5292 J . Org. Chem., Vol. 63, No. 15, 1998
Notes
solution was added 34 µL (0.26 mmol) of chlorotrimethysilane
all at once. The reaction mixture was stirred for 15 min at -60
°C and allowed to warm to 25 °C. The reaction mixture was
quenched by the addition of 10 mL of water. An additional 20
mL of chloroform was added, and the organic solution was
separated, dried over sodium sulfate, and concentrated in vacuo.
The chlorohydrins were separated by by flash chromatography
on silica gel using 50% ethyl acetate-hexane as the eluent. The
minor chlorohydrin eluted first to give 8.6 mg (23%). This was
followed by the elution of the major isomer, which was concen-
trated in vacuo to give 17 mg (46%) of 3 as a white amorphous
solid: 1H NMR (CDCl3, 300 MHz) δ 0.93-0.98 (m, 9H), 1.05 (s,
3H), 1.07 (d, 3H, J ) 7.7 Hz), 1.45 (m, 1H), 1.69 (m, 1H), 1.84
(m, 1H), 2.03 (d, 1H, J ) 3.5 Hz), 2.35 (m, 1H), 2.56 (m, 2H),
2.72 (d, 1H, J ) 13.3 Hz), 2.96 (m, 2H), 3.21 (dd, 1H, J ) 14.3,
7.1 Hz), 3.69 (m, 2H), 3.89 (s, 3H), 3.99 (dd, 1H, J ) 9.8, 2.2
Hz), 4.62 (m, 1H), 4.68 (d, 1H, J ) 9.9 Hz), 5.28 (m, 1H), 5.80
(d, 1H, J ) 15.0 Hz), 6.09 (d, 1H, J ) 8.7 Hz), 6.63 (d, 1H, J )
7.7 Hz), 6.86 (d, 1H, J ) 8.4 Hz), 6.89 (m, 1H), 7.11 (dd, 1H, J
) 8.4, 1.8 Hz), 7.26 (d, 1H, J ) 1.8 Hz), 7.30-7.40 (m, 6H); IR
(CHCl3) 2959, 1745, 1677, 1639 cm-1; MS (FD+) m/z 690 (M+).
P u r e Ep oxid e 1. To a solution of 10.0 mg (0.0145 mmol) of
3 in 5 mL of 50% acetonitrile/water was added 5 mg of sodium
carbonate. The reaction was stirred at 25 °C for 1 h and then
diluted with 10 mL of ethyl acetate. The organic solution was
washed once with water, dried over sodium sulfate and concen-
trated in vacuo to give 8.0 mg (84%) of a white amorphous solid,
which was characterized as pure epoxide 1. 1H NMR (CDCl3,
300 MHz) δ 0.88 (d, 3H, J ) 6.4 Hz), 0.89 (d, 3H, J ) 6.4 Hz),
0.93 (s, 3H), 1.07 (s, 3H), 1.18 (d, 3H, J ) 6.7 Hz), 1.60 (m, 2H),
1.82 (m, 2H), 2.41 (m, 1H), 2.64 (m, 2H), 2.95 (m, 3H), 3.22 (dd,
1H, J ) 14.2, 7.2 Hz), 3.61-3.69 (m, 2H), 3.72 (s, 1H), 3.91 (s,
3H), 4.65 (m, 1H), 5.35 (m, 1H), 5.67 (d, 1H, J ) 8.5 Hz), 5.72
(d, 1H, J ) 14.9 Hz), 6.57 (d, 1H, J ) 9.1 Hz), 6.87 (d, 1H, J )
8.5 Hz), 6.90 (m, 1H), 7.11 (d, 1H, J ) 6.7 Hz), 7.23-7.42 (m,
7H); IR (CHCl3) 2962, 1745, 1675, 1643 cm-1; MS (FD+) m/z
654 (M+).
