Achieving Enantioselectivity

Carbon–hydrogen functionalization, ketone α-alkylation, and biocatalysis are some recent advances in asymmetric synthesis.
Sep 02, 2008
Volume 9, Issue 32

Patricia Van Arnum
Strategies for asymmetric synthesis are of continuing importance to the pharmaceutical industry. Single enantiomers accounted for 75% of the new small molecules approved by the US Food and Drug Administration in 2006 (1). Carbon–hydrogen functionalization through carbene catalysis, ketone α-alkylation, and biocatalysis using enoate reductases and ketoreductases are some recent examples of improving enantioselectivity of pharmaceutical compounds.

Carbon–hydrogen functionalization

Huw Davies, professor in the Department of Chemistry at the University of Buffalo and cofounder of Dirhodium Technologies (Buffalo, NY), recently reported on an alternative method for metal-induced carbon–hydrogen insertion. Carbon–hydrogen activation is an important tool in asymmetric synthesis. It typically involves the insertion of a highly reactive metal complex into a carbon–hydrogen bond, thereby activating the system for transformation. A challenge of this approach is being able to achieve the desired catalytic activity of the metal complex. One strategy to address this problem is to use neighboring functional groups to direct the metal complexes to the carbon–hydrogen bond. An alternative approach, forwarded by Davies, is to use a divalent carbon, or carbene, or a monovalent nitrogen, or nitrene, coordinated to a metal complex for insertion into a carbon–hydrogen bond. The benefits of this approach are higher levels of regioselectivity and steroselectivity (2).

Davies reported on using carbon–hydrogen functionalization to synthesize "Ritalin" (methylphenidate), a drug to treat attention-deficit hyperactivity disorder. The synthesis involves the Rh2 (S-biDOSP)2 -catalyzed reaction of N-protected piperidine with methyl phenyldiazoacetate, followed by the removal of the protecting group to form (R, R')-(+)-methylphenidate in 86% enantiomeric excess (ee) (1). Carbon–hydrogen functionalization by metal carbenoids and metal nitreonoids may also be used for synthesizing diterpene natural products, for the enantioselective synthesis of 4-substituted indoles, and for enantioselective carbon–hydrogen amination (2).

Ketone α-alkylation

Don Coltart, an associate professor at Duke University, reported a new method for ketone α-alkylation, a reaction used to create chiral ketones with alkyl groups on the α-carbons. These structures are found in many natural products and pharmaceuticals. In traditional approaches to asymmetric ketone α-alkylations, chiral hydrazine auxiliaries are often used to direct enantioselectivity through the formation and subsequent deprotonation of hydrazones. This approach, however, requires the reaction to be run at low temperatures (–110 to –78 °C), and the chiral auxiliaries are difficult to recycle.

Coltart reported by substituting conjugated electron-withdrawing groups onto the chiral hydrazine auxiliaries, a ketone can be combined with chiral N-amino cyclic carbamates to form a hydrazone, which is reacted with an alkyl halide to form the enantiomeric product. The reactions can be run at higher temperatures (–40 to 0 °C), and the chiral auxiliaries can be recycled with an acid treatment (3). Coltart and Duke recently applied for a patent on the process, according to a Duke University press release.

Other carbene catalysis

Karl Scheidt, an assistant professor of chemistry at Northwestern University, is exploring catalytic multicomponent coupling processes, organosilicon chemistry, and new catalytic reactions with N-heterocyclic carbenes. In carbene catalysis, his research group has developed several approaches to carbonyl/acyl anion equivalents, homoenolate reactivity, hydroacylations of ketones, formal [3 + 3 ] cycloadditions, Michael reactions, aldol reactions, and acylvinyl anion equivalents (4, 5).

Scheidt's work further focuses on the construction of complex natural products containing oxygen heterocycles. Using new Lewis acid-catalyzed cyclization reactions with dioxinones, his group is researching the synthesis of tetrahydropyran-containing natural products with antitumor activity, and it recently reported the catalytic enantioselective synthesis of flavanones. The group used bifunctional thiourea catalysts to promote an asymmetric oxo-conjugate addition to β-ketoester alkylidene in high yields with enantioselectivity of 80–94% ee for aryl and alkyl substrates. Decarboxylation of the β-ketoester proceeds in a one-pot procedure to produce enantioenriched flavanones and chromanones (4, 5).