Stereoselective synthesis of (±)-rocaglaol analogues

Article abstract of DOI:10.1021/ol0479904

(Chemical equation presented) An intramolecular hydroxy epoxide opening was used to access the cyclopenta[d]benzofuran ring system of the natural product rocaglaol (2). Our route allowed the stereocontrolled preparation of the rocaglaol derivative (±)-(1S*,3S*,3aR*,8bS*)-3b. The synthesis of the (±)-(3R*)-epimer of 3b was also achieved. Our strategy is well-suited for the production of analogues with variation of the western ring.

Full text of DOI:10.1021/ol0479904

ORGANIC
LETTERS
2004
Vol. 6, No. 24
4595-4597
Stereoselective Synthesis of
)-Rocaglaol Analogues
(±
Kai Thede, Nicole Diedrichs, and Jacques P. Ragot*
Medicinal Chemistry, Pharma Research, Bayer HealthCare AG,
42096 Wuppertal, Germany
jacques.ragot@bayerhealthcare.com
Received October 1, 2004
ABSTRACT
An intramolecular hydroxy epoxide opening was used to access the cyclopenta[b]benzofuran ring system of the natural product rocaglaol (2).
Our route allowed the stereocontrolled preparation of the rocaglaol derivative ( )-(1S*,3S*,3aR*,8bS*)-3b. The synthesis of the ( )-(3R*)-epimer
of 3b was also achieved. Our strategy is well-suited for the production of analogues with variation of the western ring.
±
±
Rocaglamide (1), isolated from Aglaia elliptifolia in 1982,1
is the parent compound of a unique family of more than 50
natural products featuring a cyclopenta[b]tetrahydrobenzo-
furan skeleton. The chemistry and biological activity of
rocaglamide derivatives have been recently reviewed.2 Their
chemical diversity and biological activity, in particular
insecticidal and cytostatic activity, both contribute to make
rocaglamide derivatives interesting candidates for therapeutic
agents.
access was limited to very electron-rich benzofuranones
coming from Hoesch or Friedel-Crafts reactions. Only
rocaglaol derivatives bearing a dimethoxy- or diethoxy-
substituted western ring could be prepared.
We therefore decided to develop a synthesis of derivatives
of type 3 with a (1S*,3S*,3aR*,8bS*)-core (rocaglaol num-
bering) that would allow variation of the substituent R on
the western ring.
Several total syntheses and synthetic studies of rocaglaol
(2) and rocaglamide (1) have been published,3 the majority
of them using 3a as a common intermediate (Scheme 1).3b-e
Compound 3a was prepared efficiently by Taylor et al.3c
by a Michael addition of the benzofuranone 4 to cinnam-
aldehyde and intramolecular pinacol coupling of the aldehyde
5 mediated by samarium iodide (Scheme 1). Unfortunately,
Scheme 1. Synthesis of Rocaglaol/Rocaglamide from
Benzufuranone via Intermediate 3a by Taylor et al.
(1) King, M. L.; Chiang, C. C.; Ling, H. C.; Fujita, E.; Ochiai, M.;
McPhail, A. T. J. Chem. Soc., Chem. Commun. 1982, 1150.
(2) Proksch, P.; Edrada, R.; Ebel, R.; Bohnenstengel, F. I.; Nugroho, B.
W. Curr. Org. Chem. 2001, 5, 923.
(3) (a) Trost, B. M.; Greenspan, P. D.; Yang, B. V.; Saulnier, M. G. J.
Am. Chem. Soc. 1990, 112, 9022. (b) Kraus, G. A.; Sy, J. O. J. Org. Chem.
1989, 54, 77. (c) Davey, A. E.; Schaeffer, M. J.; Taylor, R. J. K. J. Chem.
Soc., Chem. Commun. 1991, 1137. Davey, A. E.; Schaeffer, M. J.; Taylor,
R. J. K. J. Chem. Soc., Perkin Trans. 1 1992, 2657. (d) Watanabe, T.;
Shiraga, Y.; Takeuchi, T.; Otsuka, M.; Umezawa, K. Heterocycles 2000,
53, 1051. (e) Dobler, M. R.; Brune, I.; Cederbaum, F.; Cooke, N. G.;
Diorazio, L. J.; Hall, R. G.; Irving, E. Tetrahedron Lett. 2001, 42, 8281.
10.1021/ol0479904 CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/02/2004

