Communications
(52%; 73% based on recovered starting material)[24] as a
Prinz, H. Waldmann, ChemBioChem 2004, 5, 1575 – 1579; e) M.
Manger, M. Scheck, H. Prinz, J. P. von Kries, T. Langer, K.
Saxena, H. Schwalbe, A. Fürstner, J. Rademann, H. Waldmann,
ChemBioChem 2005, 6, 1749 – 1753.
single diastereomer.[25] With 34 in hand, the stage was set for
the final spirocyclization.
With the information gathered in the model studies in
mind (see above), 34 was first subjected to exhaustive
desilylation with TASF in aqueous DMF,[26] which resulted
in the quantitative formation of hemiacetal 35. Unfortunately,
[3] A. Fürstner, M. D. B. Fenster, B. Fasching, C. Godbout, K.
Radkowski, Angew. Chem. 2006, 118, 5632 – 5636; Angew.
Chem. Int. Ed. 2006, 45, 5506 – 5510.
[4] The only other synthesis of the [5,6,6]-bis-spirocyclic entity of 1:
I. Paterson, E. A. Anderson, S. M. Dalby, O. Loiseleur, Org.
Lett. 2005, 7, 4121 – 4224.
ꢀ
however, cleavage of the remaining N O bond in 35 with the
aid of [Mo(CO)6][11] was prohibited by the presence of the free
alcohols. Therefore, the order of events was inverted, thus
starting with the reductive cleavage of the isoxazoline unit in
34 followed by treatment of the resulting product 36 with
TASF,[26] which simultaneously removed the silyl ethers and
unmasked the ketone from the cyanohydrin precursor. It was
gratifying to see that stirring of the trihydroxy diketone,[27]
thus formed with catalytic amounts of PPTS in CH2Cl2,
triggered an almost quantitative bis-spirocyclization event
and delivered the desired product 37 together with two minor
isomers in a 96% yield of the combined products with a
diastereomeric ratio of 4.1:1.7:1. No furan formation was
detected under these conditions. Routine flash chromato
graphy allowed the isolation of 37 in respectable 61% yield in
analytically pure form; this compound represents the intact
and suitably protected northern half of spirastellolide A.
Detailed spectroscopic analyses leave no doubt about its
constitution and relative configuration. Most characteristic
are the strong NOE interactions (indicated in Scheme 8) that
reflect the doubly anomeric bis-spiroacetal substructures and
the coupling constants that confirm the all-equatorial ori-
entation of the substituents residing on the pyranose rings
(see the Supporting Information).
In summary, this investigation outlines a reliable approach
to the northern hemisphere of spirastrellolide A (1); as the
complementary southern domain has also been obtained,[3]
the entire carbon frame of this remarkably complex marine
macrolide is now covered. Nevertheless, we are well aware
that this venture is no more but an auspicious start for the
conquest of this challenging natural product because of the as
of yet unanswered stereochemical issues delineated in the
introduction. Undaunted, however, we are now actively
pursuing possible end games with the hope of reaching this
monumental target soon.
[5] a) M. D. Chappell, S. J. Stachel, C. B. Lee, S. J. Danishefsky, Org.
Lett. 2000, 2, 1633 – 1636; b) M. T. Crimmins, K. A. Emmitte,
J. D. Katz, Org. Lett. 2000, 2, 2165 – 2167.
[6] Prepared according to literature precedence: a) S. Ma, X. Lu, Z.
Li, J. Org. Chem. 1992, 57, 709 – 713; b) E. Piers, J. Renaud, S. J.
Rettig, Synthesis 1998, 590 – 602; c) A. Toró, P. Nowak, P.
Deslongchamps, J. Am. Chem. Soc. 2000, 122, 4526 – 4527.
[7] D. A. Evans, M. M. Morrissey, R. L. Dorow, J. Am. Chem. Soc.
1985, 107, 4346 – 4348; good results were obtained only when the
reaction was performed at 508C; otherwise, a competing attack
of MeOMgBr at the carbamate carbonyl group of the substrate is
observed, which lowers the yield of 6.
[8] a) W. J. Scott, J. K. Stille, J. Am. Chem. Soc. 1986, 108, 3033 –
3040; b) W. D. Wulff, G. A. Peterson, W. E. Bauta, K.-S. Chan,
K. L. Faron, S. R. Gilbertson, R. W. Kaesler, D. C. Young, C. K.
Murray, J. Org. Chem. 1986, 51, 277 – 279; c) C. D. Vanderwal,
D. A. Vosburg, E. J. Sorensen, Org. Lett. 2001, 3, 4307 – 4310.
[9] Review on bis-spiroacetal formations: M. A. Brimble, F. A.
