An improved synthesis of selectively protected L-Dopa derivatives from L-tyrosine

Full text of DOI:10.1021/jo9913661

2574
J . Org. Chem. 2000, 65, 2574-2576
ester (8) from L-tyrosine (5) in six steps (34% overall
An Im p r oved Syn th esis of Selectively
P r otected L-Dop a Der iva tives fr om
L-Tyr osin e
yield). Boger’s approach utilized an acid-promoted oxida-
tive rearrangement of a benzylic hydroperoxide to obtain
the target compound (Scheme 1).
Recently J ung and Lazarova reported a five-step
synthesis of 4-O-benzyl-N-Boc-L-Dopa (12) from L-ty-
rosine (5) via sequential Reimer-Tiemann and Dakin
reactions (Scheme 2).8 However, the Reimer-Tiemann
formylation of N-Boc-tyrosine (9) required rather vigorous
reaction conditions (7.5 equiv of NaOH, CHCl3, reflux, 4
h) for a chiral amino acid,9 and gave a low yield of 10
(33% isolated yield, 64% yield based on 31% recovered
stating material).
Chen Chen, Yun-Fei Zhu, and Keith Wilcoxen
Department of Medicinal Chemistry,
Neurocrine Biosciences, Inc., 10555 Science Center Drive,
San Diego, California 92121
Received August 27, 1999
Many biologically active natural products such as the
piperazinomycin (2),1 K-13 (3a ),2 OF4949-I-IV (3b-e),3
bouvardin and deoxybouvardin,4 and RA-I-IV5 contain
a key structural unit isodityrosine (1) which is a naturally
occurring dimeric form of L-Dopa [L-3-(3,4-dihydroxyphen-
yl)alanine, 4]. L-Dopa derivatives with two differentiated
Although the Baeyer-Villiger oxidation of N-protected-
3-acetyl-L-tyrosine esters is reported in poor yields
(∼30%),10 the similar oxidation of 3-acetyl-L-tyrosine
hydrochloride (13) proceeds in 75% yield to give undif-
ferentiated L-Dopa.7f We reasoned that it may be possible
to achieve a higher yield of the desired phenol by
optimizing reaction conditions for the Baeyer-Villiger
oxidation of N-protected 3-acetyl-L-tyrosine or its ester
derivative. Herein, we report an efficient method for the
synthesis of selectively O-protected derivatives of L-Dopa,
which can be utilized as suitable intermediates in the
total synthesis of natural products such as compounds
2-3e.11 This method is based on a modified Baeyer-
Villiger oxidation of N-protected 3-acetyl-L-tyrosine es-
ters, resulting in a selective phenol introduction.12
3-Acetyl-L-tyrosine (13) was prepared according to
Boger’s protocol in 77% yield.6 Amine protection with Boc
anhydride (Boc2O, NaHCO3, dioxane-H2O, 94%) pro-
vided 14. Fully protected 3-acetyl-L-tyrosine 15 was
obtained by converting the free phenol and the acid to
the corresponding benzyl ether and benzyl ester respec-
tively, utilizing the conditions described by Boger6 to
minimize possible racemization (2.5 equiv of PhCH2Br,
2.5 equiv of K2CO3, 0.1 equiv of Et4NI, DMF, 25 °C, 91%).
The final transformation was a Baeyer-Villiger oxidation
of the acetophenone to provide the required phenol. We
investigated several different conditions and chose the
m-CPBA oxidation at room temperature. Thus, the
acetyl-L-tyrosine15wastreatedwith 2equivofm-chloroperben-
zoic acid in dichloromethane at room temperature for 7
days. Although the oxidation was sluggish it was very
protecting groups on the catechol are useful building
blocks for synthetic construction of these molecules.
Several methods toward the synthesis of selectively
protected L-Dopa derivatives have been reported in the
literature.6-8 The synthesis reported by Boger and Yo-
hannes6 provides the 4-O-benzyl-N-Cbz-L-Dopa methyl
(1) (a) Tamai, S.; Kaneda, M.; Nakamura, S. J . Antibiot. 1982, 35,
1130. (b) Kaneda, M.; Tamai, S.; Nakamura, S.; Hirata, T.; Kushi, Y.;
Suga, T. J . Antibiot. 1982, 35, 1137.
