A. K. Ghosh, A. Bischoff
FULL PAPER
(225 µL, 1.29 mmol), 2,4,6-trichlorobenzyl chloride (58 µL,
Cryptophycin B (2): To a solution of 4 (6.0 mg, 9.92 µmol) in DCM
0.37 mmol) and DMAP (90 mg, 0.37 mmol). After stirring at room (2 mL) was added dimethyldioxirane[47] (0.32 in acetone, 310 µL,
temperature for 1 h, the solvent was evaporated and the residue
was dissolved in benzene (20 mL) and stirred at room temperature
99.2 µmol) at Ϫ30 °C. The resulting mixture was stirred at Ϫ30
°C to room temperature for 12 h and then concentrated in vacuo.
for 12 h. The reaction mixture was quenched with saturated aque- Chromatographic purification [HPLC, YMC-PACK OD-AQ 5S
˚
ous NH4Cl and extracted with diethyl ether. The organic layer was
dried with Na2SO4, concentrated in vacuo and chromatograph-
ically purified (50% EtOAc in hexane) to yield 4 (169 mg, 76%) as
a white solid. M.p. 186Ϫ189 °C. [α]2D3 ϭ ϩ36.2 (c ϭ 0.72, MeOH)
{ref.[2] [α]2D3 ϭ ϩ36.7 (c ϭ 1.93, MeOH)}. 1H NMR (CDCl3,
120A 4.6 ϫ 250 mm, MeOH/H2O, 3:1, 1 mL/min, room temp.,
tR(2) ϭ 31.58 min] to yield 2 (5.4 mg, 87%, 3:1) as a white solid.
[α]2D3 ϭ ϩ20.6° (c ϭ 0.24, MeOH) {ref.[2] [α]2D3 ϭ ϩ20.4 (c ϭ 0.54,
1
MeOH)}. H NMR (CDCl3, 500 MHz): δ ϭ 7.42Ϫ7.35 (m, 3 H),
7.28Ϫ7.24 (m, 2 H), 7.12 (d, 3J ϭ 8.5 Hz, 2 H), 7.06 (dd, 3J ϭ 5.9,
500 MHz): δ ϭ 7.36Ϫ7.31 (m, 4 H), 7.26 (dd, J ϭ 7.0, J ϭ 7.0 3J ϭ 5.9 Hz, 1 H), 6.84 (d, 3J ϭ 8.5 Hz, 2 H), 6.73 (ddd, 3J ϭ 15.1,
3
3
3
3
3
3
3
Hz, 1 H), 7.13 (d, J ϭ 8.5 Hz, 2 H), 7.08 (dd, J ϭ 6.0, J ϭ 6.0
3J ϭ 10.1, J ϭ 4.8 Hz, 1 H), 5.73 (d, J ϭ 15.4 Hz, 1 H), 5.66 (d,
3
3
3
Hz, 1 H), 6.83 (d, J ϭ 8.5 Hz, 2 H), 6.73 (ddd, J ϭ 15.0, J ϭ
3J ϭ 8.2 Hz, 1 H), 5.21 (ddd, 1 H, 3J ϭ 9.5, 3J ϭ 4.8, 3J ϭ 1.6 Hz),
10.0, 3J ϭ 5.0 Hz, 1 H), 6.42 (d, 3J ϭ 15.5 Hz, 1 H), 6.03 (dd, 3J ϭ 4.84 (dd, J ϭ 9.8, J ϭ 3.3 Hz, 1 H), 4.81 (dt, J ϭ 7.2, J ϭ 6.4
3
3
3
3
3
3
3
15.5, J ϭ 9.0 Hz, 1 H), 5.77 (d, J ϭ 15.0 Hz, 1 H), 5.67 (d, J ϭ
