℃搅拌48h。反应液减压蒸干，残余物使用柱色谱纯化(硅胶，淋洗剂：EtOAc/PE＝1:10-1:2)得到淡黄色固体产物(27.6mg,90％yield)，HPLC检测：96％ee。
实施例8：
向干燥的反应管中加入Rh2(S-TFPTTL)4(1.6mg,0.001mmol)，1a(9.5mg,0.1mmol)，2a(31.8mg,0.15mmol)和分子筛(20.0mg)，之后反应管抽真空后充氩气(该操作重复三次)，反应管冷却到0℃，加入环戊烷和乙醚混合溶剂(1:1,2mL)，反应在0℃搅拌48h。反应液减压蒸干，残余物使用柱色谱纯化(硅胶，淋洗剂：EtOAc/PE＝1:10-1:2)得到淡黄色固体产物(28.9mg,94％yield)，HPLC检测：96％ee。
实施例9：
向干燥的反应管中加入Rh2(S-TFPTTL)4(3.2mg,0.002mmol)，1a(9.5mg,0.1mmol)，2a(23.3mg,0.11mmol)和分子筛(20.0mg)，之后反应管抽真空后充氩气(该操作重复三次)，反应管冷却到0℃，加入环戊烷和乙醚混合溶剂(1:1,2mL)，反应在0℃搅拌40h。反应液减压蒸干，残余物使用柱色谱纯化(硅胶，淋洗剂：EtOAc/PE＝1:10-1:2)得到淡黄色固体产物(28.9mg,94％yield)，HPLC检测：96％ee。
实施例10：
向干燥的反应管中加入Rh2(S-TFPTTL)4(1.6mg,0.001mmol)，1a(9.5mg,0.1mmol)，2b(24.0mg,0.11mmol)和分子筛(20.0mg)，之后反应管抽真空后充氩气(该操作重复三次)，反应管冷却到0℃，加入环戊烷和乙醚混合溶剂(1:1,2mL)，反应在0℃搅拌18h。反应液减压蒸干，残余物使用柱色谱纯化(硅胶，淋洗剂：EtOAc/PE＝1:10-1:4)得到黄色固体产物(28.8mg,92％yield)，熔点：108-110℃；HPLC检测：97％ee；HPLC条件：Daicel ChiralpakIC column,n-hexane/i-PrOH＝60/40,flow rate 1.0mL/min,λ＝254nm,tR＝33.32min(minor)and 39.07min(major).[α]D 28:-70.0(c＝0.1,CHCl3；97％ee).1H NMR(500MHz,CDCl3)δ7.49(s,1H),7.38-7.31(m,3H),7.16-7.08(m,1H),6.99-6.95(m,1H),6.65-6.60(m,1H),6.55(s,1H),6.18(td,J＝6.8,1.1Hz,1H),2.59(s,3H),2.38(s,3H).13C NMR(125MHz,CDCl3)δ193.8,161.9,159.3,149.1,139.5,137.3,134.9,127.1,127.0,124.4,122.1,120.9,111.1,106.4,51.5,29.2,14.6.IRνmax(film,cm-1)3099,2922,1662,1588,1536,1401,1231,1141,962,773,633.HRMS(ESI)calcd.for C17H15NNaO3S[M+Na]+:336.0665,found:336.0668.
