Solution and Solid Phase Synthesis of Unusual a-Amino Acids From

eactions such as the Ugi condensation." Furthemore, the inherent hinctionality of a-
amino acids provides a convenient handle for additional derivatizati~n.'~
O'Donnell et al." fmt reported the synthesis of unnatural a-amino acids on the
solid phase with the goal of synthesizing unnatural peptides and a number of other groups
- have expanded on O'Donnell's chernistry. A resin-bound Schiff base 6.1. generated with
the non-ionic base 2-te=-butylimino-2-dieth ylamino- l,3-dimethylperhydro- l,3,2-
diazaphos-phonne (BEMP), was alkylated with either alkyl halide~'~.".'~ or
organoborane~'~ to give the resin-bound products 6.2 in 5 1-99% yield and high purity
(>75%) (Scheme 6.1). Enantiomenc excesses range from 6499% ee depending on the
alkyl group but generally increasing with size. The peptide couid then be extended
through peptide coupling. The same authors extended the Schiff base method towards the
synthesis of a,a-disubstituted-arnino acids by starting with various amino acids and
alkylating with benzyl, allyl or Znaphthylmethyl bromide.17
Miyabe and CO-workers took a similar approach to unnatural a-amino acids, using
alkyl radicals to alkylate polyrner-supported glyoxylic oxime ethers."
6.1
Scheme 6.1
BEMP O H
or
1) HCmF
2) R-9-BEN
R
6.2
4) TFA R O
P=Merrifield, Wang R=Et, du, Bu, cyhex, Ph, Bn
O'Donnell has also used the same Schiff base methodology in the synthesis of
racemic glutamic acid derivatives via Michael reactions. The Schiff base of 6.1 was
condensed with the Michael acceptor to give the min-bound glutamic acid derivatives