Highly Stereoselective Construction of Carbon-Carbon Bonds Using Phosphonyl and Phosphoramidite Auxiliaries (Chemistry)

这项研究得到了有机和大分子化学计划的支持。自然界中复杂结构的合成需要高度特异性反应的发展。这项工作将产生基于磷原子产生的独特反应性的新试剂。本文描述了以下方面的研究：(1)与α -酰基膦酸二酯的高度立体选择性醛醇反应（酸和碱介导），(2)Mukaiyama-Michael反应的立体化学控制，以及(3)手性磷酸酰胺同烯酸盐阴离子合成子的立体选择性烷基化。这个由三部分组成的研究计划的中心特征是建立一个高度立体选择性的方法来构建无环分子内的碳-碳键。根据助剂的立体化学和空间体积以及分子内金属离子络合能力，预测了助剂的高非对映面和对映面选择性。具体来说，α -酰基-1,3,2-二氧膦酸盐的金属阴离子用于控制烯醇化的几何形状和烷基化时的非对映体偏好。将手性引入1,3,2-二氧膦基骨架会产生手性助剂的不对称转移。对过渡状态模型的考察提供了对可能控制非对选性的因素的洞察。最后，由(1S,2R)-(+)-麻黄碱和(E)-3-苯基原醛或巴豆醛衍生的手性磷酰胺缩合为前手性有机金属中间体的螯合控制对映选择性烷基化提供了合适的底物。

This research is being supported by the Organic and Macromolecular Chemistry Program. The synthesis of the complex structures that occur in nature requires the development of highly specific reactions. This work will produce new reagents based on the unique reactivity produced by a phosphorous atom. Investigations centering on (i) highly stereoselective Aldol reactions (both acid and base-mediated) with alpha-acylphosphonate diesters, (ii) stereochemical control of the Mukaiyama-Michael reaction, and (iii) the stereoselective alkylations of chiral phosphoramidite homoenolate anion synthons are described. The central feature of this three-part research program is the establishment of a highly stereoselective methodology for construction of carbon-carbon bonds within acyclic molecules. Both high diastereofacial and enantiofacial selectivity is predicted based on the stereochemistry and steric bulk of the auxiliary as well as intramolecular metal ion complexation ability. Specifically, the metal anions of alpha-acyl-1,3,2-dioxaphosphonates are used to control enolate geometry and diasteromer preference when alkylated. Introduction of chirality into the 1,3,2-dioxaphosphonyl skeleton creates potential for asymmetry transfer from the chiral auxiliary. Examination of transition state models provide insight into factors likely to control diastereoselectivy. Finally, condensation of chiral phosphoramidities derived from (1S,2R)-(+)-ephedrine and (E)-3-phenylpropenal or crotonaldehyde provide substrates suitable for chelation-controlled enantioselective alkylation of the prochiral organometallic intermediate.