(2) (a) Kase, M.; Kaneko, M.; Yamada, K. J . Antibiot. 1987, 40, 450.
(b) Yasuzawa, T.; Shirahata, C.; Sano, H. J . Antibiot. 1987, 40, 455.
(3) (a) Sano, S.; Ikai, K.; Katayama, K.; Takesako, K.; Nakamura,
T.; Obayashi, A.; Ezure, Y.; Enomoto, H. J . Antibiot. 1986, 39, 1685.
(b) Sano, S.; Ikai, K.; Kuroda, H.; Nakamura, T.; Obayashi, A.; Ezure,
Y.; Enomoto, H. J . Antibiot. 1986, 39, 1674. (c) Sano, S.; Ikai, K.;
Yoshikawa, Y.; Nakamura, T.; Obayashi, A. J . Antibiot. 1987, 40, 512.
(d) Sano, S.; Kuroda, H.; Ueno, M.; Yoshikawa, Y. Nakamura, T.;
Obayashi, A. J . Antibiot. 1987, 40, 519.
(9) No optical rotation or chiral analysis data was reported for these
compounds by J ung and Lazarova.8 Boger and Yohannes observed that
benzylation of tyrosine phenol under vigorous reaction conditions (2
equiv of K2CO3, acetone, 60 °C) results in substantial racemization
(15-20%).6 Selectively protected catechol derivatives of D,L-Dopa have
been prepared from isovanillin, see: Wilcox, M. E.; Wyler, H.; Mabry,
T. J .; Dreiding, A. S. Helv. Chim. Acta 1965, 48, 252.
(4) J olad, S. D.; Hoffmann, J . J .; Torrance, S. J .; Wiedhopf, R. M.;
Cole, J . R.; Arora, S. K.; Bates, R. B.; Gargiuro, R. L.; Krieke, G. R. J .
Am. Chem. Soc. 1977, 99, 8040.
(10) Boger, D. L.; Coleman, R. S. J . Org. Chem. 1986, 51, 5436. also
see ref 7a-e.
(5) (a) Review: Itokawa, H.; Takeya, K. Heterocycles 1993, 35, 1467.
(b) Ikokawa, H.; Takeya, K.; Mori, N.; Sonobe, T.; Mihashi, S.;
Hamanaka, T. Chem. Pharm. Bull. 1986, 34, 3762. (c) Itokawa, H.;
Takeya, K.; Mihara, K.; Mori, N.; Hamanaka, T.; Sonobe, T.; Iitaka,
Y. Chem. Pharm. Bull. 1983, 31, 1424. (d) Itokawa, H.; Takeya, K.;
Mori, N.; Kidohoro, S.; Yamamoto, H. Planta Med. 1984, 51, 313.
(6) Boger, D. L.; Yohannes, D. J . Org. Chem. 1987, 52, 5283.
(7) (a) Siuda, J . F. J . Org. Chem. 1975, 40, 3611. (b) Banerjee, N.;
Ressler, C. J . Org. Chem. 1976, 41, 3056. (c) Kawai, M.; Chorev, M.;
Marin-Rose, J .; Goodman, M. J . Med. Chem. 1980, 23, 420. (d) Cohen,
T.; Dietz, A. G., J r.; Miser, J . R. J . Org. Chem. 1977, 42, 2057. (e)
Konda, M.; Shioiri, T.; Yamada, S.-i. Chem. Pharm. Bull. 1975, 23,
1063. (f) Bretshneider, H.; Hohenlohe-Oehringen, K.; Kaiser, A.;
Wolcke, U. Helv. Chim. Acta 1973, 56, 2857.
(11) (a) Schmidt, U.; Weller, D.; Holder, A.; Lieberknecht, A.
Tetrahedron Lett. 1988, 29, 3227. (b) Boger, D. L.; Yohnnes, D.; Zhou,
J .; Patane, M. A. J . Am. Chem. Soc. 1993, 115, 3420. (c) Boger, D. L.;
Yohannes, D. J . Am. Chem. Soc. 1991, 113, 1427. (d) Boger, D. L.;
Yohannes, D. J . Org. Chem. 1991, 56, 1763. (e) Boger, D. L.; Yohannes,
D.; Meyers, J . B., J r. J . Org. Chem. 1992, 57, 1319. (f) Boger, D. L.;
Yohannes, D. J . Org. Chem. 1989, 54, 2498. (h) Boger, D. L.; Yohannes,
D. J . Org. Chem. 1990, 55, 6000.
(12) Selectively protected L-Dopa derivatives have been reported.