实施例11：
向干燥的反应管中加入Rh2(S-PTTL)4(1.3mg,0.001mmol)，1a(9.5mg,0.1mmol)，2c(19.4mg,0.11mmol)和分子筛(20.0mg)，之后反应管抽真空后充氩气(该操作重复三次)，反应管冷却到-20℃，加入环戊烷和乙醚混合溶剂(1:1,2mL)，反应在-20℃搅拌12h。反应液减压蒸干，残余物使用柱色谱纯化(硅胶，淋洗剂：EtOAc/PE＝1:10-1:4)得到淡黄色油状产物(22.0mg,85％yield)；HPLC检测：85％ee；HPLC条件：Daicel Chiralpak IE column,n-hexane/i-PrOH＝80/20,flow rate 1.0mL/min,λ＝254nm,tR＝32.37min(major)and37.03min(minor).[α]D 28:+122.0(c＝0.1,CHCl3；85％ee).1H NMR(300MHz,CDCl3)δ7.48-7.42(m,1H),7.35-7.27(m,1H),6.70(s,1H),6.63-6.56(m,1H),6.21(td,J＝6.8,1.4Hz,1H),5.53(d,J＝10.0Hz,1H),2.54(s,3H),2.41(s,3H),1.55-1.40(m,1H),0.89-0.77(m,1H),0.68-0.54(m,3H).13C NMR(75MHz,CDCl3)δ193.9,162.2,158.7,150.3,139.1,134.3,122.0,120.8,109.4,106.4,55.9,29.2,14.5,13.9,5.7,3.8.IRνmax(film,cm-1)3087,3006,1660,1569,1536,1404,1230,946,766,632.HRMS(ESI)calcd.for C16H17NNaO3[M+Na]+:294.1101,found:294.1099.
实施例12：
向干燥的反应管中加入Rh2(S-TFPTTL)4(1.6mg,0.001mmol)，1a(9.5mg,0.1mmol)，2d(37.0mg,0.11mmol)和分子筛(20.0mg)，之后反应管抽真空后充氩气(该操作重复三次)，反应管冷却到0℃，加入环戊烷和乙醚混合溶剂(1:1,2mL)，反应在0℃搅拌72h。反应液减压蒸干，残余物使用柱色谱纯化(硅胶，淋洗剂：EtOAc/PE＝1:10-1:3)得到白色固体产物(33.6mg,78％yield)，熔点：139-141℃；HPLC检测：91％ee；HPLC条件：Daicel ChiralpakIE column,n-hexane/i-PrOH＝70/30,flow rate 1.0mL/min,λ＝254nm,tR＝45.24min(major)and 50.23min(minor).[α]D 28:-91.0(c＝0.1,CHCl3；91％ee).1H NMR(400MHz,CDCl3)δ7.83-7.78(m,2H),7.62-7.56(m,3H),7.53-7.47(m,1H),7.41-7.32(m,7H),7.29-7.26(m,5H),6.67-6.63(m,1H),6.56(d,J＝0.7Hz,1H),6.20(td,J＝6.8,1.4Hz,1H).13CNMR(100MHz,CDCl3)δ191.4,162.1,156.6,150.2,139.5,137.5,136.6,135.3,133.1,129.7,129.4,129.2,129.0,128.6,128.4,128.37,128.0,127.6,121.5,121.0,114.9,106.3,55.5.IRνmax(film,cm-1)3062,2926,1663,1593,1536,1487,1447,1399,1236,1140,893,767,727,694.HRMS(ESI)calcd.for C29H21NNaO3[M+Na]+:454.1414,found:454.1414.
实施例13：
向干燥的反应管中加入Rh2(S-TFPTTL)4(1.6mg,0.001mmol)，1a(9.5mg,0.1mmol)，2e(29.5mg,0.11mmol)和分子筛(20.0mg)，之后反应管抽真空后充氩气(该操作重复三次)，反应管冷却到0℃，加入环戊烷和乙醚混合溶剂(1:1,2mL)，反应在0℃搅拌72h。反应液减压蒸干，残余物使用柱色谱纯化(硅胶，淋洗剂：EtOAc/PE＝1:10-1:5)得到白色固体产物(26.5mg,73％yield)，熔点：129-131℃；HPLC检测：85％ee；HPLC条件：Daicel ChiralpakIE column,n-hexane/i-PrOH＝70/30,flow rate 1.0mL/min,λ＝254nm,tR＝16.18min(major)and 17.74min(minor).[α]D 28:-26.0(c＝0.1,CHCl3；85％ee).1H NMR(300MHz,CDCl3)δ7.42-7.28(m,5H),7.22-7.11(m,3H),6.66-6.56(m,1H),6.42(d,J＝0.9Hz,1H),6.15(td,J＝6.8,1.4Hz,1H),4.28(q,J＝7.1Hz,2H),2.83-7.72(m,1H),1.32(t,J＝7.1Hz,3H),1.09-0.91(m,4H).13C NMR(125MHz,CDCl3)δ164.4,163.9,162.1,147.7,139.4,136.6,135.1,128.9,128.4,127.8,121.0,113.8,112.9,106.0,60.3,55.7,14.4,9.3,9.1,9.08.IRνmax(film,cm-1)2923,1711,1663,1577,1529,1414,1226,1141,1058,764,699.HRMS(ESI)calcd.for C22H21NNaO4[M+Na]+:386.1363,found:386.1361.
