An efficient enantioselective synthesis of (S)-(-)-acromelobic acid

Article abstract of DOI:10.1021/ol006363l

(Equation Presented) A highly efficient enantioselective synthesis of (S)-(-)-acromelobic acid (1) was achieved via asymmetric hydrogenation of dehydroamino acid derivative (3) using (R,R)-[Rh(DIPAMP)(COD)]BF₄ catalyst followed by removal of protective groups in >98% ee and good over all yield. The key intermediate (3) was prepared from the commercially available citrazinic acid (4) in six steps.

Full text of DOI:10.1021/ol006363l

ORGANIC
LETTERS
2000
Vol. 2, No. 22
3421-3423
An Efficient Enantioselective Synthesis
of (S)-(−)-Acromelobic Acid
Maciej Adamczyk,* Srinivasa Rao Akireddy, and Rajarathnam E. Reddy
Department of Chemistry (9NM), Building AP20, Diagnostics DiVision, Abbott
Laboratories, 100 Abbott Park Road, Abbott Park, Illinois, 60064-6016
maciej.adamczyk@abbott.com
Received July 21, 2000
ABSTRACT
A highly efficient enantioselective synthesis of (S)-(−)-acromelobic acid (1) was achieved via asymmetric hydrogenation of dehydroamino acid
derivative (3) using (R,R)-[Rh(DIPAMP)(COD)]BF4 catalyst followed by removal of protective groups in >98% ee and good over all yield. The
key intermediate (3) was prepared from the commercially available citrazinic acid (4) in six steps.
The poisonous mushroom Clitocybe acromelalga, found
exclusively in Japan, has been the source of a variety of
potent neuroexcitatory amino acids related to the kainoid
family.1 (S)-(-)-Acromelobic acid [3-(6-carboxy-2-oxo-4-
pyridyl)-L-alanine, 1] (Figure 1) was isolated by Shirahama
amino acid, (S)-(-)-1, was proposed to be derived from
L-DOPA and exhibits depolarizing activity in the preparation
of newborn rat spinal cord.2b The first synthesis of
(S)-(-)-1 was reported by chemical conversion of L-
stizolobic acid (2), a related nonproteinogenic amino acid,
which was isolated from C. acromelalga2b and Stizolobium
hassjoo.2c Subsequently, Baldwin et al.3 reported a racemic
synthesis of (()-1 starting from catechol in 13 steps. We
have been interested in the synthesis of nonproteinogenic
amino acids,4 particularly the kainoid family,4a for a variety
of applications including in neuroscience research. In this
context, we describe the first and highly efficient enantio-
selective synthesis of (S)-(-)-acromelobic acid (1) starting
from a commercially available citrazinic acid (4).
The foundation of our strategy for construction of (S)-
(-)-1 was based on the introduction of an R-amino acid chain
Figure 1. Structure of amino acids (1 and 2).
(2) (a) Yamano, K.; Hashimoto, K.; Shirahama, H. Heterocycles 1992,
34, 445-448. (b) Yamano, K.; Shirahama, H. Tetrahedron 1993, 49, 2427-
2436. (c) Senoh, S.; Imamoto, S.; Maeno, Y.; Tokuyama, T.; Sakan, T.;
Komamine, A.; Hattori, S. Tetrahedron 1964, 46, 3431-3436.
(3) Baldwin, J. E.; Spyvee, M. R.; Whitehead, R. C. Tetrahedron Lett.
1994, 35, 6575-6576.
(4) (a) Adamczyk, M.; Johnson, D. D.; Reddy, R. E. Tetrahedron:
Asymmetry 2000, 11, 3063-3068. (b) Adamczyk, M.; Akireddy, S. R.;
Reddy, R. E. Tetrahedron: Asymmetry 1999, 10, 3107-3110. (c) Adam-
czyk, M.; Reddy, R. E. Tetrahedron: Asymmetry 2000, 11, 2289-2298.
(d) Adamczyk, M.; Johnson, D. D.; Reddy, R. E. Angew. Chem., Int. Ed.
1999, 38, 3537-3539.
et al.,2a,b from the fruit bodies of this mushroom by a
combination of ion-exchange column chromatography and
paper electrophoresis. Biosynthetically, this nonproteinogenic
(1) (a) For a recent review on the kainoid amino acid chemistry, see:
Parsons, A. F. Tetrahedron 1996, 52, 4149-4174. (b) Also see: Konno,
K.; Hashimoto, K.; Ohfune, Y.; Shirahama, H.; Matsumoto, T. J. Am. Chem.
Soc. 1988, 110, 4807-4815.
10.1021/ol006363l CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/05/2000

