Asymmetric Methods for the Synthesis of Pyran-Based Anticancer Natural Products

描述（由申请人提供）：手性吡喃基环系统（例如，四氢吡喃、二氢吡喃、4-乳醇和4-内酯）在自然界中普遍存在。这些亚结构存在于许多生物活性天然产物中，包括诸如FK- 506、discodermolide、palytoxin、bryostatins和spongistatins等众所周知的合成靶标。这些研究的总体目标是开发一种有效的一般策略，用于在许多生物相关的天然产物类别中发现的吡喃类功能的不对称合成，并将这些方法扩展到其他复杂聚酮化合物系统的有效合成。一种方法，涉及直接取代的手性助剂从不对称羟醛缩合反应的产物，使用各种碳亲核试剂，将被探索用于取代的吡喃酮衍生物的快速组装。这些方法与催化不对称氢化反应相结合，将直接用于快速合成药物acutiphycin。通过这种方法，我们将在九个或更少的步骤中准备以前需要十九个步骤。这些方法的范围将通过应用于海洋天然产物Tedanlavin C而进一步扩展，Tedanlavin C是最近公开的Tedanlavin家族的成员，其所有成员都表现出针对癌细胞系的纳摩尔细胞毒性。使用本文开发的方法，将快速制备该分子的结构上不同的C1-C12半。该片段与原始tedanolides的成功路线相交，因此可用于这类极其有效的天然产物的SAR研究。此外，该片段将形成替丹替尼C的大环内酯核心的简化模型的基础，该模型将用于验证仅基于NMR分析仍不确定的天然产物中的立体化学关系。最后，进行了一个新的海洋天然产物enigmazole A的不对称全合成。这种合成的关键再次将是基于硫酮的羟醛加合物的创造性官能化，沿着复杂二丙酸酯片段的脱氧，基于缩合的片段偶联和闭环复分解。总的来说，这些项目有可能对基于吡喃的天然产物合成方法学做出真正的贡献。 这项研究关注的是开发新的方法，这将允许有效制备抗癌化合物。三个天然产物，具有很大的药用价值，尖霉素，tedanasterone C，和enigmazole A，将使用这些方法进行研究。

DESCRIPTION (provided by applicant): Chiral pyran-based ring systems (e.g. tetrahydropyrans, dihydropyrans, 4-lactols, and 4-lactones) are ubiquitous in nature. These substructures are found in numerous biologically active natural products, including such well-known synthetic targets as FK- 506, discodermolide, palytoxin, the bryostatins, and the spongistatins. The overall objective of these studies is to develop an efficient general strategy for the asymmetric synthesis of pyranoid functionality found in numerous biologically relevant natural product classes, and to extend these methods to the efficient synthesis of other complex polyketide systems. A method involving the direct displacement of thione- based chiral auxiliaries from the products of asymmetric aldol reactions, using a variety of carbon nucleophiles, will be explored for the rapid assembly of substituted pyranone derivatives. These methods, in combination with a catalytic asymmetric hydroformylation, will be directed toward an expeditious formal synthesis of the antineoplastic agent, acutiphycin. By way of this approach, we will prepare in nine steps or fewer what previously required nineteen. The scope of these methods will be further extended by application to the marine natural product, Tedanolide C, a recently disclosed member of the tedanolide family all members of which exhibit nanomolar cytotoxicity against cancer cell lines. Using the methods developed herein, the structurally distinct C1-C12 half of this molecule will be rapidly prepared. This fragment intersects successful routes to the original tedanolides and, thus, could be used for SAR studies of this extremely potent class of natural products. Moreover, this fragment will form the basis of a simplified model for the macrolide core of tedanolide C, which will be used to verify stereochemical relationships in the natural product that remain uncertain based upon NMR analysis alone. Finally, the asymmetric total synthesis of a novel marine natural product, enigmazole A, will be undertaken. Key to this synthesis again will be the creative functionalization of thione-based aldol adducts, along with the deoxygenation of a complex dipropionate segment, an esterification-based fragment coupling, and a ring-closing metathesis. Overall, these projects have the potential to make a genuine contribution to the methodology of pyran-based natural products synthesis. This research is concerned with the development of new methods that will allow for the efficient preparation of anticancer compounds. Three natural products having promising medicinal value, acutiphycin, tedanolide C, and enigmazole A, will be investigated using these methods.