N-BOC-Leu -Cr yp to A-B (16). To a solution containing 100
mg (0.221 mmol) of cryptophycin A-B trichloroethyl ester (11)
and 82 mg (0.332 mmol) of N-BOC-leucine in 5 mL of methylene
chloride was added 68 mg (0.332 mmol) of dicyclohexylcarbodi-
imide (DCC) and 5 mg of 4-(N,N-dimethylamino)pyridine (DMAP).
The reaction mixture was strirred at 25 °C for 30 min and then
diluted with 50 mL of ethyl acetate. The organic solution was
washed with 0.5 N HCl and saturated sodium bicarbonate
solution, dried over sodium sulfate, and concentrated in vacuo.
The crude material was purified by flash chromatography using
25% ethyl acetate-hexane as the eluent. The major fraction
was concentrated in vacuo to give 110 mg (62%) of a white
amorphous solid, which was characterized as 16: 1H NMR
(CDCl3, 300 MHz) δ 0.80 (d, 3H, J ) 6.5 Hz), 0.88 (d, 3H, J )
6.5 Hz), 1.09 (d, 3H, J ) 6.6 Hz), 1.42 (s, 9H), 1.46 (m, 1H), 1.63
(m, 2H), 2.49 (m, 2H), 2.58 (m, 1H), 3.04 (dd, 1H, J ) 14.1, 6.9
Hz), 3.18 (dd, 1H, J ) 14.1, 5.6 Hz), 3.83 (s, 3H), 4.17 (m, 1H),
4.65 (d, 1H, J ) 11.9 Hz), 4.77 (d, 1H, J ) 11.9 Hz), 4.95 (m,
2H), 5.86 (d, 1H, J ) 15.7 Hz), 6.01 (dd, 1H, J ) 15.7, 8.6 Hz),
6.37 (d, 1H, J ) 15.7 Hz), 6.53 (d, 1H, J ) 7.8 Hz), 6.74 (m, 1H),
6.80 (d, 1H, J ) 8.3 Hz), 7.03 (d, 1H, J ) 8.3 Hz), 7.19-7.35 (m,
7H); IR (KBr) 2959, 1739, 1707, 1678 cm-1; MS (FD+) m/z 802
(M + 2+). Anal. Calcd For C38H48N2O8Cl4: C, 56.87; H, 6.03;
N, 3.49. Found: C, 57.07; H, 6.02; N, 3.39.
mmol) of N-BOC-2,2-dimethyl-â-alanine in 10 mL of 50% THF-
DMF were added 41 mg (0.305 mmol) of N-hydroxybenzotriazole
(HOBt) and 52 mg (0.244 mmol) of 1-ethyl-3-[3-(dimethylamino)-
propyl]carbodiimide (EDC). The reaction mixture was stirred
at 25 °C for 15 min, after which time a solution containing the
TFA salt and 20 µL (0.183 mmol) of N-methylmorpholine (NMM)
in 5 mL of DMF was added. The reaction was stirred at 25 °C
for 15 h and diluted with 100 mL of ethyl acetate, and the
organic solution was washed twice with 0.5 N HCl, twice with
saturated sodium bicarbonate solution, and twice with brine.
