C O M M U N I C A T I O N S
Scheme 3. Bromonium-Initiated Epoxide-Opening Cascade
While the studies reported herein do not establish the natural
biogenesis of 1, they certainly demonstrate the feasibility of an
alternative sequence that constructs the trans-anti-trans tricycle in
a single operation (Figure 1, path a), in contrast to the iterative
ring assembly that has been proposed (path b).
Table 1. Studies of Diepoxide Model Systems
10a,13
of the diol to form ketone 11 (Scheme 4). Epoxy furan 12,
prepared by way of a Payne rearrangement of a known diepoxide,
was treated with an ylide derived from trimethylsulfonium iodide a` la
14
Falck. Hydroboration of the resulting terminal alkene in 13 (9-BBN
dimer) and in situ treatment of the alkylborane with a triflate derived
15
from 11 in the presence of Pd(Cl
2 2 3
)dppf and aqueous Cs CO at 40
°
C effected the fragment coupling in 78% yield. Temperature control
was critical to prevent side reactions involving the Br atom. Depro-
a
Isolated as a 1:1 mixture of diastereomers in all cases. Yields are not
corrected for the dr of the diepoxide starting materials (approximately 4:1 in all
cases). See Supporting Information. NBS used. Br(coll) ClO used.
2 4
tection with TBAF provided ent-1, displaying the opposite specific
rotation to that of 1, hence confirming the relative and absolute
b
c
1
configuration of the natural product.
Acknowledgment. This work was supported by the NIGMS
(
GM-72566). We thank Dr. Jeffrey H. Simpson for helpful
a
Scheme 4. Fragment Coupling and Completion of the Synthesis
discussions regarding NMR experiments, Li Li for mass spectrom-
etry data, Dr. Peter M u¨ ller for the crystal structure of 8, and Dr.
Jose J. Fern a´ ndez (Universidad de La Laguna) for providing the
1
13
H, C, and 2D NMR spectra of natural 1.
Supporting Information Available: Experimental procedures and
spectroscopic data for all new intermediates. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(
1) Manriquez, C. P.; Souto, M. L.; Gavin, J. A.; Norte, M.; Fernandez, J. J.
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(
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(
(
(
4) Hashimoto, M.; Kan, T.; Nozaki, K.; Yanagiya, M.; Shirahama, H.;
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a
Reagents and conditions: (a) NaOH, MeOH, rt, 83%; (b) NaIO
SI, n-BuLi, THF, -13 to 5 °C, 73%; (d)
TESCl, imidazole, DMF, rt, 95%; (e) (SO CF NC NCl, LHMDS, THF,
78 °C, quant.; (f) 9-BBN dimer, THF, 60 °C, 20 h; (g) PdCl (dppf), aq.
Cs CO , THF/DMF/H O, 40 °C, 36 h, 78% (h) TBAF, THF, rt, 83%.
4
, THF/
(6) Selected examples of bromotriterpene syntheses: (a) Morimoto, M.;
Nishikawa, Y.; Takaishi, M. J. Am. Chem. Soc. 2005, 127, 5806. (b)
Morimoto, Y.; Yata, H.; Nishikawa, Y. Angew. Chem., Int. Ed. 2007, 46,
2 3 3
H O, rt, 30 min, 96%; (c) (CH )
2
)
3 2
5 3
H
6
481. (c) Corey, E. J.; Ha, D.-C. Tetrahedron Lett. 1988, 29, 3171.
-
2
(
7) Bravo, F.; McDonald, F. E.; Neiwert, W. A.; Hardcastle, K. I. Org. Lett.
2
3
2
2004, 6, 4487.
(
(
8) Zakarian, A.; Batch, A.; Holton, R. A. J. Am. Chem. Soc. 2003, 125, 7822.
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(
(
(
10) (a) McDonald, F. E.; Bravo, F.; Wang, X.; Wei, X.; Toganoh, M.;
We explored the generality of this strategy with a series of related
Rodriguez, J. R.; Do, B.; Neiwert, W. A.; Hardcastle, K. I. J. Org. Chem.
1
6
model systems (Table 1). In most cases the yield did not depend
significantly upon the reagent used for bromonium formation, yet
a tert-butyl carbonate or a tert-butyl ester trapping nucleophile
generally gave a higher yield than did a primary alcohol. This brief
survey suggests that further applications of bromonium-initiated
epoxide-opening cascades would be merited.
In summary, we have achieved the first total synthesis of ent-
dioxepandehydrothyrsiferol (ent-1). The signature trans-anti-trans
,7,6-fused tricyclic polyether framework was constructed in a
2
002, 67, 2515. (b) Bravo, F.; McDonald, F. E.; Neiwert, W. A.; Do, B.;
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11) The absence of stereoselectivity has been observed in related cases (refs 4,
6
) and was not surprising in this case, given the distance between the alkene
in 6 and the nearest stereogenic center (epoxide A). A combined isolated
yield of 67% was obtained using Br(coll) ClO
2
4
.
12) Selected reviews on Suzuki-Miyaura cross coupling reactions: (a) Miyaura,
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(
13) (a) Hanson, R. M. Org. React. 2002, 60, 2. (b) Payne, G. B. J. Org. Chem.
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(
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7
single bromonium-initiated epoxide-opening cascade that incorpo-
rates both endo- and exo-selective epoxide openings, each directed
by the substitution pattern of the epoxide (Me groups).
(15) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(
16) See Supporting Information for details.
JA9052366
J. AM. CHEM. SOC. 9 VOL. 131, NO. 34, 2009 12085