CN113527173B - Heck串联反应合成吲哚萜类似物的方法 - Google Patents
Heck串联反应合成吲哚萜类似物的方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/083—Syntheses without formation of a Si-C bond
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Abstract
本发明公开了一种Heck/去芳构化串联反应合成吲哚萜类似物的方法，属于有机化学技术领域。以取代2‑萘酚和N‑取代苯基联烯胺为原料，在钯催化剂和手性亚磷酰胺配体存在下，通过Heck/去芳构化串联反应后得到吲哚萜类似物。该方法具有化学选择性和对映选择性好、收率高的优点，产物含有手性季碳中心。
Description
技术领域
本发明涉及Heck串联反应合成吲哚萜类似物的方法，属于有机化学中的不对称合成技术领域。
背景技术
吲哚萜类化合物是一类重要的天然产物，具有广泛的生物活性。目前，化学合成吲哚萜类化合物的策略主要有两大类：一是环萜化合物与吲哚的偶联策略。例如李昂采用手性原料与吲哚格氏试剂进行羰基加成得到中间体，再经分子内环化、脱保护得到天然产物xiamycin A(式a)；Sarpong通过吲哚锂试剂与手性化合物加成合成了天然产物xiamycin A(式b)；Dethe报道了环萜与吲哚偶联策略合成mycoleptodiscin A(式c)。
二是在合成环萜化合物上构筑吲哚环的策略。例如李昂以乙酸金合欢酯为原料，经金属铱催化的不对称环化、氧化等得到苯并倍半萜中间体，然后经羰基还原、氰基化、氨甲基化、N-H芳基化等步骤分子内构筑吲哚环，从而合成mycoleptodiscin A(式e)；高栓虎利用自开发分子内光致烯醇化/[4+2]环加成反应，以香紫苏内酯为原料，经开环、分子内环加成等步骤同样得到中间体，再根据文献方法构筑吲哚环合成mycoleptodiscin A(式f)。另外，indolototarol的合成中也属于该策略(式g)。
以Heck环化反应构筑吲哚骨架，以不对称去芳构化反应构筑手性环萜骨架，一步实现手性吲哚萜类骨架的构筑策略尚未见报道。
发明内容
为了解决上述技术问题，本发明首先提供了一种结构新型的吲哚萜类似物，结构如下：
其中，R选自Ts、Ns、4-tBu-C6H4SO2、4-MeO-C6H4SO2、3,5-Me2-C6H3SO2、2,4,6-Me3-C6H2SO2、C6H5SO2、Boc、Ac、Cbz；R1选自Me、Et、Bn、allyl；R2选自Me、Et、Bn、allyl、Ph、H、Br、Cl；R3选自MeO、OH、Ph、H；R4选自Me、H；R5选自Me、CF3、MeO、F、Cl、Br、CO2Me；
采用取代的2-萘酚1和N-苯基联烯胺2作为原料，在钯催化剂、手性亚磷酰胺配体和碱存在下，通过Heck/去芳构化串联反应，得到吲哚萜类似物3。该方法为吲哚萜类似物的合成提供了一种温和、简便、高效的途径。
本发明还提供了Heck串联反应合成吲哚萜类似物的方法，包括如下操作：以取代2-萘酚1和N-取代苯基联烯胺2为原料，在钯催化剂、手性亚磷酰胺配体和碱存在下，反应得到吲哚萜类似物3；反应方程式如下：
其中：R选自Ts、Ns、C6H5SO2、4-tBu-C6H4SO2、4-MeO-C6H4SO2、3,5-Me2-C6H3SO2、2,4,6-Me3-C6H2SO2、Boc、Ac、Cbz；R1选自Me、Et、Bn、allyl；R2选自Me、Et、Bn、allyl、Ph、H、Br、Cl；R3选自MeO、OH、Ph、H；R4选自Me、H；R5选自Me、CF3、MeO、F、Cl、Br、CO2Me；LG选自Cl、Br、I、OTf。
进一步地，在上述技术方案中，所述手性亚磷酰胺配体选自L1-L23，优选配体为L5、L7、L11、L12。配体对应结构如下：
进一步地，在上述技术方案中，钯催化剂选自[Pd(C3H5)Cl]2、Pd2(dba)3、Pd(OAc)2、Pd(PPh3)4、PdCl2，碱选自K2CO3、Cs2CO3、DIPEA、DBU、NaOH、KOH。
进一步地，在上述技术方案中，所述反应在溶剂中进行，溶剂选自1,2-二氯乙烷、二氯甲烷、氯仿、甲苯、乙醚、丙酮、THF、乙酸乙酯、乙腈、氯苯、二噁烷、二甲苯、三甲苯中的一种或多种。优选溶剂为甲苯。
进一步地，在上述技术方案中，取代2-萘酚1、N-取代苯基联烯胺2、钯催化剂、有机膦配体与碱摩尔比为1:1.2:0.01-0.05:0.01-0.1:1.5。
进一步地，在上述技术方案中，反应温度选自-20℃至25℃。优选温度为0℃。