The organic layer was dried over sodium sulfate and concen-
trated in vacuo to give 105 mg (95%) of a white amorphous solid,
which was characterized as 17a : 1H NMR (CDCl3, 300 MHz) δ
0.80 (d, 3H, J ) 6.2 Hz), 0.83 (d, 3H, J ) 6.1 Hz), 1.08 (d, 3H,
J ) 6.8 Hz), 1.11 (s, 3H), 1.14 (s, 3H), 1.45 (s, 9H), 2.48 (t, 1H,
J ) 5.7 Hz), 2.55 (m, 1H), 3.01 (dd, 1H, J ) 14.0, 7.8 Hz), 3.18
(m, 2H), 3.25 (m, 1H), 3.48 (d, 2H, J ) 6.8 Hz), 3.81 (s, 3H),
4.33 (m, 1H), 4.63 (d, 1H, J ) 11.8 Hz), 4.78 (d, 1H, J ) 11.8
Hz), 5.00 (m, 2H), 5.22 (m, 1H), 5.91 (d, 1H, J ) 15.8 Hz), 5.99
(dd, 1H, J ) 15.8, 8.5 Hz), 6.27 (d, 1H, J ) 6.5 Hz), 6.35 (d, 1H,
J ) 15.8 Hz), 6.71 (dt, 1H, J ) 15.8, 6.0 Hz), 6.78 (d, 1H, J )
8.5 Hz), 7.04 (dd, 1H, J ) 8.5, 1.6 Hz), 7.15-7.30 (m, 3H), 7.42
(m, 1H), 7.53 (m, 1H), 8.03 (d, 1H, J ) 8.4 Hz); IR (CHCl3) 2960,
1710, 1679, 1649 cm-1; MS (FD+) m/z 901 (M + 2+).
N-BOC-C(m on om eth yl)-Ψ[CONH]-D-A-B-OCH2CCl3
(17b). 17b was prepared in an analogous fashion using (R)-N-
BOC-2-methyl-â-alanine. The coupling reaction was carried out
by making the mixed anydride of (R)-N-BOC-2-methyl-â-alanine
(46 µL (0.27 mmol) of diisopropylamine and 35 µL (0.27 mmol)
isobutyl chloroformate to (R)-N-BOC-2-methyl-â-alanine in 5 mL
of dry THF at -15 °C). 17b was isolated as a white amorphous
solid (83% yield): [R]25 ) -8.3 (c ) 0.88, CHCl3); 1H NMR
D
(CDCl3, 500 MHz) δ 0.81 (d, 3H, J ) 6.8 Hz), 0.86 (d, 3H, J )
6.8 Hz), 1.1 (d, 3H, J ) 7.1 Hz), 1.1 (d, 3H, J ) 6.8 Hz), 1.4 (m,
1H), 1.55 (m, 1H), 1.65 (m, 1H), 2.55 (m, 1H), 2.6 (m, 2H), 3.1
(dd, 1H, J ) 14.2, 7.2 Hz), 3.2 (m, 2H), 3.86 (s, 3H), 4.4 (m, 1H),
4.68 (d, 1H, J ) 12.0 Hz), 4.80 (d, 1H, J ) 12 Hz), 5.0 (m, 1H),
5.0 (m, 1H), 5.0 (m, 1H), 5.95 (d, 1H, J ) 15.4), 6.04 (dd, 1H, J
) 15.9, 8.6 Hz), 6.12 (m, 1H), 6.4 (d, 1H J ) 15.9 Hz), 6.75 (dt,
1H, J ) 15.4, 6.4 Hz), 6.85 (d, 1H J ) 8.2), 7.05 (dd, 1H, J )
8.2, 1.5 Hz), 7.15 (d, 1H, J ) 7.6 Hz), 7.22(m, 1H), 7.22 (d, 1H,
J ) 1.5), 7.28-7.35 (m, 4H); 13C NMR (CDCl3, 125 MHz), 16.6,
21.5, 22.7, 24.5, 33.6, 36.6, 40.5, 41.3, 43.6, 51.3, 53.4, 56.1, 74.5,
76.3, 79.5, 94.4, 112.2, 122.3, 125.8, 126.2, 127.4, 128.6, 130.4,
131.2, 131.5, 136.9, 138.9, 154.1, 156.3, 165.8, 170.2, 172.6, 175.4.