Hz, 1 H), 3.81 (s, 3 H), 3.71 (d, 3J ϭ 1.7 Hz, 1 H), 3.44 (ddd, 2J ϭ
8.0 Hz, 1 H), 5.05 (ddd, 1 H, 3J ϭ 8.5, 3J ϭ 6.0, 3J ϭ 1.0 Hz), 4.87
13.6, J ϭ 12.7, J ϭ 5.5 Hz, 1 H), 3.39 (ddd, J ϭ 13.6, J ϭ 4.2,
3
3
2
3
(dd, J ϭ 10.0, J ϭ 3.0 Hz, 1 H), 4.81 (dt, J ϭ 7.5, J ϭ 7.5 Hz, 3J ϭ 4.1 Hz, 1 H), 3.15 (dd, 2J ϭ 14.6, 3J ϭ 5.6 Hz, 1 H), 3.10
3
3
3
3
1 H), 3.80 (s, 3 H), 3.42 (dd, 3J ϭ 5.0, 3J ϭ 5.0 Hz, 2 H), 3.16 (dd,
(dd, 2J ϭ 14.4, 3J ϭ 6.9 Hz, 1 H), 2.94 (dd, J ϭ 7.6, 3J ϭ 1.8 Hz,
3
2J ϭ 14.0, J ϭ 5.0 Hz, 1 H), 3.10 (dd, J ϭ 14.0, J ϭ 7.5 Hz, 1 1 H), 2.71 (m, 1 H), 2.58 (dm, 1 H, J ϭ 14.5 Hz), 2.40 (ddd, 1 H,
3
2
3
2
H), 2.70 (m, 1 H), 2.56 (m, 2 H), 2.40 (m, 1 H), 1.68 (m, 2 H), 1.36 2J ϭ 14.5, J ϭ 10.8, J ϭ 10.5 Hz), 1.81 (m, 1 H), 1.73 (m, 2 H),
3
3
3
3
3
3
(m, 1 H), 1.25 (d, J ϭ 7.5 Hz, 3 H), 1.15 (d, J ϭ 7.0 Hz, 3 H),
1.36 (m, 1 H), 1.25 (d, J ϭ 7.3 Hz, 3 H), 1.17 (d, J ϭ 6.9 Hz, 3
0.78 (d, 3J ϭ 6.5 Hz, 3 H), 0.74 (d, 3J ϭ 6.5 Hz, 3 H) ppm. 13C H), 0.88 (d, 3J ϭ 6.5 Hz, 3 H), 0.86 (d, 3J ϭ 6.5 Hz, 3 H) ppm.
NMR (CDCl3, 125 MHz): δ ϭ 176.4, 171.6, 171.2, 165.7, 159.0,
141.9, 137.1, 132.2, 130.6, 130.5, 129.0, 128.9, 128.0, 126.6, 125.5,
114.5, 77.6, 72.0, 55.6, 54.3, 42.7, 41.2, 40.1, 38.5, 36.9, 35.8, 24.9,
13C NMR (CDCl3, 125 MHz): δ ϭ 176.4, 171.5, 171.1, 165.5,
159.0, 141.6, 137.1, 130.6, 129.1, 129.0, 128.7, 126.0, 125.5, 114.6,
76.7, 71.7, 63.5, 59.5, 55.6, 54.3, 41.2, 39.8, 38.5, 37.2, 35.7, 24.9,
23.1, 21.6, 17.8, 14.6 ppm. IR (CH2Cl2): ν˜ ϭ 3420 (m), 2963 (s), 23.3, 21.7, 14.7, 14.0 ppm. IR (DCM): ν˜ ϭ 3411 (m), 2962 (s), 2935
2936 (m), 1746 (s), 1721 (s), 1680 (s), 1649 (s), 1513 (s), 1248 (s), (m), 1743 (s), 1724 (s), 1682 (s), 1513 (s), 1247 (s), 1199 (s), 1179
1179 (s) cmϪ1. HRMS (FAB): m/z calcd. C35H45N2O7 [M ϩ Hϩ] (s) cmϪ1. HRMS (FAB): m/z calcd. C35H45N2O8 [M ϩ Hϩ]
605.3227, found 605.3231.
621.3176, found 621.3160.
