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

Having optimized the addition of MeMgBr our attention turned to the addition of
other Grignard reagents to Boc-Ser(a1d)OBO ester 2.46 (Scheme 2.2 1, Table 2.2). In al1
cases the addition caused little racemization with the deprotected amino acids dl
possessing 297% ee. Diastereoselectivity of the crude product ranged from 84:16 to
88: 12 threo:erythro and yields from 40-6695. Purification by flash chromatography and
subsequent deprotection and HPLC analysis of the ion-exchange purified amino acid
showed a siight increase in diastereoselectivity. In fact, although the Rf for both
diastereomers were typically sirnilar, diastereomeric enrichment seemed to be occuning
after flash chromatography although the values detennined by 'H-NMR integration are
subject to experimental error. Steric bulk of the Grignard reagent does not appear to play
much of a role in stereoselectivity since similar thre0:erytht-o ratios are obtained for al1
reagen ts.
Table 2.2: Additions of RMgBr to Boc-Ser(ald)OBO ester 2.46.
protected aa deprotected aa 9%
% ds ratio (s,R:s,S)~ ds ratio % overall
Entry RMgBr Roduct yielda crude (s$:s,S)C eec yield
1 Et 2.50 49 84: 1 6 87: 13 98 24
2 vin y 1 2.51 40 87: 13 89: 1 1 97 16
3 Ph 2.52 66 88: 12 90: 10 98 40
a Yield reported for 2 steps (from 2.44).
Ratio determined by 'H-NMR
Ratio determined by HPLC analysis
Addition of MeMgBr to Boc-Throcet)-OB0 ester 2.47 gave protected p-
hydroxyvaline 2.57 (Scheme 2.22, Table 2.3). The reaction proceeded in good yield
(7246, over two steps) but, as with the additions to the aldehyde 2.46, TU3 analysis
indicated remaining ketone 2.47. The recovered ketone 2.47, which was stable on silica,
64