Efficient synthesis of enantiopure β-amino-γ-keto acids from L-homoserine

Article abstract of DOI:10.1021/ol0345327

(Matrix presented) A variety of β-amino-γ-keto acids were prepared in four steps from commercially available L-homoserine. The reaction sequence is highlighted by a Ni-catalyzed Grignard addition to a N-protected derivative of L-homoserine. One of the β-a

Full text of DOI:10.1021/ol0345327

ORGANIC
LETTERS
2003
Vol. 5, No. 12
2107-2109
Efficient Synthesis of Enantiopure
â-Amino-γ-Keto Acids from
L-Homoserine
Anil K. Sharma and Paul J. Hergenrother*
Department of Chemistry, Roger Adams Laboratory, UniVersity of Illinois,
Urbana, Illinois 61801
hergenro@uiuc.edu
Received March 26, 2003
ABSTRACT
A variety of â-amino-γ-keto acids were prepared in four steps from commercially available L-homoserine. The reaction sequence is highlighted
by a Ni-catalyzed Grignard addition to a N-protected derivative of L-homoserine. One of the â-amino-γ-keto acids was then used to create a
â-peptide trimer composed solely of â-amino-γ-keto acids.
â-Amino acids are key components of many natural products,
including bestatin, cryptophycin, and taxol. In addition, many
â-amino acids are biologically active compounds in their own
right. For example, the â-amino acid emeriamine has been
shown to possess potent hypoglycemic and antiketogenic
activities,1 and cispentacin is an antifungal agent (Figure 1).2
relative to their natural R-peptide counterparts.3 The biologi-
cal applications of these â-peptides are numerous. For
instance, certain â-peptides have shown antimicrobial activ-
ity;4 others can mimic an R-peptide hormone,5 whereas others
have the ability to inhibit cholesterol and fat absorption.6
Furthermore, it has recently been demonstrated that the
â-peptide analogue of the Tat sequence will translocate into
mammalian cells.7
The incorporation of the ketone functional group into
â-peptides would allow for site-specific modification of such
macromolecules through the orthogonal reactivity of ketones.
In addition, ketones can act as hydrogen bond acceptors, and
(3) (a) Woll, M. G.; Fisk, J. D.; LePlae, P. R.; Gellman, S. H. J. Am.
Chem. Soc. 2002, 124, 12447-12452. (b) Glattli, A.; Daura, X.; Seebach,
D.; van Gunsteren, W. F. J. Am. Chem. Soc. 2002, 124, 12972-12978. (c)
Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. ReV. 2001, 101, 3219-
3232. (d) Appella, D. H.; Christianson, L. A.; Klein, D. A.; Powell, D. R.;
Huang, X. L.; Barchi, J. J.; Gellman, S. H. Nature 1997, 387, 381-384.
(4) (a) Porter, E. A.; Wang, X.; Lee, H.-S.; Weisblum, B.; Gellman, S.
H. Nature 2000, 404, 565. (b) Hamuro, Y.; Schneider, J. P.; DeGrado, W.
F. J. Am. Chem. Soc. 1999, 121, 12200-12201. (c) Liu, D.; DeGrado, W.
F. J. Am. Chem. Soc. 2001, 123, 7553-7559.
Figure 1. Biologically active â-amino acids.
Oligomers composed entirely of â-amino acids can adopt
folded structures in solution and have unique properties
(1) Shinagawa, S.; Kanamaru, T.; Harada, S. Asai, M.; Okazaki, H. J.
Med. Chem. 1987, 30, 1458-1463.
(2) (a) Konishi, M.; Nishio, M.; Saitoh, K.; Miyaki, T.; Oki, T.;
Kawaguchi, H. J. Antibiot. 1989, 42, 1749-1755. (b) Oki, T.; Hirano, M.;
Tomatsu, K.; Numata, K.; Kamei, H. J. Antibiot. 1989, 42, 1756-1762.
(c) Mittendorf, J.; Benet-Buchholz, J.; Fey, P.; Mohrs, K.-H. Synthesis 2003,
1, 136-140.
(5) Gademann, K.; Kimmerlin, T.; Hoyer, D.; Seebach, D. J. Med. Chem.
2001, 44, 2460-2468.
(6) Werder, M.; Hauser, H.; Abele, S.; Seebach, D. HelV. Chim. Acta
1999, 82, 1774-1783.
(7) Umezawa, N.; Gelman, M. A.; Haigis, M. C.; Raines, R. T.; Gellman,
S. H. J. Am. Chem. Soc. 2002, 124, 368-369.
10.1021/ol0345327 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/17/2003

