Enantio- and Diastereoselective Mannich Reactions of ß‑Dicarbonyls by Second Stage Diastereoconvergent Crystallization

The
synthesis of chiral α-monosubstituted-ß-dicarbonyls
is a challenging task in asymmetric catalysis due to the rapid, typically
uncontrolled, product racemization or epimerization under most reaction
conditions. For this reason, diastereoselective additions of unsubstituted
ß-dicarbonyls to π-electrophiles are unusual. Herein, we
disclose a simple catalytic crystallization-driven enantio- and diastereoselective
Mannich reaction for the synthesis of stereodefined α-monosubstituted-ß-keto
esters, dissymmetric ß-diesters, dissymmetric ß-diketones,
and ß-keto amides that productively leverages product epimerization
in solution. Mechanistic studies suggest a scenario where the initial
enantioselective, diastereodivergent skeletal assembly is catalyzed
by a chiral tertiary amine organocatalyst, which then facilitates
second stage crystallization-induced diastereoconvergence to provide
the challenging α-stereocenter in excellent stereoselectivity.