functionalized amino acids also are useful building blocks for
the synthesis of â-lactams,9 â-fluoro-R-amino acids,10 and
sugars.11
Expedient Synthesis of threo-â-Hydroxy-r-amino
Acid Derivatives: Phenylalanine, Tyrosine,
Histidine, and Tryptophan
Over the years, several strategies have been developed for
the asymmetric syntheses of â-hydroxy-R-amino acids, including
asymmetric aldol reactions12 utilizing chiral oxazolidinones,13
alkylation of chiral enolates from oxazolidinones,14 oxazo-
lidines,15 bis-lactim ethers,16 oxazolines17 and imidazolidino-
nes,18 cycloaddition of chiral azomethine ylides,19 enzymatic
transformations,20 stereoselective hydrolysis of aziridine car-
boxylate esters,21 Sharpless asymmetric dihydroxylations,22
asymmetric aminohydroxylations,23 asymmetric epoxidations,24
sulfonamide mediated asymmetric Strecker reactions,25 imino
[1,2]-Wittig rearrangements of hydroximates,26 and numerous
others.25 Most of these protocols involve multiple steps and the
use of chiral auxiliaries or chiral catalysts and often proceed
with less than perfect stereocontrol.
David Crich* and Abhisek Banerjee
Department of Chemistry, UniVersity of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607-7061
ReceiVed June 6, 2006
In 1990, Easton and co-workers reported a method for
diastereoselective conversion of amino acids to their â-hydroxy
derivatives by direct side chain bromination of the amino acid
derivatives with NBS followed by treatment with silver nitrate
in aqueous acetone.27 For example, phenylalanine gave a 1:1
mixture of the diastereomeric bromides and, subsequently, a
5:1 mixture of the threo and erythro â-hydroxyphenylalanine
derivatives. This side chain bromination requires an N-substitu-
ent, such as phthaloyl or trifluoromethanesulfonyl, to deactivate
the R-position toward hydrogen atom abstraction.28 The phtha-
An expedient synthesis of enantiomerically pure threo-â-
hydroxy-R-amino acid derivatives of phenylalanine, tyrosine,
histidine, and tryptophan is described. The NBS-mediated
radical bromination of the N,N-di-tert-butoxycarbonyl pro-
tected R-amino acids and subsequent treatment with silver
nitrate in acetone provided the trans-oxazolidinones pre-
dominantly. Cesium carbonate catalyzed hydrolysis then
generated the â-hydroxy amino acid derivatives in excellent
overall yield.
(9) (a) Miller, M. J. Acc. Chem. Res. 1986, 19, 49. (b) Lotz, B. T.; Miller,
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J. Org. Chem. 1999, 64, 6931.
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â-Hydroxy-R-amino acids are an interesting class of mol-
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natural products. For example, â-hydroxytyrosine and â-hy-
droxyphenylalanine residues are found in clinically active
glycopeptide antibiotics, such as vancomycin,1 bouvardin,2
orienticins,3 phomopsins,4 ristocetin,5 actaplanin,5 and teicopla-
nin.5 â-Hydroxyhistidine has also been found in bleomycin,6
tallysomycin,7 exochelins MN,8a and PF244.8b These highly
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D. J.; Williams, C. E. Tetrahedron 1998, 54, 6089.
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10.1021/jo061159i CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/08/2006
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J. Org. Chem. 2006, 71, 7106-7109