Farꢁs, Tetrahedron 1999, 55, 7661 – 7706.
[10] Details will be reported in a forthcoming full paper.
[11] a) A. Guarna, A. Guidi, A. Goti, A. Brandi, F. De Sarlo,
Synthesis 1989, 175 – 178; b) P. G. Baraldi, A. Barco, S. Benetti, S.
Manfredini, D. Simoni, Synthesis 1987, 276 – 278.
[12] J. W. Bode, E. M. Carreira, J. Org. Chem. 2001, 66, 6410 – 6424.
[13] M. J. Mintz, C. Walling, Org. Synth. 1969, 49, 9 – 12.
[14] Reviews on the use of 2-isoxazolines as aldol surrogates: a) D. P.
Curran, Adv. Cycloaddit. 1988, 1, 129 – 189; b) S. Kanemasa, O.
Tsuge, Heterocycles 1990, 30, 719 – 736.
[15] a) S. Kanemasa, M. Nishiuchi, A. Kamimura, K. Hori, J. Am.
Chem. Soc. 1994, 116, 2324 – 2339; b) for an optimization and
elegant application, see: J. W. Bode, N. Fraefel, D. Muri, E. M.
Carreira, Angew. Chem. 2001, 113, 2128 – 2131; Angew. Chem.
Int. Ed. 2001, 40, 2082 – 2085.
[16] S. E. Schaus, B. D. Brandes, J. F. Larrow, M. Tokunaga, K. B.
Hansen, A. E. Gould, M. E. Furrow, E. N. Jacobsen, J. Am.
Chem. Soc. 2002, 124, 1307 – 1315.
[17] L. Alcaraz, J. J. Harnett, C. Mioskowski, J. P. Martel, T. Le Gall,
D.-S. Shin, J. R. Falck, Tetrahedron Lett. 1994, 35, 5449 – 5452.
[18] a) S. Hu, S. Jayaraman, A. C. Oehlschlager, J. Org. Chem. 1998,
63, 8843 – 8849; b) S. Hu, S. Jayaraman, A. C. Oehlschlager, J.
Org. Chem. 1996, 61, 7513 – 7520.
[19] U. S. Racherla, H. C. Brown, J. Org. Chem. 1991, 56, 401 – 404.
[20] H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev.
1994, 94, 2483 – 2547.
Received: April 26, 2006
Keywords: cycloaddition · macrolides · natural products ·
.
phosphatase inhibitors · total synthesis
[21] A. B. Smith, C. M. Adams, Acc. Chem. Res. 2004, 37, 365 – 377.
[22] a) G. Stork, L. Maldonado, J. Am. Chem. Soc. 1971, 93, 5286 –
5287; b) G. Stork, L. Maldonado, J. Am. Chem. Soc. 1974, 96,
5272 – 5274; c) for applications in natural product synthesis, see:
T. Takahashi, H. Nemoto, Y. Kanda, J. Tsuji, Y. Fukazawa, T.
Okajima, Y. Fujise, Tetrahedron 1987, 43, 5499 – 5520; d) H.
Takayanagi, Y. Kitano, Y. Morinaka, J. Org. Chem. 1994, 59,
2700 – 2706; e) A. B. Smith, C. Sfouggatakis, D. B. Gotchev, S.
Shirakami, D. Bauer, W. Zhu, V. A. Doughty, Org. Lett. 2004, 6,
3637 – 3640.
[1] a) D. E. Williams, M. Lapawa, X. Feng, T. Tarling, M. Roberge,
R. J. Andersen, Org. Lett. 2004, 6, 2607 – 2610; b) D. E. Williams,
M. Roberge, R. Van Soest, R. J. Andersen, J. Am. Chem. Soc.
2003, 125, 5296 – 5297.
[2] For previous syntheses and biological evaluations of phospha-
tase inhibitors from this group, see: a) A. Fürstner, F. Feyen, H.
Prinz, H. Waldmann, Angew. Chem. 2003, 115, 5519 – 5522;
Angew. Chem. Int. Ed. 2003, 42, 5361 – 5364; b) A. Fürstner, F.
Feyen, H. Prinz, H. Waldmann, Tetrahedron 2004, 60, 9543 –
9558; c) A. Fürstner, J. Ruiz-Caro, H. Prinz, H. Waldmann, J.
Org. Chem. 2004, 69, 459 – 467; d) A. Fürstner, K. Reinecke, H.
[23] S. S. Kim, G. Rajogopal, D. W. Kim, D. H. Song, Synth.
Commun. 2004, 34, 2973 – 2980.
5514
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 5510 –5515