进一步地，在上述技术方案中，整个反应过程需要惰性气体保护下操作，惰性气体优选氮气。
进一步地，得到吲哚萜类似物3可以进一步衍生以得到不同类型的衍生产物，采用还原剂进行还原，通过控制不同的反应温度得到具有烯丙醇5，烯丙基叔醇6，烯丙基叔醇7，环己酮8和环己醇9。
例如：产物5的转化采用硼氢化钠和甲醇，产物6的转化采用甲基格氏试剂和四氢呋喃，产物7的转化采用TMSCH2Li和四氢呋喃。产物8和9的转化采用Pd/C催化剂、氢气和甲醇。化合物5-9结构如下：
进一步地，在上述技术方案中，采用硼氢化钠和甲醇进行羰基还原生成化合物5，采用Pd/C还原生成化合物8和化合物9均选自20-25℃，采用甲基格氏试剂加成生成化合物6和采用TMSCH2Li试剂转变生成化合物7均选自0℃。
发明有益效果：
1、本发明以取代2-萘酚1和N-苯基联烯胺2为原料，通过Heck/去芳构化串联反应后，一步即可得到吲哚萜类似物3，同时具有手性季碳中心，结构新颖，未见公开资料报道。
2、反应原料易得，产物对映选择性高，反应收率和对映选择性最高分别可达92％和>99％ee。产物经过还原后衍生，得到不同类型吲哚萜类似物5-9。
附图说明
图1为实施例1中化合物3aa单晶X衍射谱图；
图2为实施例6中化合物3ga单晶X衍射谱图。
具体实施方式
实施例1
以1,3-二甲基-2-萘酚1a和N-2-碘苯基-N-Ts-联烯胺2a生成3aa为例，进行反应条件优化，反应方程式如下：
a除非特别说明，反应的步骤如下：1a(0.1mmol),2a(0.12mmol),[Pd(C3H5)Cl]2(xmol％),配体(y mol％),碱(1.5equiv),1.0mL溶剂,在N2保护下T℃反应12小时。b分离收率，c手性高效液相色谱法测定。d重结晶后分离得到的3aa产率和ee值。
在反应条件筛选过程中，首先考察了配体对反应的影响(entries1-5)。同时考察了不同溶剂、反应温度(-20℃至+25℃)、配体L、钯催化剂比例和不同的碱(如碳酸钾、碳酸铯等)对反应的影响，最终确定了L5为最佳催化剂，甲苯为最佳反应溶剂，0℃为最佳反应温度。
反应条件考察操作(以entry 18为例)：将1,3-二甲基-β-萘酚1a(0.1mmol)、N-2-碘苯基-N-Ts-烯丙胺2a(0.11mmol)和Cs2CO3(48.9mg,0.15mmol)加入到装有磁力搅拌烘干Schlenk管中。螺纹胶塞密封，抽真空，回注氮气(重复3次)。然后用注射器在0℃下注入[Pd(C3H5)Cl]2和L5([Pd(C3H5)Cl]2/L5＝1:1)/甲苯(1.0mL 0.001M溶液，1mol％)溶液。配合物在0℃搅拌12h，TLC监测反应完成。二氯甲烷(约5mL)稀释反应混合物，短硅胶柱过滤，CH2Cl2/MeOH(20/1,20mL)洗涤。滤液经真空浓缩得到粗产物，再经制备薄层色谱纯化(洗脱液:石油醚/乙酸乙酯＝8/1)得到橘黄色固体产物3aa,收率89％,93％ee.[ɑ]D 23.4＝-56.00(c 0.100,CHCl3,92％ee).[ɑ]D 26.1＝-63.19(c 0.115,CHCl3,>99％ee).m.p.181.7-183.9℃.HPLC CHIRALCEL OD-H,n-hexane/2-propan ol＝90/10,flow rate＝0.6mL/min,λ＝256nm,retention time:19.503min(major),22.840min(minor).TLC:Rf＝0.35(petroleumether/ethyl acetate＝5:1).1H NMR(400MHz,CDCl3)δ7.86-7.77(m,1H),7.49-7.44(m,2H),7.41(dd,J＝8.0,1.6Hz,1H),7.35(td,J＝8.0,1.6Hz,1H),7.27(td,J＝7.2,1.6Hz,1H),7.21-7.13(m,4H),7.13-7.06(m,2H),6.89(d,J＝0.8Hz,1H),6.48(s,1H),3.49(d,J＝14.4Hz,1H),3.07(d,J＝14.4Hz,1H),2.34(s,3H),1.68(d,J＝1.2Hz,3H),1.61(s,3H).13CNMR(100MHz,CDCl3)δ203.7,145.0,144.7,141.7,135.4,134.5,132.9,131.1,130.6,129.8,129.1,128.7,127.1,126.7,126.6,124.5,124.0,123.0,119.8,118.3,113.3,51.6,38.7,27.2,21.7,15.89.HRMS(ESI):calcd for C28H25NNaO3S(M+Na)+requires m/z478.1447,found m/z 478.1446.
