Efficient synthesis of (S,S)-ethambutol from L-methionine

Article abstract of DOI:10.1016/S0040-4020(02)01308-X

Starting from readily available amino acid L-methionine, an efficient synthesis of the tuberculostatic agent (S,S)-ethambutol has been developed. The key steps in the synthetic sequence involve: dimerization of methionine methyl ester through oxalyl diamide formation, Raney nickel desulfurization of the terminal thiomethyl groups, and a one-pot exhaustive reduction of the oxalamide and the diester functionalities to afford the desired enantiopure (S,S)-ethambutol in good overall yield.

Full text of DOI:10.1016/S0040-4020(02)01308-X

Tetrahedron 58 (2002) 9765–9767
Efficient synthesis of (S,S)-ethambutol from L-methionine
*
Christina S. Stauffer and Apurba Datta
Department of Medicinal Chemistry, University of Kansas, 4062 Malott Hall, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7582, USA
Received 9 September 2002; accepted 16 October 2002
Abstract—Starting from readily available amino acid L-methionine, an efficient synthesis of the tuberculostatic agent (S,S)-ethambutol has
been developed. The key steps in the synthetic sequence involve: dimerization of methionine methyl ester through oxalyl diamide formation,
Raney nickel desulfurization of the terminal thiomethyl groups, and a one-pot exhaustive reduction of the oxalamide and the diester
functionalities to afford the desired enantiopure (S,S)-ethambutol in good overall yield. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
epoxide constituted the key reaction step towards forming a
masked 2-amino butanol precursor with appropriate stereo-
chemistry.6 In continuation of a research program aimed at
stereoselective synthesis of natural and non-natural com-
pounds of biomedical significance, utilizing amino acids as
chiral pool starting materials,7 we report herein an efficient,
four step synthesis of (S,S)-ethambutol starting from
L-methionine.
(S,S)-Ethambutol (1), first reported in 1961 by Wilkinson
and colleagues,1 is among the frontline antimycobacterial
agents, active against nearly all strains of M. tuberculosis
and M. kansasii as well as a number of strains of M. avium.2
Ethambutol has been used with notable success in the
therapy of tuberculosis of various forms, especially when
given concurrently with isoniazid. Importantly, it was also
found to suppress the growth of most isoniazid- and
streptomycin-resistant tubercle bacilli.
2. Results and discussion
Mechanistically, the biological activity of ethambutol has
been attributed to its inhibition of mycobacterial arabinosyl
transferases involved in bacterial cell wall biosynthesis.3
From a structure–activity relationship (SAR) viewpoint, the
(S,S)-absolute configuration as present in ethambutol was
found to be essential for optimum activity.1a,4 For example,
compared to the parent (S,S)-stereoisomer, the correspond-
ing (R,R)-enantiomer and the optically inactive meso-
isomer were found to exhibit only 0.2 and 8.3% antibacterial
activity, respectively.
The first two steps in our synthetic sequence involves
esterification of L-methionine under standard reaction
conditions, followed by treatment of the free amine with
0.5 equiv. of oxalyl chloride to form the desired oxalyl
diamide derivative 2 (Scheme 1) in good yield. As evident,
the key intermediate 2 already incorporates the required
carbon framework and the absolute (S,S)-configuration as
present in the target end product. Raney nickel desulfuriza-
tion of the terminal thiomethyl groups provided the ethyl
side-chain containing penultimate intermediate 3. Finally,
in a one-pot reaction, lithium aluminium hydride assisted
exhaustive reduction of the diamide and the diester
functional groups of 3 completed an efficient synthesis of
(S,S)-ethambutol in good overall yield. The spectral and
analytical data of 1 was in good agreement with the reported
values, thereby confirming its structural and stereochemical
integrity.
The literature methods for the synthesis of ethambutol
involve direct alkylation (with 1,2-dibromoethane) or
reductive alkylation (with glyoxal) of the amino group of
(S)-2-amino-1-butanol, which in turn is obtained by
resolution of the corresponding racemic material.1,4a,5
More recently, a six step asymmetric synthesis of
ethambutol has been reported by Trost and co-workers,
wherein, a chiral palladium catalyst assisted regio- and
stereoselective addition of phthalimide to butadiene mono-
In conclusion, starting from a readily available enantiopure
amino acid and following a short sequence of reactions, a
novel, efficient and practical route to the tuberculostatic
agent ethambutol has been developed. It is expected that the
present method will provide an attractive alternative to the
existing methods for the synthesis of this valuable
therapeutic agent.
Keywords: ethambutol; tuberculostatic; L-methionine; dimerization;
desulfurization.
*
Corresponding author. Tel.: þ1-785-864-4117; fax: þ1-785-864-5326;
e-mail: adutta@ku.edu
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01308-X

