C O M M U N I C A T I O N S
Scheme 3a
Scheme 4a
a Conditions: (i) (a) (Cl3CO)2CO, THF; (b) NaN3, DMF, 49%; (ii)
TESOTf, Et3N, CH2Cl2, 99%; (iii) KHMDS, Me3O+ BF4-, CH2Cl2; (iv)
Pd/C, H2, MeOH; (v) HCl (conc.) ∆, 21% from 22; (vi) SO3‚pyr, DMF,
63%.
Acknowledgment. We are indebted to Hyunik Shin whose
insights created the initial impetus for this project, to Professor
Alexandre F. T. Yokochi for the X-ray crystal structure of 20, and
to Professor Steven Weinreb, Pennsylvania State University, for
helpful correspondence. Financial support was provided by the
National Science Foundation (0076103-CHE).
a Conditions: (i) MeOH mol. sieves, ∆, 60%; (ii) Toluene, mol. sieves,
∆; (iii) Zn, NH4Cl, THF-H2O; (iv) HCl, MeOH, 68% from 16; (v) CO(Im)2,
CH2Cl2, then K2CO3, MeOH, 85%; (vi) Dess-Martin periodinane, CH2Cl2;
(vii) L-Selectride, THF; (viii) H2/C, Pd(OH)2, EtOH, 55% from 19.
Supporting Information Available: Experimental procedures and
characterization data and X-ray crystallographic data for 20 (PDF). This
stereoisomers in the ratio 10:5:1. As predicted from conformational
analysis of 16, the major product 17 arose from an exo cycloaddition
to the re face of the terminal alkene in the orientation shown.16 In
situ reduction of 17 with zinc and ammonium chloride followed
by acidic removal of the Boc group furnished piperidine 18 in which
five of the six stereocenters correspond to those of 2. Before
inverting the C12 hydroxyl group, it was decided to bridge the
piperidine nitrogen and the amino function at C8 via a urea, and
for this purpose 18 was treated with carbonyldiimidazole to produce
19. The secondary alcohol of 19 was oxidized to a ketone, and
subsequent reduction of this substance with L-Selectride afforded
the 12â alcohol as the major product (â:R > 15:1). Hydrogenolysis
of the primary p-bromobenzyl ether gave the crystalline diol 20
whose relative stereostructure was confirmed by X-ray crystal-
lographic analysis.
Diol 20 was converted to azide 21, and the remaining secondary
hydroxyl group was protected as its triethylsilyl ether 22 (Scheme
4). Exposure of 22 to trimethyloxonium tetrafluoroborate in the
presence of potassium hexamethyldisilazide gave the O-methylated
derivative 23 which was subjected to catalytic hydrogenation over
palladium-on-carbon. The resultant primary amine underwent
spontaneous cyclization to give guanidine 24, and subsequent
exhaustive hydrolysis in concentrated hydrochloric acid led to
cleavage of silyl ethers as well as methyl ethers attached to the
pyrimidine nucleus to yield 25. This diol was shown to be identical
by comparison of 1H and 13C NMR spectra with the corresponding
racemic substance prepared by Weinreb,7 and sulfation as previously
described6 gave (-)-7-epicylindrospermopsin (2) accompanied by
the bis sulfate of 25 (ca. 2.5:1, respectively). These substances were
separated by HPLC, and purified 2 was found to have spectral data
in good agreement with those recorded for both natural5 and
synthetic7 epicylindrospermopsin. The specific rotation of synthetic
material establishes that the absolute configuration of natural
epicylindrospermopsin is 7S, 8R, 10S, 12S, 13R, 14S, as represented
by 2.
References
(1) For a recent review of the biological properties and synthetic approaches
to cylindrospermopsin, see: Murphy, P. J.; Thomas, C. W. Chem. Soc.
ReV. 2001, 30, 303.
(2) (a) Ohtani, I.; Moore, R. E.; Runnegar, M. T. C. J. Am. Chem. Soc. 1992,
114, 7941. (b) Moore, R. E.; Ohtani, I.; Moore, B. S.; DeKoning, C. B.;
Yoshida, W. Y.; Runnegar, M. T. C.; Carmichael, W. W. Gazz. Chim.
Ital. 1993, 123, 329.
(3) (a) Harada, K.; Ohtani, I.; Iwamoto, K.; Suzuki, M.; Watanabe, M. F.;
Watanabe, M.; Terav, K. Toxicon 1994, 32, 73. (b) Terav, K.; Ohmori,
S.; Igarashi, K.; Ohtani, I.; Watanabe, M. F.; Harada, K. I.; Ito, E.;
Watanabe, M. Toxicon 1994, 32, 833 and references therein.
(4) Banker, R.; Carmeli, S.; Hadas, O.; Teltsch, B.; Porat, R.; Sukenik, A. J.
Phycol. 1997, 33, 613.
(5) Banker, R.; Teltsch, B.; Sukenik, A.; Carmeli, S. J. Nat. Prod. 2000, 63,
387.
(6) Xie, C.; Runnegar, M. T. C.; Snider, B. B. J. Am. Chem. Soc. 2000, 122,
5017.
(7) Weinreb, S. M.; Heintzelman, G. R.; Fang, W. K.; Keen, S. P.; Wallace,
G. A. J. Am. Chem. Soc. 2001, 123, 8851.
(8) For earlier synthetic studies directed toward cylindrospermopsin, see: (a)
Heintzelman, G. R.; Parvez, M.; Weinreb, S. M. Synlett 1993, 551. (b)
Snider, B. B.; Harvey, T. C. Tetrahedron Lett. 1995, 36, 4587. (c)
Heintzelman, G. R.; Weinreb, S. M.; Parvez, M. J. Org. Chem. 1996, 61,
4594. (d) Snider, B. B.; Xie, C. Tetrahedron Lett. 1998, 39, 7021. (e)
McAlpine, I. J.; Armstrong, R. W. Tetrahedron Lett. 2000, 41, 1849. (f)
Keen, S. P.; Weinreb, S. M. Tetrahedron Lett. 2000, 41, 4307. (g) White,
J. D.; Hansen, J. D. Abstracts of Papers; 219th National Meeting of the
American Chemical Society, San Francisco, CA; American Chemical
Society: Washington, DC, 2000; ORGN 812. (h) Djung, J. F.; Hart, D.
J.; Young, E. R. R. J. Org. Chem. 2000, 65, 5668. (i) Looper, R. E.;
Williams, R. M. Tetrahedron Lett. 2001, 42, 769.
(9) (a) Jorgenson, K. A.; Gothelf, K. V. Chem. ReV. 1998, 98, 863. (b)
Confalone, P. N.; Huie, E. M. In Organic Reactions; Kende, A. S., Ed.;
Wiley: New York, 1998; Vol. 36, pp 3-173.
(10) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919.
(11) Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143.
(12) Grundke, G.; Keese. W.; Rimpler, M. Synthesis 1987, 1115.
(13) Reetz, M. T.; Schmitz, A.; Holdgru¨n, X. Tetrahedron Lett. 1989, 30, 5421.
(14) Langley, B. W. J. Am. Chem. Soc. 1956, 78, 2136.
(15) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639.
(16) Precedent for this mode of cycloaddition can be found in: (a) Oppolzer,
W.; Siles, S.; Snowden, R. L.; Bakker, B. H.; Petrzilka, M. Tetrahedron
1985, 41, 3497. (b) Hoffmann, R. W.; Endesfelder, A. Justus Liebig Ann.
Chem. 1986, 1823.
JA012709R
9
J. AM. CHEM. SOC. VOL. 124, NO. 18, 2002 4951