实施例2：
氮气保护下，在配有磁子Schlenk管，依次加入1-甲基-3-乙基-β-萘酚(0.1mmol)、N-2-碘苯基-N-Ts-联烯胺(0.11mmol)、[Pd(C3H5)Cl]2(1mol％)、L5(1mol％)和Cs2CO3(0.15mmol)，橡胶塞密封。注射器将1.0mL干燥甲苯打入反应管中。将反应管放在0℃，搅拌过夜。反应液快速通过短硅胶柱，二氯甲烷/甲醇＝15/1洗脱，溶液经真空浓缩后，得到粗品。接着硅胶柱色谱纯化，得到黄色固体3ba，收率91％,93％ee。1H NMR(600MHz,CDCl3)δ7.81(d,J＝7.8,1H),7.49-7.44(m,2H),7.41(d,J＝7.2Hz,1H),7.34(td,J＝7.2,1.2Hz,1H),7.29(td,J＝7.8,1.8Hz,1H),7.22(d,J＝7.8Hz,1H),7.20-7.13(m,4H),7.12-7.07(m,1H),6.87(s,1H),6.45(s,1H),3.50(d,J＝14.3Hz,1H),3.07(d,J＝14.3Hz,1H),2.34(s,3H),2.20-2.12(m,1H),2.10-2.02(m,1H),1.59(s,3H),0.75(t,J＝7.2Hz,3H).13C NMR(150MHz,CDCl3)δ203.0,144.7,144.6,140.0,138.1,135.3,134.4,131.0,130.6,129.6,129.0,128.7,127.0,126.7,126.5,124.3,123.8,122.9,119.8,118.2,113.2,51.5,38.2,27.2,22.0,21.6,12.1.HRMS(ESI):calcd for C29H27N NaO3S[M+Na]+requires m/z492.1604,found m/z 492.1598.
实施例3：
氮气保护下，在配有磁子Schlenk管，依次加入1-甲基-3-烯丙基-β-萘酚(0.1mmol)、N-2-碘苯基-N-Ts-联烯胺(0.11mmol)、[Pd(C3H5)Cl]2(1mol％)、L5(1mol％)和Cs2CO3(0.15mmol，1.5当量)，橡胶塞密封。注射器将1.0mL干燥的甲苯打入反应管中。将反应管放在0℃，搅拌过夜。反应液快速通过短硅胶柱，二氯甲烷/甲醇＝15/1洗脱，溶液经真空浓缩后，得到粗品。接着硅胶柱色谱纯化，得到黄色油状物3ca，收率91％,92％ee。1H NMR(400MHz,CDCl3)δ7.82(d,J＝8.0Hz,1H),7.51-7.45(m,2H),7.43(d,J＝7.6Hz,1H),7.37(td,J＝7.2,1.2Hz,1H),7.30(td,J＝7.6,1.6Hz,1H),7.25-7.17(m,2H),7.18-7.12(m,3H),7.10(td,J＝7.6,1.1Hz,1H),6.82(s,1H),6.43(s,1H),5.55-5.20(m,1H),4.95-4.72(m,2H),3.49(d,J＝14.0Hz,1H),3.07(d,J＝14.4Hz,1H),2.98-2.79(m,1H),2.82-2.64(m,1H),2.34(s,3H),1.62(s,3H).13C NMR(100MHz,CDCl3)δ202.8,144.9,144.7,141.5,135.4,135.0,134.9,134.5,131.0,130.5,129.8,129.3,129.0,127.2,126.8,126.7,124.5,124.0,123.0,119.9,118.0,117.0,113.3,51.8,38.8,33.0,26.9,21.7.HRMS(ESI):calcdfor C30H27NNaO3S[M+Na]+requires m/z 504.1604,found m/z 504.1601.
