Zj. Yao et al., Preparation of L-N-alpha-Fmoc-4-[di-(tert-butyl)-phosphonomethyl]phenylalaline from L-tyrosine, TETRAHEDR-A, 10(19), 1999, pp. 3727-3734
The unnatural amino acid analogue, 4-(phosphonomethyl)phenylalanine (Pmp, 2
), has proven to be a valuable tool for studying protein-tyrosine kinase de
pendent signal transduction, where it is most often incorporated into pepti
des or peptide mimetics as a phosphatase-stable phosphotyrosyl mimetic. Alt
hough Pmp has been prepared previously bearing a number of protection strat
egies, the N-alpha-Fmoc 4- [di-(tert-butyl)phosphonomethyl] phenylalanine f
orm [(N alpha-Fmoc-L-Pmp('Bu-2)-OH, 3] is particularly attractive since it
can be cleanly introduced into peptides using standard Fmoc protocols. Synt
hesis of 3 was first reported as its (D/L)-racemate, and subsequently as it
s L-3 enantiomer, with the latter synthesis having relied on induction of c
hirality using a camphor sultam auxiliary. Reported herein is an alternate
enantioselective synthesis of L-3 in high ensantiomeric purity by procedure
s which derive the stereochemistry of the final product directly from the s
tarting amino acid, without the need for chiral induction. A key feature of
the route is the racemization-free nucleophilic substitution of lithium di
-tert-butyl phosphite onto protected 4-bromomethylphenylalanine (17). (C) 1
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