Enantioselective synthesis of (2-pyridyl)alanines via catalytic hydrogenation and application to the synthesis of L-azatyrosine.

Article abstract of DOI:10.1021/ol016455q

[reaction: see text] A novel method for the synthesis of (2-pyridyl)alanines 2a-b was developed by converting (2-pyridyl)dehydroamino acid derivatives 1a-b to the corresponding N-oxides 3a-b followed by asymmetric hydrogenation using (R,R)-[Rh(Et-DUPHOS)(

Full text of DOI:10.1021/ol016455q

ORGANIC
LETTERS
2001
Vol. 3, No. 20
3157-3159
Enantioselective Synthesis of
(2-Pyridyl)alanines via Catalytic
Hydrogenation and Application to the
Synthesis of L-Azatyrosine
Maciej Adamczyk,* Srinivasa Rao Akireddy, and Rajarathnam E. Reddy
Department of Chemistry (9 NM), Building AP20, Diagnostics DiVision,
Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6016
maciej.adamczyk@abbott.com
Received July 18, 2001
ABSTRACT
A novel method for the synthesis of (2-pyridyl)alanines 2a−b was developed by converting (2-pyridyl)dehydroamino acid derivatives 1a−b to
the corresponding N-oxides 3a−b followed by asymmetric hydrogenation using (R,R)-[Rh(Et-DUPHOS)(COD)]BF [(R,R)-6] catalyst and subsequent
4
N-oxide reduction in 80−83% ee. This methodology was applied to the total synthesis of L-azatyrosine [(+)-12], an antitumor antibiotic, starting
from (5-benzyloxy)-2-pyridylmethanol (7), in >96% enantiomeric purity.
Interest in nonproteinogenic R-amino acids continues to arise
as a result of their applications in the medicinal and
biotechnological fields1,2 and utility as chiral building blocks
in organic synthesis.3 Pyridylalanines have been used as
replacements of histidine4 and shown to function as antago-
nists of phenylalanines.5 Additionally, the pyridylalanine
derivative have also been studied as antiinflammatory6 and
antitumor-antibiotic agents7 and for other pharmaceutical
applications.8 A number of methods have been developed
for synthesis of pyridylalanines, e.g., enzymatic separation
of racemates,9 organometallic coupling reactions,10 diastereo-
selective alkylation,11 and by catalytic asymmetric hydro-
genation.12 Although asymmetric hydrogenation of pyridyl-
dehydroamino acid derivatives requires high pressure and
temperature12c or addition of nonchelating agents such as
tetrafluoroboric acid,12a,b this protocol has a number of
(1) (a) Barret, G. C. Chemistry and Biochemistry of the Amino Acids:
Chapman and Hall: London, 1985. (b) Amino Acids, Peptides and Proteins;
The Chemical Society: Cambridge, 1968-1991; Vols. 1-22. (c) Greenstein,
J. P.; Wintz, M. Chemistry of the Amino Acids; Robert E. Krieger: FL,
1984; Vols. 1-3.
(2) (a) Roberts, D. C.; Vellaccio, F. The Peptides; Academic Press: New
York, 1983; Vol. 5, pp 341-449. (b) Wilson, M. J.; Hatfield, D. L. Biochim.
Biophys. Acta 1984, 781, 205-215. (c) Lea, P. J.; Norris, R. D. Phytochem-
istry 1976, 15, 585-595.
(7) (a) Inouye, S.; Shomura, T.; Ogawa, Y.; Watanabe, H.; Yoshida, J.;
Niida, T. Chem. Pharm. Bull. 1975, 23, 2669-2677. (b) Izawa, M.;
Takayama, S.; Shindo-Okada, N.; Doi, S.; Kimura, M,; Katsuki, M.,
Nishimura, S. Cancer Res. 1992, 52, 1628-1630 and references therein.
(8) (a) Japanese Patent JP 60/130591 A2, 1985. (b) European Patent EP
98609/A2, 1984. (c) Rivier, J. E.; Porter, J.; Rivier, C. L.; Perrin, M.;
Corrigan, A.; Hook, W. A.; Siraganian, R. P.; Vale, W. W. J. Med. Chem.
1986, 29, 1846-1851. (d) Folkers, K.; Bowers, C. Y.; Kubiak, T. M.;
Stepinski, J. U.S. Patent 4504414, 1985.
(3) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis: Construction
of Chiral Molecules using Amino Acids; John Wiley & Sons: New York,
1987. (b) Hanessian, S. Total Synthesis of Natural Products: The Chiron
Approach; Pergamon Press: Oxford, 1983.
(4) Hsieh, K.; Jorgensen, E. C. J. Med. Chem. 1979, 22, 1199-1206.
(5) Sullivan, P. T.; Kester, M.; Norton, S. J. J. Med. Chem. 1968, 11,
1172-1176.