实施例4：
氮气保护下，在配有磁子Schlenk管，依次加入1-甲基-3-苯基-β-萘酚(0.1mmol)、N-2-碘苯基-N-Ts-联烯胺(0.11mmol)、[Pd(C3H5)Cl]2(1mol％)、L5(1mol％)和Cs2CO3(0.15mmol)，橡胶塞密封。注射器将1.0mL干燥甲苯打入反应管中。将反应管放在0℃，搅拌过夜。反应液快速通过短硅胶柱，二氯甲烷/甲醇＝15/1洗脱，溶液经真空浓缩后，得到粗品。接着硅胶柱色谱纯化，得到黄色油状物3da，收率81％,90％ee。1H NMR(600MHz,CDCl3)δ7.85(d,J＝8.4Hz,1H),7.50-7.40(m,4H),7.35(td,J＝7.4,1.3Hz,1H),7.27-7.23(m,5H),7.21-7.16(m,1H),7.10-7.04(m,2H),7.03-6.97(m,4H),6.49(s,1H),3.58(d,J＝13.8Hz,1H),3.15(d,J＝14.4Hz,1H),2.26(s,3H),1.69(s,3H).13C NMR(150MHz,CDCl3)δ201.5,145.2,144.6,142.7,135.7,135.6,135.3,134.5,131.0,130.4,129.8,129.63,129.59,128.6,127.9,127.8,127.3,126.8,126.5,124.5,123.8,123.0,119.8,118.1,113.3,52.3,38.5,29.7,27.0,21.5；HRMS(ESI):calcd for C33H27NNa O3S[M+Na]+requires m/z540.1604,found m/z 540.1598.
实施例5：
氮气保护下，在配有磁子Schlenk管，依次加入1-甲基-3-苄基-β-萘酚(0.1mmol)、N-2-碘苯基-N-Ts-联烯胺(0.11mmol)、[Pd(C3H5)Cl]2(1mol％)、L5(1mol％)和Cs2CO3(0.15mmol)，橡胶塞密封。注射器将1.0mL干燥甲苯打入反应管中。将反应管放在0℃，搅拌过夜。反应液快速通过短硅胶柱，二氯甲烷/甲醇＝15/1洗脱，溶液经真空浓缩后，得到粗品。接着硅胶柱色谱纯化，得到黄色油状物3ea，收率62％,85％ee。1H NMR(600MHz,CDCl3)δ7.86(d,J＝8.2Hz,1H),7.46-7.39(m,3H),7.36(td,J＝7.6,1.4Hz,1H),7.29(d,J＝7.9Hz,1H),7.26-7.22(m,2H),7.16-7.09(m,4H),7.05(d,J＝8.1Hz,2H),6.93(dd,J＝7.8Hz,1H),6.66-6.60(m,2H),6.44(s,1H),6.37(s,1H),3.50(d,J＝14.4Hz,1H),3.45(d,J＝16.2Hz,1H),3.27(d,J＝16.8Hz,1H),3.05(d,J＝13.8Hz,1H),2.28(s,3H),1.65(s,3H).13C NMR(150MHz,CDCl3)δ202.8,144.7,144.5,141.8,138.6,136.5,135.4,134.4,130.5,129.6,129.3,129.2,128.9,128.4,127.0,126.6,126.5,126.0,124.5,124.0,123.0,119.8,117.6,113.2,51.8,39.3,34.8,26.4,21.6；HRMS(ESI):calcd for C34H29NNaO3S[M+Na]+requires m/z 554.1760,found m/z 554.1755.
实施例6：
氮气保护下，在配有磁子Schlenk管，依次加入1-甲基-3-氯-β-萘酚(0.1mmol)、N-2-碘苯基-N-Ts-联烯胺(0.11mmol)、[Pd(C3H5)Cl]2(1mol％)、L5(1mol％)和Cs2CO3(0.15mmol)，橡胶塞密封。注射器将1.0mL干燥甲苯打入反应管中。将反应管放在0℃，搅拌过夜。反应液快速通过短硅胶柱，二氯甲烷/甲醇＝15/1洗脱，溶液经真空浓缩后，得到粗品。接着硅胶柱色谱纯化，得到黄色固体3ga，收率82％,24％ee。1H NMR(600MHz,CDCl3)δ7.83(d,J＝7.8Hz,1H),7.51(d,J＝8.4Hz,2H),7.48-7.39(m,2H),7.31(td,J＝7.8,1.8Hz,1H),7.27(s,1H),7.22-7.15(m,3H),7.15-7.06(m,3H),6.56(s,1H),3.53(d,J＝14.4Hz,1H),3.14(d,J＝13.8Hz,1H),2.35(s,3H),1.68(s,3H).13C NMR(150MHz,CDCl3)δ196.4,144.8,144.5,142.5,135.4,134.5,130.8,130.4,130.2,129.9,129.5,129.3,127.7,127.1,124.7,124.3,123.2,119.8,117.6,113.4,54.1,39.1,27.3,21.7.HRMS(ESI):calcdfor C27H22ClNNaO3S[M+Na]+requires m/z 498.0901,found m/z 498.0901.
