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

dihydroxyester 262, generated after ring opeaing of the OB0 ester, although both the
benzyl carbarnate and methyl ester were rapidly cleaved."" However, this method has
been repocted to cause up to 3% racemization during 6 hours in refiuxing 6 N HCI.m3"'"
Purification by cation exchange (gradient elution with 0.1N to 1N NWH) or anion
exchange (elution with 0.1N to IN fonnic acid or 0.1N to 0.5 HCI) typically gave the
desired ysubstituted glutamates in 50-80% yield. Formation of the y-lactarn of 4-
substituted glutamates during prolonged hydrolysis has been observed,'" especially in the
case of diaminoglutamic acids (17%) 4.12 and 4.111.- y-ktonization has also ken
observed with 2S,4S-yhydroxyglutarnic 4.4 afier prolonged bubbling of HCl gas through
an aqueous solution (18 hour~).~~~ No cyclized product was isolated in our case,
although ESI-MS analysis of 4.11 indicated formation of a polymenc substance although
in insufficient yield for full characterization. Only the p-hydroxyglutamic acid derivative
4.104 was cleaved by TMSI, based on a previously reported synthesis from our
laboratory 7
Crystallization of the ysubstituted glutamates proved difficult and was generally
unsuccessful with the exception of the hydroxyglutamic acids 4.4 and 4.7. However,
diastereornenc and enantiomenc purities, established by denvatization and HPLC
analysis of the lyophilized powciers after ion exchange, were excellent. In most cases, the
values reported for the diastereoselectivity of addition of various electrophiles to the
enolate of Cbz-Glu(0Me)OBO ester 4.69 are based upon HPLC analysis of the
denvatives after deprotection. Since a minimal amount of racemization occurs (4%)
during hydrolysi~,~~~~~ these values are reported as >95:5 since one cannot distinguish
between racemization occurring during addition of the electrophile in basic conditions