1434
LETTERS
SYNLETT
materials. Alkene 13 should serve as a flexible platform for further
elaboration to other members of the theopederin, mycalamide, and
onnamide class of cytotoxic agents. Our improved synthesis of amide 7
from dihydropyranone 3 (49% overall in 8 steps) is capable of
delivering gram quantities of pederin and its analogs.
References
(1) Cardani, C.; Ghiringhelli, D.; Mondelli, R.; Quilico, A.
Tetrahedron Lett. 1965, 2537.
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(3) Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Pannell, L. K. J. Am.
Chem. Soc. 1988, 110, 4850.
Notes
1.
Hong and Kishi’s syntheses of onnamide A and mycalamides A
and B were also based on modifications of a late terminal alkene
(4) Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Thompson, A. M. J.
Org. Chem. 1990, 55, 223.
14,16
intermediate.
(5) Sakemi, S.; Ichiba, T.; Kohmoto, S.; Saucy, G.; Higa, T. J. Am.
Chem. Soc. 1988, 110, 4851.
2.
3.
4.
All crystalline compounds were recrystallised from ether-hexanes
unless otherwise stated.
(6) Matsunaga, S.; Fusetani, N.; Nakao, Y. Tetrahedron 1992, 48,
The (17S)-diol corresponds to mycalamide A. However, no
attempts were made to separate the diols.
8369.
(7) Fusetani, N.; Sugawara, T.; Matsunaga, S. J. Org. Chem. 1992, 57,
NMR data for theopederin D: δ (400 MHz, CDCl ) 7.51 (1H, d,
H
3
3828.
J 10.3 Hz, NH), 5.80 (1H, t, J 9.5 Hz, C10-H), 5.11 (1H, d, J 7.0
Hz, OCH H O), 4.86 (1H, d, J 7.0 Hz, OCH H O), 4.84 (1H, t,
(8) Matsuda, F.; Tomiyoshi, N.; Yanagiya, M.; Matsumoto, T.
A
B
A B
Tetrahedron 1988, 44, 7063.
J 2.0 Hz, =CH H ), 4.73 (1H, J 1.7 Hz, =CH H ), 4.42 (1H,
A
B
A B
(9) Nakata, T.; Nagao, S.; Mori, N.; Oishi, T. Tetrahedron Lett. 1985,
26, 6461.
ddd, J 14.1, 8.2, 5.9 Hz, C17-H), 4.25 (1H, d, J 3.2 Hz, C7-H),
4.19 (1H, dd, J 9.7, 6.4 Hz, C12-H), 4.11 (1H, d, J 3.2 Hz, C7-
OH), 4.01 (1H, dq, J 6.6, 2.8 Hz, C2-H), 3.80 (1H, dd, J 9.2, 6.4
Hz, C11-H), 3.54 (3H, s, OMe), 3.42 (1H, d, J 9.5 Hz, C13-H),
3.40 (1H, d, J 9.0, Hz, C15-H), 3.38 (3H, s, OMe), 2.50 (1H, m,
(10) Nakata, T.; Nagao, S.; Oishi, T. Tetrahedron Lett. 1985, 26, 6465.
(11) Kocienski, P.; Jarowicki, K.; Marczak, S. Synthesis 1991, 1191.
(12) Nakata, T.; Fukui, H.; Nakagawa, T.; Matsukura, H. Heterocycles
1996, 42, 159.
C19-H H ), 2.45 (1H, m, C19-H H ), 2.39 (1H, m, C18-H H ),
A
B
A
B
A B
2.33 (1H, d, J 13.9 Hz, C5-H), 2.24 (1H, dq, J 7.1, 2.6 Hz, C3-H),
2.18 (1H, d, J 14.1 Hz, C5-H), 1.92 (1H, m, C16-H H ), 1.76
(13) Nakata, T.; Matsukura, H.; Jian, D. L.; Nagashima, H.
A
B
Tetrahedron Lett. 1994, 35, 8229.
(1H, m, C18-H H ), 1.58 (1H, ddd, J 14.3, 8.3, 1.3 Hz, C16-
A
B
H H ) 1.18 (3H, d, J 6.6 Hz, C2-Me), 1.00 (3H, s, C14-Me ),
A
B
A
(14) Hong, C. Y.; Kishi, Y. J. Org. Chem. 1990, 55, 4242.
0.98 (3H, d, J 7.1 Hz, C3-Me), 0.86 (3H, s, C14-Me ).
B
(15) Kocienski, P. J.; Narquizian, R.; Raubo, P.; Smith, C.; Boyle, F. T.
δ
(100 MHz, CDCl ) 177.5 (0, C20), 172.3 (0, C8), 145.0 (0,
3
C
Synlett 1998, 869.
C4), 111.0 (2, C4=CH ), 99.8 (0, C6), 86.5 (2, OCH O), 79.5 (1,
2
2
(16) Hong, C. Y.; Kishi, Y. J. Am. Chem. Soc. 1991, 113, 9693.