实施例7：
氮气保护下，在配有磁子Schlenk管，依次加入1-甲基-β-萘酚(0.1mmol)、N-2-碘苯基-N-Ts-联烯胺(0.11mmol)、[Pd(C3H5)Cl]2(1mol％)、L5(1mol％)和Cs2CO3(0.15mmol)，橡胶塞密封。注射器将1.0mL干燥甲苯打入反应管中。将反应管放在0℃，搅拌过夜。反应液快速通过短硅胶柱，二氯甲烷/甲醇＝15/1洗脱，溶液经真空浓缩后，得到粗产品。接着硅胶柱色谱纯化，得到黄色固体3fa，收率79％,82％ee。1H NMR(400MHz,CDCl3)δ7.81(d,J＝8.0Hz,1H),7.49-7.36(m,4H),7.31(td,J＝7.6,1.6Hz,1H),7.24-7.05(m,7H),6.55(s,1H),5.92(d,J＝9.6Hz,1H),3.52(d,J＝14.0,1H),3.12(d,J＝14.4,1H),2.33(s,3H),1.61(s,3H).13C NMR(150MHz,CDCl3)δ203.5,145.5,144.9,144.6,135.2,134.4,130.1,129.9,129.7,129.5,127.1,126.9,126.7,125.4,124.4,124.2,123.0,119.7,118.2,113.3,51.9,37.8,27.2,21.6.HRMS(ESI):calcd for C27H23NNaO3S[M+Na]+requires m/z 464.1291,found m/z 464.1289.
实施例8：
氮气保护下，在配有磁子Schlenk管，依次加入1,5-二甲基-6-甲氧基-β-萘酚(0.1mmol)、N-2-碘苯基-N-Ts-联烯胺(0.11mmol)、[Pd(C3H5)Cl]2(1mol％)、L5(1mol％)和Cs2CO3(0.15mmol)，橡胶塞密封。注射器将1.0mL干燥甲苯打入反应管中。将反应管放在0℃，搅拌过夜。反应液快速通过短硅胶柱，二氯甲烷/甲醇＝15/1洗脱，溶液经真空浓缩后，得到粗产品。接着硅胶柱色谱纯化，得到42.9mg黄色油状物3ka，收率86％,91％ee。1H NMR(600MHz,CDCl3)δ7.81(d,J＝8.4Hz,1H),7.56(d,J＝10.2Hz,1H),7.46(d,J＝8.4Hz,2H),7.24-7.15(m,3H),7.15-7.06(m,3H),6.87(d,J＝8.4Hz,1H),6.65(s,1H),5.99(d,J＝10.2Hz,1H),3.85(s,3H),3.50(d,J＝14.4Hz,1H),3.10(d,J＝14.4Hz,1H),2.32(s,3H),2.26(s,3H),1.55(s,3H).13C NMR(151MHz,CDCl3)δ203.9,156.4,144.6,141.1,137.7,135.3,134.6,131.3,129.7,129.0,126.7,125.3,125.2,124.9,124.4,124.4,123.0,119.9,118.7,113.4,112.0,55.9,51.6,37.6,28.0,21.7,10.8.HRMS(ESI):calcd forC29H27N NaO4S[M+Na]+requires m/z 508.1553,found m/z 508.1547.
