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

stereoselectivi ty during electrophilic additions would be due to 1 -3-as ymmetric induction
of the chiral center and not a result of a bulky y-carboxy protecting group. The a-amino
group was protected as the Cbz group since it is typically more robust that han the Boc
group and the use of strong base to generate the enolate prohibited the use of the Fmoc
IFOUP*
Regioselective esterification of glutamate 4.60 was achieved using a similar
method to that reported earlier by our gmup.' Chlorotrimethylsilane (TMSCI) was
added in two separate diquots to giutamic acid 4.60 stimng in dry methanol (Scheme
4.19). Mer the removal of any residual solvent, CbzOSu was used to protect the amine
as the Cbz carbarnate to give 4.61- Purification at this point was laborious. therefon 4.61
was esterified using oxetane tosylate 2.38 to give the fully protected glutamate 4.65 in
68% and 4-66 in 62% yield over three steps. The t-butyi ester 4.67 was synthesized in
78% yield from cornrnercially availabie 4.63 and the benzyl ester d68 in 7546 yield from
4.64. Boron trifluoride etherate mediated rearrangement of 4.654.68 to the OB0 esters
4*69-4.72 gave crystalline products in 72%. 69%, 70% and 70% yield respectively after
flash chromatography. Larger arnounts (15-20 mol%) of boron trifluoride etherate could
be used to rapidly promote the rearrangement of the oxetane ester 4.65, conditions which
caused an increase in decomposition of the OB0 ester in the senne derivative 3A1
previously reported." This is presumably due to the lack of interaction of a hydroxyl
sidechain with the Lewis acid.
Lithium hexamethyldisilazane (LWMDS) was chosen as the base to generate the
dianion since other groups have reported inconsistent results and decomposition of the
enolate with However, carefiil control of the reaction conditions is necessary.