Seebach Oxazolidinone Synthesis Essay

Abstract

The title compound BDI is prepared on multigram scale, either by resolution of the precursor 2-tert-butylimidazolidin-4-one (from glycine amide and pivalaldehyde) through diastereomeric salts (Scheme 2) or by preparative chromatographic enantiomer separation on a chiral column. Lithiated BDI derivatives are highly nucleophilic species, combining the structural elements of a Li enaminate, of an enolether and of an N-Boc-enaminate (E, G). They react with complete diastereoselectivity (NMR analysis) from the face trans to the tert-butyl group. The electrophiles employed are primary and secondary alkyl, allyl, benzyl, and propargyl halides (Schemes 3 and 5), enoates (in Michael additions, Scheme 7), as well as aliphatic and aromatic aldehydes (in aldol additions, Scheme 8). When a third, exocyclic, stereocenter is formed in these reactions, there is a high degree of enantiomer differentiation (with rac.sec. halides, products 10-12) and of enantiotopic face differentiation (with enoates and aldehydes, products 40-50). The reactions are so clean that highly efficient in-situ double alkylations are feasible, in which the sequence of addition of the two different electrophiles determines the configuration at the newly formed stereogenic center (Scheme 5). In contrast to derivatives of previously reported chiral glycine reagents, the products from BDI are converted to methyl esters of amino acids under mild conditions and without concomitant formation (… and the need for recovery or removal) of a chiral auxiliary; the method is compatible with acid-sensitive side chains in the α-amino acids and α-branched α-amino acids to be synthesized (Schemes 4 and 6). The addition of Li-BDI to aldehydes furnishes, after hydrolysis, α-amino-β-hydroxy acids of erythro configuration (allo-threonine analogs, Scheme 8); a model for the stereochemical course of this reaction (rel. topicity unlike) is proposed, and compared with the corresponding conversions of analogous oxazolidinone and imidazolidinone Li enolates which occur with rel. topicity like.

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