Interrogation of Enantioselectivity in the Photomediated Ring Contractions of Saturated Heterocycles

We recently reported a chiral phosphoric acid (CPA) catalyzed
enantioselective
photomediated ring contraction of piperidines and other saturated
heterocycles. By extruding a single heteroatom from a ring, this transformation
builds desirable C(sp3)–C(sp3) bonds
in the ring contracted products; however, the origins of enantioselectivity
remain poorly understood. In this work, enantioselectivity of the
ring contraction has been explored across an expanded structurally
diverse substrate scope, revealing a wide range of enantioselectivities
(0–99%) using two distinct CPA catalysts. Mechanistic investigations
support rate-determining excitation that generates short-lived achiral
intermediates that are intercepted by the CPA in an enantiodetermining
ring closure. The effects of competitive uncatalyzed reactivity and
light-driven reversibility of the enantiodetermining ring closure
on enantioselectivity have been elucidated. Statistical models were
built by regressing the range of enantioselectivities from the substrate
scope against key structural features of the products for both CPA
catalysts. The resultant models suggested distinct factors that influence
the enantioselectivity response for each catalyst and enabled rational
modification of a pharmaceutically relevant target molecule to improve
enantioselectivity. Finally, density functional theory (DFT)-based
transition state analysis identified distinct noncovalent interactions
with each catalyst that correlated with the unique selectivity-relevant
features uncovered through statistical modeling. Our findings not
only offer comprehensive insight into the origins of enantioselectivity
in this system but should also aid future development of related photomediated
CPA-catalyzed reactions.