These methods have relied on the monoprotection of the unsymmetrical
catechol of Dopa derivatives,7a-c,e-f diazotization of 3-amino-L-tyrosine
derivatives and subsequent copper(I)-promoted phenol introduction,7d
or Baeyer-Villiger oxidation of 3-acetyl-L-tyrosine derivatives.10 All
these methods provide the desired compounds in yield 30% or less.
(8) J ung, M. E.; Lazarova, T. I. J . Org. Chem. 1997, 62, 1553.
10.1021/jo9913661 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/21/2000

Notes
J . Org. Chem., Vol. 65, No. 8, 2000 2575
Sch em e 1
Sch em e 3a
Sch em e 2
a
Reagents: (a) AcCl/AlCl3/PhNO2/100 °C, 77%; (b) Boc2O/
NaHCO3/dioxane-H2O, 94%; (c) BnBr/K2CO3/Et4NI(cat.)/DMF/rt,
91%; (d) mCPBA/CH2Cl2, rt, 81%; or CH3CO3H/CH2Cl2/rt, 83%;
(e) NH3MeOH, rt, 74% from 15.
In conclusion, we have described here an efficient
synthesis of the important selectively protected L-Dopa
derivative 17 from L-tyrosine (5) via a modified Baeyer-
Villiger oxidation. This compound can be used in the
synthesis of natural products such as compounds 2-3e.
Exp er im en ta l Section
N-(ter t-Bu tyloxyca r bon yl)-3-(3-a cetyl-4-h yd r oxyp h en yl)-
L-a la n in e (14). l-3-(3-Acetyl-4-hydroxyphenyl)alanine hydro-
chloride6 (13, 18 g, 50 mmol) was suspended in dioxane-water
(1:1, 250 mL) and treated portionwise with sodium bicarbonate
(12.6 g, 150 mmol). This solution was then treated with Boc2O
(1.2 equiv), and the mixture was vigorously stirred at room-
temperature overnight before it was concentrated in vacuo to
about 100 mL. This residue was acidified with 2 N HCl to pH 2,
and the product was extracted with ethyl acetate. The extract
was washed with brine, dried over MgSO4, and concentrated in
vacuo. The crude product was dissolved in hot dichloromethane
and treated with hexanes to precipitate a white solid (23 g,
clean, and the corresponding acetoxy derivative 16 was
isolated in 81% yield after a simple aqueous workup and
crystallization. These conditions were tested on 0.1 to 10
g scales, and the yields were very consistent. Similar re-
sults were obtained when peracetic acid was used as
oxidizing reagent (83% yield).13 Heating the reaction in
dichloromethane solvent did not help since more oxidant
was required for complete conversion and the yield was
lower, consistent with results reported by Boger.6 The
acetyl group was cleaved by treatment of the reaction
mixture with methanolic ammonia for 1 h before workup
to afford the desired L-Dopa 17 in an overall yield of 74%
for the two steps (Scheme 3). Thus, in a four-step
procedure, the selectively monoprotected L-Dopa deriva-
tive, N-Boc-L-3-(3-hydroxy-4-benzoxyphenyl)alanine (17),
was synthesized from L-tyrosine (5) in 49% overall yield.
To determine the optical purity of the (L)-3-hydroxy-
tyrosine derivatives, compound 16 was converted to L-3-
(3-hydroxy-4-benzoxyphenyl)alanine (18) hydrochloride
salt (4 N HCl in dioxane), which was then coupled with
(R)-(+)-R-methoxy-R-trifluoromethylphenylacetic acid and
(S)-(-)-R-methoxy-R-trifluoromethylphenylacetic acid
(EDC, DMAP, DMF, rt) (Scheme 4). The two Mosher’s
amide derivatives14 (19a and 19b) were characterized by
both proton and fluorine NMR spectra, which showed a
single isomer for both 19a and 19b (ee > 95%).
