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

Glu(y-Me)(OMe)OBO ester 4.73. However, both mutes failed to give the dimeth ylated
product 4.a instead giving cis 4.89 and am 4.W 2S,4S-Cbz-N-Me-Glu(y-
Me)(OMe)OBO (Scheme 4.22) in 36% yield with remaining starting material regardless
of base used. This is presumably due to the sterically hindered nature of the y-carbon
once monomethylated, leading to N-methylation at the elevated temperatures (-40°C to
0°C) required to drive the reaction.
Scheme 4.22
%
1) LiHMDS. -78%
42) Md. 4% CbzH CbzH
Serendipitously, while exploring the methylation of 4.69 in non-polar solvents.
the y-methyl derivative was found to be quite soluble in toluene. The use of a non-polar
solvent with a broad temperature range was ideal for variable temperature NMR studies.
Experiments over the range of 233 K (4°C) to 363 K (90°C) in toluene-da showed
coalescence of the minor methyl doublet at 330K (57OC) indicating the existence of
rotamers in Cbz-LGlu(y-Me)(OMe)OBO ester 4.73 (Figure 4.6). The fkee energy
difference (AG0) was calculated to be 1.31 kcal mol" and the free-energy of activation