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

Table 4.2: Optimization of Hydroxyiatioa of CauL-Glu(0Me)OBO ester 4.69.
Entry Condi tionsa 4.94
Yield (%)
4.95 4.96
1 L ï S ( 3 eq.), 4.92 (1.5 eq.) 28 46 20
2 LiHMDS(3 eq.), 4.92 (5 eq.) 5 64 23
3 KHMDS (3 eq.), 4.92 (1.25 eq.) 30 34 22
4 NaHMDS (3 eq.), 4.92 (1.25 eq.) 19 39 45
5 LHMDS(3 eq.), 4.92 (1 -5 eq.), NaBa (20 eq.) 5 69 10
6 LiHMDS(3 eq.), 4.92 (1.5 eq.), NaB& (20 eq.lb 6 58 9
7 LDA (3 eq.), 4.92 (1. l eq.) 35 O 55
8 LDA (3 eq.), 4.W (5 eq.) 12 O 79
a Reaction performed in THF at -78°C unless otherwise noted.
Performed at 4°C
Only one stereoisomer of Cbz-Glu(y-OH)(OMe)OBO ester 4.96 could be
detected by TLC, 'H-NMR and ' 3 ~ and - subsequent ~ ~ ~ HPLC analysis. An X-ray
structure of 4.96 was obtained confirming the same stereochemical outcome (2S,4S) as
observed with alkylation (Figure 4.8) and showing a strong hydrogen-bond between the
hydrogen of the y-hydroxyl group and the double bonded oxygen in the carbarnate
(Appendix C). The excellent diastereoselectivity observed in the electrophilic y-
hydroxylation of Cbz-Glu(0Me)OBO ester 4.69 is in contrat to that reported by
Hanessain and Vanasse in which a 9:1 (2S,Qs:2S94R) stereoselectivity was obsewed."
This is pnsumably due to the higher stenc dernand of the OB0 ester protecting group
over that of the methyl ester in the chelated transition state mode1 described in Figure 4.9
(Section 4.2.10).