Brønsted酸催化甲基二硅基酮乙酰酯与甲醇或水的不对称质子化反应

研究论文介绍

Brønsted酸催化甲基二硅基酮乙酰酯与甲醇或水的不对称质子化反应

2019/7/2
研究论文介绍
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羧酸（特别是手性α-取代羧酸）是合成化学中重要的中间体，且广泛存在于各种具有生物活性的化合物和药物中，因此该化合物的合成受到化学团体的广泛关注。但直接催化游离羧酸的不对称α-官能团化和α-烷基化反应存在较大的挑战，往往需要多个步骤才能合成该化合物。甲硅烷基烯醇醚和甲硅烷基乙烯酮缩醛的不对称质子化是合成α-取代羧酸较为常见的方法[1]，但这些反应中烯醇几何构型不易控制，且反应条件较苛刻，例如：反应温度需要低温、底物仅局限于空间位阻较大的质子源以及加入试剂要缓慢加入等(Figure 1)。到目前为止，还没有关于简单的质子源与二硅基酮乙酰酯的反应合成α-取代羧酸的报道。在上述研究背景的基础上，德国马克斯-普朗克研究所 Benjamin List课题组报道了消旋的α-支链羧酸发生两次去质子化作用生成的二硅基酮乙酰酯（bis-SKAs）再发生对映选择性质子化作用实现α-支链羧酸的去消旋化，其中质子源只需使用简单的水和甲醇。相关研究成果发表于

Deracemizing-Branched Carboxylic Acids by Catalytic Asymmetric Protonation of bis-Silyl Ketene Acetals with Water or Methanol

Francesca Mandrelli, Aurélie Blond, Thomas James, Hyejin Kim and Benjamin List•

Angew. Chem. Int. Ed. 2019, Just Accepted Manuscript DOI: 10.1002/anie.201905623

论文作者介绍

论文作者：Benjamin List

研究经历

1968, Born in Frankfurt/Germany
1993, Chemistry Diplom, Free University Berlin
1997, PhD, University Frankfurt (J. Mulzer)
1997–1998, Post-Doc, Scripps Research Institute, La Jolla, USA
1999–2003, Assistant Professor (Tenure Track), Scripps Research Institute, La Jolla, USA
2003–2005, Group Leader at the Max-Planck-Institut für Kohlenforschung
since 2004, Honorary Professor at the University of Cologne
since 2005, Scientific member of the Max-Planck-Society
since 2005, Director at the Max-Planck-Institut für Kohlenforschung
2012-2014, Managing Director at the Max-Planck-Institut für Kohlenforschung
since 2018, Member of The German National Academy of Sciences Leopoldina

奖励荣誉

1994, NaFöG-Award from the City of Berlin
1997, Feodor-Lynen Fellowship of the Alexander von Humboldt Foundation
2000, Synthesis-Synlett Journal Award
2003, Carl-Duisberg-Memorial Award of the German Chemical Society
2004, Degussa Prize for Chirality in Chemistry
2004, “Lecturer’s Award” of the Fonds der Chemischen Industrie
2004, Lieseberg-Price of the University of Heidelberg
2005, The Society of Synthetic Chemistry, Japan: 2005 Lectureship Award
2005, Visiting Professor at Gakushuin University, Tokyo/Japan
2005, AstraZeneca European Lecturer 2005
2005, Novartis Young Investigator Award
2006, Wiechert Lectureship, FU-Berlin, Germany
2006, JSPS Fellowship Award, Japan
2006, 100 Masterminds of Tomorrow, Germany
2007, Award of the Fonds der Chemischen Industrie
2007, OBC-Lecture Award
2007, AstraZeneca Award in Organic Chemistry
2008, Visiting Professor at Sungkyunkwan University, Korea
2009, Boehringer-Ingelheim Lectureship, Canada
2009, Organic Reactions Lectureship, USA
2009, Thomson Reuters Citation Laureate
2011, ERC Advanced Grant
2011, Boehringer-Ingelheim Lectureship, Harvard University, USA
2012, Novartis Chemistry Lectureship Award
2012, Otto-Bayer-Preis
2013, Horst-Pracejus-Preis
2013, Mukaiyama Award 2013
2013, Ruhrpreis, Mülheim, Germany
2014, Cope Scholar Award, USA
2014, Thomson Reuters Highly Cited Researcher
2015, Carl Shipp Marvel Lectures, University of Illinois at Urbana-Champaign, USA
2016, Gottfried Wilhelm Leibniz-Prize
2017, Ta-shue Chou Lectureship, Institute of Chemistry, Academia Sinica, Taipei, Taiwan
2017, Prof. U. R. Ghatak Endowment Lecture, Kolkata, India
2018, Member of the German National Academy of Science Leopoldina
2019, Herbert C. Brown Lecture, Purdue University, Indiana, USA

研究领域

Research Topics, Organocatalysis, Aminocatalysis, Brønsted Acid Catalysis, Organic Lewis Acid Catalysis, Asymmetric Couteranion Directed Catalysis (ACDC), Synthesis of Natural Products and Biologically Active Compounds.

论文概要

以α-苯基-α-甲基二硅基酮乙酰酯1a作为模板底物，作者对各种反应条件进行反复筛选，确定最佳条件为(Table 1)：1.1 equiv MeOH为质子源，2 mol％手性二磺酰亚胺2c为催化剂，DCM为溶剂，在室温条件下反应15 min后水解，能以73%的收率和91％的对映选择性得到相应产物3。

在最优反应条件下，作者对该反应的底物范围进行了考察(Table 2)。各种烷基取代（如乙基、苄基）、各种芳基取代的二硅基酮乙酰酯均能适应反应条件，能以良好至优秀的收率和优秀的对映选择性得到相应产物。但异丙基取代二硅基酮乙酰酯的对映选择性较差，说明该反应对空间位阻的影响较大。非甾体类抗炎药衍生的二硅基酮乙酰酯和α-烷基-α-烷基二硅基酮乙酰酯均具有良好的耐受性，能以良好至优秀的的收率和对映选择性得到相应产物。同时，用水作为质子源，各种底物也能较好的适应反应条件。