via asymmetric hydrogenation of the appropriately function-
alized dehydroamino acid derivative 3 using a transition
metal catalyst.5 Although the application of hydrogenation
protocol for the synthesis of (S)-(-)-1 looked promising in
light of recent success in the preparation of a variety of
R-amino acids,5 there were only a few reports in the literature
related to the hydrogenation of pyridyl dehydroamino acid
derivatives.6 Catalytic asymmetric hydrogenation of hetero-
cyclic systems appeared to be difficult due to the participation
of a heteroatom (e.g., pyridine ring nitrogen) which blocked
the formation of active metal-substrate complex.6 The
asymmetric hydrogenation reaction of 3,4-pyridyl dehy-
droamino acid derivatives, however, was facilitated either
transformed to the corresponding methoxy derivative 6 in
96% yield8 by treatment with sodium methoxide in refluxing
MeOH for 48 h. The NaOMe was added in two portions in
order to avoid the formation of the corresponding bis-
methoxy derivative. Reduction of the acid functionality in 6
by using a BH3-THF complex in THF at room temperature
for 5 h cleanly afforded the alcohol 7 in 74% yield after
purification by silica gel column chromatography. The chloro
functionality in alcohol 7 was then transformed into an ester
by reaction with carbon monoxide (1 atm pressure) in the
presence of palladium acetate, 1,3-bis(diphenylphosphino)-
propane (DPPP), 1-propanol, and K2CO3 in DMF at 90 °C
to obtain ester 8 in 45% yield. Compound 8 was oxidized to
the corresponding aldehyde 9 in 30% yield using MnO2 in
chloroform at room temperature for 48 h. Finally, aldehyde
9 was reacted with N-(benzyloxycarbonyl) phosphonoglycine
trimethyl ester (10) in the presence of N,N,N′,N′-tetrameth-
ylguanidine (TMG) in THF at 0 °C to room temperature for
6 h to afford the dehydroamino acid derivative (3) as a
mixture of Z/E isomers (ratio 93:7, determined by analysis
of 1H NMR of the crude compound). The Z and E
geometrical isomers of 3 were separated by silica gel column
chromatography (25% EtOAc in hexanes) to afford Z-isomer
3 in 76% yield.9
6c
by higher temperature and pressure6b or by addition of HBF4
to provide the corresponding pyridylalanine derivatives in
70-99% ee.6b,c Our proposed asymmetric hydrogenation
strategy for (S)-(-)-1 was strengthened by the notion that a
pyridine system such as 3, which contains substituents at
both the 2- and 6-positions, might reduce the participation
of a ring nitrogen in the formation of an active metal-
substrate complex due to steric hinderence. Nevertheless, our
first goal in the commencement of asymmetric hydrogenation
protocol for the synthesis of (S)-(-)-1 was to prepare
dehydroamino acid derivative 3, which was envisioned from
a commercially available inexpensive citrazinic acid (4).
Accordingly, citrazinic acid (4) (Scheme 1) was converted
to the 2,6-dichloroisonicotinic acid (5) in 71% yield by
Next step in the synthesis of (S)-(-)-acromelobic acid (1)
was the crucial asymmetric hydrogenation to introduce the
R-amino acid chain. Thus, hydrogenation of dehydroamino
acid derivative 3 was carried out (Scheme 2) using a catalytic
Scheme 1. Synthesis of Key Intermediate (3)
Scheme 2. Completion of the Synthesis of (S)-(-)-1
amount (0.05 equiv) of (R,R)-[Rh(DIPAMP)(COD)]BF4 in
anhydrous MeOH10 at 48 °C and 65 psi of pressure. After
(6) (a) Cativiela, C.; Mayoral, J. A.; Melendez, E.; Oro, L. A.; Pinillos,
M. T.; Uson, R. J. Org. Chem. 1984, 49, 2502-2504. (b) Bozell, J. J.;
Vogt, C. E.; Gozum, J. J. Org. Chem. 1991, 56, 2584-2487. (c) Dobler,
C.; Kreuzfeld, H.-J.; Machalik, M.; Krause, H. W. Tetrahedron: Asymmetry
1996, 7, 117-125.
treatment with phosphorus oxychloride and tetramethyl-
(7) Henegar, K. E.; Ashford, S. W.; Baughman, T. A.; Sih, J. C.; Gu,
Rui-Lin. J. Org. Chem. 1997, 62, 6588-6597.
ammonium chloride.7 One of the chloro groups in 5 was then
(8) The spectroscopic and physical properties (e.g., 1H NMR, 13C NMR,
HPLC, ESI-MS, HRMS) of all new compounds were fully consistent with
those of the assigned structures.
(5) (a) For recent studies on asymmetric hydrogenation, see: Noyori,
R. Asymmetric Catalysis in Organic Synthesis; Wiley and Sons: New York,
1994; Chapter 2, pp 16-94. (b) Ohkuma, T.; Kitamura, M.; Noyori, R. In
Catalytic Asymmetric Hydrogenation; Ojima, I., Ed.; Wiley-VCH: New
York, 2000; Chapter 1, pp 1-110.
(9) Dehydroamino acid derivative 3: analytical RP HPLC, MeCN:0.05%
1
aq acetic acid/60:40, 2.0 mL/min at 225 nm; tR 5.95 min, 96%; H NMR
(CDCl3) δ 7.74 (d, 1 H, J ) 0.8 Hz), 7.36-7.25 (m, 5 H), 7.16 (s, 1 H),
6.91 (s, 1 H, J ) 0.6 Hz). 6.74 (brs, 1 H), 5.07 (s, 2 H), 4.29 (t, 2 H, J )
3422
Org. Lett., Vol. 2, No. 22, 2000