thus oligomers containing this functionality could have
unique hydrogen bonding and folding patterns. We are
interested in preparing a wide variety of â-amino-γ-keto acids
to explore the oligomeric properties of such compounds, as
well as for their use as chiral building blocks in combinatorial
library synthesis and as modules in protease inhibitors. While
there have been many synthetic efforts directed toward the
preparation of â-amino acids,8 there are almost no reports
of the synthesis of â-amino-γ-keto acids.9 Herein we describe
an efficient preparation of several â-amino-γ-keto acids from
commercially available L-homoserine and the synthesis of a
trimer derived from one of these compounds.
Table 1. Reaction of N-Protected Homoserine with Grignard
Reagents
entry
R
X
product
yielda
1
2
3
4
5
6
7
8
propyl
butyl
pentyl
hexyl
cyclohexyl
cyclopentyl
phenyl
benzyl
Br
Br
Br
Br
Cl
Br
Br
Cl
3a
3b
3c
3d
3e
3f
67
50
56
46
62
36
47
51
The synthetic route for the preparation of â-amino-γ-keto
acids is depicted in Scheme 1. The synthesis commenced
3g
3h
Scheme 1. Synthesis of â-Amino-γ-keto Acids
a Yields include a small amount (5-10%) of the secondary alcohol
product. This compound, together with 3a-h, is oxidized to 4a-h in the
next step of the reaction sequence.
moderate to good yields (Table 1); 6 equiv of the Grignard
reagent was used in each transformation. These reactions
typically were run for 5-7 days, and even then 20-30% of
the unreacted starting material could be recovered. Although
a small amount (<10%) of secondary alcohol was also
present after this Grignard addition, we did not observe the
formation of the tertiary alcohol that would result from over-
addition of the Grignard reagent. Subsequent Jones oxidation
of the primary alcohol in 3a-h to the carboxylic acid, and
of any secondary alcohol to the corresponding ketone, gave
the protected â-amino acids 4a-h (Table 2).
Table 2. Jones Oxidation to Provide Protected â-Amino-γ-keto
Acids
with protection of the amine of L-homoserine.10 A robust
protecting group was required, as the ketone side chain was
to be installed through a Grignard addition. On this basis,
L-homoserine was treated with phenylsulfonyl chloride to
provide the phenylsulfonamide derivative 2. Facile crystal-
lization from chilled concentrated HCl gave the pure product
in 89% yield.
Under standard Grignard reaction conditions sulfonamide
acid 2 was unreactive. However, use of a nickel catalyst11
enabled the successful addition of several Grignard reagents
to the carboxyl group of 2 to provide ketones 3a-h in
entry
R
product
yield
1
2
3
4
5
6
7
8
propyl
butyl
pentyl
hexyl
cyclohexyl
cyclopentyl
phenyl
benzyl
4a
4b
4c
4d
4e
4f
62
52
53
52
64
68
70
50
(8) (a) Juaristi, E.; Quintana, D.; Lamatsch, B.; Seebach, D. J. Org. Chem.
1991, 56, 2553-2557. (b) Juaristi, E.; Escalante, J.; Lamatsch, B.; Seebach,
D. J. Org. Chem. 1992, 57, 2396-2398. (c) Liu, M.; Sibi, M. P. Tetrahedron
2002, 58, 7991-8035. (d) Juaristi, E.; Lopez-Ruiz, H. Curr. Med. Chem.
1999, 6, 983-1004. (e) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 12964-12965. (f) Tang, W.; Zhang, X. Org. Lett. 2002, 4,
4159-4161.
(9) Seki, M.; Kubota, H.; Moriya, T.; Yamagishi, M.; Nishimoto, S.;
Matsumoto, K. Chem. Pharm. Bull. 1986, 34, 4516-4522.
(10)
L-Homoserine can be synthesized from L-aspartic acid. See: Sutherland,
A.; Caplan, J. F.; Vederas, J. C. Chem. Commun. 1999, 555-556.
(11) Fiandanese, V.; Marchese, G.; Ronzini, L. Tetrahedron Lett. 1983,
24, 3677-3680.
4g
4h
The direct conversion of carboxylic acid 2 into ketones
3a-h obviated the need for protection of the hydroxyl
functionality of 2. This protection would have been necessary
if standard conditions (conversion of the acid into the acid
chloride and then reaction with the Grignard reagent) had
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Org. Lett., Vol. 5, No. 12, 2003

