An Improved Synthesis of
Fmoc-N-methyl-r-amino Acids
SCHEME 1. Freidinger Synthesis of N-Methylated
a
Suode Zhang, Thavendran Govender,
Thomas Norstr o¨ m, and Per I. Arvidsson*
Department of Chemistry, Organic Chemistry, Uppsala
University Box 599, SE-751 24 Uppsala, Sweden
Received May 9, 2005
a
Reagents and conditions: (a) (CH2O)n, p-toluenesulfonic acid
(cat.), toluene, azeotropic removal of water; (b) Et3SiH, CF3COOH,
CHCl3.
racemization or use large excesses of, often, expensive
4
reagents. One of the mildest and most general proce-
dures for producing N-methyl amino acids is based on
the reduction of 5-oxazolidinones. The preparation of
5
-oxazolidinones from N-protected amino acids and
paraformaldehyde was originally suggested by Ben-
5
6
Ishai. Freidinger et al. later developed the methodology
for reducing the 5-oxazolidinone with triethylsilane and
trifluoroacetic acid (TFA), Scheme 1.
A highly efficient and environmentally more benign synthe-
sis of Fmoc-N-methyl-R-amino acids from the corresponding
Fmoc-amino acid, via intermediate 5-oxazolidinones, has
been developed by using Lewis acid catalysis for the reduc-
tive opening of the oxazolidinone ring.
This methodology is known to be free of racemization
and may be applied to acid-stable N-carbamate protected
amino acids, i.e., CBz- and Fmoc-protected. This process
also tolerates functionalized side chains, provided that
they are protected with non-acid-labile protecting groups.
Although powerful, this method suffers from the use
of large excess, typically 3 equiv or more, of triethylsilane
and consumes large quantities of TFA. Silane reducing
agents are costly; however, attempts to replace them with
other hydride donors has proven difficult, as other
reducing agents may cause cleavage of the carbamate
protecting group or may be too weak to affect the
reduction of the intermediate N-acyliminium ion. The
trifluoroacetic acid used for the ionic hydrogenation is
also expensive, extremely corrosive, and very destructive
to tissue of mucous membranes.7
N-Methylated R-amino acids are widespread in nature,
as part of larger peptidic natural products. They also find
broad application for the design of biologically active
1
substances in medicinal chemistry. N-Methylation of
amino acids is known to increase membrane perme2-
ability, proteolytic stability, and conformational rigidity.
Recently, several peptides incorporating one or more
N-methylated amino acids have been reported as potent
inhibitors of amyloidosis formation, e.g., as inhibitors of
the Aâ-peptide aggregation related to Alzheimer’s disease
and the IAPP aggregation associated with diabetes type
3
II.
Several procedures exist for the synthetic preparation
of N-methylated amino acids; however, many of these
methods suffer from limitations in terms of yield or
Because of these limitations, we became interested in
developing a more efficient methodology for the reduction
of the intermediate 5-oxazolidinone. Initially, we at-
tempted the method developed by Reddy et al. for the
reduction of Cbz- and Boc-protected oxazolidinones with
8
*
To whom correspondence should be addressed. Phone: +46-18-
71 3787, Fax: +46-18-471 3818.
1) (a) Fairlie, D. P.; Abbenante, G.; March, D. R. Curr. Med. Chem.
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4
3
NaCNBH and TMSCl; however, upon attempting this
(
1
methodology we failed to reduce the Fmoc-protected
oxazolidinones investigated. Instead, we focused our
attention on using various Lewis acids as replacements
for the trifluoroacetic acid used to affect the ionic
hydrogenation reaction.
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10.1021/jo050916u CCC: $30.25 © 2005 American Chemical Society
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J. Org. Chem. 2005, 70, 6918-6920
Published on Web 07/26/2005