L. C. Dias et al. / Tetrahedron Letters 48 (2007) 7683–7686
7685
Acknowledgments
OTBS
O
O
P
1. Ba(OH)2.8H2O
THF/H2O
18
14
PMBO
(OMe)2
We are grateful to FAEP-UNICAMP, FAPESP (Fun-
TBS
4
O
O
O
Me
Np
Me Me
`
dac¸ao de Amparo a Pesquisa do Estado de Sao Paulo)
˜
˜
8
H
O
10
and CNPq (Conselho Nacional de Desenvolvimento
5
´
´
Cientıfico e Tecnologico) for financial support. We also
thank Professor Carol H. Collins for helpful suggestions
about English grammar and style.
90%
TBS
H2
OTBS
O
O
O
Me
Pd(OH)2
14
18
8
10
PMBO
PMBO
O
Np
EtOAc
E:Z > 95:05
Me Me
18
18h, 90%
References and notes
TBS
OTBS
O
O
O
HF-CH3CN
1. (a) Celmer, W. D.; Cullen, W. P, Maeda, H.; Tone, J. US
Patent 4, 547, 523; (b) Cullen, W. P.; Celmer, W. D.;
Chappel, L. R.; Huang, L. H.; Jefferson, M. T.; Ishiguro,
M.; Maeda, H.; Nishiyama, S.; Oscarson, J. R.; Shibak-
awa, R.; Tone, J. J. Ind. Microbiol. 1988, 2, 349.
8
18
14
10
OH
THF, rt, 18h
90%
Me Me
3
O
2. Chaney, M. O.; Demarco, P. V.; Jones, N. D.; Occolowitz,
J. L. J. Am. Chem. Soc. 1974, 96, 1932.
OH
H
Me
H
O
3. David, L.; Kergomard, A. J. Antibiot. 1976, 29, 424.
4. Westley, J. W.; Liu, C. M.; Blount, J. F.; Shello, L. H.;
Troupe, N.; Miller, P. A. J. Antibiot. 1983, 36, 1725.
5. Yaginuma, S.; Awata, M.; Muto, N.; Kinoshita, K.
J. Antibiot. 1987, 40, 239.
6. Taylor, R. W.; Kauffman, R. K.; Pfeifer, D. R. In
Polyether Antibiotics. Naturally Occurring Acid Iono-
phores; Marcel Dekker: New York, 1982; Vol. 1, p 103.
7. For design and synthesis of spiroketal derivatives, see: (a)
Zinzalla, G.; Milroy, L. G.; Ley, S. V. Org. Biomol. Chem.
2006, 4, 1977; (b) Iglesias-Arteaga, M. A.; Simuta-Lopez,
E. M.; Xochihua-Moreno, S.; Vinas-Bravo, O.; Smith, S.
M.; Reyes, S. M.; Sandoval-Ramirez, J. S. J. Braz. Chem.
Soc. 2005, 16, 381.
8. Reviews about spiroketals: (a) Perron, F.; Albizati, K. F.
Chem. Rev. 1989, 89, 1617; (b) Vaillancourt, V.; Pratt, N.
E.; Perron, F.; Albizati, K. F. In The Total Synthesis of
Natural Products; Apsimon, John, Ed.; John Wiley &
Sons, 1992; Vol. 8, p 533; (c) Mead, K. T.; Brewer, B. N.
Curr. Org. Chem. 2002, 6, 1; (d) Francke, W.; Kitching,
W. Curr. Org. Chem. 2001, 5, 233; (e) Brimble, M. A.
Molecules 2004, 9, 394; (f) Brimble, M. A.; Furkert, D. P.
Curr. Org. Chem. 2003, 7, 1.
PMBO
O
14
10
O
H
OPMB
18
O
OH
O
2
Me
H
Me
Me
C8-C20 fragment
Scheme 4. Synthesis of spiroketal 2.
Hydrogenation of the double bond (H2, Pd(OH)2,
EtOAc, 18 h) with concomitant hydrogenolysis of the
ester function at C8 provided carboxylic acid 3 in 90%
yield, leaving the PMB group intact.18 All that remained
was to carry out the necessary spiroketalization.21 Treat-
ment of ketone 3 with HF–CH3CN in THF at rt
occurred with efficient removal of both TBS protecting
groups positioned at C10 and C18, followed by cycliza-
tion to give spiroketal 2 in 90% isolated yield, after puri-
fication by silica-gel column chromatography.
It is noteworthy that under these conditions, spiroketal
2, with two anomeric stabilizations, was isolated as the
only observed isomer.21 The relative stereochemistry
for spiroketal 2 was confirmed by NMR analysis
(Scheme 4). For spiroketal 2 (needed for the synthesis
of routiennocin), the 13C chemical shift of the spiro
carbon C14 (96.4 ppm) was typical for a bis-axial orien-
tation with two anomeric stabilizations. In addition,
the 13C chemical shift of the methyl group at C17
(12.7 ppm) was typical for axial position.22,23
9. (a) Kotecha, N. R.; Ley, S. V.; Mantegani, S. Synlett 1992,
´
395; (b) Dıez-Martin, D.; Kotecha, N. R.; Ley, S. V.;
´
´
Menendez, J. C. Synlett 1992, 399; (c) Dıez-Martin, D.;
´
Kotecha, N. R.; Ley, S. V.; Mantegani, S.; Menendez, J.
C.; Organ, H. M.; White, A. D.; Banks, B. J. Tetrahedron
1992, 48, 7899.
10. For a stereoselective synthesis of the spiroketal core of
routiennocin, see: Yadav, J. S.; Muralidhar, B. Tetra-
hedron Lett. 1998, 39, 2867.
11. Numbering of 1, and 2 as well as of each intermediate
follows that suggested in Ref. 1.
12. Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 83.
13. (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem.
Soc. 1981, 103, 2127; (b) Evans, D. A.; Taber, T. R.
Tetrahedron Lett. 1980, 21, 4675; (c) Dias, L. C.; Shim-
okomaki, S. B.; Shiota, R. T. J. Braz. Chem. Soc. 2005, 16,
482.
14. Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun.
1982, 12, 989.
15. For reviews on the chemistry of Weinreb amides, see: (a)
Khlestkin, V. K.; Mazhukin, D. G. Curr. Org. Chem.
2003, 7, 967; (b) Mentzel, M.; Hoffmann, H. M. R. J.
Prakt. Chem. 1997, 339, 517.
3. Conclusions
We described here an asymmetric total synthesis of the
spiroketal core of the ionophore antibiotic routiennocin.
Notable features of this approach include a high yield-
ing syn aldol reaction, a very efficient and diastereoselec-
tive Horner–Wadsworth–Emmons coupling between
ketophosphonate and an aldehyde, followed by spiro-
ketalization under acidic conditions. The route to the
spiroketal core of routiennocin described here might
easily afford access to additional analogues with poten-
tial relevance to biological studies. The results will be
described in a full account of this work.24
16. (a) Dias, L. C.; Bau´, R. Z.; Sousa, M. A.; Zukerman-
Schpector, J. Org. Lett. 2002, 4, 4325; (b) Dias, L. C.;
Aguilar, A. M. Org. Lett. 2006, 8, 4629.