ORGANIC
LETTERS
2005
Vol. 7, No. 19
4111-4112
Facile Synthesis of Highly
Functionalized N-Methyl Amino Acid
Esters without Side-Chain Protection
Kimberly N. White and Joseph P. Konopelski*
Department of Chemistry and Biochemistry, UniVersity of California,
Santa Cruz, California 95064
Received June 21, 2005
ABSTRACT
The facile, two-pot synthesis of N-methyl amino acid esters by way of reductive amination is presented. Side chain protection schemes are
not required, the starting materials are all commercially available, and the synthetic method is straightforward and affords desired product in
very high yield.
The occurrence of N-methyl amino acids (NMA) and their
derivatives in natural products1 and proteins2 has attracted
an interest in these compounds as valuable synthetic building
blocks. Indeed, incorporation of NMA into synthetic peptides
has been shown to afford increased resistance to proteolysis,
unique membrane permeability, and uncommon conforma-
tional preferences dictated by the decreased hydrogen bond-
ing capability. However, while various procedures for the
production of NMA have been developed over the years,3
few syntheses effectively combine the elements of simplicity
and generality, particularly when dealing with amino acids
bearing functionalized side chains.
material, albeit with side-chain protection, in a six-step
procedure with an overall yield of 30%.5 In our hands, this
procedure was less successful, affording the desired material
in approximately 12% yield. Thus, we set out to develop an
alternative route that would be amenable to the production
of significant quantities of desired material in synthetically
useful yields.
Herein, we report the preparation of N-methyl derivatives
of side-chain-functionalized amino acid esters in high yield
through facile laboratory manipulations. The procedure is
performed, without resorting to side-chain protection, via
consecutive reductive amination reactions, first with ben-
zaldehyde, then with paraformaldehyde. Both sequences of
imine (iminium) formation/reduction are performed in the
same flask without isolation. Following isolation of the
N-benzyl-N-methyl amino acid derivative, removal of the
benzyl protecting group affords desired material. This
method, which shows no trace of racemization, employs
commercially available and relatively inexpensive amino acid
esters as starting materials and affords the desired N-
methylated compounds in a two flask sequence.
Work in our laboratory synthesizing models of the active
site of cytochrome c oxidase4 required us to have a viable
and efficient source of N-methyl L-histidine esters. A recent
procedure by Hughes and co-workers produced the desired
(1) (a) Wen S. J.; Yao Z. J. Org. Lett. 2004, 6, 2721-2724. (b) Chu, K.
S.; Negrete, G. R.; Konopelski, J. P. J. Org. Chem. 1991, 56, 5196-5202.
(c) Boger, D. L.; Teramoto, S.; Cai, H. Bioorg. Med. Chem. 1997, 5, 1577-
1589. (d) Greico, P. A.; Perez-Medrano, A. Tetrahedron Lett. 1988, 29,
4225-4228. (e) Boger, D. L.; Yohannes, D. J. Org. Chem. 1988, 53, 487-
499.
(2) Fairlie, D. P. Curr. Med. Chem. 1995, 2, 654-686.
(3) Aurelio, L.; Brownlee, R. T. C.; Hughes, A. B. Chem. ReV. 2004,
104, 5823-5846.
(4) Cappuccio, J. A.; Ayala, I.; Elliot, G. I.; Szundi, I.; Lewis, J.;
Konopelski, J. P.; Barry, B. A.; Einarsdottir. J. Am. Chem. Soc. 2002, 124,
1750-1760.
As shown in Scheme 1, our method involves treatment of
the amino acid ester, in methanol, first with benzaldehyde
(5) (a) Aurelio, L.; Box, J. S.; Brownlee, R. T. C.; Hughes, A. B.; Sleebs,
M. M. J. Org. Chem., 2003, 68(7), 2652-2667. (b) Aurelio, L.; Brownlee,
R. T. C.; Hughes, A. B. Org. Lett. 2002, 4, 3767-3769.
10.1021/ol051441w CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/18/2005