Mechanistic Insight into Asymmetric Hetero-Michael Addition of α,β-Unsaturated Carboxylic Acids Catalyzed by Multifunctional Thioureas

Carboxylic
acids and their corresponding carboxylate anions are
generally utilized as Brønsted acids/bases and oxygen nucleophiles
in organic synthesis. However, a few asymmetric reactions have used
carboxylic acids as electrophiles. Although chiral thioureas bearing
both arylboronic acid and tertiary amine were found to promote the
aza-Michael addition of BnONH2 to α,β-unsaturated
carboxylic acids with moderate to good enantioselectivities, the reaction
mechanism remains to be clarified. Detailed investigation of the reaction
using spectroscopic analysis and kinetic studies identified tetrahedral
borate complexes, comprising two carboxylate anions, as reaction intermediates.
We realized a dramatic improvement in product enantioselectivity with
the addition of 1 equiv of benzoic acid. In this aza-Michael reaction,
the boronic acid not only activates the carboxylate ligand as a Lewis
acid, together with the thiourea NH-protons, but also functions as
a Brønsted base through a benzoyloxy anion to activate the nucleophile.
Moreover, molecular sieves were found to play an important role in
generating the ternary borate complexes, which were crucial for obtaining
high enantioselectivity as demonstrated by DFT calculations. We also
designed a new thiourea catalyst for the intramolecular oxa-Michael
addition to suppress another catalytic pathway via a binary borate
complex using steric hindrance between the catalyst and substrate.
Finally, to demonstrate the synthetic versatility of both hetero-Michael
additions, we used them to accomplish the asymmetric synthesis of
key intermediates in pharmaceutically important molecules, including
sitagliptin and α-tocopherol.