Synthesis of optically active 4-substituted 2-cyclohexenones.

Recently, Nicolaou and Baran independently synthesized optically active 4-substituted 2-cyclohexenones via an efficient LiOH-mediated intramolecular aldol condensation. Thus far, application of their cyclization approach has been limited to ketoaldehydes where the R-group is branched. It is demonstrated that the LiOH-mediated cyclization, when applied to substrates containing unbranched R-groups, results in significant erosion of optical purity. A mechanistic justification is provided, and a set of neutral, organocatalyzed conditions is identified that enables cyclization with little loss in optical purity.

Use of bifunctional ureas to increase the rate of proline-catalyzed alpha-aminoxylations.

The rate of the proline-catalyzed alpha-aminoxylation of aldehydes is significantly increased in the presence of a bifunctional urea. Structure-activity relationship data indicate that both an amine and a urea are crucial for rate enhancement. The evidence presented herein suggests that this rate enhancement originates from the hydrogen bonding interaction between the bifunctional urea and an oxazolidinone intermediate to increase the rate of enamine formation. Proline derivatives that are incapable of forming oxazolidinones exhibit no rate enhancement in the presence of the bifunctional urea. The rate enhancement is general for a variety of aldehydes, and the faster reactions do not reduce yields or selectivities.

Mechanism and application of a microcapsule enabled multicatalyst reaction.

In this paper, we describe the development and application of a multistep one-pot reaction that is made possible by the site isolation of two otherwise incompatible catalysts. We prepared a microencapsulated amine catalyst by interfacial polymerization and used it in conjunction with a nickel-based catalyst for the transformation of an aldehyde to a Michael adduct via a nitroalkene intermediate. The amine-catalyzed conversion of an aldehyde to a nitroalkene was found to proceed through an imine rather than a nitroalcohol. Kinetic studies indicated that the reaction is first order in both the nickel catalyst and the shell of the encapsulated amine catalyst. Furthermore, we provide evidence against interaction between amine and nickel catalysts and present kinetic data that demonstrates that there is a rate enhancement of the Michael addition due to the urea groups on the surface of the microencapsulated catalyst. We applied our one-pot reaction to the development of a new synthetic route for pregabalin that proceeds with an overall yield of 74%.

Microcapsule enabled multicatalyst system.

We present a new microencapsulated catalyst and report its use in a tandem multicatalyst reaction. Using an encapsulation technique, we developed an active, site-isolated amine catalyst that is capable of catalyzing the addition of nitromethane to an aldehyde. When a second Lewis acid catalyst is added, the nitroalkene intermediate is trapped and converted to the corresponding Michael adduct. We show that if the amine catalyst is not encapsulated, the two catalysts cannot function together. Moreover, if the two reactions are performed in sequence rather than in tandem, the first reaction results in an undesired dinitro product and the desired Michael adduct is not formed.