NEW METHODS FOR STEREOSELECTIVE ADDITIONS TO CARBONYLS

这个项目的长期目标是开发新的方法 通过对立体控制的理解实现不对称合成 元素，并将我们所学到的应用到 新反应的设计。我们主要感兴趣的反应是 不对称地形成C-C键。我们的方法侧重于 手性氧碳正离子的产生，可以被认为是被激活的 酮或醛。然后这些化合物可能会经历 非对映选择性加成反应或Diels Alder反应，如果 氧碳正离子是α-β不饱和的，其中不对称 诱导是由氧碳正离子的手性衍生出来的。在 提案的第一部分，我们已经明确地用一个重氢来表示 手性缩醛加成反应的标记实验 由W.S.约翰逊以氧碳正离子的方式进行。这些反应 可以显示超高级别的非对映选择性，&gt；300：1 案例，从而提供了手性氧碳正离子可以提供 加成反应中高水平的不对称诱导。我们是 扩大我们的氢化缩醛研究以探索其机理 添加到无环缩醛中。我们还在研究激活 α-β不饱和羰基衍生物转化为 氧碳正离子。Diels Alder中氧碳正离子的形成 反应，为远程控制提供了新的机会 立体化学。我们已经提出了一种简短的胆固醇合成方法。 使用这种方法的生物合成抑制剂二氢紧凑素，并且是 检查它的范围。我们还提出了一种催化变异体，其中手性 在催化量中使用TMS醚以控制绝对 Diels Alder反应中的立体化学。最后，我们描述了一个 手性α-二茂铁阳离子，我们希望它将作为 用于各种反应的对映选择性催化剂。这种试剂是 类似于已被证明是有效的三苯基阳离子 用于包括Aldol反应在内的许多反应的Lewis酸催化剂， 三烷基硅烷与酮的还原，硅基的1，4加成 亲核剂对α-β不饱和酮和酯的等价物，以及 Diels Alder反应。我们描述了一种对映体选择性的合成 催化剂前体，并刚刚开始检查其作为一种 不对称催化剂。我们发现的方法可以用来合成 各种具有医疗价值的分子。

The long term objectives of this project are to develop new methods of asymmetric synthesis by gaining an understanding of the stereocontrol elements in existing methods, and applying what we have learned to the design of new reactions. We are primarily interested in reactions that form C-C bonds enantioselectively. Our approach focuses on the generation of chiral oxocarbenium ions, which can be considered activated ketones or aldehydes. these compounds may then undergo diastereoselective addition reactions, or Diels Alder reactions if the oxocarbenium ion is alpha-beta unsaturated, where the asymmetric induction is derived from the chirality of the oxocarbenium ion. In the first part of the proposal, we have unequivocally shown by a deuterium labeling experiment that the chiral acetal addition reactions discovered by W.S. Johnson proceed by way of an oxocarbenium ion. These reactions can display exceptional levels of diastereoselectivity, >300:1 in many cases, thus providing evidence that chiral oxocarbenium ions can provide high levels of asymmetric induction in addition reactions. We are extending our deuterated acetal studies to probe the mechanism of addition to acyclic acetals. We are also examining the activation of alpha-beta unsaturated carbonyl derivatives by their conversion to oxocarbenium ions. formation of the oxocarbenium ions in the Diels Alder reaction, allowing for new opportunities for controlling remote stereochemistry. We have proposed a short synthesis of the cholesterol biosynthesis inhibitor dihydrocompactin using this method, and are examining its scope. We also propose a catalytic variant where a chiral TMS ether is used in catalytic amounts to control the absolute stereochemistry in the Diels Alder reaction. Finally, we describe a chiral alpha-ferrocenyl cation which we hope will serve as an enantioselective catalyst for a variety of reactions. This reagent is similar to the trityl cation which has been shown to be an effective Lewis acid catalyst for numerous reactions including the aldol reaction, reduction of ketones with trialkylsilanes, 1,4 addition of silyl nucleophiles to alpha-beta unsaturated ketones and ester equivalents, and Diels Alder reactions. We describe an enantioselective synthesis of the catalyst precursor and have just begun to examine its reactivity as an asymmetric catalyst. The methods we discover can be used to synthesize a variety of molecules of medicinal interest.