been employed to convert the acid into a ketone. The ability
of the nickel catalyst to suppress over-addition to the
carboxyl group is consistent with previous literature results.11
Removal of the phenylsulfonamide proved to be somewhat
troublesome. When SmI2, Na/Hg amalgam, or Li-NH3 was
employed, little or no free â-amino acid was obtained.
However, refluxing in HBr/phenol provided the desired
â-amino-γ-keto acids 5a-h in good yields and purity without
the need for chromatography.
Scheme 2. Synthesis of a Trimeric â-Peptide Composed of
â-Amino-γ-keto Acid Monomers
To determine if any racemization of the preexisting
stereogenic center had occurred during the course of the
synthesis, Mosher amide derivatives of several of the final
compounds were synthesized and analyzed. In all cases, the
compounds were found to have enantiomeric ratios (ers) of
greater than 99.5:0.5. The optical rotations of 5a-h are
reported in Figure 2.
into peptides, we created a â-peptide trimer of the cyclo-
hexyl-substituted â-amino-γ-keto acid 5e (Scheme 2). The
synthesis of this â-amino acid peptide was performed using
standard techniques for peptide coupling and purification.
Thus, Fmoc-protected acid 6 was coupled to the methyl ester
derivative 7 to provide the dimer 8. After Fmoc deprotection
and a further round of coupling, the trimer 9 was obtained
(Scheme 2). Although â-peptide 9 is a homopolymer, the
synthesis of heteropolymers consisting of various â-amino-
γ-keto acids, or the selective incorporation of one ketonic
functionality into a standard â-peptide can easily be envi-
sioned. Thus, the facile synthesis of a variety of â-amino-
γ-keto acids as described herein should also allow for the
production of an array of â-peptides containing ketone side
chains.
Described herein is a four-step synthesis of â-amino-γ-
keto acids from commercially available L-homoserine. This
synthetic route requires only one chromatographic purifica-
tion, and provides the desired products with no detectable
racemization of the stereocenter. These compounds will be
useful as chiral building blocks for combinatorial synthesis
and as monomers for â-peptide formation. Using standard
amino acid couplings, a trimer was created from the
cyclohexyl-substituted compound 5e. Application of these
chiral â-amino-γ-keto acids to a variety of problems of
biological interest will be reported in due course.
Figure 2. â-Amino-γ-keto acids and their optical rotations.
As ketones provide easily exploitable reactivity, their
incorporation into biopolymers allows for facile, site-specific
modification of macromolecules.12 In addition, a peptide
composed entirely of â-amino-γ-keto acids would be ex-
pected to have markedly different H-bonding properties
relative to other â-peptides. To demonstrate that the â-amino-
γ-keto acids synthesized herein can readily be incorporated
Acknowledgment. We thank the University of Illinois
and the National Science Foundation (NSF-CAREER Award
to P.J.H., CHE-0134779) for support of this research. P.J.H.
is the recipient of a Research Innovation Award from the
Research Corporation and of a Beckman Young Investigator
Award.
(12) (a) Canne, L. E.; Ferre-D’Amare, A. R.; Burley, S. K.; Kent, S. B.
H. J. Am. Chem. Soc. 1995, 117, 2998-3007. (b) Mahal, L. K.; Yarema,
K. J.; Bertozzi, C. R. Science 1997, 276, 1125-1128. (c) Cornish, V. W.;
Hahn, K. M.; Schultz, P. G. J. Am. Chem. Soc. 1996, 118, 8150-8151. (d)
Datta, D.; Wang, P.; Carrico, I. S.; Mayo, S. L.; Tirrell, D. A. J. Am. Chem.
Soc. 2002, 124, 5652-5653.
Supporting Information Available: Full experimental
protocols and spectral data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0345327
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