Scheme 2. Frondosin B Retrosynthetic Analysis
Scheme 3. Synthesis of Benzofuranyldiazoacetate 8
was generated only in the case of cis-piperylene. In all
instances, the formal [4 + 3] cycloadducts were obtained in
moderate to high yield (43-92%) and high diastereoselec-
tivity (>94% de) and enantioselectivity (91-98% ee). The
relative configuration of the products was determined by
and diene 5 would be needed as substrates in the initial
cyclopropanation and the benzofuran moiety would need to
be a reactive component in the subsequent Cope rearrange-
ment. A further requirement would be the regeneration of
the benzofuran ring by means of tautomerization. This paper
describes the successful development of the tandem cyclo-
propanation/Cope rearrangement between benzofuranyldi-
azoacetates and dienes and its application to the synthesis
of 2.
Table 1. Rh2(R-DOSP)4-Catalyzed Reactions of 8 with Dienes
To test the effectiveness of this reaction, the benzofura-
nyldiazoacetate 8 was synthesized and reacted with a series
of conjugated dienes. 8 was readily synthesized from the
commercially available coumaran-3-one 6 by treatment with
methyl(triphenylphosphoranylidene)acetate in refluxing xy-
lenes14 followed by a diazo transfer reaction on the resulting
benzofuranacetate 7 with p-acetamidobenzenesulfonyl azide
(p-ABSA) (Scheme 3).
With the desired benzofurandiazoacetate 8 in hand, its
reactions with a variety of cyclic and acyclic conjugated
dienes were examined under Rh2(R-DOSP)4-catalyzed condi-
tions (Table 1). The standard reaction was conducted with 1
mol % of Rh2(R-DOSP)4, to which 8 was added to the
reaction mixture at -78 °C, and then the mixture was
warmed to room temperature. In some cases where the diene
has a cis-substituent, more vigorous conditions were required
to drive the Cope rearrangement of the cis-divinylcyclopro-
pane.15 A significant amount of the trans-divinylcyclopropane
(7) (a) Inoue, M.; Carson, M. W.; Frontier, A. J.; Danishefsky, S. J. J.
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McDonald, J.; Thompson, K.; Boulton, D. A.; Kopka, I. E.; Hand, K. M.;
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J.; Humes J. L. J. Med. Chem. 1990, 33, 908.
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a Diastereoselectivity determined from the 1H NMR of the crude reaction
mixture. b Cope rearrangement required heating to 110 °C. c Cope rear-
rangement required heating to 140 °C. d Initial cyclopropane was produced
in a 2.7:1 diastereomeric ratio.
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Org. Lett., Vol. 10, No. 4, 2008