(6) Shimeno, H.; Soeda, S.; Nagamatsu, S. H. Chem. Pharm. Bull. 1977,
25, 2983-2987.
(9) (a) Hoes, C.; Raap, J.; Bloemhoff, W.; Kerling, K. E. T. J. R. Neth.
Chem. Soc. 1980, 99, 99-104. (b) Cooper, M. S.; Seton, A. W.; Stevens,
M. F. G.; Westwell, A. D. Bioorg. Med. Chem. Lett. 1996, 6, 2613-2616.
(10) (a) Ye, B.; Otaka, A.; Burke, T. R., Jr. Synlett 1996, 459-460. (b)
Ye, B.; Burke, T. R., Jr. J. Org. Chem. 1995, 60, 2640-2641.
(11) (a) Croce, P. D.; Rosa, C. L., Pizzatti, E. Tetrahedron: Asymmetry
2000, 11, 2635-2642. (b) Myers, A. G.; Gleason, J. L. J. Org. Chem. 1996,
61, 813-815. (c) Schow, S. R.; DeJoy, S. Q.; Wick, M. M.; Kerwar, S. S.
J. Org. Chem. 1994, 59, 6850-6852.
10.1021/ol016455q CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/07/2001

advantages over other methods available for synthesis of
R-amino acids. This is due to the compatibility of a variety
of groups to the reaction conditions and, more importantly,
the excellent optical purity with which R-amino acids can
be produced.12e,13 However, attempts to prepare 6-unsubsti-
tuted (2-pyridyl)alanines (2) by asymmetric hydrogenation
protocol (Figure 1) have not been successful as a result of
Scheme 1. Synthesis of (2-Pyridyl)alanine Derivatives 2a-b
via Asymmetric Hydrogenation
corresponding N-oxides 3a-b in 30-39% yields after
purification by silica gel column chromatography. Oxidation
of 1a-b with m-CPBA was found to be very slow, and even
after 6 days, only a 10% of the desired N-oxide (e.g., 3a)
was isolated. Asymmetric hydrogenation of N-oxide 3a was
initially carried out using a catalytic amount (0.05 equiv) of
(R,R)-[Rh(DIPAMP)(COD)]BF4 [(R,R)-5]17 in anhydrous
MeOH at 48 °C and 60 psi. After the reaction was complete
as determined by TLC, the reaction mixture was concen-
trated, and the crude compound was purified by silica gel
column chromatography to afford (S)-4a in 89% yield. The
optical purity of (S)-4a was determined by converting to
Mosher’s amide and found to be 20% ee (Table, entry 1).18
Alternatively, the hydrogenation of N-oxide derivative 3a
using (R,R)-[Rh(Et-DUPHOS)(COD)]BF4 [(R,R)-6] in an-
hydrous MeOH at room temperature and 45 psi gave (S)-4a
91% yield. To our delight, the optical purity of 4a was found
to be 83% ee (entry 2).18,19 Hydrogenation of 3a with (S,S)-6
to gave (R)-4a in 83% ee (entry 3). Similarly the hydrogena-
Figure 1. General strategy for the synthesis of (2-pyridyl)alanines
(2) via asymmetric hydrogenation.
the participation of ring nitrogen in the formation of metal-
substrate complex.11 It is pertinent to note that when the
6-position on pyridine ring is substituted with groups such
as OMe, asymmetric hydrogenation proceeds to give
2-pyridylalanines.12e To overcome this difficulty, we envi-
sioned (Figure 1) that by converting the pyridine ring
nitrogen to its derivatives, e.g., N-oxide, its participation in
the formation of complex with metal catalyst could be
prevented and thereby asymmetric hydrogenation of the
double bond be accomplished. After the asymmetric induc-
tion step, the N-oxide could easily be removed by reduction
under mild conditions using metals such as zinc. In this
paper, we describe a general method for enantioselective
synthesis of (2-pyridyl)alanine derivatives 2a-b via asym-
metric hydrogenation of the N-oxide derivatives of (2-
pyridyl) dehydroamino acids 3a-b and subsequent reduction
of N-oxide. Application of this methodology to the total
synthesis of L-azatyrosine (12), an antibiotic exhibiting
interesting antitumor properties,7,14 is also described.
(14) (a) Chung, D. L.; Brandt-Rauf, P.; Murphy, R. B.; Nishimura, S.;
Yamaizumi, Z.; Weinstein, I. B.; Pincus, M. R. Anticancer Res. 1991, 11,
1373-1378. (b) Fujita-Yoshigaki, J.; Yokoyama, S.; Shindo-Okada, N.;
Nishimura, S. Oncogene 1992, 7, 2019-2024. (c) Campa, M. J.; Glickman,
J. F.; Yamamoto, K.; Chang, K.-J. Proc. Natl. Acad. Sci. U.S.A. 1992, 89,
7654-7658. (d) Kyprianou, N.; Taylor-Papadimitriou, J. Oncogene 1992,
7, 57-63. (e) Nomura, T.; Ryoyama, K.; Okada, G.; Matano, S.; Nakamura,
S.; Kameyama, T. Jpn. J. Cancer Res. 1992, 83, 851-858. (f) Shindo-
Okada, N.; Makabe, O.; Nagahara, H.; Nishimura, S. Mol. Carcinog. 1989,
2, 159-167.