实施例14：
向干燥的反应管中加入Rh2(S-TFPTTL)4(1.6mg,0.001mmol)，1b(15.3mg,0.1mmol)，2a(23.3mg,0.11mmol)和分子筛(20.0mg)，之后反应管抽真空后充氩气(该操作重复三次)，反应管冷却到0℃，加入环戊烷和乙醚混合溶剂(1:1,2mL)，反应在0℃搅拌72h。反应液减压蒸干，残余物使用柱色谱纯化(硅胶，淋洗剂：EtOAc/PE＝1:10-1:2)得到淡黄色固体产物(23.4mg,64％yield)，熔点：146-148℃；HPLC检测：89％ee；HPLC条件：DaicelChiralpak IE column,n-hexane/i-PrOH＝70/30,flow rate 1.0mL/min,λ＝254nm,tR＝49.83min(major)and 59.76min(minor).[α]D 28:-54.0(c＝0.1,CHCl3；89％ee).1H NMR(500MHz,CDCl3)δ7.42-7.33(m,5H),7.26(s,1H),7.20(d,J＝7.2Hz,2H),6.67(d,J＝7.2Hz,1H),6.48(s,1H),3.92(s,3H),2.59(s,3H),2.38(s,3H).13C NMR(125MHz,CDCl3)δ193.7,165.0,161.8,159.7,148.6,140.4,136.0,135.6,129.1,128.7,127.8,122.7,122.2,112.3,104.6,55.9,52.9,29.2,14.6.IRνmax(film,cm-1)2924,1732,1670,1597,1537,1405,1257,1106,954,756,701,634.HRMS(ESI)calcd.for C21H19NNaO5[M+Na]+:388.1155,found:388.1163.
实施例15：
向干燥的反应管中加入Rh2(S-TFPTTL)4(1.6mg,0.001mmol)，1c(12.3mg,0.1mmol)，2a(23.3mg,0.11mmol)和分子筛(20.0mg)，之后反应管抽真空后充氩气(该操作重复三次)，反应管冷却到0℃，加入环戊烷和乙醚混合溶剂(1:1,2mL)，反应在0℃搅拌72h。反应液减压蒸干，残余物使用柱色谱纯化(硅胶，淋洗剂：EtOAc/PE＝1:10-1:5)得到淡黄色油状产物(15.4mg,46％yield)；HPLC检测：92％ee；HPLC条件：Daicel Chiralpak IDcolumn,n-hexane/i-PrOH＝60/40,flow rate 1.0mL/min,λ＝254nm,tR＝14.86min(major)and 22.56min(minor).[α]D 28:-8.0(c＝0.1,CHCl3；92％ee).1H NMR(300MHz,CDCl3)δ9.54(s,1H),7.89-7.81(m,2H),7.47-7.39(m,3H),7.37(s,1H),7.25-7.19(m,2H),6.68(d,J＝9.2Hz,1H),6.53(s,1H),2.61(s,3H),2.39(s,3H).13C NMR(75MHz,CDCl3)δ193.5,186.2,161.9,160.0,147.8,144.4,135.7,135.5,129.3,129.1,127.8,122.3,121.1,118.5,112.9,56.4,29.2,14.7.IRνmax(film,cm-1)2956,2921,2851,1659,1541,1442,1400,1226,1121,959,833,698,628.HRMS(ESI)calcd.for C20H17NNaO4[M+Na]+:358.1050,found:358.1048.