94%): mp 110-112 °C; [R]22 +21.6° (c 2.2, MeOH); 1H NMR
D
(CDCl3, 300 MHz): 1.33 (s, 0.4 × 9H), 1.42 (s, 0.6 × 9H), 2.60
(s, 3H), 3.02 (m, 2H), 4.35 (m, 0.4H), 4.61 (m, 0.6H), 5.09 (d, J
) 7.8 Hz, 0.6H), 6.74 (d, J ) 6.9 Hz, 0.4H), 6.92 (d, J ) 8.1 Hz,
1H), 7.30 (d, J ) 8.1 Hz, 1H), 7.55 (s, 1H), 8.42 (brs, 2H); CI-
MS, m/e 234 (M + H - Boc). Anal. Calcd for C16H21NO6: C,
59.43; H, 6.55; N, 4.33. Found: C, 59.21; H, 6.93; N, 4.24.
N -(t er t -B u t y lo x y c a r b o n y l)-3-(3-a c e t y l-4-b e n zy lo x y -
p h en yl)-L-a la n in e Ben zyl Ester (15). A solution of N-(tert-
butyloxycarbonyl)-3-(3-acetyl-4-hydroxyphenyl)-L-alanine (14, 13
g, 40 mmol) in dry DMF (150 mL) at room temperature was
treated with potassium carbonate (14 g, 100 mmol), benzyl
bromide (17.1 g, 100 mmol), and tetraethylammonium iodide (1.2
g, 5 mmol). The resulting reaction mixture was stirred at room-
temperature overnight and partitioned into ether and water. The
aqueous phase was extracted with ether, and the combined ether
extract was washed with 1 N HCl and brine, dried over MgSO4,
and concentrated in vacuo. The crude product was chromato-
graphed on silica gel to give the product as a colorless oil (18.3
1
g, 91% yield), [R]22 -2.9° (c 1.4, MeOH); H NMR (CDCl3, 300
D
MHz): 1.42 (s, 9H), 2.57 (s, 3H), 3.00 (dd, J ) 6.3, 13.8 Hz, 1H),
3.07 (dd, J ) 5.1, 13.8 Hz, 1H), 4.58 (m, 1H), 5.02 (d, J ) 8.1
Hz, 1H), 5.12 (s, 2H), 5.13 (d, J ) 5.7 Hz, 1H), 5.15 (d, J ) 5.7
(14) a) Erickson, S. D.; Simon, J . A.; Still, W. C. J . Org. Chem. 1993,
58, 1305. (b) Tsuda, Y.; Hosoi, S.; Ishida, K.; Sangai, M. Chem. Pharm.
Bull. 1994, 42, 204.
(13) On one millimole scale using peracetic acid (32 wt % in acetic
acid, 2 equiv, room temperature, 10 days).

2576 J . Org. Chem., Vol. 65, No. 8, 2000
Notes
Sch em e 4a
a
Reagents: (a) 4 N HCl in dioxane, rt; (b) EDC/DMAP/DMF/Et3N/rt.
Hz, 1H), 6.88 (d, J ) 8.4 Hz, 1H), 7.12 (dd, J ) 2.4, 8.4 Hz, 1H),
7.38 (m, 10H), 7.51 (d, J ) 2.4 Hz, 1H); 13C NMR (CDCl3, 75
MHz) δ 28.0, 31.1, 36.9, 54.3, 66.8, 70.4, 79.5, 112.7, 127.2, 127.8,
128.0, 128.1, 128.2, 128.3, 128.4, 128.6, 130.9, 134.0, 134.8, 135.7,
154.7, 162.0, 171.1, 198.7; CI-MS m/e 404 (M + H - Boc). Anal.
Calcd for C30H33NO6: C, 71.55; H, 6.61; N, 2.78. Found: C, 71.17;
H, 6.70; N, 2.76.
