of the pancratistatin alkaloids. The key intermediates in our
synthetic design are 1-aryl-1-deoxy analogues (5) of con-
duritol F, incorporating most of the structural and stereo-
chemical complexity of the target alkaloids (Scheme 1). We
Scheme 1
Figure 1.
ners,9 the problem of supply has not been solved. The limited
availability has also plagued structure-activity studies, and
although some SAR data are available for the pancratistatin
analogues with the modified cyclitol ring C,10 the structural
and electronic requirements of the aromatic ring A have not
been studied to the best of our knowledge. One of us has
previously coauthored a report describing utilization of the
ring-closing metathesis process in the rapid construction of
the cyclitol rings of conduritols B and F as well as L-chiro-
and myo-inositols starting from readily available monosac-
charides such as D-xylose.11,12 We intend to apply this
powerful strategy to the more challenging cyclitol structures
(8) Eight total syntheses of pancratistatin have been reported to date:
(a) Danishefsky, S.; Lee, J. Y. J. Am. Chem. Soc. 1989, 111, 4829. (b)
Hudlicky, T.; Tian, X.; Ko¨nigsberger, K.; Maurya, R.; Rouden, J.; Fan, B.
J. Am. Chem. Soc. 1996, 118, 10752. (c) Trost, B. M.; Pulley, S. R. J. Am.
Chem. Soc. 1995, 117, 10143. (d) Magnus, P.; Sebhat, I. K. J. Am. Chem.
Soc. 1998, 120, 5341. (e) Rigby, J. H.; Maharoof, U. S. M.; Mateo, M. E.
J. Am. Chem. Soc. 2000, 122, 6624. (f) Doyle, T. J.; Hendrix, M.;
VanDerveer, D.; Javanmard, S.; Haseltine, J. Tetrahedron 1997, 53, 11153.
(g) Pettit, G. R.; Melody, N.; Herald, D. L. J. Org. Chem. 2001, 66, 2583.
(h) Kim, S.; Ko, H.; Kim, E.; Kim, D. Org. Lett. 2002, 4, 1343.
(9) Deoxypancratistatin: (a) Paulsen, H.; Stubbe, M. Liebigs Ann. Chem.
1983, 535. (b) Tian, X.; Maurya, R.; Ko¨nigsberger, K.; Hudlicky, T. Synlett
1995, 1125. (c) Keck, G. E.; McHardy, S. F.; Murry, J. A. J. Am. Chem.
Soc. 1995, 117, 7289. (d) Chida, N.; Jitsuoka, M.; Yamamoto, Y.; Ohtsuka,
M.; Ogawa, S. Heterocycles 1996, 43, 1385. (e) Reference 8b. (f) Keck,
G. E.; Wager, T. T.; McHardy, S. F. J. Org. Chem. 1998, 63, 9164. (g)
Acen˜a, J. L.; Arjona, O.; Leo´n, M. L.; Plumet, J. Org. Lett. 2000, 2, 3683.
Narciclasine: (h) Reference 8e. (i) Keck, G. E.; Wager, T. T.; Rodriquez,
J. F. D. J. Am. Chem. Soc. 1999, 121, 5176. (j) Elango, S.; Yan, T.-H. J.
Org. Chem. 2002, 67, 6954. (k) Hudlicky, T.; Rinner, U.; Gonzalez, D.;
Akgun, H.; Schilling, S.; Siengalewicz, P.; Martinot, T. A.; Pettit, G. R. J.
Org. Chem. 2002, 67, 8726. 7-Deoxynarciclasine: (l) Ohta, S.; Kimoto, S.
Chem. Pharm. Bull. 1976, 24, 2977. (m) Reference 9a. (n) Martin, S. F.;
Tso, H.-H. Heterocycles 1993, 35, 85. (o) Chida, N.; Ohtsuka, M.; Ogawa,
S. J. Org. Chem. 1993, 58, 4441. (p) Hudlicky, T.; Olivo, H. F.; McKibben,
B. J. Am. Chem. Soc. 1994, 116, 5108. (q) Keck, G. E.; Wager, T. T.;
Rodriquez, J. F. D. J. Am. Chem. Soc. 1999, 121, 5176. (r) Elango, S.;
Yan, T.-H. Tetrahedron 2002, 58, 7335.
envision that these compounds will be converted to trans-
4,4a-oxycarbamates either via R-selective aziridination and
subsequent trans-diaxial ring opening with an oxygen-based
nucleophile or via allylic alcohol-directed â-selective ep-
oxidation, followed by epoxide ring opening with a nitrogen-
based nucleophile. A regioselective Bischler-Napieralski-
type cyclization could potentially complete the synthesis of
each target alkaloid.
Herein, we report an efficient multigram synthesis of
various 1-aryl-1-deoxyconduritols F, which establishes a firm
foundation for achieving a practical synthesis of not only
pancratistatin alkaloids themselves but also their aryl ana-
logues, paving the way for more systematic SAR studies of
these promising anticancer agents.
A brief retrosynthetic analysis of the target conduritols 5
reveals that application of an RCM process for construction
of the cyclitol ring would require an efficient pathway to
3,4,5-trialkoxy-6-aryloctadienes 8 (Scheme 2).
Although we envisioned that the three alkoxy stereocenters
of dienes with general structure 8 could originate from readily
(10) McNulty, J.; Mao, J.; Gibe, R.; Mo, R. W.; Wolf, S.; Pettit, G. R.;
Herald, D. L.; Boyd, M. R. Bioorg. Med. Chem. Lett. 2001, 11, 169.
(11) (a) Kornienko, A.; d’Alarcao, M. Tetrahedron: Asymmetry 1999,
10, 827.
(12) For other cyclitol syntheses from carbohydrates utilizing RCM,
see: (a) Seepersaud, M.; Al-Abed, Y. Org. Lett. 1999, 1, 1463. (b) Sellier,
O.; Van de Weghe, P.; Eustache, J. Tetrahedron Lett. 1999, 40, 5859. (c)
Ackermann, L.; El Tom, D.; Fu¨rstner, A. Tetrahedron 2000, 56, 2195. (d)
Marco-Contelles, J.; de Opazo, E. Tetrahedron Lett. 2000, 41, 2439. (e)
Hanna, I.; Ricard, L. Org. Lett. 2000, 2, 2651. (f) Marco-Contelles, J.; de
Opazo, E. J. Org. Chem. 2000, 65, 5416. (g) Boyer, F.-D.; Hanna, I.; Nolan,
S. P. J. Org. Chem. 2001, 66, 4094. (h) Jorgensen, M.; Iversen, E. H.;
Paulsen, A. L.; Madsen, R. J. Org. Chem. 2001, 66, 4630. (i) Nishikawa,
A.; Saito, S.; Hashimoto, Y.; Koga, K.; Shirai, R. Tetrahedron Lett. 2001,
42, 9195. (j) Conrad, R. M.; Grogan, M. J.; Bertozzi, C. R. Org. Lett. 2002,
4, 1359. (k) Ble´riot, Y.; Giroult, A.; Mallet, J.-M.; Rodriguez, E.; Vogel,
P.; Sinay¨, P. Tetrahedron: Asymmetry 2002, 13, 2553. (l) Heo, J.-N.;
Holson, E. B.; Roush, W. R. Org. Lett. 2003, 5, 1697.
832
Org. Lett., Vol. 6, No. 5, 2004