C O M M U N I C A T I O N S
Scheme 3. [3+2]-Annulation Reaction of 2 and 3
deprotection of the three trifluoroacetate esters by treatment with
KCN in MeOH provided synthetic (+)-asimicin. The spectroscopic
properties of synthetic asimicin were in excellent agreement with
literature data (see Supporting Information).
In summary, we have developed a convergent strategy for
synthesis of asimicin that features two highly stereoselective chelate-
controlled [3 + 2] annulation reactions that set all of the stereo-
chemistry of the bis-tetrahydrofuran unit. Efforts to extend this
strategy to other members of the acetogenin family are in progress
and will be reported in due course.
Acknowledgment. This work is supported by a grant from the
National Institutes of Health (GM 38907).
Supporting Information Available: Experimental procedures and
spectroscopic data for all new compounds. This material is available
Scheme 4. Completion of the Asimicin Total Synthesis
References
(1) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504.
(2) Representative acetogenin total syntheses: (a) Marshall, J. A.; Jiang, H.
J. Org. Chem. 1999, 64, 971. (b) Kuriyama, W.; Ishigami, K.; Kitahara,
T. Heterocycles 1999, 50, 981. (c) Marshall, J. A.; Jiang, H. J. Nat. Prod.
1999, 62, 1123. (d) Hu, T.-S.; Wu, Y.-L.; Wu, Y. K. Org. Lett. 2000, 2,
887. (e) Emde, U.; Koert, U. Eur. J. Org. Chem. 2000, 1889. (f) Hoppen,
S.; Baurle, S.; Koert, U. Chem.-Eur. J. 2000, 6, 2382. (g) Dixon, D. J.;
Ley, S. V.; Reynolds, D. J. Angew. Chem., Int. Ed. 2000, 39, 3622. (h)
Harcken, C.; Bruckner, R. New J. Chem. 2001, 25, 40. (i) D’Souza, L. J.;
Sinha, S. C.; Lu, S.-F.; Keinan, E.; Sinha, S. C. Tetrahedron 2001, 57,
5255. (j) Makabe, H.; Hattori, Y.; Tanaka, A.; Oritani, T. Org. Lett. 2002,
4, 1083. (k) Crimmins, M. T.; She, J. J. Am. Chem. Soc. 2004, 126, 12790.
(l) Zhang, Q.; Lu, H.; Richard, C.; Curran, D. P. J. Am. Chem. Soc. 2004,
126, 36. (m) Nattrass, G. L.; Diez, E.; McLachlan, M. M.; Dixon, D. J.;
Ley, S. V. Angew. Chem., Int. Ed. 2005, 44, 580.
(3) Previous syntheses of asimicin: (a) Hoye, T. R.; Tan, L. S. Tetrahedron
Lett. 1995, 36, 1981. (b) Sinha, S. C.; Sinha, A.; Yazbak, A.; Keinan, E.
Tetrahedron Lett. 1995, 36, 9257. (c) Avedissian, H.; Sinha, S. C.; Yazbak,
A.; Sinha, A.; Neogi, P.; Sinha, S. C.; Keinan, E. J. Org. Chem. 2000,
65, 6035. (d) Marshall, J. A.; Hinkle, K. W. J. Org. Chem. 1997, 62,
5989.
reductive cleavage of the pivaloate group (DIBAL, -78 °C), and
Parikh-Doering oxidation of the primary alcohol then provided
aldehyde 19. Finally, treatment of 19 with the chiral γ-silylallyl-
borane reagent 7 at -78 °C afforded the expected â-hydroxy-
allylsilane. Protection of the resulting hydroxyl group as a TBS
ether was accomplished in acceptable yields by treatment with
excess TBSCl and imidazole in diethyl formamide (DEF) at ca. 50
°C for 5-6 days.10
Treatment of allylsilane 2 with 2 equiv of aldehyde 3 mediated
by SnCl4 (1 equiv) afforded the bis-tetrahydrofuran 20 as a single
diastereomer in 80% yield (Scheme 3). The high selectivity of this
reaction is attributed to the matched facial selectivity of the chiral
allylsilane and the SnCl4-chelated chiral aldehyde in the favored
syn-synclinal transition state 21.7,15 Significant amounts of an
allylation byproduct were obtained when the [3 + 2] annulation
reaction was performed at temperatures below 0 °C (see SI), and
drastically reduced yields of 20 were obtained if the starting
concentration of 2 was less than 0.2 M.