3-(3-Acetoxy-4-ben zyloxyp h en yl)-L-a la n in e Ben zyl Ester
Hyd r och lor id e (18). A solution of N-(tert-butyloxycarbonyl)-
3-(3-acetoxy-4-benzyloxyphenyl)-L-alanine benzyl ester (16, 2.5
g, 4.8 mmol) in 20 mL of CH2Cl2 was treated with 4 M HCl in
dioxane (10 mL) and stirred overnight at room temperature
under nitrogen. After overnight, some solid had formed, and the
solution was triturated with 100 mL of ether. The suspension
was stirred for 1 h and filtered to give a white solid, which was
dried to yield compound 18 as a white solid, 1.86 g (85%); mp
N -(t er t -Bu t yloxyca r b on yl)-3-(3-a ce t oxy-4-b e n zyloxy-
p h en yl)-L-a la n in e Ben zyl Ester (16). A solution of N-(tert-
butyloxycarbonyl)-3-(3-acetyl-4-benzyloxyphenyl)-L-alanine ben-
zyl ester (15, 1.01 g, 2 mmol) and mCPBA (57-84%, 1.25 g, ∼2
equiv) in dichloromethane (20 mL) was stirred at room temper-
ature for 7 days. The solution was diluted with ether (200 mL)
and washed with saturated sodium thiosulfate, saturated sodium
bicarbonate, and brine, dried over sodium bicarbonate, filtered,
and concentrated in vacuo. The residue was crystallized from
ether-hexanes to give the product as a white solid (841 mg, 81%
yield), mp 88-90 °C, [R]22D -5.6° (c 2.2, MeOH); 1H NMR (CDCl3,
300 MHz): 1.56 (s, 9H), 2.26 (s, 3H), 3.02 (m, 2H), 4.58 (m, 1H),
4.99 (d, J ) 8.1 Hz, 1H), 5.04 (s, 2H), 5.09 (d, J ) 12.6 Hz, 1H),
5.17 (d, J ) 12.6 Hz, 1H), 6.78 (s, 1H), 6.84 (s, 2H), 7.31 (m,
10H); 13C NMR (CDCl3, 75 MHz) δ 20.6, 28.2, 37.2, 54.3, 66.9,
70.5, 79.8, 113.7, 123.5, 126.9, 127.3, 127.7, 128.2 (brs), 128.3,
128.7, 135.0, 136.5, 139.8, 149.0, 154.8, 168.6, 171.3; CI-MS m/e
420 (M + H - Boc). Anal. Calcd for C30H33NO7: C, 69.35; H,
6.40; N, 2.70. Found: C, 69.18; H, 6.45; N, 2.68.
1
194-6 °C; H NMR (TMS/CD3OD): 2.25 (s, 3H), 3.10 (dd, J )
6.9, 13.8 Hz, 1H), 3.18 (dd, J ) 6.3, 13.8 Hz, 1H), 4.31 (dd, J )
6.3, 6.9 Hz, 1H), 5.09 (s, 2H), 5.23 (d, J ) 10.8 Hz, 1H), 5.24 (d,
J ) 10.8 Hz, 1H), 6.92 (d, J ) 2.1 Hz, 1H), 6.98 (d, J ) 2.1, 8.4
Hz, 1H), 7.02 (d, J ) 8.4 Hz, 1H), 7.35 (m, 10H); CIMS m/e 420
(M + 1). Anal. Calcd for C25H26ClNO5: C, 65.86; H, 5.75; N, 3.07.
Found: C, 65.82; H, 5.70; N, 3.00.
N-[(R)-(+)-r-Meth oxy-r-tr iflu or om eth ylp h en yla cetyl]-3-
(3-acetoxy-4-ben zyloxyph en yl)-L-alan in e Ben zyl Ester (19a).
