Simultaneous Amino and Carboxyl Group Protection for .alpha.-Branched Amino Acids

Abstract

In the areas of peptide engineering and pharmaceutical chemistry, a-branched amino acids have found widespread and significant application. a-Alkyl amino acids exhibit helix-inducing propensities and are useful building blocks for de novo design of peptides and pr0teins.l a-Branched amino acids are useful as enzyme inhibitors and drugs. For example, a-methyl-DOPA (Aldomet), a commercial antihypertensive, reached over $140 million in sales in 1990.2 We have been particularly interested in a-vinyl amino acids. Several of these, such as a-vinylhi~tidine,~ a-vinyl~rnithine,~ a-vinyl-DOPA,6 a-vinylmtyr~s ine ,~ and a-vinyl~erine,~ and a-vinylglutamate,6 are known enzyme inhibitors. We recently reported a convenient procedure for the synthesis of a-vinyl amino acids from the parent amino acids.' Given the chemical versatility of the vinyl functionality, these derivatives may be viewed as simple building blocks for more complex, chain-extended, a-branched amino acids. Such schemes require the presence of suitable protecting groups for the amino and carboxyl groups. However, initial attempts to introduce the benzyloxycarbonyl (Cbz) group onto the a-amino group of free a-vinyl amino acids using the usual Schotten-Baumann conditions [CbzCl, NaOH (aq)I8 met with little success. Under these conditions, benzyl chloroformate is apparently hydrolyzed faster than it reacts with the a-amino group of a-vinyl amino acids. Other established N-benzyloxycarbonylation reagents, including 0(benzyloxycarbonyl)-N-hydroxysuccinimide ( Z-OSU)~ and [p-((benzyloxycarbonyl)oxy)phenylldimethylsulfonium methyl sulfate (Z-ODSP),lO also failed, presumably due to the sterically congested environment about the amino group. Indeed, the problems associated with amino group