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

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.