Enantioselective Iridium-Catalyzed Vinylogous Reformatsky-Aldol Reaction from the Alcohol Oxidation Level: Linear Regioselectivity by ay of Carbon-Bound Enolates

摘要

A catalytic enantioselective vinylogous Reformatsky-type addition has been described in which asymmetric carbonyl addition occurs with equal facility from the alcohol or aldehyde oxidation level. Good to excellent levels of regioselectivity and uniformly high levels of enantioselectivity are observed across a range of alcohols 2a-2i and aldehydes 3a-3i. Furthermore, as demonstrated in the case of α-chiral alcohol 2 k, exceptional levels of catalyst-directed diastereoselectivity may be achieved. Insight into the structure-interaction features of the catalytic system vis-a-vis partitioning of linear and branched adducts suggests a Curtin-Hammett scenario, wherein carbonyl addition occurs selectively from an equilibrating mixture of primary and secondary σ-allyl haptomers. The collective data are consistent with carbonyl addition from the secondary α-C-bound iridium enolate to form the less-substituted C-C bond owing to the absence of gauche interactions in the transition state. Notably, in reactions conducted from the alcohol oxidation level, the only stoichiometric by-products formed are carbon dioxide and tert-butanol. Future studies will focus on the development of related C-C bond-forming processes that combine oxidation/construction event and thus bypass discrete alcohol oxidation and stoichiometric organometallic reagents while gaining access to more tractable synthetic intermediates in the form of alcohols.