Large numbers of biologically and pharmacologically important compounds contain an amine functionality. Examples include non-proteinogenic amino acids, alkaloids, and amino alcohols. The biological activity of these compounds is almost always restricted to one enantiomer. The development of mehtods which do not require resolution of racemic intermediates for efficient chemical synthesis of enantiomerical pure products is an area of considerable interest. This proposal describes research to develop a new general method for enantioselective synthesis of amino acids and other amine natural products. The project is based upon the modification of reaction types previously used only for the synthesis of racemic amine derivatives. These modifications will provide for generation of chiral centers with extremely high stereoselectivity as demonstrated by successful preliminary studies. The project design is based on the known chemistry of acylimines and acyliminiumions as reactive electrophiles. We will utilize a chiral alkoxycarbonyl group as the acyl group in these intermediates. The precursors to these electrophiles will be generated either by electrochemical oxidatin of N-alkyl-compound. A key feature will be the study of the effectiveness of several chiral auxiliaries for this type of asymmetric induction. Only systems known to be extremely efficient chiral auxiliaries in structurally related intermediates will be examined. The chiral acyliminium ions will be captured by carbon nucleophiles such as trimethylsilylcyanide (modified Strecker synthesis), arenes, and activated alkenes to give a new carbamate structure containing one or more new chiral centers. The stereoselectivity of these reactins will be a function of both the diastereofacial selectivity of the chiral auxiliaries and the conformation of the reactive intermediates. It is expected that the diastereoselectivity in many of these reactions will be extremely high so the tedious separation of diastereomers will not be necessary. Cleavage of the carbamate functinality in the new product will regenerate the chiral alcohol (chiral auxiliary)and liberate the optically active amine product. These methods will be applied to the synthesis of unusual non-proteinogenic amijno acids, amino alcohols, and alkaloids.
| Xiao, Ziwei; Kappen, Lizzy S; Goldberg, Irving H (2006) Development of new simple molecular probes of DNA bulged structures. Bioorg Med Chem Lett 16:2895-9 |
