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

pnirn mimetics such as the pyroliidines 4.15, pyyrolizidinow 4.16 and indolizidines
4.17 (Scheme 4.3). Lubeil and coworkers have reported the Claisen condensation of PhFl
glutamates 4.45 (P=PhFl. Ri=tBu, R2=Me) giving the adduct 4.114 which was
subsequently decarboxylated 4.115 and cyclized to give indolizidinone 4.116 in good
overall yield (Scheme 4.31).Im However, the stereoselective introduction of various
substituents proved to be problematic, with diastereoselectivities ranging from 1 : 1 to 15: 1
depending on substrate. base and ele~trophile.'~'
Scheme 4.31
A variety of conditions were examined for the Claisen condensation of Cbz-L-
Glu(0Me)OBO ester 4.69 including various addition conditions, concentrations, counter-
ion and temperature (Table 4.3). NaHMDS, the preferred base reported by Lubell and
Lombart,lm failed to give any of the desired product 4.117, instead giving a complex
mixture of products including 4.69 (Scheme 4.32). Cbz-L-Glu(0Bn)OBO ester 4.72 is
presumably formeci by transesterification with benzyl alcohol liberated from the Cbz of
4.69 by adventitious hydrolysis (entry 2 and 3). L,jHMI)S (entry 5) gave the desired
Claisen condensation product 4.117 in 48% yield Decarboxylation of the f3-keto ester
4.117 to the ketone 4.118 failed under a number of therrnodynamic conditions including
NaOH in dioxane,lm NaCl in DMSO/H20,lm and Cs2Ca in MeOH/H20.'m The highly