Solution and solid phase synthesis of unusual alpha-amino acids from ortho ester protected synthons

Abstract

Non-proteinacous amino acids are important components of numerous biologically active compounds. As a consequence, there is much interest in the development of straightforward routes for their synthesis. A novel strategy for the synthesis of several classes of non-proteinacous a-amino acids from a variety of a-amino acids is presented in this thesis.

A general strategy of protecting the a-carboxyl group of serine, threonine, aspartic acid and glutamic acid as a cyclic ortho ester (OBO), sufficiently reduces the acidity of the a-proton to allow the use of a variety of basic reagents minimizing racemization at the a-proton.

The sidechain hydroxyl group in Boc/OBO protected serine and threonine is oxidized to the corresponding aldehyde and ketone without enolization. Grignard and Reformatsky additions produced predominantly threo-b-hydroxy-a-amino acids in good selectivity with no racemization. Adaptation of the methodology onto the solid phase also gave threo-b-hydroxy-a-amino acids albeit with some racemization.

The addition of various electrophiles to the enolate of N-Cbz-a-OBO-y-methyl ester glutamic acid gave the 2S,4S stereoisomers with excellent selectivity and good yield. Alkylation, acylation, Aldol and Claisen reactions and the electrophilic addition of various heteroatoms is described.

Electrophilic additions to the enolate of N-Cbz-a-OBO-y-methyl ester aspartic acid gave the more difficult to synthesize 2S,3S stereoisomer with varying degrees of stereoselectivity and yields depending on the electrophile.

The stereochemistry of addition for the enolate chemistry is also explored.