实施例16：
向干燥的反应管中加入Rh2(S-TFPTTL)4(1.6mg,0.001mmol)，1d(13.0mg,0.1mmol)，2a(23.3mg,0.11mmol)和分子筛(20.0mg)，之后反应管抽真空后充氩气(该操作重复三次)，反应管冷却到0℃，加入环戊烷和乙醚混合溶剂(1:1,2mL)，反应在0℃搅拌72h。反应液减压蒸干，残余物使用柱色谱纯化(硅胶，淋洗剂：EtOAc/PE＝1:10-1:4)得到淡黄色油状产物(17.4mg,51％yield)；HPLC检测：82％ee；HPLC条件：Daicel Chiralpak IDcolumn,n-hexane/i-PrOH＝80/20,flow rate 1.0mL/min,λ＝254nm,tR＝16.50min(major)and 24.79min(minor).[α]D 28:-31.0(c＝0.1,CHCl3；82％ee).1H NMR(500MHz,CDCl3)δ7.51-7.48(m,2H),7.43-7.38(m,3H),7.27(s,1H),7.17(d,J＝9.7Hz,1H),6.94(d,J＝9.7Hz,1H),6.40(s,1H),2.57(s,3H),2.36(s,3H).13C NMR(125MHz,CDCl3)δ194.0,159.0,158.5,149.1,137.8,135.5,133.8,131.9,128.9,128.8,128.7,122.2,111.8,58.4,29.2,14.6.IRνmax(film,cm-1)2922,1675,1584,1565,1508,1398,1229,1132,948,836,699,634.HRMS(ESI)calcd.for C18H15ClN2NaO3[M+Na]+:365.0663,found:365.0670；[M+Na]+:367.0634,found:367.0646.
Claims (5)
1.一种呋喃卡宾化学选择性和对映选择性插入2-吡啶酮或3-哒嗪酮的N-H键的方法，其特征在于，所述方法为：向干燥的反应管中加入手性铑催化剂、2-吡啶酮或3-哒嗪酮和烯炔酮，在氩气保护下加入溶剂，搅拌反应得到手性2-吡啶酮或3-哒嗪酮的N-呋喃烷基化衍生物；
所述手性铑催化剂为：
得到的2-吡啶酮或3-哒嗪酮的N-呋喃烷基化衍生物的结构如下式所示：
其中：
R1为Ph，4-MeC6H4，4-MeOC6H4，4-ClC6H4，4-FC6H4，4-EtO2CC6H4，3-FC6H4，3-MeC6H4，3-MeOC6H4，2-FC6H4，3,4-Me2C6H3，3,5-Me2C6H3，2-萘基，3-噻吩基，甲基，环丙基；
R2为乙酰基，丙酰基，异丁酰基，苯甲酰基，CO2Me，CO2Et；
R3为Me，Et，iPr，Ph，环丙基；
R为3-Cl，3-Me，4-Me，4-Br，4-MeO2C，4-BnO，5-Me，5-F，5-Br，5-I，5-CF3，5-MeO2C，5-CHO；
X＝CH或N。
2.根据权利要求1所述的呋喃卡宾化学选择性和对映选择性插入2-吡啶酮或3-哒嗪酮N-H键的方法，其特征在于，所述手性铑催化剂、2-吡啶酮或3-哒嗪酮和烯炔酮的摩尔比为：
0.005～0.025:1:1～1.5。
3.根据权利要求1所述的呋喃卡宾化学选择性和对映选择性插入2-吡啶酮或3-哒嗪酮N-H键的方法，其特征在于，所述溶剂为：乙醚，二氯甲烷，二氯乙烷，氯仿，四氯化碳，甲苯，三氟甲苯，氯苯，甲基环己烷，环己烷，环戊烷，正己烷，甲基叔丁基醚，环戊烷与乙醚混合溶剂或环戊烷与甲基叔丁基醚混合溶剂。
4.根据权利要求1所述的呋喃卡宾化学选择性和对映选择性插入2-吡啶酮或3-哒嗪酮N-H键的方法，其特征在于，所述反应温度为：-20～40℃，反应时间为12-72h。
5.根据权利要求1所述的呋喃卡宾化学选择性和对映选择性插入2-吡啶酮或3-哒嗪酮N-H键的方法，其特征在于，所述反应还包括添加剂，添加剂为分子筛、分子筛、分子筛，其添加量为20mg/0.1mmol。
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