α,α′-annulation of 2,6-prenyl-substituted cyclohexanone derivatives with malonyl chloride: Application to a short synthesis of (±)-clusianone. Formation and rearrangement of a biogenetic-like intermediate

Article abstract of DOI:10.1021/ol062736s

(Chemical Equation Presented) Conditions were found for the successful Effenberger α,α′-annulation of 3,3-dimethyl-2,4,6-triprenyl cyclohexanone silyl enol ethers with malonyl chloride to give the corresponding bicyclo[3.3.1]nonane-trione in 35% yield, th

Full text of DOI:10.1021/ol062736s

ORGANIC
LETTERS
2007
Vol. 9, No. 2
287-289
r,r′-Annulation of
2,6-Prenyl-Substituted Cyclohexanone
Derivatives with Malonyl Chloride:
Application to a Short Synthesis of
(±)-Clusianone. Formation and
Rearrangement of a Biogenetic-Like
Intermediate
Philippe Nuhant, Marc David, Thomas Pouplin, Bernard Delpech,* and
Christian Marazano*
Institut de Chimie des Substances Naturelles, CNRS, 1 AVenue de la Terrasse,
91198 Gif-sur-YVette, France
marazano@icsn.cnrs-gif.fr
Received November 8, 2006
ABSTRACT
Conditions were found for the successful Effenberger
malonyl chloride to give the corresponding bicyclo[3.3.1]nonane-trione in 35% yield, this result allowing a short synthesis of (
r
,
r′-annulation of 3,3-dimethyl-2,4,6-triprenyl cyclohexanone silyl enol ethers with
)-clusianone.
±
An isomeric rearranged bicyclo[3.3.1]nonane-trione was also isolated in 25% yield, and changing the Lewis acid resulted in formation of a
lavandulyl-substituted phloroglucinol derivative in 38% yield. The mechanism of formation of these two last products mimics the biogenetic
pathway to PPAPs.
A number of polyprenylated acylphloroglucinol derivatives
(PPAPs) have been isolated from plants and trees of the
family Clusiaceae (Guttiferae).1 Some representative ex-
amples are depicted in Figure 1. Clusianone 12 is one of the
simplest members in this series, and hyperforin 2 and
garsubellin A 3, considering their interesting biological
activities, recently became targets for total synthesis.3 Our
interest in this field came from the observation4 that
xanthochymol 4 was active in vitro in a tubulin disassembly
(1) For recent reviews, see: (a) Ciochina, R.; Grossman, R. B. Chem.
ReV. 2006, 106, 3963-3986. (b) Cuesta-Rubio, O.; Piccinelli, A. L.;
Rastrelli, L. In Studies in Natural Product Chemistry (BioactiVe Natural
Products, Part L); Atta-ur Rahman, Ed.; Elsevier: Amsterdam, 2005; Vol.
32, pp 671-720.
(2) Piccinelli, A. L.; Cuesta-Rubio, O.; Chica, M. B.; Mahmood, N.;
Pagano, B.; Pavone, M.; Barone, V.; Rastrelli, L. Tetrahedron 2005, 61,
8206-8211.
(3) Two total syntheses of garsubellin A were published recently: (a)
Siegel, D. R.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 1048-
1049. (b) Kuramochi, A.; Usuda, H.; Yamatsugu, K.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2005, 127, 14200-14201.
(4) Roux, D.; Hadi, H. A.; Thoret, S.; Gue´nard, D.; Thoison, O.; Pa¨ıs,
M.; Se´venet, T. J. Nat. Prod. 2000, 63, 1070-1076.
10.1021/ol062736s CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/22/2006