Cr yp to Dim eth yl C-D Am id e Styr en e 19a . To a solution
of 100 mg (0.111 mmol) of 17a in 15 mL of glacial acetic acid
was added 400 mg of activated zinc dust. The suspension was
sonicated for 45 min and stirred at room temperature for an
additional 30 min. The mixture was filtered over a pad of Celite
and the filtrate concentrated in vacuo. The resulting oily solid
was treated with 10 mL of TFA and stirred at room temperature
for 2 h. The solution was concentrated, and the resulting yellow
foam was used without further purification. To a solution
containing 85 mg (0.108 mmol) of the crude amino acid 18a in
5 mL of DMF was added 113 µL (0.648 mmol) of diisopropyl-
ethylamine, followed by the addition of 54 mg (0.140 mmol) of
pentafluorophenyl diphenylphosphinate. The reaction mixture
was stirred at room temperature for 4 h and diluted with 100
mL of ethyl acetate and the organic phase washed with 1 N HCl
(2×), saturated sodium bicarbonate solution (2×), and brine (2×).
The solution was dried and concentrated in vacuo. The crude
material was purified by flash chromatography on silica gel
using 50% ethyl acetate-hexane as the eluent to give 58 mg
(83%) of a white amorphous solid, which was characterized as
19a : 1H NMR (CDCl3, 300 MHz) δ 0.74 (d, 3H, J ) 5.9 Hz),
0.75 (d, 3H, J ) 5.6 Hz), 1.15-1.22 (m, 9H), 1.38 (m, 2H), 1.49
(m, 1H), 2.38 (m, 1H), 2.55 (m, 2H), 2.98 (dd, 1H, J ) 14.4, 7.7
Hz), 3.15 (m, 2H), 3.46 (dd, 1H, J ) 12.6, 10.4 Hz), 3.87 (s, 3H),
4.43 (m, 1H), 4.65 (m, 1H), 5.12 (m, 1H), 5.61 (d, 1H, J ) 6.4
Hz), 5.73 (d, 1H, J ) 14.9 Hz), 5.90 (d, 1H, J ) 8.3 Hz), 6.00
(dd, 1H, J ) 15.8, 8.6 Hz), 6.39 (d, 1H, J ) 15.8 Hz), 6.75 (m,
1H), 6.84 (d, 1H, J ) 8.3 Hz), 6.94 (d, 1H, J ) 8.2 Hz), 7.03 (d,
1H, J ) 8.2 Hz), 7.18-7.40 (m, 6H); IR (KBr) 3415, 3319, 2961,
1740, 1653 cm-1; MS (FD+) m/z 651 (M+).
N -BOC-C(d im e t h yl)-Ψ[CONH ]-D-A-B-OCH 2CCl3
(17a ). To a solution containing 92 mg (0.115 mmol) of 16 in 2
mL of methylene chloride was added 2 mL of trifluoroacetic acid
(TFA). The reaction mixture was stirred at 25 °C for 1 h and
concentrated in vacuo to give 100 mg of a white amorphous solid,
which was characterized as the corresponding TFA salt on the
basis of its 1H NMR spectrum: 1H NMR (CDCl3, 300 MHz) δ
0.77 (d, 3H, J ) 5.4 Hz), 0.85 (d, 3H, J ) 5.2 Hz), 1.13 (d, 3H,
J ) 6.7 Hz), 1.72 (m, 3H), 2.41 (m, 1H), 2.60 (m, 2H), 2.99 (dd,
1H, J ) 14.4, 7.1 Hz), 3.18 (dd, 1H, J ) 14.4, 5,8 Hz), 3.85 (s,
3H), 4.07 (m, 1H), 4.65 (d, 1H, J ) 11.9 Hz), 4.81 (d, 1H, J )
11.9 Hz), 4.93 (m, 1H), 5.08 (m, 1H), 5.90 (d, 1H, J ) 15.4 Hz),
5.99 (dd, 1H, J ) 15.8, 8.5 Hz), 6.42 (d, 1H, J ) 15.8 Hz), 6.73
(m, 2H), 6.83 (d, 1H, J ) 8.5 Hz), 7.01 (d, 1H, J ) 8.0 Hz), 7.15-
7.40 (m, 7H), 8.15 (bs, 3H). This material was used without
further purification. To a solution containing 53 mg (0.244