Synthesis of a New Conformation-Constrained L-Tyrosine Analogue
crop (8, 700 mg) as a white solid followed by the second crop
(8, 150 mg), in a total yield of 60% for two steps. Mp: 185.0-
186.0 °C. [R]20D: -27.1 (c 1.63, CHCl3). 1H NMR (300 MHz,
CDCl3): δ 7.30-7.10 (m, 3 H), 7.05 (d, J ) 8.7 Hz, 2 H), 6.75-
6.65 (m, 4 H), 5.40 (d, J ) 9.9 Hz, 1 H), 5.35 (dd, J ) 8.7, 3.9
Hz, 1 H), 4.65 (t, J ) 8.7 Hz, 1 H), 4.10 (dd, J ) 8.7, 3.9 Hz,
1H), 3.80 (s, 3 H), 3.10 (m, 1 H), 2.20 (m, 1 H), 2.00-1.80 (m,
3 H), 1.40 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3): δ 172.1,
169.1, 158.8, 152.9, 137.5, 129.6, 129.5, 128.9, 128.2, 125.2,
114.1, 80.2, 69.9, 62.2, 57.5, 55.1, 45.6, 32.6, 28.0, 27.4 ppm.
EIMS (m/z): 467 (1.07), 466 (1.05), 411 (7.65), 410 (7.29), 193
(100). IR (KBr): 3060, 2082, 1772, 1217, 760, 557 cm-1. Anal.
Calcd for C26H30N4O6: C, 63.15; H, 6.11; N, 11.33. Found: C,
63.08; H, 6.15; N, 11.40. de > 99.80% by HPLC (a Kromasil
C18 cloumn, UV detector 220 nm, eluent CH3CN/H2O (1:1 to
100:0), flow rate 1.0 mL/min).
(2S,3R)-2-Azid o-3-(4-m eth oxyp h en yl)h exa n ed ioic Acid
6-ter t-Bu tyl Ester 1-Meth yl Ester (9). To a solution of azide
8 (1.86 g, 3.76 mmol) in THF (57 mL) and water (19 mL) at
-5 to 0 °C was added H2O2 (30% aq, 1.82 mL, 16.1 mmol) over
5 min. LiOH‚H2O (253 mg, 6.03 mmol) was added in three
portions. After the mixture was stirred for 30 min, saturated
Na2SO3 (15 mL) was added to the reaction mixture, and the
THF was removed in vacuo. The resulting mixture was
extracted with Et2O. The aqueous phase was then acidified to
pH 3-4 and extracted with CH2Cl2. The combined CH2Cl2
extracts were dried over anhydrous Na2SO4 and concentrated
in vacuo to give a white solid. To a solution of this white solid
in Et2O (20 mL) at 0 °C was added CH2N2 in Et2O until the
solution turned yellow. After the mixture was stirred for
another 20 min, excess CH2N2 was destroyed with glacial
acetic acid. The reaction mixture was concentrated in vacuo,
and the residue was purified by flash column chromatography
to give 9 as a colorless oil (1.30 g, 95%). [R]20D: +17.8 (c 2.40,
CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.10 (m, 2 H), 6.85 (m,
2 H), 3.90 (d, J ) 7.8 Hz, 1 H), 3.80 (s, 3 H), 3.60 (s, 3 H), 3.10
(m, 1 H), 2.20-1.90 (m, 4 H), 1.40 (s, 9 H) ppm. EIMS (m/z):
321 [(M - N3)+, 1.23], 264 (9.39), 193 (100), 147 (55.78). IR
(film): 2979, 2109, 1743, 1728, 1252, 1150, 832 cm-1. Anal.
Calcd for C18H25N3O5: C, 59.49; H, 6.93; N, 11.56. Found: C,
59.32; H, 6.92; N, 11.41. (The auxiliary was recycled in 80%
yield.)
1H NMR (300 MHz, CDCl3): δ 7.05 (m, 2 H), 6.85 (m, 2 H),
5.50 (d, J ) 9.6 Hz, 1H), 4.50 (m, 1 H), 3.80 (s, 3 H), 3.70 (s,
3 H), 3.50 (s, 3 H), 2.95 (m, 1 H), 2.30-2.00 (m, 4 H) ppm.
EIMS (m/e): 340 (MH+, 0.40), 323 (0.69), 280 (2.22), 262 (3.28),
193 (100). ESI-MS (m/z): 341 [(M + 2H)+, 15], 340 (MH+, 100).
