An efficient synthesis of (S)-m-tyrosine

Full text of DOI:10.1021/jo9706584

6690
J . Org. Chem. 1997, 62, 6690-6691
Sch em e 1
An Efficien t Syn th esis of (S)-m -Tyr osin e
David M. Bender and Robert M. Williams*
Department of Chemistry, Colorado State University
Fort Collins, Colorado 80523
Received April 14, 1997
The amino acid (S)-m-tyrosine1 (1) has found wide use
in the area of medicinal chemistry since its discovery.
This amino acid has been utilized extensively in the study
of the metabolic pathways of the central nervous system.2
The biological effects of this molecule have been shown
to be identical to that of L-Dopa (3,4-dihydroxyphenyl-
alanine), which has been used in the treatment of
Parkinson’s disease.3 More recently, this unnatural
amino acid has been found in a new class of peptidyl-
nucleoside antibiotics, the mureidomycins4 and the pacida-
mycins.5 In addition, (S)-m-tyrosine has been used in the
synthesis of several aminodiol HIV protease inhibitors.6
Despite the simplicity of this amino acid, there exist very
few methods reported in the literature7,8 for its synthesis
in optically pure form. The method most frequently used
to obtain this amino acid appears to be resolution of d,l-
m-tyrosine.1a,c We report here a very simple and conve-
nient procedure that can be utilized to unambiguously
prepare either (S)- or (R)-m-tyrosine in high optical
purity.
tion of the sodium enolate (NaHMDS, THF, HMPA, -78
°C). The alkylation product (4) was obtained in 87% yield
with a diastereomeric excess of >95%. This substance
was conveniently converted into m-tyrosine (1) by cata-
lytic hydrogenation (74% overall from 4) (Scheme 1).
Mosher amide analysis11 of this material by NMR and
GC revealed that the product was obtained in an enan-
tiomeric excess of >96%.
The current methodology provides a mild and efficient
means to prepare m-tyrosine in optically active form of
high enantiomeric purity. Since both antipodes of 2 are
commercially available,9 this procedure permits the ste-
reochemically unambiguous synthesis of either (R)- or
(S)-m-tyrosine in a rapid and convenient manner.
Exp er im en ta l Section 12
P r ep a r a tion of m -(Ben zyloxy)ben zyl Br om id e. Com-
mercially available 3-benzyloxy benzyl alcohol (Aldrich) (5.0 g,
23.4 mmol) was converted to the benzyl bromide derivative 3
by reaction with Ph3P (6.74 g, 25.7 mmol) and CBr4 (8.50 g, 25.7
mmol) in THF (100 mL) at 25 °C for 1 h. Solid material was
removed by filtration, and the crude product was purified by
flash chromatography (hexanes) to yield 3 (5.89 g, 91%) as a
white solid (recryst hexanes), mp 37-39 °C (dec) 1H NMR (300
MHz, CDCl3): δ 4.39 (2H, s), 4.98 (2H, s), 6.83-6.95 (3H, m),
7.17-7.39 (6H, m). 13C NMR (300 MHz, CDCl3): δ 33.6, 70.2,
115.1, 115.6, 121.7, 127.7, 128.2, 128.8, 130.0, 136.9, 139.4, 159.1.
IR (NaCl/CH2Cl2): 3013, 2985 cm-1 HRMS (ES+) calcd for
Optically active (>98% ee) oxazinone 29,10 was con-
densed with m-(benzyloxy)benzyl bromide (3) via forma-
(1) (a) Sealock, R. R.; Speeter, M. E.; Schweet, S. J . Am. Chem. Soc.
1951, 73, 5386; (b) Tong, J . H.; Petitclerc, C.; D’Iorio, A.; Benoiton, N.
L. Can. J . Biochem. 1971, 49, 877. (c) Smith, I. K.; Fowden, L.
Phytochemistry 1968, 7, 1065. (d) Byrkjedal, A.; Mostad, A.; Romming,
C. Acta Chem. Scand. 1974, B28, 750.
(2) (a) Hollunger, G.; Persson, S.-A. Acta. Pharmacol Toxicol. 1974,
34, 391. (b) Fell, V.; Greenway, A. M.; Hoskins, J . A. Biochem. Med.
1979, 22, 246.
C
13H13OBr 276.0150, found 276.0145.
(3S,5S,6R)-4-[(Ben zyloxy)ca r bon yl)]-5,6-d ip h en yl-3-{[3′-
(b en zyloxy)p h en yl]m et h yl}-2,3,5,6-t et r a h yd r o-4H -1,4-ox-
a zin -2-on e (4). NaHMDS (12.3 mL, 12.3 mmol, 1 M solution
in THF) was added dropwise to a solution of oxazinone 29 (3.17
g, 8.20 mmol) (Aldrich) and m-(benzyloxy)benzyl bromide (3)
(2.50 g, 9.02 mmol) in THF (160 mL) and HMPA (16 mL) at
-78 °C. After 3 h, the reaction mixture was poured into ethyl
acetate and extracted with brine and H2O. The organic extracts
were dried (MgSO4) and concentrated to a yellow oil which was
purified by flash chromatography (CH2Cl2/MeOH, 99:1) to give
4 (4.15 g, 87%) as a white solid (recryst CH2Cl2/hexanes), mp
146-148 °C (dec). 1H NMR (300 MHz, DMSO-d6, 393 K): δ 3.37
(1H, dd, J ) 13.8, 3.9 Hz), 3.49 (1H, dd, J ) 13.5, 8.1 Hz), 5.04
(2H, s), 5.09 (2H, s), 5.14 (2H, s), 5.47 (1H, s (br)), 6.59 (2H, d,
J ) 7.5 Hz), 6.83-7.42 (22H, m). 13C NMR (300 MHz, DMSO-
d6): δ 39.3, 59.9, 67.7, 69.9, 78.4, 114.8, 122.7-138.6 (unre-
solved), 154.6, 159.6, 168.6. IR (KBr): 1698, 1750, 2950, 3030
(3) Ungerstedt, U.; Fuxe, K.; Goldstein, M.; Battista, A.; Ogawa, M.;
Anagnoste, B. Eur. J . Pharmacol. 1973, 21, 230.