Removal of the two C-SiPhMe2 substituents from 20 proved
to be challenging. Initial attempts at protiodesilylation of 20 by
treatment with TBAF, KOtBu, and 18-crown-6 in wet DMSO (a
modification of Hudrlik’s conditions, with TBAF added to deprotect
the promixal TBS ethers)7,16 provided modest yields of tetraol 22.
However, this procedure proved to be nonreproducible, could not
be scaled up, and frequently gave very low yields of 22.
Alternatively, treatment of 20 with TBAF in a 1:1 mixture of THF
and DMF gave clean, reproducible cleavage of the sp3 C-Si bonds
and deprotection of the four TBS ethers.17 In this way, tetraol 22
was obtained in 55-60% yield from 20 (Scheme 4). Finally, the
butenolide ring was installed using a procedure developed by
Marshall and co-workers.3d Thus, per-trifluoroacetylation of 22
followed by Pd(0)-catalyzed hydroxycarbonylation, Ag(I)-promoted
cyclization of the resulting allenyl carboxylic acid, and then
(4) For reviews of reactions of allylsilanes: (a) Masse, C. E.; Panek, J. S.
Chem. ReV. 1995, 95, 1293. (b) Chabaud, L.; James, P.; Landais, Y. Eur.
J. Org. Chem. 2004, 3173.
(5) (a) Panek, J. S.; Yang, M. J. Am. Chem. Soc. 1991, 113, 9868. (b) Panek,
J. S.; Beresis, R. J. Org. Chem. 1993, 58, 809. (c) Beresis, R.; Panek, J.
S. Bioorg. Med. Chem. Lett. 1993, 3, 1609. (d) Micalizio, G. C.; Roush,
W. R. Org. Lett. 2001, 3, 1949. (e) Smitrovich, J. H.; Woerpel, K. A.
Synthesis 2002, 2778. (f) Peng, Z.-H.; Woerpel, K. A. Org. Lett. 2002, 4,
2945. (g) Heo, J.-N.; Micalizio, G. C.; Roush, W. R. Org. Lett. 2003, 5,
1693.
(6) (a) Roberson, C. W.; Woerpel, K. A. J. Am. Chem. Soc. 2002, 124, 11342.
(b) Peng, Z.-H.; Woerpel, K. A. Org. Lett. 2001, 3, 675.
(7) Micalizio, G. C.; Roush, W. R. Org. Lett. 2000, 2, 461.
(8) (a) Oberlies, N. H.; Chang, C.; McLaughlin, J. L. J. Med. Chem. 1997,
40, 2102. (b) Shimada, H.; Grutzner, J. B.; Kozlowski, J. F.; McLaughlin,
J. L. Biochemistry 1998, 37, 854. (c) Rupprecht, J. K.; Chang, C.-J.;
Cassady, J. M.; McLaughlin, J. L. Heterocycles 1986, 24, 1197. (d) Rieser,
M. J.; Hui, Y.-H.; Rupprecht, J. K.; Kozlowski, J. F.; Wood, K. V.;
McLaughlin, J. L.; Hanson, P. R.; Zhuang, Z.; Hoye, T. R. J. Am. Chem.
Soc. 1992, 114, 10203.
(9) Roush, W. R.; Pinchuk, A. N.; Micalizio, G. C. Tetrahedron Lett. 2000,
41, 9413.
(10) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.
(11) Parikh, J. R.; von Doering, E. W. J. Am. Chem. Soc. 1967, 89, 5505.
(12) Schmid, C. R.; Bradley, D. A. Synthesis 1992, 587.
(13) Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.; Pawlak, J.
M.; Vaidyanathan, R. Org. Lett. 1999, 1, 447.
(14) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(15) Keck, G. E.; Savin, K. A.; Cressman, E. N. K.; Abbott, D. E. J. Org.
Chem. 1994, 59, 7889.
(16) Hudrlik, P. F.; Hudrlik, A. M.; Kulkarni, A. K. J. Am. Chem. Soc. 1982,
104, 6809.
(17) Heitzman, C. L.; Lambert, W. T.; Mertz, E.; Shotwell, J. B.; Tinsley, J.
M.; Va, P.; Roush, W. R. Org. Lett. 2005, 7, 2405.
JA051986L
9
J. AM. CHEM. SOC. VOL. 127, NO. 31, 2005 10819