Kinetic resolution of chiral secondary alcohols by dehydrogenative coupling with recyclable silicon-stereogenic silanes
Kinetic resolution of chiral secondary alcohols by dehydrogenative coupling with recyclable silicon-stereogenic silanes
复制标题
DOI：
10.1002/anie.200502631
复制
发表时间：
2005-01-01
影响因子：
16.6
通讯作者：
Oestreich, M
中科院分区：
文献类型：
--
作者：
Rendler, S;Auer, G;Oestreich, M
外消旋混合物的非酶动力学拆分[1]是制备手性结构单元的不对称合成中的竞争策略。[2，3]一般方法依赖于手性试剂进行或手性催化剂促进一种对映异构体相对于另一种的立体选择性反应。在前一种情况的主题内，我们设计了一种新的概念，其基于硅-立体硅烷A和外消旋醇rac-B的前所未有的非对映选择性过渡金属催化的分解性硅-氧偶联（方案1）。[4]我们设想，如果A与（S）-B的优先反应产生非对映体富集的C是可行的，则光学对映体（R）-B将保持对映体富集的形式。此外，C中硅-氧键的立体特异性还原裂解将允许拆分试剂A的完全回收。重要的是，硅-氧键的形成和裂解都必须在硅原子上的立体化学信息没有任何侵蚀的情况下进行。在这里，我们描述了这种新的概念，利用siliconstereogenic硅烷A的动力学拆分反应。我们最初寻求硅烷醇解的合适反应条件，特别强调在硅原子上的立体化学过程。几种非均相和均相催化剂是可用的，[5，6]并且我们选择了由Lorenz和Schubert引入的铜（i）催化的双偶联。[7]氧敏感的[{（Ph 3 P）CuH} 6][8]被Buchwald及其同事[9]报道的稳健的预催化剂（CuCl、Ph 3 P、NaOtBu）有效地替代，这也使得膦配体能够简单变化。然后，我们在几种不对称取代的硅烷[10] 1-3（图1）的甲醇分解中筛选了这种催化剂，然后用铝进行立体保留还原。[11]令我们高兴的是，1-3总是在完全保留构型的情况下被回收，从而验证了在不对称取代的硅原子处铜（i）催化的分解性硅-氧偶联的立体特异性。[12]这些实验确保了在整个这两步过程中硅的立体化学完整性的关键保留。[13]然后我们讨论了特权硅烷（SiR）-1与外消旋醇的加成硅氧偶联反应的立体选择性。[14]选择的实验（rac-4！(SiS，S）-5，方案2）表明未官能化的仲醇基本上是无效的（dr 60：40）。这些令人沮丧的观察结果使我们考虑在基底中引入侧给体（Do）（Do= CH，4中，Do= N，6中），其为铜催化剂提供临时驻留位点。我们推断，能够两点结合的醇将在铜中心周围产生更多的刚性，这反过来可能有利于非对映选择性。与我们的假设一致，我们高兴地发现，外消旋-6和（SiR）-1的双偶联以显著改善的非对映选择性和增强的反应速率进行（外消旋-6！(SiS，S）-7，方案2）。在单齿和双齿膦和N-杂环卡宾配体的广泛筛选中鉴定了用于该转化的理想膦配体三（3，5-二甲苯基）膦（L1 f）（L1、L2和L3，表1）。研究了配体对rac-6双偶联反应速率和非对映选择性的影响
Non-enzymatic kinetic resolution [1] of racemic mixtures is a competitive strategy in asymmetric synthesis for the preparation of chiral building blocks.[2, 3] The general approach relies on either a chiral reagent to undergo or a chiral catalyst to promote a stereoselective reaction of one enantiomer over the other. Within the theme of the former scenario, we devised a novel concept based on an unprecedented diastereoselective transition-metal-catalyzed dehydrogenative silicon–oxygen coupling of silicon-stereogenic silanes A and racemic alcohols rac-B (Scheme 1).[4] We envisioned that if a preferential reaction of Awith (S)-B to produce diastereoenriched C were viable, the optical antipode (R)-B would remain in enantioenriched form. Moreover, stereospecific reductive cleavage of the silicon–oxygen bond in C would allow complete recovery of the resolving reagent A. Importantly, both silicon–oxygen bond formation and cleavage would have to proceed without any erosion of stereochemical information at the silicon atom. Herein, we describe this novel concept of utilizing siliconstereogenic silanes A in a kinetic resolution reaction. We initially sought suitable reaction conditions for silane alcoholysis with a particular emphasis on the stereochemical course at the silicon atom. Several heterogeneous and homogeneous catalysts are available,[5, 6] and we selected the copper (i)-catalyzed dehydrogenative coupling introduced by Lorenz and Schubert.[7] Oxygen-sensitive [{(Ph3P) CuH} 6][8] is effectively replaced by a robust precatalyst (CuCl, Ph3P, NaOtBu) reported by Buchwald and co-workers [9] which also enables simple variation of the phosphine ligand. We then screened this catalyst in the methanolysis of several asymmetrically substituted silanes [10] 1–3 (Figure 1) followed by stereoretentive reduction with aluminum hydrides.[11] To our delight, 1–3 were invariably recovered with complete retention of configuration, thereby verifying the stereospecificity of the copper (i)-catalyzed dehydrogenative silicon–oxygen coupling at the asymmetrically substituted silicon atom.[12] These experiments secured the pivotal preservation of the stereochemical integrity at silicon throughout this two-step process.[13] We then addressed the stereoselectivity of the dehydrogenative silicon–oxygen coupling of racemic alcohols with privileged silane (SiR)-1.[14] A selected experiment (rac-4!(SiS, S)-5, Scheme 2) showed that unfunctionalized secondary alcohols are essentially ineffective (dr 60: 40). These discouraging observations led us to consider the introduction of a pendant donor (Do) in the substrate (Do= CH in 4, Do= N in 6), which provides a temporary residence site for the copper catalyst. We reasoned that alcohols capable of twopoint binding would create more rigidity around the copper center, which in turn could be beneficial to diastereoselectivity. Consistent with our hypothesis, we were pleased to find that dehydrogenative coupling of rac-6 and (SiR)-1 proceeded with substantially improved diastereoselectivity and enhanced reaction rate (rac-6!(SiS, S)-7, Scheme 2). The ideal phosphine ligand for this transformation, tri (3, 5-xylyl) phosphane (L1 f), was identified in an extensive screening of mono-and bidentate phosphine and N-heterocyclic carbene ligands (L1, L2, and L3, Table1). We aimed to elucidate the influence of the ligand on the reaction rate and diastereoselectivity of the dehydrogenative coupling of rac-6