Biocatalytic Michael-Type Additions of Acetaldehyde to Nitroolefins with the Proline-Based Enzyme 4-Oxalocrotonate Tautomerase Yielding Enantioenriched γ-Nitroaldehydes

摘要

γ-Nitroaldehydes are versatile and practical precursors for chiral γ-aminobutyric acids (GABAs). In particular, prominent GABA analogues, such as marketed pharmaceuticals phenibut[1] (GABA_B receptor agonist, anxiolytic), pregabalin[ 2] (anticonvulsant), baclofen[3] (GABA_B receptor agonist, anti-alcoholism), and rolipram[4] (type IV phosphodiesterase inhibitor, antidepressant) can be readily obtained from diverse chiral g-nitroaldehydes by two, well-precedented, chemical synthesis steps.[5] One of the most important strategies to construct g-nitroaldehydes is the Michael-type addition of unmodified aldehydes to nitroolefins.[6] Following this approach, construction of the appropriate g-nitroaldehyde precursors for above-mentioned, pharmaceutically active GABA analogues would require the Michael-type addition of acetaldehyde to various nitroolefin acceptors (Scheme 1). The Michael-type addition of unmodified aldehydes to nitroolefins has recently become viable by the development of proline- and peptide-based organocatalysts.[7, 8] However, examples including acetaldehyde as the donor are scarce since acetaldehyde is a relatively reactive and difficult to tame chemical and 10-20 mol% of organocatalyst is typically applied.[9] Alternative procedures for the asymmetric synthesis of g-nitroaldehydes from acetaldehyde and nitroolefins are therefore of great interest. Although a few examples of enzyme-catalyzed carbon-carbon bond-forming Michael- type additions are known, these do not involve acetaldehyde as the donor and mainly exhibit low stereoselectivities.[ 10]