Organo catalytic strategies towards α, α [alpha, alpha] disubstituted amino acid derivatives

The class of non-proteinogenic a, a u2011disubstituted amino acids and their derivatives is of high interest to biochemical and pharmacological research. This predicates on their ability to alter certain chemical and physicochemical properties of peptides and related structures. Moreover, the close structural relatedness to biologically relevant endogenous amino acid derivatives qualifies them in many cases to act as enzyme inhibitors or receptor antagonists. In the present study, the development of new strategies towards the synthesis of N u2011protected a, a u2011disubstituted amino aldehydes and their derivatives is demonstrated. Starting from ketones, a, a u2011disubstituted aldehydes were prepared in two or three steps. These aldehydes were subjected to stereoselective organo-catalysed a u2011amination reactions. The transfer of a procedure known for the a u2011amination of a u2011unbranched aldehydes with azodicarboxylates to racemic a u2011branched aldehydes delivered N u2011protected aminoaldehydes in up to 87 % yield and 86 % ee. The conversion of the amination products to the corresponding N u2011protected 4,4 u2011disubstituted oxazolidinones was accomplished, after in situ-reduction, in two additional steps. In addition to this method, a new strategy was devised using sulfonyl azides as aminating agent to deliver a u2011sulfamidated a, a u2011disubstituted aldehydes in up to 55 % yield and 86 % ee. A mechanism was proposed, which differs fundamentally from the mechanistic model usually ascribed to enamine catalysis. The transformation of the sulfamidation product into the free amino acid was accomplished in two steps. Since the two concepts follow different mechanistic routes, different enantiomers of N u2011protected, a, a u2011disubstituted aminoaldehydes are accessible by one catalyst. All reactions involved in the latter approach are free of transition metals. Therefore, the presented strategy could prove to be especially useful for medicinal chemistry.