Scheme 3. Synthesis of Vinyl Iodide 2a
Scheme 4. Synthesis of Trihydroxy Acetamide 13a
a Reaction conditions: (a) Amberlyst 15, CH3OH, rt, 3 days; 80%.
Although the stereoselective reactions reported so far have
proved to be highly reliable, we decided at this point to
corroborate the configuration of the stereocenters embedded
1
in 2. Analysis of the H and 13C NMR spectra19 of 9-12
and 2 proved the C24-C25 anti and C23-C24 syn relation-
ships existing between these chiral centers (see Scheme 4).
Additionally, experimental data for 13 previously reported3c
gave us the opportunity to correlate our assignment. With
this proposal, trihydroxy amido 13 was easily obtained from
alcohol 11 in 80% yield after chromatographic purification.
Even though the specific rotation of the compound prepared
in this way, [R]D +32.4 (c 0.85, CH3OH), was exceptionally
high,20 the good agreement between its NMR spectroscopic
data and those reported by D’Auria et al. confirms our
stereochemical assignment.
Eventually, the synthesis of the key sulfone 3 (see Scheme
1) was addressed as envisaged. However, it was discovered
after several unsuccessful attempts that a suitable functional
group manipulation could give quick access to an alternative
and more elaborated model for the C18-C27 appendage,
as shown in Scheme 5. After removing the silicon protecting
group of 4, the new synthetic sequence began with the
efficient preparation (84% yield) of the azido sulfone 15
through a Mitsunobu reaction followed by oxidation of the
resulting thioether. With this advanced intermediate in hand,
a Reaction conditions: (a) (i) Me3P, H2O, THF, rt, 12 h; (ii) Ac2O,
Et3N, CH2Cl2, rt, 1 h; 88%. (b) TBAF‚3H2O, THF, rt, 30 h; 99%.
(c) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 1 h. (d) CHI3, CrCl2,
THF, rt, 12 h; 95:5 E/Z, 61%.
surprisingly, Takai’s olefination procedure12 was expected
to play a pivotal role in this transformation. Then, given that
chromium(II) would easily reduce the azido group in 4,13
we first confronted its conversion into the required amide.
Reduction of azides with Ph3P (Staudinger reaction)14 and
subsequent hydrolysis of the corresponding phosphazenes
constitutes one of the mildest and selective ways of access
to primary amines.15 This procedure generally provides the
desired amine in quantitative yields, but use of Ph3P requires
high temperatures and chromatographic purification to
remove the resulting Ph3PdO. Having recognized that
replacement of Ph3P by more nucleophilic trialkylphosphines,
particularly Me3P, overcomes the above-mentioned draw-
backs,16,17 azido polyol 4 was easily reduced (Me3P/H2O) at
room temperature and acylated (Ac2O/Et3N) into the aceta-
mide derivative 10 in 88% yield. Removal of the silicon
protecting group furnished primary alcohol 11 quantitatively.
With use of Swern conditions, 11 was smoothly oxidized to
aldehyde 12, which was immediately submitted to the next
reaction. Finally, the Takai olefination was performed with
CHI3 and CrCl2 in THF, providing a 95:5 ratio of E/Z vinyl
iodide 2 in 61% yield over two steps.18
Scheme 5. Synthesis of Acetamide 17a
(8) Ferrero´, M.; Galobardes, M.; Mart´ın, R.; Montes, T.; Romea, P.;
Rovira, R.; Urp´ı, F.; Vilarrasa, J. Synthesis 2000, 1608.
(9) Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990,
112, 6348.
(10) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560.
(11) Greene, T. W.; Wuts, R. G. M. In ProtectiVe Groups in Organic
Synthesis; John Wiley & Sons: New York, 1999.
(12) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.
(13) Bartra, M.; Romea, P.; Urp´ı, F.; Vilarrasa, J. Tetrahedron 1990,
46, 587.
(14) For a review on the Staudinger reaction and phosphazene chemistry,
see: Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353.
(15) (a) Vaultier, M.; Knouzi, N.; Carrie, R. Tetrahedron Lett. 1983,
24, 763. (b) Scriven, E. F. V.; Turnbull, K. Chem. ReV. 1988, 88, 297.
(16) (a) Ariza, X.; Urp´ı, F.; Vilarrasa, J. Tetrahedron Lett. 1999, 40,
7515. (b) Nyffeler, P. T.; Liang, C.-H.; Koeller, K. M.; Wong, C.-H. J.
Am. Chem. Soc. 2002, 124, 10773. (c) For a review on trialkyl phosphines,
see: Valentine, D. H.; Hillhouse, J. H. Synthesis 2003, 317.
a Reaction conditions: (a) TBAF‚3H2O, THF, rt, 12 h; 91%. (b)
(i) Ph(CN4)SH, Ph3P, DEAD, THF, rt, 4 h; (ii) (NH4)2MoO4, H2O2,
THF, rt, 24 h; 84%. (c) LHMDS, (E)-2-methyl-2-butenal, 1,2-
dimethoxyethane, -65 °C to room temperature; 94:6 EE/ZE, 72%.
(d) Me3P, AcCl, benzene, rt, 5 h; 64%.
Org. Lett., Vol. 5, No. 24, 2003
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