基于动态动力学拆分的2-取代吲哚不对称氢化

过渡金属催化的不对称氢化反应是合成手性化合物的重要手段之一，过去几十年里学术界对其进行了深入探究，形成了一系列较为成熟的催化体系和广泛的底物范围。芳杂环不对称氢化已经发展成为一种制备手性杂环化合物简单而直接的方法。其中，吲哚的不对称氢化可以快速构建在天然产物或生理活性化合物中常见的手性吲哚啉骨架。然而，吲哚不对称氢化局限于2号位单取代或者2,，3号位二取代的吲哚，因此只能构建含环内手性中心的吲哚啉产物。此外，与吲哚N上有保护基的吲哚相比，NH吲哚的直接高对映选择性氢化仍然极具挑战，只有少数例子可以在2,,3-二取代的NH吲哚上同时实现对映和非对映选择性控制。

为了拓宽吲哚啉化合物化学空间，借助动态动力学拆分（DKR）策略，我们发展了一种新颖的Pd(CF₃CO₂)₂/双膦催化体系催化的消旋α-烷基和α-芳基取代的吲哚-2-乙酸酯直接不对称氢化，高效构筑同时含有环内和环外连续手性中心的吲哚啉化合物，突破了以往芳杂环不对称还原只能构筑环内手性中心的瓶颈。机理试验表明，酸添加剂能促进芳香性吲哚和无芳香性的环外烯胺中间体之间的快速互变异构，从而实现外消旋底物的对映异构体之间快速相互转化。此外，我们对反应获得高非对映选择性的原因进行了推测，主要是因为底物上酯基与吲哚NH之间可能存在分子内氢键，从而生成较为刚性的六元环过渡态，进而诱导非对映选择性。

该反应可以在克级规模上进行，且产物可以转化为非天然的β-氨基酸、γ-氨基醇和吲哚上二溴取代的溴化物，β-氨基酸可以进一步缩合生成Weinreb酰胺和新型多肽，γ-氨基醇可以进一步转化为γ-氨基碘化物，在有机合成或药物研发领域具有潜在用途。同时，该方法为其他芳香杂环通过DKR策略进行不对称转化构建环外手性中心提供了示范。

