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