实施例9：
氮气保护下，在配有磁子Schlenk管，依次加入1,3-二甲基-β-萘酚(0.1mmol)、N-2-碘苯基-N-苯磺酰基联烯胺(0.11mmol)、[Pd(C3H5)Cl]2(1mol％)、L5(1mol％)和Cs2CO3(0.15mmol)，橡胶塞密封。注射器将1.0mL干燥甲苯打入反应管中。将反应管放在0℃搅拌过夜。反应液快速通过短硅胶柱，二氯甲烷/甲醇＝15/1洗脱，溶液经真空浓缩后，得到粗品。接着硅胶柱色谱纯化，得到黄色油状物3ab，收率88％,92％ee。1H NMR(400MHz,CDCl3)δ7.84(d,J＝8.4Hz,1H),7.61-7.55(m,2H),7.54-7.47(m,1H),7.44-7.32(m,4H),7.27(td,J＝7.4,1.2Hz,1H),7.23-7.16(m,2H),7.14-7.06(m,2H),6.86(s,1H),6.48(s,1H),3.50(d,J＝14.0Hz,1H),3.07(d,J＝14.0Hz,1H),1.66(d,J＝1.2Hz,3H),1.61(s,3H).13C NMR(100MHz,CDCl3)δ203.6,144.9,141.6,138.4,134.5,133.6,132.9,131.0,130.6,129.2,129.1,128.7,127.1,126.6,124.6,123.9,123.1,119.9,118.5,113.3,51.5,38.7,27.2,15.9.HRMS(ESI):calcd for C27H23KNO3S[M+K]+requires m/z 480.1030,found m/z480.1033.
实施例10：
氮气保护下，在配有磁子Schlenk管，依次加入1,3-二甲基-β-萘酚(0.1mmol)、N-2-碘苯基-N-1-萘磺酰基联烯胺(0.11mmol)、[Pd(C3H5)Cl]2(1mol％)、L5(1mol％)和Cs2CO3(0.15mmol)，胶塞密封。注射器将1.0mL干燥甲苯打入反应管中。将反应管放在0℃，搅拌过夜。反应液快速通过短硅胶柱，二氯甲烷/甲醇＝15/1洗脱，溶液经真空浓缩后，得到粗品。接着硅胶柱色谱纯化，得到黄色固体3ah，收率90％,91％ee。1H NMR(400MHz,CDCl3)δ8.47-8.38(m,1H),8.02(d,J＝8.4Hz,1H),7.92-7.84(m,1H),7.82-7.72(m,2H),7.59-7.49(m,2H),7.42(t,J＝7.6Hz,1H),7.35(d,J＝7.6,1H),7.29-7.05(m,5H),6.82(dd,J＝7.6,1.6Hz,1H),6.65(s,1H),6.52(s,1H),3.47(d,J＝14.0Hz,1H),3.04(d,J＝14.0Hz,1H),1.60(d,J＝1.2Hz,3H),1.59(s,3H).13C NMR(100MHz,CDCl3)δ203.7,144.8,141.6,135.2,134.8,134.6,134.3,132.8,130.5,130.4,129.1,128.9,128.74,128.72,128.5,128.3,127.3,127.0,126.5,124.5,124.2,124.1,123.9,122.9,119.9,117.5,113.2,51.5,38.9,26.6,15.8.HRMS(ESI):calcd for C31H25NNa O3S[M+Na]+requires m/z 514.1447,foundm/z 514.1452.
实施例11：
氮气保护下，在配有磁子Schlenk管，依次加入1,3-二甲基-β-萘酚(0.1mmol)、N-2-碘苯基-N-Cbz-联烯胺(0.11mmol)、[Pd(C3H5)Cl]2(1mol％)、L5(1mol％)和Cs2CO3(0.15mmol)，胶塞密封。注射器将1.0mL干燥甲苯打入反应管中。将反应管放在0℃，搅拌过夜。反应液快速通过短硅胶柱，二氯甲烷/甲醇＝15/1洗脱，溶液经真空浓缩后，得到粗品。接着硅胶柱色谱纯化，得到黄色油状物3ak，收率50％,70％ee。1H NMR(600MHz,CDCl3)δ8.02(s,1H),7.46(d,J＝7.8Hz,1H),7.42-7.35(m,5H),7.33(td,J＝7.8,1.2Hz,1H),7.23-7.17(m,3H),7.14-7.04(m,2H),6.96(s,1H),6.58(s,1H),5.34(d,J＝12.0Hz,1H),5.28(d,J＝12.6Hz,1H),3.49(d,J＝14.4Hz,1H),3.09(d,J＝14.4Hz,1H),1.72(s,3H),1.64(s,3H).13CNMR(100MHz,CDCl3)δ203.8,145.1,141.6,135.2,132.8,130.7,130.6,128.8,128.7,128.6,128.5,128.2,126.9,126.6,124.3,123.2,122.6,119.3,117.0,114.7,68.3,51.6,39.0,26.6,15.7.HRMS(ESI):calcd for C29H25NNaO3[M+Na]+req uires m/z 458.1727,found m/z 458.1730.
