tion reaction. In 1995, Minale et al. reported the isolation of
two new types of pentacyclic guanidine alkaloids, celero-
mycalin and fromiamycalin, from two New Caledonian
starfishes, Celerina heffernani and Fromia mononilis, to-
gether with known ptilomycalin A (1), crambescidin 800,
and the hydroxyspermidine 3 linked to a long chain fatty
acid.6 Those five compounds were examined in a CME 4
cell infection assay with HIV-1 and were found to be highly
cytotoxic toward the target cells except for the hydroxysper-
midine 3. On the basis of these investigations, Minale and
co-workers proposed that the biological activities of these
ptilomycalin A type alkaloids are mostly caused by the
pentacyclic guanidine portion (vessel part) in the molecule.9
In 2000, Braekman reported the isolation of new penta-
cyclic guanidine alkaloids dehydrobatzelladine C, crambes-
cidin 359 (4), and crambescidin 431 from the marine sponge
of the genus Monanchora, guided by the toxic activities
against nauplii of brine shrimp Artemia salina.10 Among
them, crambescidin 359 (4) is the first derivative which lacks
the side chain of carboxylate at C14 of ptilomycalin A.
Though those structures were elucidated with 1D and 2D
NMR experiments, the absolute configurations were not
determined. Intrigued by the structure of crambescidin 359
(4) and the poorly defined biological activities of the “vessel
part” of ptilomycalin A, we planned to synthesize 4 stereo-
selectively on the basis of the successive 1,3-dipolar cyclo-
addition protocol.11
Scheme 2. Synthesis of Olefin (+)-13
derived from the D-mannitol was reacted with methylmag-
nesium bromide in the presence of copper(I) cyanide to give
the alcohol 11 in 80% yield. The secondary alcohol of 11
was protected as the tert-butyldimethylsilyl ether, and
subsequent deprotection of the benzyl group with Pearlman’s
catalyst13 gave the alcohol 12 in 76% yield. Oxidation of
the alcohol 12 under Swern conditions followed by elonga-
tion of the side chain with the Wittig reaction using
1-pentenyl-5-triphenylphosphonium bromide gave 13 in 62%
yield.
With the olefins 13 and 1514 in hand, a successive 1,3-
DC reaction protocol was next applied (Scheme 3). The 1,3-
DC reaction of the optically active nitrone 1415 with (2R)-
2-tert-butyldimethylsilyloxy-6-heptene (15) in toluene stereo-
selectively gave the isoxazolidine 1616 in 67% yield. The
secondary alcohol on the pyrrolidine ring was removed by
means of the following stepwise reactions: (1) thiocarbonate
formation with phenyl chlorothionoformate17 and (2) reduc-
Our synthetic plan is outlined in Scheme 1. Pentacyclic
guanidine 4 could be prepared from double N,O-acetalization
of guanylated dihydroxy-diketone 5, which can be obtained
via 6 through successive 1,3-dipolar cycloaddition (1,3-DC)
between the nitrone 7 and olefins 8 and 9.
n
tion with Bu3SnH in the presence of AIBN catalyst. The
resulting isoxazolidine 17 was subjected to m-CPBA oxida-
tion in dichloromethane at 0 °C, and a nitrone moeity was
regenerated regioselectively to give 18.18 The second 1,3-
DC reaction of 18 and the olefin 13 took place regio- and
Scheme 1. Retrosynthetic Analysis for Crambescidin 359 (4)
(7) (a) Overman, L. E.; Rabinowitz, M. H.; Renhowe P. A. J. Am. Chem.
Soc. 1995, 117, 2657. (b) Coffey, D. S.; McDonald, A. I.; Overman, L. E.;
Stappenbeck, F. J. Am. Chem. Soc. 1999, 121, 6944.
(8) For other synthetic studies, see: (a) Grillot, A. L.; Hart, D. J.
Tetrahedron 1995, 51, 11377. (b) Anderson, G. T.; Alexander, M. D.;
Taylor, S. D.; Smithrud, D. B.; Benkovic, S. J.; Weinreb, S. M. J. Org.
Chem. 1996, 61, 125.
(9) Palagiano, E.; De Marino, S.; Minale, L.; Riccio, R.; Zollo, F.; Iorizzi,
M.; Carre, J. B.; Debitus, C.; Lucarain, L.; Provost, J. Tetrahedron 1995,
51, 3675.
(10) Braekman, J. C.; Daloze, D.; Tavares, R.; Hajdu, E.; Van Soest, R.
W. M. J. Nat. Prod. 2000, 63, 193.
(11) Nagasawa, K.; Georgieva, A.; Nakata, T. Tetrahedron 2000, 56,
187.
(12) Takano, S.; Inamura, Y.; Ogasawara, K. Tetrahedron Lett. 1981,
22, 4479.
(13) Pearlman, W. M. Tetrahedron Lett. 1967, 1663.
(14) Nagasawa, K.; Georgieva, A. Takahashi, H.; Nakata, T. Tetrahedron
2001, 57, 9726.
(15) Goti, A.; Cacciarini, M.; Cardona, F.; Brandi, A. Tetrahedron Lett.
1999, 40, 2853.
(16) NOEs were observed from H-10â to H-12 and H-15, from H-15 to
H12.
Synthesis of the olefin 13 corresponding to 9 is sum-
marized in Scheme 2. The optically active epoxide 1012
(17) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574. (b) Barton, D. H. R.; Jaszberenyi, J. C. Tetrahedron Lett.
1989, 30, 2619.
(18) (a) Tufariello, J. J.; Mullen, G. B.; Tegeler, J. J.; Trybulski, E. J.;
Wong, S. C.; Ali, Sk. A. J. Am. Chem. Soc. 1979, 101, 2435. (b) Tufariello,
J. J.; Puglis, J. M. Tetrahedron Lett. 1986, 27, 1489.
(6) (a) Murphy, P. J.; Williams, H. L.; Hursthouse, M. B.; Abdul Malik,
K. M. J. Chem. Soc., Chem. Commun. 1994, 119. (b) Murphy, P. J.;
Williams, H. L. J. Chem. Soc., Chem. Commun. 1994, 819. (c) Murphy, P.
J.; Williams, H, L.; Hibbs, D. E.; Hursthouse, M. B.; Abdul Malik, K. M.
Tetrahedron 1996, 52, 8315.
178
Org. Lett., Vol. 4, No. 2, 2002