Our point of departure entailed construction of the C(3-
11) subtarget 8 (Scheme 2). Monoprotection of the sym-
metrical diol (+)-107 (NaH, TBSCl, 84% yield) followed
by treatment with TESOTf and 2,6-lutidine furnished the
differentially protected diol (+)-11.8 Exhaustive ozonolysis,
removal of the TES group, and exposure of the resulting
lactol to acetic anhydride then led to 12,8 a 2:1 mixture of
acetates, favoring the equatorial isomer (57% yield, three
steps). Reduction of the aldehyde (NaBH4), protection of the
resulting alcohol (BPSCl), and treatment with silyl enol ether
139 in the presence of ZnCl2 afforded aldehyde (-)-88 as
the only observed product (62% yield, three steps). The
relative configuration of (-)-8 was established by NOE
analysis.10
Scheme 1
Scheme 2
Construction of vinyl acetal 6, substrate for the Petasis-
Ferrier rearrangement, was achieved as outlined in Scheme
3. Aldol condensation of known oxazole 94i with silyl ketene
acetal 1411 in the presence of 2 mol % of the Carreira
titanium catalyst12 derived from (R)-(+)-NOBIN (e.g., 15)
furnished (+)-78 in 84% yield (g98% ee; determined by
Mosher ester analysis).13 Hydrolysis of the benzyl ester
(LiOH, H2O2; >99%), bis-silylation with hexamethyldi-
silazane (HMDS), and condensation with aldehyde (-)-8
promoted by TMSOTf14 provided dioxanone (-)-168 in 61%
yield, along with 18% of the C(11) epimer, readily removed
by flash chromatography. Methylenation of (-)-16 with the
Petasis-Tebbe reagent (Cp2TiMe2)15 completed construction
targets 3, 4, and 5 (Scheme 1). In the synthetic direction,
this analysis holds the potential for macrocyclization at either
the C(2-3) or the C(19-20) π bonds, after introduction of
the C(1-2) moiety. Completion of the carbon skeleton would
then entail attachment of the C(29) side chain. Focusing on
the C(11-15) cis-fused tetrahydropyran, we explored the
Petasis modification5 of the Ferrier rearrangement6 of vinyl
acetal 6 to assemble 5. To the best of our knowledge, the
Petasis-Ferrier rearrangement has not been utilized in the
construction of complex synthetic targets. Continuing with
this analysis, disconnection of 6 leads to hydroxy acid 7,
available from known oxazole 9,4i and to trans-tetrahydro-
pyran 8, to arise from known diol (+)-10.7
(7) Rychnovsky, S. D.; Griesgraber, G.; Zeller, S.; Skalitzky, D. J. J.
Org. Chem. 1991, 56, 5161.
(8) The structure assigned to each new compound is in accord with its
1
infrared, 500 MHz H NMR, and 125 MHz 13C NMR spectra, as well as
appropriate ion identification by high-resolution mass spectrometry.
(9) (a) Tino, J. A.; Lewis, M. D.; Kishi, Y. Heterocycles 1987, 25, 97.
(b) Jung, M. E.; Blum, R. B. Tetrahedron Lett. 1977, 43, 3791.
(10) A nuclear Overhauer enhancement was observed between H(5) and
H(7); irradiation of H(5) did not enhance the H(9) resonance.
(11) Slougui, N.; Rousseau, G.; Conia, J.-M. Synthesis 1982, 58.
(12) (a) Carreira, E. M.; Singer, R. A.; Lee, W. J. Am. Chem. Soc. 1994,
116, 8837. (b) Smrcina, M.; Lorenc, M.; Hanus, V.; Sedmera, P.; Kocovsky,
P. J. Org. Chem. 1992, 57, 1917.
(13) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (b)
Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143.
(c) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc.
1991, 113, 4092.
(4) For other synthetic efforts, see: (a) Lee, C. S.; Forsyth, C. J.
Tetrahedron Lett. 1996, 37, 6449. (b) Cink, R. D.; Forsyth, C. J. J. Org.
Chem. 1997, 62, 5672. (c) Ahmed, F.; Forsyth, C. J. Tetrahedron Lett. 1998,
39, 183. (d) Ye, T.; Pattenden, G. Tetrahedron Lett. 1998, 39, 319. (e)
Pattenden, G.; Plowright, A. T.; Tornos, J. A.; Ye, T. Tetrahedron Lett.
1998, 39, 6099. (f) Paterson, I.; Arnott, E. A. Tetrahedron Lett. 1998, 39,
7185. (g) Wolbers, P.; Hoffman, H. M. R. Tetrahedron 1999, 55, 1905. (h)
Misske, A. M.; Hoffman, H. M. R. Tetrahedron 1999, 55, 4315. (i)
Williams, D. R.; Clark, M. P.; Berliner, M. A. Tetrahedron Lett. 1999, 40,
2287. (j) Williams, D. R.; Clark, M. P. Tetrahedron Lett. 1999, 40, 2291.
(k) Wolbers, P.; Hoffman, H. M. R. Synthesis 1999, 5, 797. (l) Evans, D.
A.; Cee, V. J.; Smith, T. E.; Santiago, K. J. Org. Lett. 1999, 1, 87.
(5) Petasis, N. A.; Lu, S.-P. Tetrahedron Lett. 1996, 36, 141.
(14) (a) Harada, T.; Yoshida, T.; Kagamihara, Y.; Oku, A. J. Chem. Soc.,
Chem. Commun. 1993, 1367. (b) Seebach, D.; Imwinkelried, R.; Stucky,
G. HelV. Chim. Acta 1987, 70, 448.
(6) Ferrier, R. J.; Middleton, S. Chem. ReV. 1993, 93, 2779.
(15) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392.
910
Org. Lett., Vol. 1, No. 6, 1999