1554 J . Org. Chem., Vol. 62, No. 5, 1997
Notes
N-[(1,1-Dim eth yleth oxy)ca r bon yl]-L-tyr osin e (7). Tri-
ethylamine (5.81 mL, 41.4 mmol) was added to a solution of
L-tyrosine (3) (Aldrich, 5 g, 27.6 mmol) in 1/1 dioxane/water (100
mL). The reaction flask was cooled to 0 °C with an ice/water
bath, and di-tert-butyl dicarbonate (6.6 g, 30.4 mmol) was added
in one batch. After 30 min, the cold bath was removed, and the
reaction mixture was stirred at ambient temperature for 18 h.
Sch em e 1
The reaction mixture was then concentrated on
a rotary
evaporator and the residue diluted with water and ethyl acetate.
The aqueous layer was washed with ethyl acetate, acidified to
pH 1 with 1 N HCl, and back-extracted with ethyl acetate. The
organic extracts were washed with brine, dried over MgSO4, and
evaporated to give the protected amino acid, N-Boc-L-tyrosine
(7) as a white foam (7.12 g, 92%), which was used in the next
step without further purification: 1H NMR (CDCl3, 200 MHz) δ
7.0 (2H, d, J ) 7.8 Hz, C3-H, C5-H), 6.74 (2H, d, J ) 7.8 Hz,
C2-H, C6-H), 5.92 (1H, bs, OH), 5.06 (1H, bs, NH), 4.58
(unresolved m, 1H, RH), 3.02 (2H, unresolved m, âH), 1.42 (9H,
s, Boc); 13C NMR (MeOD, 90 MHz) δ 175.5, 157.7, 157.1, 131.2,
129.1, 116.1, 80.5, 57.8, 37.8, 28.6; IR (neat) νmax 3445, 2962,
1690, 1518 cm-1
.
N-[(1,1-Dim eth yleth oxy)ca r bon yl]-3-(3-for m yl-4-h yd r ox-
yp h en yl)-L-a la n in e (8). Powdered sodium hydroxide (1.71 g,
42.72 mmol) was added to a suspension of N-Boc L-tyrosine (7)
(2 g, 7.12 mmol), water (0.256 mL, 14.13 mmol), and chloroform
(30 mL). The mixture was refluxed for 4 h. Additional sodium
hydroxide was added (0.42 g, 10.68 mmol) after 1 and 1.5 h. The
reaction was then diluted with water and ethyl acetate, and the
aqueous layer was acidified to pH 1 with 1 N HCl and back-
extracted with ethyl acetate. The organic extracts were washed
with brine, dried over MgSO4, and concentrated. Flash column
chromatography (silica gel, 12/1 CHCl3/MeOH 1% acetic acid
eluent) afforded the desired product 8 as a brown oil (0.72 g,
33%) and recovered starting material 7 (0.62 g, 31%). The yield
of 8 based on recovered starting material was 66%: 1H NMR
(CDCl3, 360 MHz) δ 10.90 (1H, s, OH), 9.84 (1H, s, CHO), 7.36
(1H, s, C2-H), 7.33 (1H, d, J ) 8.3 Hz, C6-H), 6.93 (1H, d, J )
8.3 Hz, C5-H), 5.28 (1H, bs, NH), 4.96 (1H, unresolved m, RH),
3.17 (1H, unresolved m, âH), 3.04 (1H, unresolved m, âH), 1.40
(9H, s, Boc); 13C NMR (CDCl3, 90 MHz) δ 196.6, 175.6, 160.5,
155.3, 138.1, 134.2, 127.6, 120.4, 117.7, 80.4, 54.2, 36.8, 28.2;
chloroform and solid sodium hydroxide in the presence
of a small amount of water, gave the desired 2-formyl
compound 8 in 64% yield based on unrecovered starting
material. Benzylation of the phenol of 8 was easily
accomplished using potassium carbonate and benzyl
bromide to give the benzyl ether aldehyde 9 in 71% yield.
The final transformation is the Dakin oxidation of the
aryl aldehyde to give the required phenol. Many sets of
conditions have been developed13 to raise the yield of this
oxidation, and we investigated several of these before
choosing the Syper process13e of using arylselenium
compounds as activators for this oxidation. Therefore,
treatment of the aldehyde 9 with 2.5 equiv of 30%
hydrogen peroxide in the presence of 4% diphenyl dis-
elenide in dichloromethane for 18 h gave the desired aryl
formate 10 in excellent yield. This ester was cleaved by
treatment with methanolic ammonia for 1 h to afford the
desired phenol 4 in an overall yield of 78% for the two
steps. This final conversion of the aldehyde 9 into 4 could
be accomplished without isolation of the formate by
allowing the oxidation mixture to stir for an extended
period of time, e.g., 36 h, but at a slight cost in the yield.