IR (film): 3330, 2955, 1716, 1249, 833 cm-1. HR-EIMS: calcd
for C16H21NO7 339.1318, found 339.1346.
(S)-Meth oxyca r bon yla m in o-[(1R)-6-m eth oxy-4-oxo-2,3-
d ih yd r on a p h th a len -1-yl]a cetic Acid Meth yl Ester (12).
To a solution of acid 11 (1.03 g, 3.04 mmol) in dry CH2Cl2 (4
mL) and CS2 (24 mL) at 0 °C was added (COCl) (0.80 mL,
2
9.33 mmol), followed by the slow addition of dry DMF (70 uL,
0.91 mmol). The mixture was warmed to room temperature
and stirred for 2 h. The solvent was removed to give a yellow
oil. To the solution of this oil in dry CH2Cl2 (50 mL) at 0 °C
was added AlCl3 (1.30 g, 9.74 mmol) in one portion. The
reaction mixture was warmed to room temperature and stirred
for 5 h. Ice was added, and the reaction mixture was extracted
with CH2Cl2 (50 mL × 3). The CH2Cl2 extracts were washed
with brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by flash column chromatography to give
ketone 12 as a white solid (795 mg, 81%). Mp: 132.0-133.0
°C. [R]20D: +124.3 (c 1.11, CHCl3). 1H NMR (300 MHz,
CDCl3): δ 7.55 (d, J ) 3.0 Hz, 1 H), 7.15 (d, J ) 8.7 Hz, 1 H),
7.05 (dd, J ) 8.7, 3.0 Hz, 1 H), 5.25 (d, J ) 8.7 Hz, 1 H), 4.95
(m, 1 H), 3.85 (s, 3 H), 3.65 (s, 3H), 3.60 (s, 3 H), 3.30 (m, 1
H), 2.90 (m, 1 H), 2.60 (m, 1 H), 2.15 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ 196.9, 172.4, 158.9, 156.6, 134.2, 133.5,
129.2, 121.3, 109.8, 56.0, 55.3, 52.4, 52.1, 40.9, 35.2, 24.3 ppm.
EIMS (m/z): 290 [(M - MeO)+, 0.88], 246 (4.08), 187 (5.23),
175 (100). IR (KBr) 3405, 2954, 1723, 1682, 1288, 1049, 828
cm-1. Anal. Calcd for C16H19NO6: C, 59.81; H, 5.96; N, 4.36.
Found: C, 59.71; H 5.99; N, 4.30.
(1R,9R,12S)-5-Meth oxy-8-oxo-11-a za tr icyclo[7.3.1.02,7]-
tr id eca -2(7),3,5-tr ien e-12-ca r boxylic Acid Meth yl Ester
(13). To a solution of ketone 12 (220 mg, 0.68 mmol) in dry
CH3CN (10 mL) was added TMSI (0.50 mL, 3.50 mmol). After
being refluxed for 40 min, the mixture was cooled to 0 °C and
methanol (5.0 mL) was added slowly. The solvent was re-
moved, the residue was redissolved in ethanol (10 mL), and
HCHO (36% aq, 110 µL, 1.32 mmol) was added. After being
refluxed for 12 h, the reaction mixture was cooled to room
temperature. Ethanol was removed in vacuo, and the residue
was extracted with Et2O. The aqueous phase was basified with
saturated NaHCO3, saturated with solid NaCl, and extracted
with CH2Cl2 again. The combined CH2Cl2 extracts were
washed with brine, dried over Na2SO4, and concentrated in
vacuo. The residue was purified by flash column chromatog-
raphy to give 13a as a white solid (64 mg) and 13b as a
colorless oil (16 mg) in 43% total yield). Data for 13a . Mp:
(2S,3R)-2-Meth oxycar bon ylam in o-3-(4-m eth oxyph en yl)-
h exa n ed ioic Acid 6-ter t-Bu tyl Ester 1-Meth yl Ester (10).