A solution of 3-(3-acetoxy-4-benzyloxyphenyl)-L-alanine benzyl
ester hydrochloride (18, 200 mg, 0.44 mmol), (R)-(+)-R-methoxy-
R-trifluorophenylacetic acid (105 mg, 0.45 mmol), EDC (115
mg, 0.6 mmol), triethylamine (0.14 mL, 1.0 mmol), and a
catalytic amount of DMAP in DMF (5 mL) was stirred under
nitrogen for 3 days. The reaction mixture was partitioned
between ether (100 mL) and 1 N HCl (30 mL). The organic layer
was separated and washed with brine (2 × 50 mL), dried over
magnesium sulfate, and concentrated in vacuo. The product was
purified on silica gel (Rf ) 0.6, 30% EtOAc in hexane) to give
the title compound as a colorless oil. 1H NMR (TMS/CDCl3):
2.26 (s, 3H), 3.08 (dd, J ) 8.4, 14.0 Hz, 1H), 3.13 (dd, J )
5.4, 14.0 Hz, 1H), 3.20 (d, J H,F ) 1.2 Hz, 3H), 4.70 (brs, 1H),
4.90 (m, 1H), 5.05 (s, 2H), 5.10 (d, J ) 12.0 Hz, 1H), 5.19 (d, J
) 12.0 Hz, 1H), 6.80 (s, 1H), 6.84 (s, 2H), 7.36 (m, 14H), 7.48
(m, 1H); 19F NMR (CFCl3/CDCl3): -69.8; CIMS m/e 636 (M +
1); HRMS (FAB) calcd for C35H32F3NO7 m/e 636.2209, found
636.2230.
N-(ter t-Bu t yloxyca r b on yl)-3-(3-h yd r oxy-4-b en zyloxy-
p h en yl)-L-a la n in e Ben zyl Ester (17). A solution of N-(tert-
butyloxycarbonyl)-3-(3-acetyl-4-benzoxyphenyl)-L-alanine benzyl
ester (15, 1.01 g, 2 mmol) was dissolved in dichloromethane (20
mL) and treated with m-chloroperbenzoic acid (57%-84%, 1.25
g). This solution was stirred at room temperature for 7 days. A
2 M solution of ammonia in methanol (4 mL) was added, and
the mixture was stirred for another 1 h. The resultant mixture
was concentrated in vacuo, and the residue was diluted with
ether (200 mL) and washed with saturated sodium thiosulfate,
saturated sodium bicarbonate and brine, dried over sodium
bicarbonate, filtered, and concentrated in vacuo. The crude
product was purified on silica gel with 1:2 ethyl acetate-hexanes
N-[(S)-(-)-r-Meth oxy-r-tr iflu or om eth ylp h en yla cetyl]-3-
(3-acetoxy-4-ben zyloxyph en yl)-L-alan in e Ben zyl Ester (19b).
The product was obtained by coupling of 18 with (S)-(-)-R-
methoxy-R-trifluorophenylacetic acid as described above. Color-
less oil; 1H NMR (TMS/CDCl3): 2.25 (s, 3H), 3.01 (m, 2H), 3.40
(d, J ) 1.8 Hz, 3H), 4.99 (m, 1H), 5.01 (s, 2H), 5.11 (d, J ) 12.0
Hz, 1H), 5.20 (d, J ) 12.0 Hz, 1H), 6.53 (m, 2H), 6.66 (d, J ) 9.0
Hz, 1H), 7.02 (m, 1H), 7.37 (m, 15H). 19F NMR (CFCl3/CDCl3):
-69.1; CIMS m/e 636 (M + 1); HRMS (FAB) calcd for C35H32F3-
NO7 m/e 636.2209, found 636.2229.
to give the title compound as a colorless syrup (706 mg, 74%
1
yield), [R]22 -4.0° (c 1.0, MeOH); H NMR (CDCl3, 300 MHz):
D
1.41 (s, 9H), 2.96 (d, J ) 5.7 Hz, 2H), 4.56 (m, 1H), 5.02 (s, 2H),
5.04 (brs, 1H), 5.09 (d, J ) 12.0 Hz, 1H). 5.14 (d, J ) 12.0 Hz,
1H), 5.84 (brs, 1H), 6.48 (d, J ) 8.4 Hz, 1H), 6.68 (d, J ) 1.5 Hz,
1H), 6.73 (d, J ) 8.4 Hz, 1H), 7.32 (m, 10H); 13C NMR (CDCl3,
75 MHz) δ 28.2, 37.5, 54.5, 66.9, 71.0, 79.8, 112.0, 115.7, 120.6,
126.7, 127.6, 128.1, 128.2, 128.3, 128.5, 129.2, 135.0, 136.1, 144.7,
145.0, 154.9, 171.5; CI-MS m/e 288 (M + H - Boc). Anal. Calcd
for C28H31NO6: C, 70.42; H, 6.54; N, 2.93. Found: C, 70.18; H,
6.73; N, 2.76.
J O9913661