Scheme 2
We first investigated the reaction starting from the
trimethylsilyl enol ether of 2,6-diprenyl cyclohexanone 14.
We were pleased to find rapidly satisfying conditions leading
to the bicyclo[3.3.1]nonane-trione 15 (Scheme 3). Thus,
Figure 1. Some PPAPs of current interest.
Scheme 3
inhibition test and from our recent results concerning
isolation of analogues, oblongifolins A-D.5
The biosynthetic pathway to natural PPAPs is summarized
in Scheme 1.1a Prenyl transfer to the phloroglucinol ring of
Scheme 1. Biosynthetic Pathways to Natural PPAPs
treatment, at -10 °C, of a toluene solution of the silyl enol
ether 14 with a slight excess of malonyl chloride and TMS
triflate as a Lewis acid, followed by base treatment (DMAP),
afforded three products. The desired cycloadduct 15 was
obtained after chromatography over silica gel in 35% yield.
It was accompanied by the corresponding cyclic ether 16
and cyclohexanone 13 (43%). Considering cyclohexanone
13 as recovered starting material, the corrected yield of the
cyclization process is 86% (61% and 25% for 15 and 16,
respectively).
Encouraged by these first observations, we then directly
devoted our efforts to the study of the reaction sequence of
Scheme 2 (R ) prenyl). For this purpose, an isomeric
mixture of cyclohexanones 23 and 24 was prepared in five
steps and in an overall yield of 58% from substituted dione
18 according to the route depicted in Scheme 4.9
5 produces intermediate 6. The addition of a fourth prenyl
unit generates a lavandulyl cation 7. This cation can eliminate
a proton to give a lavandulyl-substituted derivative 8 or
cyclizes to give triones 9 (type B cyclization) or 10 (type A
cyclization).
Scheme 4
Several strategies have emerged concerning PPAP syn-
thesis.1 Among them, R,R′-annulation of substituted cyclo-
hexanones with malonyl chloride6,7 is particularly attractive
because it has the capability to form the key bicyclo[3.3.1]-
nonane-2,4,9-trione system in one step.
Very recently, Simpkins et al. reported the synthesis of
the bicyclic methyl enol ether 11 (Scheme 2) and the first
total synthesis of (()-clusianone starting from this intermedi-
ate.8 For our study, we targeted a short synthesis of the
bicyclo[3.3.1]nonane-trione 12.
(5) Hamed, W.; Brajeul, S.; Mahuteau-Betzer, F.; Thoison, O.; Mons,
S.; Delpech, B.; Hung, N. V.; Sevenet, T.; Marazano, C. J. Nat. Prod. 2006,
69, 774-777.
(6) Scho¨nwa¨lder, K.-H.; Kollatt, P.; Stezowski, J. J.; Effenberger, F.
Chem. Ber. 1984, 117, 3280-3296.
(7) Spessard, S. J.; Stoltz, B. M. Org. Lett. 2002, 4, 1943-1946.
A mixture of silyl enol ethers 25 was then prepared from
the mixture of cyclohexanones 23 and 24 (Scheme 5).
288
Org. Lett., Vol. 9, No. 2, 2007

Scheme 5
Scheme 6. Completion of (()-Clusianone Synthesis
A mechanism for the formation of rearrangement products
26 and 27 is proposed in Scheme 7.11 Formation of the
Scheme 7
Treatment of 25 with malonyl chloride in the presence of
TMSOTf in toluene (conditions used for the preparation of
bicyclononane-trione 15, see Scheme 3) was unsuccessful.
Using dichloromethane as solvent at -10 °C, the desired
bicyclononane-trione 12 was obtained after chromatography
over silica gel, but only in a disappointing yield of 6%.
Another product was isolated in 11% yield. Allowing the
reaction mixture to warm to 15 °C during 5 h, before base
treatment, resulted only in an increased yield of 38% for
this last product, the structure of which was established by
spectroscopic methods as lavandulyl-substituted phloroglu-
cinol derivative 27. The relative stereochemistry of this com-
pound was assigned considering its probable mechanism of
formation (vide infra). Changing the Lewis acid to BF3‚Et2O
gave finally an appreciable 35% yield of 12 with recovery
of the mixture of cyclohexanones 23-24 in 22% yield. It is
thus a remarkable result considering that two quaternary
carbon centers, with one being contiguous to an another one
(gem-dimethyl), are formed during this crucial step. To our
surprise, another bicyclononane-trione was isolated from the
reaction mixture in 25% yield, the structure of which was
established as 26 using intensive spectroscopic methods. The
formation of lavandulyl derivative 27 was not observed with
BF3‚Et2O as a Lewis acid, meaning that the reaction pathway
can be controlled by changing the nature of the Lewis acid.
Completion of (()-clusianone total synthesis from 12 was
achieved by C-acylation with benzoyl cyanide,10 according
to Scheme 6. This clusianone synthesis involves seven steps
from readily available intermediate 19 with an overall yield
of approximately 14% (Simpkins et al. reported a nine-step
synthesis and a similar overall yield from the methyl enol
ether analogue of 19).10
second carbon-carbon bond, in the reaction with malonyl
chloride, is likely to produce an oxonium intermediate 28
which can produce a cationic species 29 by a fragmentation
process. Cationic intermediate 29 can recyclize to give trione
30 or afford the lavandulyl derivative 31. Liberation, in both
cases, of one molecule of acid leads to the observed cyclic
ether derivatives 26 or 27. Intermediate cation 29 possesses
striking analogies with the biogenetic cationic intermediate
7 in Scheme 1, whereas derivatives 30 and 31 can be con-
sidered as analogues of 7-epi nemorosone and weddellianone
A, respectively.
Future work will try to take advantage of these new
observations to extend the scope of this chemistry to natural
PPAP synthesis.
Supporting Information Available: Experimental pro-
cedures, copies of NMR spectra for compounds 1, 12-16,
23, 24, 26, and 27, and nOe data for 26. This material is
available free of charge via the Internet at http://pubs.acs.org.
(8) Rodeschini, V.; Ahmad, N. M.; Simpkins, N. S. Org. Lett. 2006, 8,
5283-5285.
(9) Slight variations of now classical procedures have been used. See
refs 7 and 8 and refs therein as well as the Supporting Information section
for more details.
OL062736S
(10) Nicolaou, K. C.; Vassilikogiannakis, G.; Montagnon, T. Angew.
Chem., Int. Ed. 2002, 41, 3276-3281.
(11) For a rather similar discussion, see: Le Roux, C.; Mandrou, S.;
Dubac, J. J. Org. Chem. 1996, 61, 3885-3887.
Org. Lett., Vol. 9, No. 2, 2007
289