Our retrosynthetic approach was based on the idea of
installing the (3aR*,8bS*)-stereochemistry using an intra-
molecular epoxide opening (Scheme 2). The necessary
perature (140 °C), the double bond migrated to produce an
inseparable mixture of 6 and its regioisomer 4-(4-methoxy-
phenyl)-3-phenylcyclopent-2-en-1-one. The R-bromination
of 6 proved to be difficult due to the formation of di- and
tribrominated side-products. Although different reaction
conditions were tried (pyridinium tribromide in pyridine/
DCM or oxone followed by treatment with NaBr and
triethylamine in CCl4), addition of Br2 to the enone 6
followed by elimination of HBr with triethylamine was the
preferred method and gave the desired R-bromoenone 8 in
35% yield.
Scheme 2. Retrosynthetic Approach
The western side of the molecule was installed using a
Pd-mediated Suzuki coupling (Scheme 4). Phenol 9 was
Scheme 4
epoxy-cyclopentanol would be obtained in a stereoselective
manner via the corresponding cyclopentenone. This would
itself be constructed from the unsymmetrical cyclopentenone
6 using Pd methodology. In a successful implementation of
this idea, we were able to prepare (()-(1S*,3S*,3aR*,8bS*)-
3b (R ) H).4
Symmetrical 3,4-diaryl-cyclopent-2-enones are readily
available via cyclization of R,â-diketones with acetone
followed by elimination of water.5 Unsymmetrical ones,
however, are more troublesome to prepare. An elegant
solution was developed at Bayer by Schoop et al.6 Cycliza-
tion of allyldienetriphenylphosphorane with R-bromoketones
followed by reaction with HCl provided regioselectively
unsymmetrical cyclopentenones (Scheme 3, reaction with
2-bromo-1-(4-methoxyphenyl)-2-phenylethanone).
protected as a benzyl ether which was converted into boronic
acid 10 with n-BuLi and trimethyl borate. This boronic acid
10 was then reacted with the bromocyclopentenone 8 to give
11.
Table 1 shows the optimization of the reduction of ketone
11. NaBH4 and DIBAL-H gave no selectivity. Low selectiv-
ity was obtained with the Luche reduction. L-Selectride gave
Table 1. Diastereoselective Reduction of Cyclopentenone 11
Scheme 3
method
12:13
yield 12 (%)a
DIBAL-H (1.1 equiv), DCM, -78 °C
NaBH4 (2 equiv), MeOH, 0 °C
NaBH4 (5 equiv), MeOH, 0 °C-rt
NaBH4/CeCl3 (2/1), MeOH-DCM, 0 °C
NaBH4/CeCl3 (1/1), MeOH-DCM, rt
L-Selectride (1.1 equiv), THF, -78 °C
50:50
50:50
51:49
63:37
66:33
>99:1
5
37
51
40
60
70
Following Schoop’s methodology, cyclopentenone 7 was
successfully prepared in multigram quantity and improved
yield (80% over two steps) and served as starting material
for our synthesis (Scheme 3).
Heating 7 at 110 °C in wet DMSO for 12 h afforded the
decarboxylated cyclopentenone 6. At a more elevated tem-
a Isolated yield.
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Org. Lett., Vol. 6, No. 24, 2004

the best results, and the syn-alcohol 12 was obtained in 70%
yield with complete diastereoselectivity. The stereochemistry
of 12 was assigned on the basis of chemical analogy and
confirmed with NOESY experiments.7
The corresponding anti isomer 13 was isolated in 37%
yield with NaBH4/CeCl3 in MeOH-DCM. With the allylic
alcohols 12 and 13 in our hand, we could install the
remaining two stereocenters at positions 3a and 8b with a
stereoselective epoxidation reaction (Scheme 5). Gratifyingly,
of epoxyalcohols 14 and 15 were based on chemical analogy
and confirmed with NOESY experiments.7
The last step was the cyclization to form the benzofuran
ring after the removal of the benzyl group (Scheme 5). We
expected that the deprotected phenolic group would react at
C-3a and open the epoxide. Because of the fixed geometry
of the epoxide, the opening would be stereospecific and lead
to the desired stereoisomer (()-3b possessing the rocaglaol
core. The deprotection was best achieved using Pd/C (10%)
in ethyl acetate (ethanol led to degradation products). We
were delighted to see that the cyclization proceeded spon-
taneously under the deprotection conditions and 3b was
obtained from 14 in 57% yield. The epimer (()-(3R)-16 was
obtained in 50% yield from epoxyalcohol 15 following the
same method.
Scheme 5. Stereoselective Formation of the Rocaglaol Core
In conclusion, a new methodology for obtaining rocaglaol
derivatives in a stereoselective way was successfully devel-
oped and exemplified by the preparation of (()-3b. This
method also permitted the preparation of 3-epi-rocaglaol
derivatives, as was demonstrated for 16. Simple variation
of the boronic acid 10 would allow the preparation of a range
of rocaglaol analogues having different substitution patterns
on the western ring.
Acknowledgment. We thank Peter Schmitt for the
measurement and interpretation of NMR spectra and Stefan
Golinski for the preparation of compound 7.
Supporting Information Available: Full experimental
procedures and structural characterization data for all com-
pounds prepared; H NMR spectra for compounds 3b and
16; NOESY spectra for compounds 12, 14, and 15; and
COSY spectra for compounds 12 and 15. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
the use of m-chloroperbenzoic acid led to a complete control
of the stereochemistry, which was directed by the hydroxy
group (Henbest’s rule).8 The structure and stereochemistry
(4) All compounds prepared are racemic. The relative stereochemistry
is shown.
OL0479904
(5) Polo, E.; Barbieri, A.; Traverso, O. Eur. J. Inorg. Chem. 2003, 2,
324.
(7) Spectra of NOESY experiments are included in Supporting Informa-
tion.
(6) Schoop, A.; Greiving, A.; Goehrt, A. Tetrahedron Lett. 2000, 41,
12, 1913.
(8) Henbest, H. B.; Wilson, R. A. J. Chem. Soc. 1957, 1958.
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