实施例12：
在反应瓶中，加入3fa(44.1mg，0.1mmol)和MeOH(5mL)，完全溶解后，加入NaBH4(10mg，0.25mmol)，室温下搅拌反应。TLC监测反应完全，水和乙酸乙酯萃取，饱和食盐水洗，无水硫酸镁干燥，减压浓缩，柱色谱法纯化得到5(95％yield,96％ee)。1H NMR(400MHz,CDCl3)δ7.93(d,J＝8.4Hz,1H),7.72(d,J＝8.4Hz,2H),7.19-7.20(m,3H),7.17-7.03(m,4H),6.99(s,1H),6.88(td,J＝7.6,1.6Hz,1H),6.77(d,J＝7.6Hz,1H),6.48(dd,J＝9.6,1.6Hz,1H),5.96(dd,J＝9.6,3.2Hz,1H),4.43-4.31(m,1H),3.21(d,J＝13.6Hz,1H),3.03(d,J＝13.6Hz,1H),2.35(s,3H),1.24(s,3H).13C NMR(101MHz,CDCl3)δ144.8,140.7,135.5,132.6,132.4,131.0,129.8,128.3,127.5,127.2,127.1,127.0,126.3,125.6,124.2,122.9,119.9,119.5,113.6,74.0,43.6,29.9,26.9,22.7,21.7；HRMS calcd forC27H25NNaO3S(M+Na)+requires m/z 466.1447,found m/z 466.1455.
实施例13：
氮气保护下，在配有磁子Schlenk管，加入3fa(44.1mg,0.1m mol)和THF(1mL)。降温至0℃，加入CH3MgBr(0.3mmol)，反应2小时。采用碳酸氢钠水溶液淬灭，乙酸乙酯萃取，无水硫酸钠干燥，减压浓缩，柱色谱纯化得到6(90％yield,93％ee)。1H NMR(600MHz,CDCl3)δ7.87(d,J＝8.4Hz,1H),7.70-7.62(m,2H),7.21(d,J＝8.4Hz,2H),7.18-7.14(m,1H),7.08-7.01(m,2H),7.00-6.96(m,1H),6.85(d,J＝7.8Hz,1H),6.63(td,J＝7.8,1.8Hz,1H),6.55(s,1H),6.42(d,J＝9.6Hz,1H),6.34(d,J＝7.8Hz 1H),5.89(d,J＝9.6Hz,1H),3.28(d,J＝13.8Hz,1H),2.96(d,J＝13.8Hz,1H),2.34(s,3H),1.73(s,1H),1.26(s,3H),1.23(s,3H).13C NMR(150MHz,CDCl3)δ144.8,140.8,137.5,135.5,134.6,132.7,132.0,129.8,127.0,126.9,126.9,126.8,126.7,126.1,125.2,124.0,122.8,120.2,119.7,113.4,47.0,28.3,23.5,21.7,16.4.HRMS(ESI):calcd for C28H27 NNaO3 S(M+Na)+requires m/z 480.1604,found m/z 480.1614.
实施例14：
氮气保护下，在配有磁子Schlenk管，加入3fa(44.1mg,0.1m mol)和THF(1mL)。降温至0℃，加入三甲基硅甲基锂(0.3mmol)反应2小时。采用碳酸氢钠水溶液淬灭，乙酸乙酯萃取，无水硫酸钠干燥，减压浓缩，柱色谱纯化得到7(86％yield,95％ee)。1H NMR(400MHz,CDCl3)δ7.88(d,J＝8.0Hz,1H),7.68(d,J＝8.4Hz,2H),7.25-7.12(m,3H),7.11-6.95(m,3H),6.89(d,J＝8.0Hz,1H),6.66(td,J＝7.7,2.0Hz,1H),6.53(s,1H),6.42(d,J＝9.6Hz,1H),6.34(d,J＝7.6Hz,1H),6.01(d,J＝9.6Hz,1H),3.32(d,J＝13.6Hz,1H),2.93(d,J＝13.8Hz,1H),2.35(s,3H),1.70(s,1H),1.26(s,3H),1.03(s,2H),0.06(s,9H).13C NMR(101MHz,CDCl3)δ144.8,141.1,137.7,135.5,134.6,132.6,132.3,129.8,126.99,126.95,126.8,126.7,126.6,126.0,125.1,124.0,122.8,120.6,119.7,113.4,79.6,48.8,28.0,25.0,21.7,16.3,0.9；HRMS(ESI):calcd for C31H35NNaO3SSi(M+Na)+requires m/z552.1999,found m/z 552.1992.
