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Catalytic synthesis of beta3-amino acid derivatives from alpha-amino acids.

The synthesis of b-amino acids and their derivatives has garnered considerable interest over the past decades. These one-carbon homologues of a-amino acids are vital components of several pharmaceutics and have important roles in medicinal chemistry and biochemistry. Pioneering work by Seebach et al. and Gellman et al. has revealed that incorporating b-amino acids into peptide chains induces new secondary and tertiary structures and leads to biological activity in select cases. Central to all of these applications is the use of stereochemically pure b-amino acids, and recently reported enantioselective routes include Mannich reactions, Kowalsky rearrangements, radical reactions, isoxazoline intermediates, organocatalysis, and enzymatic hydrolysis of b-lactams. The use of transition-metal catalysis shows promise for the generation of enantiomerically pure b-amino acid derivatives and current research focuses on asymmetric hydrogenation reactions using Rh catalysts. Classic synthetic methods such as the Arndt–Eistert protocol work well for the b-amino acids, but the hazardous nature of diazomethane and high cost of silver render it undesirable for large-scale synthesis. Given our previous work on the carbonylation of heterocycles, we were interested in two reports from Jia and coworkers on the catalytic carbonylation of 2-oxazolines to give 2-oxazin-6-ones, which are precursors to b-amino acids. The system featured benzyl tetracarbonylcobalt(I) as the catalyst, and although 2-phenyl-2-oxazoline was converted cleanly to oxazinone (19 turnovers in 48 h), 4and 5substituted oxazolines were quite challenging (< 10 turnovers in 48 h). We believed that our Lewis acid based carbonylation catalysts could effect this transformation quickly and efficiently. Though these catalysts may improve the carbonylation step, the benefit of this method is the ease and generality of substrate synthesis (Scheme 1). There are many synthetic pathways to oxazolines; we focused on those using b-amino alcohols due to their commercial availability and accessibility by a-amino acid reduction. The overall synthetic pathway, shown in Scheme 1, begins with a biorenewable, stereochemically rich resource and yields enantiomerically pure b-amino acids. We began investigating catalysts of the form [Lewis acid][Co(CO)4] , which demonstrate good activity for epoxide, aziridine, and b-lactone carbonylation. Though these complexes showed poor activity for oxazoline carbonylation, we continued to pursue an active catalyst system for this transformation. Related work by Murai and co-workers on the carbonylation of epoxides, oxetanes, and benzylic esters using HSiR3/[Co2(CO)8] systems led to the selection of [Ph3SiCo(CO)4] (1) as a candidate. The complex is readily synthesized by the addition of two equivalents of Ph3SiH to a hexanes solution of [Co2(CO)8]. [17,19] Our initial experiments focused on the carbonylation of a representative substrate, 4-ethyl-2-phenyl-2-oxazoline, which proceeded smoothly in 75% yield using 1 in tetrahydropyran (THP) [Eq. (1)]. We examined the effect of a tert-butyl group