the mixture was stirred for 16 h, the solvent was removed
and the residue was purified by silica gel column chroma-
tography to afford the amino acid derivative (S)-(+)-11 in
The final step in the synthesis of (S)-(-)-1 was to remove
all protective groups (i.e., methyl ether, Cbz group, n-propyl,
and methyl esters) in (S)-(+)-11 preferably in one-pot by
using iodotrimethylsilane (TMS-I). However, reaction of (S)-
(+)-11 with excess TMS-I (10 equiv) in chloroform under
reflux conditions cleaved only the Cbz and methyl ether
groups. Alternately, (S)-(+)-11 was first treated with LiOH
in THF-water to hydrolyze the esters and the resulting diacid
was then subjected to the reaction with TMSI in chloroform
under reflux. After 7 h, MeOH was added to the reaction
mixture and (S)-(-)-acromelobic acid (1) was isolated by
Dowex CCR-3 ion exchange (eluent: water) followed by
Biorad AG II A8 resin (eluent: water) chromatography in
68% yield. The synthetic (S)-(-)-1 was consistent with the
89% yield11 {[R]23 +50.5 (c 0.525, CHCl3)}. The optical
D
purity of compound (S)-(+)-11 was determined by analysis
of the corresponding Mosher amide 12 by 19F NMR, which
was found to be >98% ee. Mosher amide 12 was obtained
in 81% yield in two steps from (S)-(+)-11 by hydrogenation
(10% Pd/C, MeOH, H2, rt, 2 h) followed by treatment of
the resulting amine with (R)-(-)-MTP-Cl (methylene chlo-
ride at room temperature, 3 h)12 in 70% overall yield.
6.8 Hz), 4.01 (s, 3 H), 3.85 (s, 3 H), 1.84-1.72 (m, 2 H), 1.01 (t, 3 H, J
) 7.4 Hz); 13C NMR (CDCl3) δ 164.9, 164.8, 164.4, 152.7, 145.9, 145.0,
135.4, 128.5, 128.4, 128.2, 127.5, 125.4, 118.2, 114.2, 67.8, 67.1, 53.8,
53.1, 22.0, 10.4; ESI-MS (m/z) 429 (M + H)+, 451 (M + Na)+; HRMS
(FAB, m/z) calcd for C22H25N2O7 (M + H)+ 429.1662,obsd 429.1667.
(10) For a review on the asymmetric hydrogenation using chiral
phosphine ligands, see: Knowles, W. S. Acc. Chem. Res. 1983, 16, 106-
112.
literature data including optical rotation,2b [R]23 -139.1
D
(c 0.0575, H2O), lit.2 [R]23 -131.0 (c 0.05, H2O).
D
In summary, a highly efficient enantioselective synthesis
of an important nonproteinigenic amino acid, (S)-(-)-
acromelobic acid (1), was achieved starting from the com-
mercially available citrazinic acid (4) by applying a catalytic
asymmetric hydrogenation protocol.
(11) (S)-(+)-11: analytical RP HPLC, MeCN:0.05% aqueous acetic acid/
60:40, 2.0 mL/min at 225 nm; tR, 5.44 min, 99%; [R]23 +50.5 (c 0.525,
D
1
CHCl3); H NMR (CDCl3) δ 7.47 (d, 1 H, J ) 1.1 Hz), 7.38-7.30 (m, 5
H), 6.68 (d, 1 H, J ) 0.8 Hz), 5.33 (d, 1 H, J ) 7.9 Hz), 5.10 (s, 2 H), 4.69
(dd, 1 H, J ) 13.4, 6.0 Hz), 4.30 (t, 2 H, J ) 6.8 Hz), 3.99 (s, 3 H), 3.74
(s, 3 H), 3.17 (dd, 1 H, J ) 13.7, 5.8 Hz), 3.07 (dd, 1 H, J ) 13.7, 6.3 Hz),
1.86-1.74 (m, 2 H), 1.02 (t, 3 H, J ) 7.4 Hz); 13C NMR (CDCl3) δ 171.2,
165.0, 164.3, 155.5, 148.3, 145.9, 135.9, 128.5, 128.2, 128.0, 119.5, 115.3,
67.1, 53.9, 53.6, 52.6, 37.4, 22.0, 10.4; ESI-MS (m/z) 431 (M + H)+, 453
(M + Na)+; HRMS (FAB, m/z) calcd for C22H27N2O7 (M + H)+ 431.1818,
obsd 431.1824.
OL006363L
(12) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543-2549.
Org. Lett., Vol. 2, No. 22, 2000
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