Arenastatin A (5): To a solution of 36 (5.2 mg, 8.81 µmol) in DCM
(2 mL) was added dimethyldioxirane[45] (0.23 in acetone, 383 µL,
88.1 µmol) at Ϫ30 °C. The resulting mixture was stirred at Ϫ30
°C to room temperature for 12 h and then concentrated in vacuo.
Chromatographic purification [HPLC, YMC-PACK OD-AQ 5S
Deoxyarenastatin A (36): A mixture of 35 (56.9 mg, 74.4 µmol) and
TFA (10 mL) was stirred at room temperature for 2 h. The reaction
was concentrated in vacuo and the residue was dissolved in THF
(10 mL). To this solution were successively added iPr2NEt (12 µL,
74.4 µmol), 2,4,6-trichlorobenzyl chloride (12 µL, 74.4 µmol) and
DMAP (36.0 mg, 298 µmol). After 1 h of stirring at room tempera-
ture, the solvent was evaporated and the residue was dissolved in
benzene (10 mL) and stirred at room temperature for 1 h. The reac-
tion was quenched with saturated aqueous NH4Cl and the mixture
extracted with diethyl ether. The organic layer was dried with
Na2SO4, concentrated in vacuo and chromatographically purified
(65% EtOAc in hexane) to yield 36 (35.2 mg, 81%) as a white solid.
˚
120A 4.6 ϫ 250 mm, MeOH/H2O 3:1, 1 mL/min, room temp.,
tR(5) ϭ 30.86 min] to yield 5 (4.0 mg, 75%, 3:1) as a colorless film.
[α]2D3 ϭ ϩ48.1 (c ϭ 0.09, CHCl3) {ref.[33] [α]2D3 ϭ ϩ48.7 (c ϭ 0.87,
1
CHCl3)[. H NMR (CDCl3, 500 MHz): δ ϭ 7.43Ϫ7.24 (m, 5 H),
7.11 (d, 3J ϭ 8.5 Hz, 2 H), 7.04 (t, 3J ϭ 5.9 Hz, 1 H), 6.83 (d, 3J ϭ
3
3
3
8.6 Hz, 2 H), 6.72 (ddd, J ϭ 15.1, J ϭ 10.2, J ϭ 4.8 Hz, 1 H),
3
3
5.72 (d, J ϭ 15.2 Hz, 1 H), 5.65 (d, J ϭ 8.2 Hz, 1 H), 5.21 (ddd,
3
3
3
3
3
1 H, J ϭ 9.4, J ϭ 4.8, J ϭ 1.5 Hz), 4.90 (dd, J ϭ 9.8, J ϭ 3.4
3
3
M.p. 182Ϫ188 °C. [α]2D3 ϭ ϩ33.5 (c ϭ 0.09, CH2Cl2) {ref.[2] [α]2D3
ϭ
Hz, 1 H), 4.75 (dt, J ϭ 7.3, J ϭ 6.3 Hz, 1 H), 3.78 (s, 3 H), 3.71
(d, 3J ϭ 1.8 Hz, 1 H), 3.46 (ddd, 2J ϭ 13.4, 3J ϭ 12.6, 3J ϭ 5.5 Hz,
ϩ34.0 (c ϭ 1.36, CH2Cl2)}. 1H NMR (CDCl3, 400 MHz): δ ϭ
2
3
3
7.36Ϫ7.26 (m, 4 H), 7.23 (dd, 3J ϭ 7.8, 3J ϭ 7.8 Hz, 1 H), 7.12 (d,
1 H), 3.41 (ddd, J ϭ 13.5, J ϭ 4.2, J ϭ 4.2 Hz, 1 H), 3.15 (dd,
2J ϭ 14.6, J ϭ 5.3 Hz, 1 H), 3.08 (dd, J ϭ 14.5, J ϭ 6.7 Hz, 1
