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J . Org. Chem. 1999, 64, 9294-9296
of a base1d-f,10 and (ii) deprotection of the N-Boc group of
the resulting ester with an acid such as hydrochloric
acid,1e-g,11 trifluoroacetic acid,1d,12 or boron trifluoride.13
Although the overall yields are usually satisfactory, this
method is limited, especially for large scale preparation,
as a result of the safety concern with diazomethane and
the competitive N-methylation in the case of iodo-
methane.14 Treatment of N-Boc-O-methyl tyrosine with
methanolic HCl was reported by Rosenberg and co-
workers in a footnote without experimental details or
yield to give O-methyl tyrosine methyl ester hydro-
chloride.15
A F a cile Meth od for th e Tr a n sfor m a tion of
N-(ter t-Bu toxyca r bon yl) r-Am in o Acid s to
N-Un p r otected r-Am in o Meth yl Ester s
Bang-Chi Chen,* Amanda P. Skoumbourdis, Peng Guo,
Mark S. Bednarz, Octavian R. Kocy,
J oseph E. Sundeen, and Gregory D. Vite
Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical
Research Institute, Princeton, New J ersey 08543
Received February 18, 1999
MeOH/TMSCl is a facile system for the preparation of
methyl esters from carboxylic acids.16 Compared to the
conventional gaseous HCl in methanol used for esterifi-
cation, use of TMSCl is more advantageous not only
because it is more convenient to use and measure but
also because it acts as a water scavenger so that the
esterification is faster and cleaner. In theory, at least 1
equiv of HCl is generated in the esterification of carbox-
ylic acid with TMSCl/MeOH. We envisioned that this HCl
generated in situ may affect the deprotection of the N-Boc
group if an N-Boc R-amino acid is used. Thus, treatment
of L-N-Boc-phenylalanine in methanol with TMSCl at
room temperature for 2 h gave 19% of the desired
product, phenylalanine methyl ester (4, M + H ) 180),
in addition to two intermediate peaks and complete
disappearance of the starting material by reverse-phase
HPLC and LC/MS. The major peak, moving more slowly
than 4 or 1, was N-Boc-phenylalanine methyl ester (2,
62%, M + H ) 280), whereas the fastest eluting peak
was the N-Boc deprotection intermediate phenylalanine
(3, 19%). Upon further stirring, both 2 and 3 underwent
N-Boc deprotection and esterification, respectively, to
give 4, with the former reaction being faster than the
latter. After stirring overnight, the desired product,
L-phenylalanine methyl ester hydrochloride (4), was
obtained in 94% yield by removing the solvent and
crystallizing the product with ether (Scheme 1 and Table
1, entry 1). Importantly, no racemization took place in
Methyl N-unprotected R-amino esters are important
intermediates in organic synthesis.1 They can be con-
veniently prepared by a Fisher-type esterification of the
corresponding free R-amino acids in methanol using
gaseous HCl,1a SOCl2,1b or TMSCl.1c In addition, an
increasing number of methods have been developed for
the preparation of R-amino acids with the R-nitrogen
atom already protected by a Boc group.2-7 For example,
oxidations of N-Boc â-amino alcohols,2 N-Boc benzyl-
amines,3 N-Boc furfurylamines,4 and N-Boc allylamines5
afford directly N-Boc R-amino acids. Reduction of N-Boc
R-amino-R,â-unsaturated carboxylic acids also gives N-
Boc R-amino acids.6 It is therefore of importance to
develop a method for the direct transformation of N-Boc
R-amino acids to methyl N-unprotected R-amino esters
without prior deprotection of the N-Boc group and
isolation of the free R-amino acid intermediate.
Previously, the transformation of N-Boc R-amino acids
to methyl N-unprotected R-amino esters was carried out
in two steps: (i) ester formation of the carboxylic acid
using diazomethane1d,8,9 or iodomethane in the presence
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10.1021/jo990311w CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/10/1999