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C. S. Stauffer, A. Datta / Tetrahedron 58 (2002) 9765–9767
addition of a solution of oxalylchloride (2.4 mL, 27 mmol)
in dichloromethane (25 mL) with stirring. After completion
of addition the mixture was allowed to attain room
temperature and stirred overnight. The reaction was then
quenched by addition of water (100 mL) and stirred for
15 min. The organic layer was separated, aqueous layer
extracted with chloroform (3£75 mL) and the combined
organic extract washed sequentially with 10% HCl,
saturated NaHCO3, and brine, dried (Na2SO4) and concen-
trated. Flash column chromatography (hexanes/ethyl acetate
1:1!1:3) of the residual liquid yielded 2 as a white solid
(8.2 g, 85%): [a]2D2¼þ34.0 (c¼0.51, CHCl3); mp 109–
1
1108C; IR (thin film, cm21) 3273, 1747, 1655, 1521; H
NMR (400 MHz, CDCl3) d 2.10 (m, 1H), 2.11 (s, 3H), 2.21
(m, 1H), 2.53 (t, J¼7.1 Hz, 2H), 3.79 (s, 3H), 4.73 (m, 1H),
7.81 (d, J¼8.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d
15.4, 29.8, 31.3, 51.7, 52.7, 158.9, 170.9; MS (FABþ) 381
(MHþ). Anal. calcd for C14H24N2O6S2 (380.11): C, 44.19;
H, 6.36; N, 7.36. Found: C, 44.21; H, 6.25; N, 7.23.
3.1.2. (S,S)-2-[(1-Methyoxycarbonyl-propylamino-
oxalyl)-amino]-butyric acid methyl ester (3). To a stirred
solution of the oxamide 2 (1.0 g, 2.63 mmol) in 9:1
methanol–water (20 mL), freshly prepared W-4 Raney
nickel8 (,5 g) was added and the mixture refluxed for 6 h.
The reaction mixture was cooled to room temperature,
filtered, and the residual catalyst washed with methanol
(3£20 mL). The combined filtrate was concentrated, the
residual semi-solid redissolved in 9:1 methanol–water
(20 mL), W-4 Raney nickel (,5 g) added to the resulting
solution and the mixture refluxed overnight. After cooling to
room temperature, the reaction mixture was filtered and the
catalyst washed thoroughly with methanol (3£25 mL). The
combined filtrate was concentrated and the crude product
purified by flash column chromatography (hexanes/ethyl
acetate 3:2) to yield the desulfurized product 3 as a white
solid (0.48 g, 64%): [a]2D2¼þ2.88 (c¼2.5, CHCl3); mp
130–1318C; IR (thin film, cm21) 3283, 1746, 1649, 1526;
1H NMR (400 MHz, CDCl3) d 0.95 (t, J¼7.4 Hz, 3H), 1.81
(m, 1H), 1.94 (m, 1H), 3.76 (s, 3H), 4.53 (m, 1H), 7.80 (d,
J¼7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 10.1, 25.6,
52.7, 54.1, 159.5, 171.7; MS (FABþ) 289 (MHþ). Anal.
calcd for C12H20N2O6 (288.13): C, 49.99; H, 6.99; N, 9.72.
Found: C, 49.81; H, 6.87; N, 9.47.
Scheme 1. (a) MeOH, AcCl; (b) ClCOCOCl (0.5 equiv.), pyridine, CH2Cl2;
(c) Raney Ni (W-4), MeOH–H2O (9:1), D; (d) LiAlH4, THF, D.
3. Experimental
3.1. General methods
All of the solvents and reagents used were obtained
commercially and used as such unless noted otherwise.
NMR spectra (1H at 400 MHz and 13C at 100 MHz) were
recorded with a Bruker DRX-400 spectrometer with the
chemical shifts (d) reported in ppm relative to Me4Si (for
1H) and CDCl3 (for 13C) as internal standards, respectively.