C13), 79.2 (1, C17), 76.0 (1, C15), 74.0 (1, C12), 73.6 (1, C10),
71.6 (1, C7), 69.5 (1, C11), 69.5 (1, C2), 61.7 (3, C12-OMe), 48.5
(3, C6-OMe), 41.3 (1, C3), 41.1 (0, C14), 35.0 (2, C16), 33.3 (2,
C5), 28.7 (2, C19), 28.0 (2, C18), 22.6 (3, C14-Me), 18.0 (3, C2-
Me), 14.1 (3, C14-Me), 12.0 (3, C3-Me).
(17) Toyota, M.; Yamamoto, N.; Nishikawa, Y.; Fukumoto, K.
Heterocycles 1995, 40, 115.
(18) Toyota, M.; Nishikawa, Y.; Fukumoto, K. Heterocycles 1998, 47,
675.
5.
NMR data for 17-epi-theopederin D: δ (400 MHz, CDCl ) 7.41
(19) Marron, T. G.; Roush, W. R. Tetrahedron Lett. 1995, 36, 1581.
H
3
(1H, d, J 9.4 Hz, NH), 5.83 (1H, t, J 9.2 Hz, C10-H), 5.12 (1H, d,
J 7.0 Hz, OCH H O), 4.87 (1H, d, J 6.8 Hz, OCH H O), 4.87
(20) Carpino, L. A.; Tsao, J.-H.; Ringsdorf, H.; Fell, E.; Hettrich, G. J.
Chem. Soc., Chem. Commun. 1978, 358.
A
B
A B
(1H, t, J 2.0 Hz, =CH H ), 4.75 (1H, J 1.7 Hz, =CH H ), 4.48
A
B
A B
(21) Sharpless, K. B.; Amberg, W.; Beller, M.; Chen, H.; Hartung, J.;
Kawanami, Y.; Lübben, D.; Manoury, E.; Ogino, Y.; Shibata, T.;
Ukita, T. J. Org. Chem. 1991, 56, 4585.
(1H, ddd, J 12.1, 9.1, 6.4, C17-H), 4.26 (1H, d, J 2.4 Hz, C7-H),
4.19 (1H, dd, J 9.7, 6.5 Hz, C12-H), 4.05 (1H, dq, J 2.8, 6.6 Hz,
C2-H), 3.83 (1H, d, J 2.5 Hz, C7-OH), 3.82 (1H, dd, J 9.0, 6.5 Hz,
C11-H), 3.65 (1H, dd, J 9.8, 1.5 Hz, C15-H), 3.54 (3H, s, OMe),
3.44 (1H, d, J 9.7 Hz, C13-H), 3.30 (3H, s, OMe), 2.49 (2H, m,
(22) Nakamura, E.; Kuwajima, I. Org. Synth. Coll. Vol. VIII 1993, 277.
(23) Fukuzawa, S.; Nakanishi, A.; Fujinami, T.; Sakai, S. J. Chem.
Soc., Chem. Commun. 1986, 624.
C19-H ), 2.36 (1H, d, J 13.9 Hz, C5-H), 2.28 (1H, dq, J 7.1, 2.7
2
Hz, C3-H), 2.20 (1H, m, C18-H H ), 2.16 (1H, bd, J 14.1 Hz,
A
B
(24) Cahiez, G.; Alexakis, A.; Normant, J.-F. Tetrahedron Lett. 1978,
C5-H), 1.83-1.70 (2H, m, C16-H H and C18-H H ), 1.60 (1H,
A
B
A B
3013.
dd, J 9.7, 3.0 Hz, C16-H H ), 1.19 (3H, d, J 6.6 Hz, C2-Me),
A
B
(25) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
1.02 (3H, s, C14-Me ), 0.99 (3H, d, J 7.1 Hz, C3-Me), 0.84 (3H,
A
s, C14-Me ).
B
(26) Bloch, R.; Brillet, C. Synlett 1991, 829.
6.
The minor (17R)-diol gave mp 36-38°C (CHCl ).
3
(27) Richter, A.; Kocienski, P.; Raubo, P.; Davies, D. E. Anti-Cancer
Drug Design 1997, 12, 217.
Acknowledgements. We thank Zeneca Pharmaceuticals and the
EPSRC for financial support. We thank Mr Jim Tweedie for the large
scale synthesis of key intermediates.
(28) Thompson, A. M.; Blunt, J. W.; Munro, M. H. G.; Perry, N. B.;
Pannell, L. K. J. Chem. Soc., Perkin Trans. 1 1992, 1335.
(29) Kocienski, P.; Raubo, P.; Davis, J. K.; Boyle, F. T.; Davies, D. E.;
Richter, A. J. Chem. Soc., Perkin Trans. 1 1996, 1797.
(30) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226.