(15) (2-Pyridyl)dehydroamino acid derivatives 1a-b were prepared from
commercially available pyridine-2-carboxaldehyde and 5-bromo-pyridine-
2-carboxaldehyde, respectively, in 78-89% yield by treatment with
N-(benzyloxycarbonyl)phosphonoglycine trimethyl ester in the presence of
N,N,N′,N′-tetramethylguanidine (TMG) in THF at room temperature for 6
h.
To validate this strategy, our first goal was to prepare the
required pyridinium N-oxide derivatives 3a-b needed for
asymmetric hydrogenation. Accordingly, (Scheme 1) the (2-
pyridyl)dehydroamino acid derivatives 1a-b15 were oxidized
with urea-hydrogen peroxide (UHP) complex and trifluoro-
acetic anhydride (TFAA) in acetonitrile16 to afford the
(16) Caron, S.; Do, N. M.; Sieser, J. Tetrahedron Lett. 2000, 41, 2299-
2302.
(12) (a) Jones, S. W.; Palmer, C. F.; Paul, J. M.; Tiffin, P. D. Tetrahedron
Lett. 1999, 40, 1211-1214. (b) Dobler, C.; Kreuzfeld, H.-J.; Michalik, M.;
Krause, H. W. Tetrahedron: Asymmetry 1996, 7, 117-125. (c) Cativiela,
C.; Mayoral, J. A.; Melendez, E.; Oro, L. A.; Pinillos, M. T.; Uson, R. J.
Org. Chem. 1994, 49, 2502-2504. (d) Bozell, J. J.; Vogt, C. E.; Gozum,
J. J. Org. Chem. 1991, 56, 2584-2487. (e) Adamczyk, M.; Akireddy, S.
R.; Reddy, R. E. Org. Lett. 2000, 2, 3421-3423.
(13) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley
and Sons: New York, 1994; pp 16-94. (b) Takaya, H.; Ohta, T.; Noyori,
R. In Catalytic Asymmetric Hydrogenation; Ojima, I., Ed.; VCH Publish-
ers: Weinheim, 1993; pp 1-39.
(17) For a review on the asymmetric hydrogenation using phosphine
ligands, see: Knowles, W. S. Acc. Chem. Res. 1983, 16, 106-112.
(18) The optical purity (% ee) of 4a-b was determined by converting
4a-b to the corresponding Mosher’s amide in three steps [(1) Zn, 30%
aqueous NH4Cl solution, THF, rt, 30 min; (2) 10% Pd/C and 1 N aq HCl,
H2, 1 atm, rt, 2 h; (3) (R)-MTP-Cl, Et3N, CH2Cl2, rt, 12 h] and analyzed by
19F NMR.
(19) The absolute configuration of the newly generated chiral center in
4a using (R,R)-6 catalyst was determined to be (S) by cleavage of protective
groups to the corresponding known R-amino acid and comparison of its
rotation; see: ref 9a.