Mass spectroscopy was performed on a ZAB VG analytical
spectrometer. IR spectra were recorded on a Nicolet FT-IR
spectrophotometer. Optical rotations were measured on a
Rudolph AUTOPOL IV automatic polarimeter. Melting
points were obtained using a Thomas Hoover capillary
melting point apparatus and are uncorrected. Elemental
analyses were obtained from QTI, NJ.
3.1.1. (S,S)-2-[(Methoxycarbonyl-3-methylsulfanyl-pro-
pylaminooxalyl)-amino]-4-methylsulfanyl-butuyric acid
methyl ester (2). To ice-cold methanol (100 mL) was added
dropwise acetyl chloride (15 mL) with stirring. The
resulting solution was stirred at the same temperature for
another 10 min, followed by addition of L-methionine
(8.5 g, 57 mmol) in one lot and stirring continued for
another 10 min. The resulting solution was then refluxed for
4 h and stirred overnight at room temperature. Solvent was
removed under vacuum, the resulting ester hydrochloride
taken into chloroform (100 mL) and neutralized to pH 7–8
by careful addition of saturated aq. NaHCO3 solution. The
organic layer was separated and the aqueous layer extracted
with chloroform (3£50 mL). The combined organic extract
was dried (Na2SO4), concentrated, and the residue kept
under high vacuum for 2 h to afford the amino ester
derivative as a colourless oily liquid (crude yield 8.35 g,
90%; 51.2 mmol). To a well-stirred, ice-cold solution of the
methionine methyl ester in anhydrous dichloromethane
(100 mL) under argon atmosphere, anhydrous pyridine
(9 mL, 113 mmol) was added, followed by dropwise
3.1.3. (S,S)-Ethambutol (1). To a stirred suspension of
lithium aluminum hydride (0.46 g, 12.2 mmol) in anhydrous
THF (10 mL) at room temperature and under argon
atmosphere was added dropwise a solution of the diamide
diester 3 (0.35 g, 1.2 mmol) in THF (10 mL). After
completion of addition, the resulting solution was stirred
at room temperature for another 30 min and then refluxed
overnight. After cooling to room temperature, the reaction
was quenched by careful addition of 10% aq. NaOH
solution (1.0 mL) followed by addition of an equal amount
of water. After stirring the mixture for 30 min, the
precipitated solid was removed by filtration, washed with
ethylacetate (3£25 mL), the combined filtrated dried
(Na2SO4), concentrated and the residual product was
crystallized (ethyl acetate/hexane) to yield pure ethambutol
(1) as a white solid (0.19 g, 75%): [a]2D2¼þ13.3 (c¼1.9,
H2O) {lit.1c [a]D25¼þ13.7 (c¼2, H2O)}; mp 83–858C {lit.1c
mp 87.5–88.88C}; IR (thin film, cm21) 3267, 3124, 1567,

C. S. Stauffer, A. Datta / Tetrahedron 58 (2002) 9765–9767
9767
1454; 1H NMR (400 MHz, CDCl3) d 0.92 (t, J¼7.5 Hz, 3H),
1.41 (m, 2H), 2.54 (m, 1H), 2.67 (m, 1H), 2.84 (m, 1H), 3.03
(br s, 2H, exchangeable with D2O), 3.36 (dd, J¼7.4,
10.9 Hz, 1H), 3.62 (dd, J¼3.4, 10.9 Hz, 1H); 13C NMR
(400 MHz, CDCl3) d 10.9, 24.6, 47.0, 60.8, 63.7; MS
(FABþ) 205 (MHþ). Anal. calcd for C10H24N2O2 (204.18):
C, 58.79; H, 11.84; N, 13.71. Found: C, 58.35; H, 11.45; N,
13.33.
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