Science of Synthesis

Eckhardt, M., Science of Synthesis, (2007) 25, 492.

Most methods for the synthesis of 2-aminoaldehydes employ either the oxidation of 2-amino alcohols or the reduction of 2-aminocarboxylic acid derivatives.[‌106‌] Hydride reduction of the esters of amino acids or Weinreb-type amino acid amides is particularly useful for the synthesis of enantiopure 2-aminoaldehydes.[‌107‌–‌109‌] Among the many oxidizing agents available for the preparation of aldehydes from 2-amino alcohols, dimethyl sulfoxide based reagents, such as the combination with sulfur trioxide–pyridine complex, are very effective.[‌110‌] 2-Aminoaldehydes are much more labile than ordinary aldehydes and are best used immediately after their generation. Extended exposure to significantly acidic or basic workup procedures, including purification by chromatography, should be avoided to prevent racemization or epimerization of the α-stereogenic carbon, or α,β-elimination in the case of aminoaldehydes that have a leaving group at the β-carbon atom. Aldehydes bearing an α-nitrogen atom with an electron-withdrawing group are particularly prone to decomposition and epimerization, although some compounds with unusual configurational stability are known.[‌109‌] Trityl- or 9-phenylfluorenyl-substituted α-amino groups exhibit remarkable stability;[‌111‌,‌112‌] however, the trityl protecting group is cleaved quite easily under acidic conditions, limiting its applicability. Fortunately, N-(9-phenylfluorenyl)amino derivatives can be chromatographed intact and show considerable resilience to both acidic and basic conditions. Treatment of N-(9-phenylfluorenyl)-derivatized 2-aminoaldehydes with organometallic compounds, enolates, or Horner–Wadsworth–Emmons reagents gives the corresponding products in high yields and with full stereochemical integrity.[‌112‌] For long-term storage of 2-aminoaldehydes, conversion into the corresponding hydroxy sulfonate salts (“bisulfite addition products”) is recommended, because they are generally crystalline solids.[‌110‌] These hydroxy sulfonate salts are readily prepared by treatment of the 2-aminoaldehyde with an alkali metal bisulfite in aqueous media; they show no change in optical purity even after extended periods of storage. The aldehydic function can be recovered under mild conditions by exposure to a weak base in aqueous solution.

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