Thus, in either four or five operations, one can convert
L-tyrosine (3) into the selectively monoprotected L-Dopa
derivative, N-Boc-L-3-[3-hydroxy-4-(phenylmethoxy)phen-
yl]alanine (4), in 33% overall yield. Compounds such as
4 have been used in the synthesis of isodityrosine
antibiotics.8
IR (neat) νmax 3400, 2980, 1713, 1659, 1489 cm-1
.
N -[(1,1-D i m e t h y le t h o x y )c a r b o n y l]-3-[3-fo r m y l-4-
(p h en ylm eth oxy)p h en yl]-L-a la n in e (9). A solution of anhy-
drous potassium carbonate (0.506 g, 3.66 mmol) in 2/1 chloroform/
methanol (6 mL) was refluxed for 15 min. The 3-formyl-N-Boc-
L-tyrosine 8 (0.257 g, 0.832 mmol) and benzyl bromide (0.148
mL, 1.25 mmol) were added, and the mixture was refluxed for
4 h. The reaction was then diluted with water and ethyl acetate.
The aqueous layer was acidified to pH 1 with 1 N HCl and back-
extracted with ethyl acetate. The organic extracts were washed
with brine, dried over MgSO4, and concentrated to give the
desired product 9 as a yellow oil (0.237 g, 71%), which was used
in the next step without further purification: 1H NMR (CDCl3,
360 MHz) δ 10.52 (1H, s, CHO), 7.67 (1H, s, C2-H), 7.41 (6H,
m, C6-H, Ph), 7.04 (1H, d, J ) 8.6 Hz, C5-H), 5.18 (2H, s,
CH2Ph), 4.98 (1H, bs, NH), 4.58 (1H, unresolved m, RH), 3.18
(1H, unresolved m, âH), 3.10 (1H, unresolved m, âH), 1.42 (9H,
s, Boc); 13C NMR (CDCl3, 90 MHz) δ 189.9, 175.3, 160.2, 155.3,
137.0, 136.0, 129.2, 128.7, 128.2, 127.3, 124.8, 113.3, 80.3, 70.5,
Thus, we have developed a new route to the important
selectively protected L-Dopa derivative 4 from L-tyrosine
(3) via applications of the Reimer-Tiemann reaction and
the Dakin oxidation. The use of this compound for the
synthesis of such derivatives is under investigation in
our laboratories and will be reported in due course.
54.1, 36.9, 28.2; IR (neat) νmax 3343, 2980, 1686, 1611, 1499 cm-1
.
N -[(1,1-D im e t h y le t h o x y )c a r b o n y l]-3-[3-h y d r o x y -4-
(p h en ylm eth oxy)p h en yl]-L-a la n in e (4). To a solution of the
3-formyl-4-(benzyloxy)-N-Boc-L-tyrosine 9 (0.096 g, 0.24 mmol)
in dichloromethane (3 mL) were added diphenyl diselenide (0.003
g, 0.01 mmol) and 30% aqueous hydrogen peroxide (0.062 mL,
0.614 mmol). The reaction mixture was stirred at ambient
temperature for 18 h. The mixture was then diluted with water
and ethyl acetate, washed with brine, dried over MgSO4, and
concentrated on a rotary evaporator. The residue was dissolved
in methanol (3 mL), and gaseous ammonia was bubbled through
the solution for 20 min. The reaction mixture was then stirred
Exp er im en ta l Section
Dichloromethane and methanol were distilled prior to use,
the former from calcium hydride and the latter from magnesium.
Dioxane and chloroform were of analytical grade and were used
without further purification. Other reagents were used as
provided. All reactions were carried out under
nitrogen pressure. Flash chromatography was performed on
a positive
ICN silica 32-63.
(13) (a) Chatterjee, A.; Ganguly, D.; Sen, R. Tetrahedron 1976, 32,
2407. (b) Hocking, M. B.; Ong, J . H. Can. J . Chem. 1977, 55, 102. (c)
Hocking, M. B.; Ko, M.; Smyth, T. A. Can. J . Chem. 1978, 56, 2646.
(d) Matsumoto, M.; Kobayashi, H.; Hotta, Y. J . Org. Chem. 1989, 54,
4740. (e) Syper, L. Synthesis 1989, 167.
at ambient temperature for
1 h. The mixture was then
concentrated and the residue redissolved in water. The aqueous
solution was acidified to pH 1 with 1 N HCl and back-extracted
with ethyl acetate. The organic extracts were washed with