To a solution of ester 9 (1.30 g, 3.58 mmol) in methanol (30
mL) was added Pd/C (10%, 260 mg). After the mixture was
stirred at room temperature for 5 h under 1 atm of H2, Pd/C
was filtered off and the filtrate was concentrated in vacuo. To
a solution of the above residue in dioxane (20 mL) and water
(20 mL) were added K2CO3 (720 mg, 7.20 mmol) and ClCOOMe
(0.34 mL, 4.40 mmol). After the mixture was stirred for 2 h at
room temperature, dioxane was removed in vacuo, and the
resulting mixture was extracted with EtOAc. The combined
organic extracts were washed with brine, dried over Na2SO4,
and concentrated in vacuo. The residue was purified by flash
column chromatography to give 10 as a colorless oil (1.29 g,
1
133.0-134.0 °C. [R]20D: +114.4 (c 0.56, CHCl3). H NMR (500
MHz, CDCl3): δ 7.50 (d, J ) 2.8 Hz, 1 H), 7.25 (d, J ) 8.4 Hz,
1 H), 7.10 (dd, J ) 8.4, 2.8 Hz, 1 H), 3.90-3.80 (m, 6 H), 3.55
(s, 1 H), 3.45 (s, 1 H), 3.20 (dd, J ) 11.7, 3.0 Hz, 1 H), 3.10 (d,
J ) 11.7 Hz, 1 H), 2.55 (s, 1 H), 2.30 (m, 1 H), 2.05 (m, 1 H)
ppm. 13C NMR (75 MHz, CDCl3): δ 201.1, 173.4, 159.0, 138.5,
135.2, 128.8, 121.8, 108.7, 60.0, 55.5, 52.2, 46.8, 42.4, 35.7, 29.3
ppm. EIMS (m/z): 277 [(M + 2H)+, 1.63], 276 (MH+, 7.34),
275 (M+, 1.68), 274 (12.19), 216 (100). IR (KBr): 3383, 2951,
2932, 1731, 1679, 1232, 1029, 844, 548 cm-1. Anal. Calcd for
91%). [R]20
:
+3.0 (c 1.93, CHCl3). 1H NMR (300 MHz,
D
CDCl3): δ 7.05 (m, 2 H), 6.85 (m, 2 H), 5.30 (d, J ) 9.0 Hz, 1
H), 4.50 (m, 1 H), 3.80 (s, 3 H), 3.65 (s, 3 H), 3.55 (s, 3 H), 2.90
(m, 1 H), 2.20-1.90 (m, 4 H), 1.40 (s, 9 H) ppm. EIMS (m/e):
396 (MH+, 0.41), 395 (M+, 0.88), 394 (1.45), 340 (16.16), 193
(100). ESIMS (m/z): 396.1 (MH+). IR (film): 3352, 2978, 1728,
1514, 834 cm-1. HR-EIMS: calcd for C20H29NO7 395.1944,
found 395.1976.
C
15H17NO4: C, 65.44; H, 6.22; N, 5.09. Found: C, 65.02; H,
6.31; N, 4.90. Data for 13b. [R]20D: +137.8 (c 0.90, CHCl3). 1H
NMR (300 MHz, CDCl3): δ 7.50 (d, J ) 2.7 Hz, 1 H), 7.05 (dd,
J ) 8.1, 2.7 Hz, 1 H), 6.85 (d, J ) 8.1 Hz, 1 H), 3.90 (s, 3 H),
3.60 (s, 3 H), 3.25 (s, 1 H), 3.15-3.05 (m, 2 H), 2.70 (d, J ) 2.4
Hz, 1 H), 2.45 (d, J ) 11.4 Hz, 1 H), 2.40 (m, 1 H), 2.10 (d,
J ) 13.2 Hz, 1 H), 1.80 (m, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ 200.4, 172.3, 158.5, 137.9, 134.6, 128.8, 121.4, 108.4,
61.5, 55.6, 51.3, 49.3, 42.4, 36.5, 28.6 ppm. EIMS (m/z): 260
[(M - CH3)+, 15.0]. IR (film): 3002, 2950, 1733, 1687,
1496, 1281, 1172, 1023, 786, 541 cm-1. HR-ESI: calcd for
(C15H17NO4 + H) 276.1236, found 276.1230.
(2S,3R)-2-Meth oxycar bon ylam in o-3-(4-m eth oxyph en yl)-
h exa n ed ioic Acid 1-Meth yl Ester (11). To a solution of ester
10 (1.29 g, 3.26 mmol) in CH2Cl2 (6.8 mL) was added Et3SiH
(1.40 mL, 8.67 mmol), followed by TFA (3.30 mL, 44.6 mmol).
After being stirred at room temperature for 1 h, the reaction
mixture was concentrated in vacuo to give a colorless oil, which
was purified by flash column chromatography to give acid 11
as a white wax (1.03 g, 93%). [R]20D: +12.0 (c 1.00, CHCl3).
J . Org. Chem, Vol. 68, No. 17, 2003 6683