Organocatalyzed Kinetic Resolution of α‑Functionalized Ketones: The Malonate Unit Leads the Way

• Published in: ACS catalysis Vol. 10; no. 5; pp. 2882 - 2893
• Main Authors: Liu, Jian, Vasamsetty, Laxmaiah, Anwar, Muhammad, Yang, Shuang, Xu, Weici, Liu, Jinggong, Nagaraju, Sakkani, Fang, Xinqiang
• Format: Journal Article
• Language: English
• Published: American Chemical Society 06-03-2020
• Subjects: two-key-step resolution mode; cascade annulation; conjugated acyl azolium; catalytic kinetic resolution; α-functionalized ketone
• ISSN: 2155-5435; 2155-5435
• DOI: 10.1021/acscatal.9b05608

Developing a catalytic kinetic resolution (KR) protocol affording enantioenriched α-functionalized ketones with broad substrate scope and high efficiency has been a longstanding challenge. Here, we report a successful protocol toward addressing this issue via an organocatalyzed cascade annulation. The protocol could afford 11 classes of enantioenriched α-functionalized ketones using a single catalytic system and avoid the frequent alterations of reaction conditions used in conventional methods. Up to 684 of the selectivity factor (s) is observed, and in most case, the s values are higher than 100. An aminolactam additive proves essential in promoting the resolution efficiency. Moreover, many previously unavailable enantiopure α-functionalized ketones are now accessible, and the annulation products are also useful building blocks and can be further transferred to densely substituted ketones without erosion of the optical purity. Mechanistically, in sharp contrast to the currently used direct one-step resolution patterns, a two-key-step resolution mode, wherein the enantiomer discrimination happens at the second aldol step and the enatioenriched ketones are recovered by the reversible initial Michael reaction, is proposed, which provides opportunities addressing the challenging tasks that could not be solved by conventional resolution techniques.