524
C. A. Quesnelle et al. / Bioorg. Med. Chem. Lett. 13 (2003) 519–524
In summary, several compounds have been prepared
that proved to be potent antifungal agents against Can-
dida strains. Acetylenic ketones were the most potent,
displayed modest therapeutic indices but, like all the
derivatives tested, modest CYP inhibition profiles.
Moreover, this studydemonstrates the clear necessityof
non-polar, medium sized functionalityin this portion of
the molecule. Potencies decrease as polar functionality
is introduced as is the case with increasing size.
10. Experimental conditions: For alcohol 14: To a solution of
12 (920 mg, 1.88 mmol) in CH2Cl2 (40 mL) was added Dess–
Martin periodinane (797 mg, 1.88 mmol) and the contents
stirred at room temperature overnight. NaHCO3 (10 mL, aq
satd) and Na2S2O3 (10 mL, 1 M) were added and stirred vig-
orouslyfor 30 min. The reaction was diluted with CH 2Cl2, the
organic phase separated and dried (MgSO4), filtered,
concentrated and the residue purified byflash chromato-
graphy(4:1 hexane/EtOAc) to afford the product (770 mg,
84%) as a colourless oil: 1H NMR (C6D6, 400 MHz) d 4.91 (s,
1H), 4.33–4.17 (m, 3H), 3.71 (m, 1H), 3.66 (ddd, 1H, J=12.1,
12.1, 5.8 Hz), 3.46 (m, 1H), 3.40–3.29 (m, 2H), 2.79 (dd, 1H,
J=2.5, 1.5 Hz), 2.13 (dd, 1H, J=14.2, 4.3 Hz), 2.07–1.88 (m,
4H), 1.76 (s, 3H), 1.75 (s, 3H), 1.53–1.40 (m, 2H), 1.33–1.22
(m, 3H), 1.13–1.03 (m, 2H), 0.98 (d, 3H, J=6.8 Hz), À0.15 (s,
9H). For ketone 15: To a solution of 12 (266 mg, 0.542 mmol)
in CH2Cl2 (10 mL) was added Dess–Martin periodinane (518
mg, 1.221 mmol) and the contents stirred at room temperature
for 2 h. NaHCO3 (4 mL, aq satd) and Na2S2O3 (4 mL, 1M)
were added and stirred vigorouslyfor 30 min. The reaction
was diluted with CH2Cl2, the organic phase separated and
dried (MgSO4), filtered, concentrated and the residue purified
byflash chromatography(4:1 hexane/EtOAc) to afford the
product (242 mg, 92%) as a white foam: 1H NMR (C6D6,
400 MHz) d 5.00 (s, 1H), 4.24 (m, 1H), 4.11 (m, 1H), 3.66 (m,
1H), 3.44 (m, 1H), 3.38–3.27 (m, 3H), 3.15 (d, 1H, J=18.4
Hz), 3.09 (s, 1H), 2.06–1.61 (m, 11H), 1.75 (s, 3H), 1.68 (s,
3H), 1.46–1.21 (m, 7H), 0.91 (d, 3H, J=7.1 Hz), À0.14 (s,
9H).
Acknowledgements
The authors would like to thank Dr. Thomas Tullyand
colleagues for supplying sordarin and Henry Wong for
providing keysnythetic intermediates. The authors
would also like to thank Dr. TonyShaw for his invalu-
able assistance with NMR structural elucidation of
compounds 14 and 15.
References and Notes
1. Hauser, D.; Sigg, H. P. Helv. Chim. Acta 1971, 54, 1178.
2. (a) Dominguez, J. M.; Martin, J. J. Antimicrob. Agents
Chemother. 1998, 42, 2274. (b) Capa, L.; Mendoza, A.;
Lavandra, J. L.; Gomez de Las Heras, F.; Garcia-Bustos, J. F.
Antimicrob. Agents Chemother. 1998, 42, 2279. (c) Justice,
M. C.; Hsu, M. J.; Tse, B.; Ku, T.; Balkovec, J.; Schmatz, D.;
Nielsen, J. J. Biol. Chem. 1998, 273, 3148.
3. (a) Odds, F. C. Exp. Opin. Ther. Pat. 2001, 11, 283. (b)
Ziegelbauer, K.; Spaltmann, F. Drugs Future 2000, 25, 63. (c)
Gargolla-Viola, D. Curr. Opin. Anti-infective Invest. Drugs
1999, 1, 297. (d) Herreros, E.; Almela, M. J.; Lozano, S.;
Gomez de las Heras, F.; Gargallo-Viola, D. Antimicrob.
Agents Chemother. 2001, 45, 3132 and references cited therein.
4. Rambelli, F.; Brigotti, M.; Zamboni, M.; Denaro, M.;
Montanaro, L.; Sperti, S. Biochem. J. 1989, 259, 307.
5. Dominguez, J. M.; Gomez-Lorenzo, M. G.; Martin, J. J. J.
Biol. Chem. 1999, 274, 22423.
11. Arigoni, D.; Vasella, A.; Sharpless, K. B.; Jensen, H. P. J.
Amer. Chem. Soc. 1973, 95, 7917.
12. Snider, B. B. In Comprehensive Organic Synthesis; Trost,
B. M. Ed., Pergamon Press: New York, 1991; Vol. 2, p 527.
13. However, upon oxidation of 12 under Swern conditions,
the ketone 15 is the onlyproduct isolated. Under the proposed
Swern oxidation mechanism, the initiallyformed activated
alcohol becomes oxidized upon addition of the base and there-
fore 14 is formed, even at À78ꢀ C. Interestingly, the rate of the
following step appears much quicker than with the Dess–Mar-
tin reagent as the alcohol 14 is transformed to ketone 15 even at
this low temperature before the reagent is destroyed. This
dichotomyin the rates for the second step maybe due to the
greater steric encumbrance of the Dess–Martin periodinane
over that of the activated DMSO for the Swern oxidation.
14. Alternatively, the reaction may be envisioned to proceed
via initial acetate (from the Dess–Martin reagent) abstraction
of the seeminglynon-acidic allylic proton.
6. Balkovec, J. M.; Tse, B. Sordarin Derivatives, WO
9815178, 1998.
7. Gilman, H.; Beel, J. A.; Brannen, C. G.; Bullock, M. W.;
Dunn, G. E.; Miller, L. S. J. Am. Chem. Soc. 1949, 71, 1499.
Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404.
8. Freshly prepared alkynyl lithium reagents were prepared by
treatment of the appropriate alkyne with s-BuLi in THF or
Et2O at À78 ꢀC and were used directly.
15. MICs were determined according to NCCLS standards
against fungal strains obtained from the American Type Cul-
ture Collection.
16. Tse, B.; Balkovec, J. M.; Blazey, C. M.; Hsu, M. J.;
Nielsen, J.; Schmatz, D. Bioorg. Med. Chem. Lett. 1998, 8,
2269.
9. Serrano-Wu, M. H.; St Laurent, D. R.; Mazzucco, C. E.;
Stickle, T. M.; Barrett, J. F.; Vyas, D. M.; Balasubramanian,
B. N. Bioorg. Med. Chem. Lett. 2002, 12, 943.