实施例15：
在配有磁子Schlenk管中，加入3fa(0.44g，1mmol)和Pd/C(10mol％)，然后加入EtOH(20mL)。抽真空，置换3次后，在氢气氛围下(1atm)室温反应3小时。反应完成后，混合物硅藻土过滤，水和乙酸乙酯萃取分层。有机相饱和食盐水洗涤，无水硫酸镁干燥，减压浓缩，柱色谱纯化得到8(52％yield,96％ee)和9(39％yield,96％ee)。产品8:1H NMR(600MHz,CDCl3)δ7.86(d,J＝8.4Hz,1H),7.54(d,J＝7.8Hz,2H),7.36(d,J＝7.8Hz,1H),7.29(t,J＝7.8Hz,1H),7.22-7.14(m,4H),7.10-7.04(m,4H),6.99(d,J＝7.8Hz,1H),6.62(s,1H),3.49(d,J＝13.8Hz,1H),2.93(d,J＝13.8Hz,1H),2.68-2.56(m,1H),2.51-2.40(m,1H),2.33(s,3H),2.22-2.06(m,2H),1.57(s,3H).13C NMR(150MHz,CDCl3)δ214.4,144.8,141.4,136.5,135.4,134.5,131.2,129.8,128.1,127.2,126.8,125.0,124.5,123.1,120.0,118.8,113.4,52.6,38.5,36.4,27.8,27.3,21.7；HRMS calcd for C27H25NNaO3S[M+Na]+466.1447,found m/z 466.1448.产品9:1H NMR(600MHz,CDCl3)δ7.96(d,J＝8.4Hz,1H),7.70(d,J＝8.4Hz,2H),7.25-7.22(m,2H),7.20(d,J＝7.8Hz,2H),7.14-7.07(m,3H),7.05(s,1H),7.00-6.93(m,2H),3.80(dd,J＝9.0,3.6Hz,1H),3.10(d,J＝14.0Hz,1H),3.05(d,J＝14.0Hz,1H),2.97-2.80(m,2H),2.33(s,3H),1.95-1.80(m,2H),1.67(s,1H),1.30(s,3H).13C NMR(150MHz,CDCl3)δ144.8,142.1,135.5,135.0,134.9,132.6,129.8,129.0,127.5,126.9,126.2,125.9,125.5,124.3,123.0,120.2,119.8,113.7,73.9,42.7,31.3,26.8,26.7,26.6,21.7；HRMS(ESI):calcd for C27H27NNaO3S(M+Na)+requires m/z 468.1604,found m/z 468.1602.
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。
Claims (6)
1.Heck/去芳构化串联反应合成吲哚萜类似物3的方法，其特征在于，包括如下步骤：以取代2-萘酚1和N-取代苯基联烯胺2为原料，在[Pd(C3H5)Cl]2、手性亚磷酰胺配体和碱存在下，反应得到吲哚萜类似物3；
所述手性亚磷酰胺配体结构如下：
其中：R选自Ts、Ns、C6H5SO2、4-tBu-C6H4SO2、4-MeO-C6H4 SO2、3,5-Me2-C6H3SO2、2,4,6-Me3-C6H2SO2、Boc、Ac、Cbz；R1选自Me、Et、Bn、allyl；R2选自Me、Et、Bn、allyl、Ph、H、Br、Cl；R3选自MeO、OH、Ph、H；R4选自Me、H；R5选自Me、CF3、MeO、F、Cl、Br、CO2Me；LG选自Cl、Br、I、OTf。
2.根据权利要求1所述合成吲哚萜类似物3的方法，其特征在于：反应在溶剂中进行，反应溶剂选自1,2-二氯乙烷、二氯甲烷、氯仿、甲苯、乙醚、丙酮、THF、乙酸乙酯、乙腈、氯苯、二噁烷、二甲苯或三甲苯。
3.根据权利要求1所述合成吲哚萜类似物3的方法，其特征在于：碱选自K2CO3、Cs2CO3、DIPEA、DBU、NaOH或KOH。
4.根据权利要求1所述合成吲哚萜类似物3的方法，其特征在于：反应温度选自-20℃至25℃。
5.根据权利要求1所述合成吲哚萜类似物3的方法，其特征在于：整个反应过程在惰性气体保护下操作。
6.合成吲哚萜类似物5-9的方法，其特征在于，反应方程式为：
包括如下步骤：采用权利要求1-5所述方法得到吲哚萜类似物3，随后吲哚萜类似物3在硼氢化钠存在下，甲醇溶剂中，将羰基还原得到烯丙醇5；在甲基格氏试剂存在下，四氢呋喃溶剂中，将羰基加成为烯丙基叔醇6；在TMSCH2Li存在下，四氢呋喃溶剂中，将羰基转变为烯丙基叔醇7；在Pd/C催化剂存在下，乙醇溶剂中进行催化加氢还原反应，得到将双键还原环己酮8和将羰基及双键同时还原产物环己醇9。
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