Enantioselective Prins-type cyclizations via small molecule H-bonding catalysis

 描述(由申请人提供)：富含SP3的立体化学分子是治疗多种人类疾病的特殊化学支架，通常具有强大和特定的生物活性。然而，由于这些类型的分子通常很难制备和修饰，它们在化合物库中的药物开发中一直没有得到充分利用。因此，开发新的合成方法来以通用、高效和立体控制的方式获得这些结构是至关重要的。这项研究建议的中心假设是，使用小分子手性硫脲的氢键给体催化是制备高对映体富集型分子的一般策略，它避免了潜在的有毒过渡金属和Lewis酸，并消除了对底物中能够与手性催化剂共价相互作用的官能团的要求。相反，这些催化剂通过利用氢键和其他非共价相互作用来模拟酶的活性部位，从而实现高效和选择性的转化，而不需要更大的酶结构。具体地说，这一假设将在第一个具有高度对映选择性的Prins环化反应的开发中得到验证。这些反应包括直链烯醇(或烯胺)和醛的酸催化缩合，然后环化氧碳正离子/亚胺中间体，是制备生物上普遍存在的含氧和含氮脂肪杂环的一种非常通用的合成策略，但使用传统的不对称方法尚未成功地实现对映体选择性。拟议的研究将采用合作催化方法，探索具有能够参与的功能的手性硫脲催化剂。 在阳离子-π反应中，氧碳正离子/亚胺中间体与溴酸合在一起，其共轭碱有效地与硫脲结合，生成紧密结合的手性离子对，这对环化的立体化学结果起着重要的控制作用。随着Prins和aza-Prins对映体选择性方法的建立，本建议的目的是1)将Prins类对映体选择性环化应用于生物活性分子的合成，2)研究反应机理和模拟催化剂-底物相互作用，以阐明对映体诱导的起源。特别是，拟议研究的人工智能将侧重于引入药理作用部分，并最大限度地提高对映体选择性转化的普遍性和结构多样性。这些特定目标的成功实现将代表着重大的实践和概念上的进步，解决了一个重要的合成问题，并有助于氢键供体催化剂的实用和基础理解。此外，这种可行的合成方法将使含有生物活性的脂肪族杂环分子能够被有效地制备和修饰，以开发各种富含SP3的化合物文库，从而研究和改进现有的治疗方法，并发现治疗人类疾病的新方法。

 DESCRIPTION (provided by applicant): Stereochemically complex sp3-rich molecules represent privileged chemical scaffolds for the treatment of a broad range of human diseases, often with potent and specific biological activities. However, because these types of molecules are often challenging to prepare and modify, they have been underutilized in compound libraries for drug discovery. Therefore, the development of novel synthetic methods to access these structures in a general, efficient, and stereocontrolled manner is essential. The central hypothesis of this research proposal is that hydrogen bond donor catalysis using small molecule chiral thioureas is a general strategy for the preparation of highly enantioenriched molecules, which avoids potentially toxic transition metals and Lewis acids and obviates the requirement for functionality in the substrate that is capable of covalently interacting with a chiral catalyst. Instead, these catalysts mimic the active site of enzymes by utilizing hydrogen bonding and other non-covalent interactions to effect highly efficient and selective transformations without requiring the larger enzyme architecture. Specifically, this hypothesis will be tested in the development of the first highly enantioselective Prins-type cyclization reactions. These reactions, which involve the acid-catalyzed condensation of linear alkenols (or alkenylamines) and aldehydes followed by cyclization of an oxocarbenium/iminium intermediate, are a highly versatile synthetic strategy for the preparation of biologically prevalent oxygen- and nitrogen-containing aliphatic heterocycles, but have not been successfully rendered enantioselective using traditional asymmetric approaches. The proposed research will employ a cooperative catalysis approach by exploring chiral thiourea catalysts with functionality that is able to engage in cation-π interactions with the oxocarbenium/iminium intermediate in concert with Brønsted acid co-catalysts whose conjugate bases effectively bind to the thiourea to generate a tightly bound chiral ion pair that exerts significant control over the stereochemical outcome of the cyclization. With the establishment of a successful enantioselective method for the Prins and aza-Prins variants, this proposal will aim to 1) apply enantioselective Prins-type cyclizations to the synthesis of bioactive molecules, and 2) study the reaction mechanism and model catalyst-substrate interactions to elucidate the origin of enantioinduction. In particular, the synthetic ai of the proposed research will focus on introducing pharmacophoric moieties and maximizing the generality and structural diversity of the enantioselective transformations. The successful achievement of these specific aims would represent a significant practical and conceptual advance, solving an important synthetic problem and contributing to the utility and fundamental understanding of hydrogen bond donor catalysts. Moreover, this enabling synthetic method will allow biologically active aliphatic heterocycle-containing molecules to be prepared and modified efficiently for the development of diverse sp3-rich compound libraries in order to study and improve existing therapies and to discover new therapies for the treatment of human diseases.