H), 2.94 (dd, 3J ϭ 7.6, 3J ϭ 1.8 Hz, 1 H), 2.58 (m, 3 H), 2.39 (ddd,
1 H, 3J ϭ 7.6, 3J ϭ 7.5, 3J ϭ 7.5 Hz), 1.75Ϫ1.69 (m, 3 H), 1.32
3
2
3
3
3
3J ϭ 8.8 Hz, 2 H), 7.02 (dd, J ϭ 4.5, J ϭ 4.5 Hz, 1 H), 6.82 (d,
3J ϭ 8.8 Hz, 2 H), 6.71 (ddd, J ϭ 15.2, J ϭ 10.4, J ϭ 4.8 Hz, 1
H), 6.40 (d, J ϭ 15.6 Hz, 1 H), 6.01 (dd, J ϭ 15.6, J ϭ 8.5 Hz,
3
3
3
3
3
3
3
3
3
3
(m, 1 H), 1.15 (d, J ϭ 6.9 Hz, 3 H), 0.84 (d, J ϭ 6.5 Hz, 3 H),
0.83 (d, 3J ϭ 6.5 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ ϭ
173.2, 171.1, 171.0, 165.8, 159.0, 141.5, 137.1, 130.6, 129.1, 128.9,
128.7, 126.0, 125.5, 114.5, 77.5, 71.7, 63.5, 59.5, 55.6, 54.5, 42.7,
40.1, 36.9, 35.6, 34.6, 32.9, 24.8, 23.1, 21.7, 14.0 ppm. IR (film):
ν˜ ϭ 3410 (m), 2963 (s), 2932 (m), 1742 (s), 1726 (s), 1679 (s), 1513
(s), 1246 (s), 1200 (m), 1180 (s) cmϪ1. HRMS (FAB): m/z calcd.
C34H43N2O8 [M ϩ Hϩ] 607.3019, found 607.3025.
1 H), 5.73 (d, J ϭ 15.2 Hz, 1 H), 5.59 (d, J ϭ 8.0 Hz, 1 H), 5.05
(ddd, 1 H, 3J ϭ 9.6, 3J ϭ 6.8, 3J ϭ 1.3 Hz), 4.90 (dd, 3J ϭ 9.6,
3
3
3J ϭ 3.6 Hz, 1 H), 4.74 (dd, J ϭ 7.2, J ϭ 6.4 Hz, 1 H), 3.78 (s,
2
3
3 H), 3.55 (m, 1 H), 3.42 (m, 1 H), 3.14 (dd, J ϭ 14.4, J ϭ 6.0
Hz, 1 H), 3.05 (dd, J ϭ 14.4, J ϭ 7.6 Hz, 1 H), 2.54 (m, 4 H),
2.36 (dt, J ϭ 14.0, J ϭ 11.2 Hz, 1 H), 1.68 (m, 2 H), 1.40 (m, 1
2
3
2
3
3
3
H), 1.14 (d, J ϭ 6.8 Hz, 3 H), 0.74 (d, J ϭ 6.0 Hz, 3 H), 0.71 (d,
3J ϭ 6.0 Hz, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ ϭ 173.3,
171.2, 171.1, 165.9, 159.0, 141.9, 137.1, 132.2, 130.6, 130.5, 129.0,
128.9, 128.0, 126.6, 125.5, 114.5, 77.0, 72.0, 55.6, 54.5, 42.7, 40.1,
36.8, 35.6, 34.6, 32.9, 24.8, 23.0, 21.7, 17.7 ppm. IR (film): ν˜ ϭ
2957 (s), 2925 (s), 1741 (s), 1730 (s), 1678 (s), 1650 (s), 1513 (s),
1372 (m), 1247 (s), 1175 (s) cmϪ1. HRMS (FAB): m/z calcd.
C34H43N2O7 [M ϩ Hϩ] 591.3070, found 591.3080. LRMS (LCQ):
m/z (%) ϭ 591.1 (22) [M ϩ Hϩ], 387.9 (100), 360.0 (35).
Acknowledgments
Financial support by the National Institutes of Health is grate-
fully acknowledged.
[1]
R. E. Schwartz, C. F. Hirsch, D. E. Sesin, J. E. Flor, M. Char-
2140
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2004, 2131Ϫ2141