0
antagonist. Liphagal (2 ) was isolated in 2006 by Andersen and
co-workers from the Caribbean sponge Aka coralliphagum
and was demonstrated to have inhibitory activity against
Although challenging, it is important that we continue
to develop efficient strategies for the synthesis of 6,7,
5-tricyclic molecules that can be widely used. During our
6
PI3K, with an IC50 of 100 nM.
14
investigation into such cycloadditions, an intermolecular
1
5
The excellent biological activities of these compounds
have inspired several research groups to develop complete
7
syntheses of these compounds. The first enantioselective
[4 þ 3]-cycloaddition wasfound that serves asanefficient
strategy for the construction of the 6,7,5-tricyclic skeleta.
The application of this type of cycloaddition to the synthe-
sis of such natural products was therefore investigated, and
efficient syntheses of frondosin B and liphagal were devel-
oped and are described herein.
total synthesis of frondosin B (1) was completed by Da-
nishefsky and co-workers in 2001 using a classical Friedelꢀ
8
Crafts reaction. Subsequently, Trauner and Hughes em-
ployed two palladium-catalyzed reactions to produce the
As shown in the retrosynthetic analysis in Scheme 1,
liphagal and frondosin B were divided into two compo-
nents: diene 4 and allylic alcohol 5 which would be united
via a [4 þ 3] strategy. The precursors 3a and 3b would be
required for 1 and 2, respectively, and these would be the
corresponding products of the [4 þ 3]-cycloaddition of 4
and 5 and be capable of being converted into the targets by
normal transformations.
9
key core. In 2006, Andersen and co-workers reported the
0
10
first biosynthesis of liphagal (2 ). Shortly thereafter, a
biomimetic ring expansion was reported by Adlington
and co-workers in the asymmetric synthesis of these
targets. Tandem pinacol rearrangement/benzyldeprotection/
hemiketalization/dehydration was also used in the total synth-
esis of liphagal. However, the most efficient synthesis of this
type of target was achieved by MacMillan and co-workers in a
synthesis of frondosin B that involved only three linear steps
via FriedelꢀCrafts alkylation.
11
12
13
Scheme 2. Synthesis of (()-Frondosin B and (()-5-epi-Liphagal
Scheme 1. Retrosynthesis of Frondosin B and Liphagal
(
7) (a) Kerr, D. J.; Willis, A. C.; Flynn, B. L. Org. Lett. 2004, 6, 457.
(b) Hughes, C. C.; Trauer, D. Tetrahedron 2004, 60, 9675. (c) Li, X.;
Ovaska, T. V. Org. Lett. 2007, 9, 3837. (d) Olson, J. P.; Davies, H. M. L.
Org. Lett. 2008, 10, 573. (e) Ovaska, T. V.; Sullivan, J. A.; Ovaska, S. I.;
Winegrad, J. B.; Fair, J. D. Org. Lett. 2009, 11, 2715. (f) Lee, D. W.;
Pandey, R. K.; Lindeman, S.; Donaldson, W. A. Org. Biomol. Chem.
2011, 9, 7742. (g) Inoue, M.; Frontier, A. J.; Danishefsky, S. J. Angew.
The synthesis began from easily prepared allylic
1
6
Chem., Int. Ed. 2000, 39, 761. (h) Garayalde, D.; Kr u€ ger, K.; Nevado, C.
Angew. Chem., Int. Ed. 2011, 50, 911. (i) Masters, K.-S.; Flynn, B. L.
Org. Biomol. Chem. 2010, 8, 1290.
alcohol 5 and diene 4. [4 þ 3]-Cycloaddition requires
(
8) Inoue, M.; Carson, M. W.; Frontier, A. J.; Danishefsky, S. J.
(13) Reiter, M.; Torssell, S.; Lee, S.; MacMillan, D. W. C. Chem. Sci.
2010, 1, 37.
J. Am. Chem. Soc. 2001, 123, 1878.
(
(
9) Hughes, C. C.; Trauner, D. Angew. Chem., Int. Ed. 2002, 41, 1569.
10) Marion, F.; Williams, D. E.; Patrick, B. O.; Hollander, I.;
(14) Zhou, G. L.; Xie, Z. X.; Li, Y. Org. Lett. 2008, 10, 721.
(15) Winne, J. M.; Catak, S.; Waroquier, M.; Speybroeck, V. V.
Angew. Chem., Int. Ed. 2011, 50, 11990.
(16) Commercially available 2,2-dimethylcyclohexanone and β-
cyclocitral were converted to the dienes 4a and 4b following standard
procedures. The requisite benzofuranones 6a and 6b were easily pre-
Mallon, R.; Kim, S. C.; Roll, D. M.; Feldberg, L.; Soest, R. V.;
Andersen, R. J. Org. Lett. 2006, 8, 321.
(
11) George, J. H.; Baldwin, J. E.; Adlington, R. M. Org. Lett. 2010,
2, 2394.
12) Enrique, A.-M.; Rachid, C.; Esteban, A.; Ma, J.; Ali, H.;
1
(
pared according to Danishefsky’s procedure, (ref 8) and NaBH
tion quantitatively generated benzofuranol 5a and 5b.
4
reduc-
Ram oꢀ n, A.-M. Org. Lett. 2010, 12, 4450.
Org. Lett., Vol. 14, No. 17, 2012
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