(4) (a) Inukai, M.; Isono, F.; Takahashi, S.; Enokita, R.; Sakaida,
Y.; Haneishi, T. J . Antibiot. 1989, 42, 662. (b) Isono, F.; Inukai, M.;
Takahashi, S.; Haneishi, T. J . Antibiot. 1989, 42, 667. (c) Isono, F.;
Katayama, T.; Inukai, M.; Haneishi, T. J . Antibiot. 1989, 42, 674.
(5) (a) Karwowski, J . P.; J ackson, M.; Theriault, R. J .; Chen, R. H.;
Barlow, G. J .; Maus, M. L. J . Antibiot. 1989, 42, 506. (b) Chen, R. H.;
Buko, A. M.; Whittern, D. N.; McAlpine, J . B. J . Antibiot. 1989, 42,
512. (c) Fernandes, R. B.; Swanson, R. N.; Hardy, D. J .; Hanson, C.
W.; Coen, L.; Rasmussen, R. R. J . Antibiot. 1989, 42, 521.
(6) Chen, P.; Cheng, P. T. W.; Alam, M.; Beyer, B. D.; Bisacchi, G.
S.; Dejneka, T.; Evans, A. J .; Greytok, J . A.; Hermsmeier, M. A.;
Humphreys, W. G.; J acobs, G. A.; Kocy, O.; Lin, P.-F.; Lis, K. A.;
Marella, M. A.; Ryono, D. E.; Sheaffer, A. K.; Spergel, S. H.; Sun,
C.-q.; Tino, J . A.; Vite, G.; Colonno, R. J .; Zahler, R.; Barrish, J . C. J .
Med. Chem. 1996, 39, 1991.
(7) Dugave, C., J . Org. Chem. 1995, 60, 601.
cm-1 [a]25
)
+52.45° (c 2.0, CHCl3). Anal. Calcd for
38H33NO5: C, 78.19; H, 5.69; N, 2.39. Found: C, 78.18; H, 5.52;
N, 2.19.
D
(8) For reviews on methods to prepare R-amino acids, see: (a)
Williams, R. M. Organic Chemistry Series, Vol. 7: Synthesis of
Optically Active a-Amino Acids; Baldwin, J . E., Magnus, P. D., Eds.;
Pergamon Press, Oxford, 1989. (b) Duthaler, R. O., Tetrahedron 1994,
50, 1539.
(9) Both antipodes of 3 are commercially available from Aldrich
Chemical Co.: 3, catalog #33,187-2; antipode of 3, catalog #33-185-6.
(10) (a) Williams, R. M.; Im, M.-N. Tetrahedron Lett. 1988, 29, 6075.
(b) Williams, R. M.; Im, M.-N. J . Am. Chem. Soc. 1991, 113, 9276. (c)
Williams, R. M. Aldrichimica Acta 1992, 25, 11.
C
Syn th esis of (S)-m -Tyr osin e Hyd r och lor id e. To a solu-
tion of compound 4 (0.5 g, 0.857 mmol) in ethanol (5 mL) and
(11) Dale, J . A.; Hull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543.
(12) For general experimental conditions, see ref 10b.
S0022-3263(97)00658-0 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 19, 1997 6691
THF (5 mL) was added PdCl2 (0.045 g, 0.254 mmol). The
reaction mixture was hydrogenated at 50 psi for 18 h. The
mixture was purged with nitrogen and filtered through Celite
to remove the catalyst. Removal of the solvents in vacuo,
followed by trituration with Et2O, produced 0.154 g (99%) of
m-tyrosine (1). This compound was dissolved in 1 N HCl and
concentrated, followed by trituration with Et2O, to give (S)-m-
was combined with (+)-R-methoxy-R-(trifluoromethyl)phenyl-
acetyl chloride (24.6 mL, 0.132 mmol) and propylene oxide (40
mL, 0.571 mmol) in THF (1 mL) and heated at 50 °C for 2 h.
Optical purity was measured by examination of the 1H NMR
spectrum of the resulting Mosher amide and glc analysis (Alltech
AT-1, nonpolar polymethylsiloxane) (>96% ee).
tyrosine hydrochloride. [a]25D -7.4° (c 2.0, 1 N HCl) (lit.1b [a]25
D
(S)-m-tyrosine hydrochloride -7.9° (c 2.0, 1 N HCl)) . 1H NMR
(300 MHz, D2O vs HOD): δ 3.11 (1H, dd, J ) 14.7, 7.5 Hz), 3.24
(1H, dd, J ) 14.4, 5.4 Hz), 4.29 (1H, dd, J ) 7.5, 5.7 Hz), 6.71-
6.85 (3H, m), 7.26 (1H, t).
Ack n ow led gm en t. We are indebted to the National
Science Foundation (CHE 8717017) and Microcide
Pharmaceutical Co. (in part) for providing financial
support. Mass spectra were obtained on instruments
supported by the National Institutes of Health Shared
Instrumental Grant GM49631.
Deter m in a tion of Op tica l P u r ity. Oxalyl chloride (48.0
mL, 0.550 mmol) was added dropwise to a solution of the amino
acid 1 in ethanol (1 mL) at 0 °C, followed by refluxing for 2 h.
The reaction mixture was cooled to room temperature and
concentrated in vacuo. The crude amino ester hydrochloride salt
J O9706584