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

2S,3 R = major diastemorner
2.49 R = CH3
2.50 R = Et
2.51 R = vinyl
2.52 R = Ph
As summarized in Table 2.1, the type of Grignard reagent, solvent and
temperature were examined in an attempt to optirnize the addition. Little difference in
yield was obtained with various halide counter ions and thus MeMgBr was used as the
reagent of choice due to its commercial availability. Temperature and solvent played a
more important role in determining both yield and diastereomenc ratios. Increased
temperatures resulted in lower yields due to the formation of complex mixtures of by-
products that were not isolated. The moderate increased reactivity of the Grignard
reaction in toluene at O°C (entry 5) is an anomaly, although not without precedent? This
enhanced reactivity through the use of a non-polar and noncwrdinating solvent has been
previously described? However, when the addition was performed in toluene at -78"C,
the increased reactivity experienced at O°C was not observed although the
srereoselectivity was increased. The reaction failed to proceed to completion even with
extended reaction times (entry 10) for al1 solvents at -78°C.
The major by-product of the additions was unreacted Boc-Ser(a1d)OBO ester
2.46. One of the most fkequent side reactions encountered with Grignard reagents is
enolization.' Formation of the enolate of the ddehyde 2.46Jketone 2.47 would compete
with the addition reaction and upon work-up produce the aldehyde, albeit racemic. In
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