Convenient Titanium(III)-Catalyzed Synthesis of Cyclic Aminoketones and Pyrrolidinones-Development of a Formal [4+1] Cycloaddition
Convenient Titanium(III)-Catalyzed Synthesis of Cyclic Aminoketones and Pyrrolidinones-Development of a Formal [4+1] Cycloaddition
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DOI：
10.1002/anie.201302460
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发表时间：
2013-07-08
影响因子：
16.6
通讯作者：
Streuff, Jan
中科院分区：
文献类型：
--
作者：
Frey, Georg;Hieu-Trinh Luu;Streuff, Jan
george Frey, Hieu-Trinh Luu, Plamen Bichovski, Markus Feurer， and Jan Streuff* α-氨基羰基化合物是合成生物活性分子的重要组成部分因此，环α-胺化酮和相关的吡咯烷-3- 1单元是许多天然产物和候选药物的结构基序，因此非常需要一个方便的途径目前已有几种合成这些化合物的方法[3,4]，但当需要在胺化α-碳上进行完全取代时，构建这些分子的方法非常有限据我们所知，目前还没有直接制备α-氨基酮或吡咯烷酮的方法。在2006年，Oltra, Cuerva， Gansäuer和同事们报道了一种由二茂钛催化的羰基化合物在michael型加成物中的还原反应。[6-8] 2011年，我们建立了Michael受体交叉偶联产生1,4或1,6双官能化产物的原理这导致了酮和腈之间的对映选择性交叉偶联的发展，最近发表了tiiii催化的半动物杂交本文报道了这种钛催化还原混合策略的应用，通过在羰基碳和α-胺化碳之间直接构建CÀC键来合成氨基酮和吡罗烷酮构建块（方案1）。通过这种方式，两个基序都可以从相应的亚胺腈中获得，而亚胺腈可以通过标准缩合方案从商业上可用的或文献上已知的酮中轻松获得。重要的是，氯胺酮的形成和吡咯烷酮的还原反应是一种正式的[4+ 1]环加成反应，迄今为止报道的例子很少。[12,13]我们最初的想法是TiIII催化剂（由TiIV前驱体和锌金属生成）可以通过单电子转移到亚胺和随后氨基甲基自由基对腈官能团的攻击来促进这种转变[Eq.(1)]。进一步减少和
Georg Frey, Hieu-Trinh Luu, Plamen Bichovski, Markus Feurer, and Jan Streuff* α-Aminated carbonyl compounds represent important building blocks for the synthesis of bioactive molecules.[1] Therefore, a convenient access to cyclic α-aminated ketones and the related pyrrolidin-3-one units, which are structural motifs in many natural products and pharmaceutical drug candidates, is highly desirable.[2] There are several established procedures for synthesizing these compounds,[3, 4] but when full substitution at the aminated α-carbon is required, the methods for constructing these molecules are very limited.[5] To our knowledge no straightforward method for the preparation of such α-aminoketones or pyrrolidin-3-ones has been published so far.In 2006, Oltra, Cuerva, Gansäuer, and co-workers reported a titanocene-catalyzed reductive umpolung of carbonyl compounds in a Michael-type addition.[6–8] In 2011 we established this principle for the cross-coupling of Michael acceptors to yield 1, 4-or 1, 6-difunctionalized products.[9] This led to the development of an enantioselective cross-coupling between ketones and nitriles [10] and more recently a TiIII-catalyzed umpolung of hemiaminals was published.[11] We herein report the application of this titanium-catalyzed reductive umpolung strategy in the synthesis of aminoketone and pyrrolidinone building blocks through the direct construction of the CÀC bond between the carbonyl carbon and the α-aminated carbon (Scheme 1). In this way, both motifs become available from the corresponding iminonitriles, which can be easily accessed from either commercially available or literature-known ketones by standard condensation protocols. Importantly, the sequence of ketimine formation followed by the reductive umpolung to the pyrrolidinone product represents a formal [4+ 1] cycloaddition, for which only few examples have been reported to date.[12, 13] Our initial idea was that a TiIII catalyst (generated from a TiIV precursor and zinc metal) could be capable of promoting this transformation by a single-electron transfer to an imine and subsequent attack of the aminomethyl radical to the nitrile functionality [Eq.(1)]. Further reduction and