[1] (a) Knowles, W. S.; Sabacky, M. J.; Vineyard, B. D. Catalytic asymmetric hydrogenation. J. Chem. Soc. Chem. Commun. 1972,10–11.; (b) Knowles, W. S., Asymmetric Hydrogenations (Nobel Lecture). Angew. Chem. Int. Ed., 2002, 41, 1998-2007.）
[2] Pablo Etayo and Anton Vidal-Ferran. Rhodium-catalysed asymmetric hydrogenation as a valuable synthetic tool for the preparation of chiral drugs. Chem. Soc. Rev., 2013, 42, 728-754
[3] A. Fabrello, A. Bachelier, M. Urrutigo ̈ıty and P. Kalck, Coord. Chem. Rev., 2010, 254, 273.
[4] Duo-Sheng Wang, Qing-An Chen, Sheng-Mei Lu, and Yong-Gui Zhou. Asymmetric Hydrogenation of Heteroarenes and Arenes. Chem. Rev. 2012, 112, 2557–2590
[5] Bird,C. W.Tetrahedron 1992,48,335.
[6] Murata,S.;Sugimoto,T.;Matsuura,S. Heterocycles1987, 26, 763.
[7] Ohta, T.; Miyake, T.; Seido, N.; Kumobayashi, H.; Takaya, H.; J. Org. Chem. 1995, 60, 357.
[8] Fuchs,R.EuropeanPatentApplicationEP803502, 1997; Chem. Abstr. 1998, 128, 13286.
[9] Bianchini,C.; Barbaro, P.; Scapacci, G.; Farnetti, E.; Graziani,M. Organometallics 1998, 17, 3308.
[10] Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G. J. Am. Chem. Soc. 2003, 125, 10536.
[11] Ramachandran Gunasekar, Ross L. Goodyear, Ilaria Proietti Silvestri and Jianliang Xiao.; Recent developments in enantio- and diastereoselective hydrogenation of N-heteroaromatic compounds. Org. Biomol. Chem., 2022, 20, 1794
[12] Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am. Chem. Soc. 2000, 122, 7614.
[13] Lei Shi.; Zhi-Shi Ye.; Liang-Liang Cao.; Ran-Ning Guo.; Yue Hu.; Yong-Gui Zhou. Enantioselective Iridium-Catalyzed Hydrogenation of 3,4-Disubstituted Isoquinolines. Angew. Chem. Int. Ed. 2012, 51, 8286 –8289.
[14] (a) Ishikura, M.; Abe, T.; Choshi, T.; Hibino, S. Simple Indole Alkaloids and Those with a Non-Rearranged Monoterpenoid Unit. Nat. Prod. Rep. 2013, 30, 694−752. (b) Modern Alkaloids; Fattorusso, E., Taglialatela-Scafati, O., Eds.; Wiley-VCH: Weinheim, 2008. For recent reviews on indoline synthesis, see: (c) Hua, T.-B.; Xiao, C.; Yang, Q.-Q.; Chen, J.-R. Recent Advances in Asymmetric Synthesis of 2-Substituted Indoline Derivatives. Chin. Chem. Lett. 2020, 31, 311− 323. (d) Zhang, B.; Qin, W.; Duan, Y.; Yu, B.; Zhang, E.; Liu, H. Recent Development on the Synthetic Methods of Chiral Indoline Derivatives. Chin. J. Org. Chem. 2012, 32, 1359−1367. (e) Liu, D.; Zhao, G.; Xiang, L. Diverse Strategies for the Synthesis of the Indoline Scaffold. Eur. J. Org. Chem. 2010, 2010, 3975−3984.
[15] Kuwano,R.; Kashiwabara,M. Org.Lett.2006, 8, 2653.
[16] Baeza,A.; Pfaltz,A. Chem.-Eur.J. 2010,16,2036.
[17] Wang, D.-S.; Chen, Q.-A.; Li, W.; Yu, C.-B.; Zhou, Y.-G.; Zhang, X. J. Am. Chem. Soc. 2010, 132, 8909.
[18] Ying Duan.; Lu Li.; Mu-Wang Chen.; Chang-Bin Yu.; Hong-Jun Fan and Yong-Gui Zhou. Homogenous Pd-Catalyzed Asymmetric Hydrogenation of Unprotected Indoles: Scope and Mechanistic Studies. J. Am. Chem. Soc. 2014, 136,7688-7700.
[19] (a) Touge, T.; Arai, T. Asymmetric Hydrogenation of Unprotected Indoles Catalyzed by η6-Arene/N-Me-sulfonyldiamine- Ru(II) Complexes. J. Am. Chem. Soc. 2016, 138, 11299−11305. (b) Yang, Z.; Chen, F.; He, Y.; Yang, N.; Fan, Q.-H. Highly Enantioselective Synthesis of Indolines: Asymmetric Hydrogenation at Ambient Temperature and Pressure with Cationic Ruthenium Diamine Catalysts. Angew. Chem., Int. Ed. 2016, 55, 13863−13866.
[20] Liu, G.; Zheng, L.; Tian, K.; Wang, H.; Chung, L.; Zhang, X.; Dong, X.-Q. Ir-Catalyzed Asymmetric Hydrogenation of Unprotected Indoles: Scope Investigations and Mechanistic Studies. CCS Chem. 2023, 5, 1398−1410.
[21] Huerta, F. F.; Minidis, A. B. E.; Bäckvall, J. E. Racemization in asymmetric synthesis. Dynamic Kinetic Resolution and Related Processes in Enzyme and Metal Catalysis. Chem. Soc. Rev. 2001, 30, 321−331.
[22] E. J. Ebbers, G. J. A. Ariaans, J. P. M. Houbiers, A. Bruggink and B. Zwanenburg, Tetrahedron, 1997, 53, 9417.
[23] Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H. Stereoselective Hydrogenation via Dynamic Kinetic Resolution. J. Am. Chem. Soc. 1989, 111, 9134– 9135
[24] (a)Zhou, Z.-T.; Xie, J.-H.; Zhou, Q.-L. Enantioselective Synthesis of Chiral β-Aryloxy Alcohols by Asymmetric Hydrogenation of α-Aryloxy Aldehydes via Dynamic Kinetic Resolution Adv. Synth. Catal. 2009, 351, 363– 366. (b)Li, X.; List, B. Catalytic Asymmetric Hydrogenation of Aldehydes Chem. Commun. 2007, 1739– 1741
[25] Corbett M T, Johnson J S. Diametric stereocontrol in dynamic catalytic reduction of racemic acyl phosphonates: divergence from α-keto ester congeners[J]. J. Am. Chem. Soc. 2013, 135(2): 594-597.
[26] Tanyu Cheng, Qunqun Ye, Qiankun Zhao, and Guohua Liu. Dynamic Kinetic Resolution of Phthalides via Asymmetric TransferHydrogenation: A Strategy Constructs 1,3-Distereocentered 3 (2-Hydroxy-2-arylethyl)isobenzofuran-1(3H) one. Org. Lett. 2015, 17, 20, 4972–4975
[27] Ros, A.; Magriz, A.; Dietrich, H.; Ford, M.; Fernández, R.; Lassaletta, J. M. Adv. Synth. Catal. 2005, 347, 1917.
[28] Ming-Zhi Zhang , Qiong Chen , Guang-Fu Yang. A review on recent developments of indole-containing antiviral agents. European Journal of Medicinal Chemistry. 2015, 89, 421-441.
[29] Xu S.-M., Wei, L.; Shen, C.; Xiao, L.; Tao, H.-Y.; Wang, C.-J. Nat. Commun. 2019, 10, 5553.
[30] Betageri, R.; Beaulifu, P. L.; Llinas-Brunet, M.; Ferland, J. M.; Cardozo, M.; Patel, U.; Proudfoot, J. R. WO9931066 A1, 1999.

[31] Song, Z.; Wu Y.; Xin, T.; Jin, C.; Wen, X.; Sun, H.; Xu, Q.-L. Chem. Commun. 2016, 52, 6079-6082.

[32] Chan, W.-W.; Yeung, S.-H.; Zhou, Z.; Chan, A.S. C.; Yu, W.-Y. Ruthenium Catalyzed Directing Group-Free C2-Selective Carbenoid Functionalization of Indoles by α-Aryldiazoesters. Org. Lett. 2010, 12, 604-607.