3158
Org. Lett., Vol. 3, No. 20, 2001

normal phenotypic behavior to transformed cells bearing
oncogenic Ras genes.14 Additionally, (S)-(+)-12 has been
found to inhibit chemical carcinogen-induced tumor growth
in mice harboring normal human c-Ha Ras genes.7b The
synthesis of (S)-(+)-12 was accomplished (Scheme 2) via
asymmetric hydrogenation protocol starting from a 5-ben-
zyloxy-2-pyridylmethanol (7).21 Accordingly, the compound
721c was oxidized using manganese dioxide in chloroform,
and the resulting aldehyde was subjected to a reaction with
N-(benzyloxycarbonyl)phosphonoglycine trimethyl ester in
the presence of N,N,N′,N′-tetramethylguanidine (TMG) in
THF. Purification of the crude product by silica gel column
chromatography afforded the dehydroamino acid derivatives
8 in 84% yield. Oxidation of the dehydroamino acid
derivatives 8 with urea-hydrogen peroxide (UHP) complex
and trifluoroacetic anhydride gave the corresponding N-oxide
9 in 49% yield. Asymmetric hydrogenation of N-oxide 9 in
the presence of (R,R)-[Rh(Et-DUPHOS)(COD)]BF4 [(R,R)-
6] catalyst in anhydrous MeOH at 48 °C and 45 psi afforded
(S)-(-)-10 in 80% yield and 83% ee. Crystallization of (S)-
(-)-10 in CH2Cl2/hexanes improved the ee to >96%.22 The
(S)-(-)-10 (ee >96%) was then reduced with activated zinc
powder and 30% aqueous ammonium chloride solution in
THF20 at room temperature to afford the amino acid
derivative (S)-(+)-11 in excellent yield (92%) after silica
gel column chromatography The R-amino acid derivative (S)-
(+)-11 was then subjected to hydrolysis with LiOH to afford
the corresponding free carboxylic acid, which was then
hydrogenated in the presence of 10% Pd/C and 1 N HCl in
MeOH. The crude product was purified by preparative
reversed phase HPLC23 followed by ion exchange chroma-
tography using Dowex 50 WX4-100 resin to afford L-
azatyrosine [(+)-12] in 82% yield, [R]23D +56.41 (c 0.78, 1
Table 1. Asymmetric Hydrogenation of N-Oxides 3a-b
entry N-oxide (3), R ) catalyst 5/6 product (4), R )
eea
1
2
3
4
3a , R ) H
3a , R ) H
3a , R ) H
3b, R ) Br
(R,R)-5
(R,R)-6
(S,S)-6
(R,R)-6
(S)-4a , R ) H
(S)-4a , R ) H
(R)-4a , R ) H
(S)-4b, R ) Br
20%
83%
83%
80%
a The optical purity (% ee) of 4a-b was determined by 19F NMR of the
Mosher amide (see ref 18).
tion of N-oxide 3b, which contains bromine at the 5-position
of the pyridine ring, with (R,R)-6 catalyst gave (S)-4b in
85% yield and 80% ee (entry 4). It is pertinent to mention
that the direct hydrogenation of (2-pyridyl)dehydroamino
acid derivatives 1a-b using 0.05-0.15 equiv of catalysts
(R,R)-5 or (R,R)-6 at a higher temperature (up to 50 °C) and/
or pressure (up to 60 psi H2) was not successful. Thus,
transformation of the pyridine ring nitrogen to its N-oxide
derivative allowed the catalytic asymmetric hydrogenation
of the double bond in 3a-b using (R,R)-6 catalyst to give
4a-b in 80-83% ee’s. The N-oxide in (S)-4a, (S)-4b was
then easily reduced with activated zinc powder and 30%
Scheme 2. Synthesis of L-Azatyrosine (12)
N HCl) {lit.7a [R]25 +55 (c 1.1, 1 N HCl)}.
D
In summary, a novel method was developed for enantio-
selective synthesis of (2-pyridyl)alanines 2a-b via asym-
metric hydrogenation protocol. This methodology was suc-
cessfully applied to the total synthesis of L-azatyrosine [(+)-
12], an antitumor antibiotic, in >96% enantiomeric excess
and good overall yield.
OL016455Q
(21) For synthesis of azatyrosine [(5-hydroxy-2-pyridyl)glycine], see: (a)
Norton, S. J.; Skinner, C. G.; Shive, W. J. Org. Chem. 1970, 26, 1495-
1498. (b) Norton, S. J.; Sullivan, P. T. J. Heterocycl. Chem 1970, 7, 699-
702. (c) Herdeis, C.; Gebhard, R. Heterocycles 1986, 24, 1019-1024. (c)
Schow, S. R.; Deloy, S. Q.; Wick, M. M.; Kerwar, S. S. J. Org. Chem.
1994, 59, 6850-6852. (d) Ye, B.; Burke, T. R. J. Org. Chem. 1995, 60,
2640-2641. (e) Coopre, M. S.; Seton, A. W.; Stevens, M. F. G.; Westwell,
A. D. Bioorg. Med. Chem. Lett. 1996, 6, 2613-2616. (f) Myers, A. G.;
Gleason, J. L. J. Org. Chem. 1996, 60, 813-815.
aqueous ammonium chloride solution in THF at room
temperature.20 Purification of the crude product by silica gel
column chromatography afforded the amino acid derivatives
(S)-2a and (S)-2b, respectively, in excellent yield (84-92%).
L-Azatyrosine [(+)-12] is an antibiotic isolated from
Streptomyces chibaensis7a that has been shown to restore
(22) The enantiomeric excess (% ee) of (S)-(-)-10 before and after
crystallization was determined by converting to Mosher’s amide in three
steps; see ref 18 for details.
(23) Preparative reversed phase HPLC was carried out on a Waters,
Symmetry, C18, 7.0 µ, 40 × 100 mm column using 2:98 MeCN/0.1%
aqueous trifluoroacetic acid, 25 mL/min at 225 nm.
(20) Aoyagi, Y.; Abe, T.; Ohta, A. Synthesis 1997, 891-894.
Org. Lett., Vol. 3, No. 20, 2001
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