A new analogue of rocaglamide by an oxidative dihydrofuran synthesis

Article abstract of DOI:10.1016/S0040-4039(00)00021-6

A new analogue of rocaglamide 1 has been synthesised. The tricyclic core structure that is lacking the C-8b hydroxy group was generated in an oxidative addition of 1,3-cyclohexanedione to a cyclopentene moiety forming a tricyclic dihydrofuran system. Further transformation gave analogue 12 with the desired configuration. Although this C-8b deoxy derivative exhibits no insecticidal activity, it provides important information in understanding the structure-activity relationship. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00021-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1913–1916
A new analogue of rocaglamide by an oxidative dihydrofuran
synthesis†
Andreas Schoop,∗ Helmut Greiving and Axel Göhrt
Central Research, Bayer AG, D-51638 Leverkusen, Germany
Received 15 November 1999; accepted 21 December 1999
Abstract
A new analogue of rocaglamide 1 has been synthesised. The tricyclic core structure that is lacking the C-8b
hydroxy group was generated in an oxidative addition of 1,3-cyclohexanedione to a cyclopentene moiety forming
a tricyclic dihydrofuran system. Further transformation gave analogue 12 with the desired configuration. Although
this C-8b deoxy derivative exhibits no insecticidal activity, it provides important information in understanding the
structure–activity relationship. © 2000 Elsevier Science Ltd. All rights reserved.
The natural product rocaglamide 1 which was isolated from Aglaia elliptifolia in 1982 and described
to exhibit antileukemic activity,1 was rediscovered about 10 years later due to its insecticidal activity.2–5
Meanwhile, the first total syntheses have been described.6–8 Still, a shorter synthesis that allows an
agrochemical application is needed. In particular, the synthesis of the tricyclic core structure bearing
a highly functionalised cyclopentane moiety with five stereogenic centres is a challenge.
In the investigation of the structure–activity relationship we have been interested in a facile access to
analogues of the cyclopentabenzofuran structure. The synthetic approach we investigated was based on
the idea of connecting a benzene moiety and a cyclopentane system in a furan synthesis. We have been
able to realise this idea by an oxidative addition of a 1,3-dicarbonyl compound to a cyclopentene in an
oxidative fashion.
∗
†
Corresponding author. E-mail: andreas.schoop.as@bayer-ag.de (A. Schoop)
This paper is dedicated to Pol Bamelis on the occasion of his 60th birthday.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00021-6
tetl 16301

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Starting from allylidenetriphenylphosphorane 29 the cyclopentadiene 4 was prepared in one step
and 87% yield by alkylation with bromoketone 310 and intramolecular Wittig reaction in the presence
of cesium carbonate (Scheme 1). The vinyl ether 4 was cleaved with HCl to give ketone 5 and
reduction with NaBH4 in ethanol yielded alcohol 6 as a single diastereoisomer (81%). According
to literature protocols11,12 olefin 6 was subjected to a reaction of 1,3-cyclohexanedione and cerium
ammonium nitrate (CAN). Despite some side product formation the major compound turned out to be
the desired cis-fused dihydrofuran 7 which was isolated in 35% yield. The stereochemical assignment
was possible by crystallisation and X-ray analysis of dihydrofuran 9 which was obtained from dimedone
and cyclopentene 8 in 44% yield (Fig. 1). The X-ray structure demonstrates that the two aryl substituents
are in the desired cis arrangement and the ester is in an anti orientation. However, the stereocentre at C-1
has the opposite configuration compared to rocaglamide 1.
Scheme 1.
Treatment of 7 with iodine in methanol led to the formation of the methyl ether and the aromatisation
in one step to give intermediate 10 (Scheme 2). Because of side product formation, the reaction was
stopped before complete conversion, yielding 33% aromatised product 10 and recovered starting material
(30%). To invert the configuration at C-1, alcohol 10 was subjected to an oxidation–reduction sequence.
While Swern oxidation resulted in low yields, oxidation of 10 by Dess–Martin periodinane afforded
ketoester 11 in 63% yield. In a final reduction 11 was transformed to the hydroxyester 12. Standard
conditions (NaBH4, ethanol) resulted in low conversion and poor diastereoselectivity (3:1). Instead,
dichloromethane and Bu4NBH4 gave better conversions and a selectivity of 5.5:1 yielding 12 in 37%
after purification.

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Fig. 1. X-Ray structure of dihydrofuran 913
Scheme 2.
The relative configuration of analogue 12 was assigned by 1H NMR data in comparison to the epimer
10. The configuration of C-2 is confirmed by the coupling constant of 12 (J2,3=14.1 Hz) indicating the
ester substituent to be trans to the 3-aryl substituent as in compound 10 (J2,3=13.6 Hz). The coupling
constant J1,2 is larger for the epimer 10 (10: J1,2=9.1 Hz, 12: J1,2=5.0 Hz) as seen in the rocaglamide
series.7 The configuration of C-1 was also assigned by comparing the chemical shifts. A low field shift
at 5.14 ppm of compound 12 compared to the signal at 4.73 ppm of epimer 10 indicated a configuration
at C-1 that no longer orientates the carbinol proton in the anisotropic cone of the benzofuran moiety.
Interestingly, when analogue 12 was tested against Spodoptera littoralis, no insecticidal activity was
observed. Although the influence of the C-6 methoxy substituent of rocaglate esters is not clear, it seems

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most likely that the drastic loss in activity is due to the missing hydroxy group at the bridgehead atom
C-8b.
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