In- or In(I)-Employed Tailoring of the Stereogenic Centers in the Reformatsky-Type Reactions of Simple Ketones, α-Alkoxy Ketones, and β-Keto Esters

Comprehensive studies were carried out on efficient In- or In(I)-based diastereoselective Reformatsky-type reactions of simple ketones, α-alkoxy ketones, and β-keto esters. High anti selectivity
was established in the addition of the branched α-halo ester derivatives to simple ketones using
indium metal under THF-refluxing conditions. The stereochemistry undoubtedly indicated that
the involvement of a cyclic transition state, formed from the ketone and stereochemically preferred
transient E-enolate derived from the branched α-halo ester. Next, with the view of tailoring high
degree of stereoselection, the concept of chelation-controlled addition of indium enolates was
envisioned. In this line, marvelously syn selective additions to α-alkoxy ketones and β-keto esters
were established. Interestingly, these diastereoselective additions to α-alkoxy ketones and β-keto
esters require either In(I)X or In−InCl3 systems in toluene under ultrasonication, while very poor
efficiency and diastereoselectivity were obtained using indium metal or THF as solvent. The
stereochemistry of key products was unambiguously determined by the single-crystal X-ray structure
analyses. On the basis of the observed astonishing diastereoselectivities due to strong chelation
plausibly, a low-valent RIn(I)-type transient spices could be projected as very reactive spices in
the Reformatsky-type reactions.

本研究针对以金属铟（Indium）或一价铟（In(I)）为介导的非对映选择性瑞福马斯基型（Reformatsky-type）反应展开了系统性探究，反应底物涵盖简单酮、α-烷氧基酮以及β-酮酸酯。在四氢呋喃（THF）回流条件下，以金属铟为试剂将支链α-卤代酯衍生物加成至简单酮的反应中，实现了优异的反式选择性。该反应的立体化学特征明确表明，其反应历程涉及由酮与支链α-卤代酯衍生的、立体偏好的瞬态反式烯醇盐所形成的环状过渡态。随后，为了构建高立体选择性的反应体系，研究人员提出了铟烯醇盐的螯合控制加成策略。基于该思路，针对α-烷氧基酮与β-酮酸酯的加成反应实现了极佳的顺式选择性。值得注意的是，这类针对α-烷氧基酮与β-酮酸酯的非对映选择性加成反应，需在甲苯溶剂、超声条件下，采用一价卤化铟（In(I)X）或铟-三氯化铟（In-InCl3）体系方可进行；而若使用金属铟或以四氢呋喃作为溶剂，则反应效率与非对映选择性均极差。关键产物的立体化学构型通过单晶X射线衍射结构分析得到了明确确证。基于观测到的、由强螯合作用带来的优异非对映选择性，研究人员推测低价态RIn(I)型瞬态中间体可作为瑞福马斯基型反应中的高活性反应中间体。