Asymmetric Total Synthesis of Shagenes†A and B.

We report the first total synthesis of shagenes A and B, which are tricyclic terpenoids containing a cis-substituted cyclopropane, via ring-closing metathesis of an enamide and Ir-catalyzed double-bond isomerization of an alkylidenecyclopropane. Chemo- and diastereoselectivity in the distorted cis-substituted structures were controlled by the alkylidenecyclopropane reactivity and using the ketone functionality as a remote directing group for the Ir catalyst, respectively. The total synthesis suggested the absolute configuration of shagenes.

Mechanistic Insight into Asymmetric Hetero-Michael Addition of α,ß-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,ß-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.