A biomimetic approach to the rocaglamides employing photogeneration of oxidopyryliums derived from 3-hydroxyflavones

Article abstract of DOI:10.1021/ja044798o

A unified biomimetic approach to the aglain-forbaglin-rocaglamide classes of natural products is reported. The approach involves photogeneration of oxidopyryliums via excited-state intramolecular proton transfer (ESIPT) of 3-hydroxyflavones followed by [3

Full text of DOI:10.1021/ja044798o

Published on Web 10/01/2004
A Biomimetic Approach to the Rocaglamides Employing Photogeneration of
Oxidopyryliums Derived from 3-Hydroxyflavones
Baudouin Gerard, Guilford Jones, II, and John A. Porco, Jr.*
Department of Chemistry and Center for Chemical Methodology and Library DeVelopment, Boston UniVersity,
Boston, Massachusetts 02215
Received August 28, 2004; E-mail: porco@chem.bu.edu
The plant genus Aglaia, native to the tropical rain forests of
Indonesia and Malaysia, is the source of a unique group of densely
functionalized natural products (Figure 1).1 The rocaglamides,
including the parent (1)2 and the recently isolated dioxanyloxy-
modified derivative silvestrol (2),3 possess the cyclopenta[b]-
tetrahydrobenzofuran ring system. The structurally related cyclopenta-
[bc]benzopyran-containing aglains (e.g., 3 and 4) have also been
isolated from Aglaia.4 The forbaglins (e.g., 5, Figure 1) are benzo-
[b]oxepines derived from formal oxidative cleavage of the aglain
core. The rocaglamides exhibit potent anticancer2 and antileukemic
activity,5 as well as NF-κB inhibitory activity at nanomolar
concentrations in human T cells.6 The rocaglate silvestrol 2 displays
cytotoxic activity against human cancer cells comparable to the
anticancer drug Taxol.3
Figure 1. Rocaglamides and related compounds from Aglaia.
As proposed by Proksch and co-workers1 and Bacher and co-
workers,7 the rocaglamides may be biosynthetically derived from
Scheme 1. Unified Biomimetic Approach to the
Aglains-Forbaglins-Rocaglamides
reaction of 3-hydroxyflavone (3-HF) with cinnamide derivatives
to afford the aglain core followed by skeletal rearrangement.
Although the rocaglamides have been the subject of a number of
synthetic investigations,8 syntheses of the related aglains,4 ag-
laforbesins,4 and forbaglins have not been reported. Moreover, a
unified synthetic approach to these molecules based on biosynthetic
considerations still remains to be developed.8c Herein, we report a
biomimetic approach to the rocaglamides and the related aglains
and forbaglins involving excited-state intramolecular proton transfer
(ESIPT) of 3-HF derivatives9 and dipolar cycloaddition of the
resulting oxidopyrylium10 species.
Our approach is outlined in Scheme 1. Generation of oxidopy-
ryllium 8 from 3-HF derivative 6 or 7 and subsequent dipolar
cycloaddition to cinnamate derivatives should directly afford the
aglain core 9. Literature reports have documented excited-state
Scheme 2. Photochemical [3+2] Cycloaddition
intramolecular proton transfer9 of 3-HF derivatives leading to the
formation of the requisite oxidopyrylliums 8. Oxidative cleavage
of 9 to forbaglin 10 core may be conducted using Pb(OAc)4.11 Core
structure 9 may alternatively be converted to dehydrorocaglate 11
by R-ketol (acyloin) rearrangement.12 Such rearrangements have
been conducted using acidic or basic conditions or employing metal
catalysis and have been used with success in a number of natural
product syntheses.13 Hydroxyl-directed reduction of 118b should
afford rocaglates 12.
[b]cyclobutapyran-8-one 16 is observed during silica gel purification
resulting from an acid-mediated ketol shift.15 This equilibrium
between the two core structures was found to be controlled by
heating the mixture (EtOAc, 65 °C) to afford 15. Monitoring of
the photocycloaddition by 1H NMR (CD3CN) also confirmed
formation of 15 as the major product.14 Compound 14 (14%) was
identified as a cyclopenta[b]tetrahydrobenzofuran by further con-
version into a crystalline derivative.14 In contrast to 15, compound
14 is derived from exo [3+2] cycloaddition to an aglaforbesin-
type derivative (cf. 4, Figure 1) followed by acyloin rearrangement
during the photoirradiation process.16
In initial studies, we evaluated photoirradiation of commercially
available 3-hydroxyflavone 6 and dipolarophile 13 using a 450 W
medium-pressure mercury lamp (uranium filter, λ > 350 nm,
Scheme 2). After irradiation in MeCN (rt, 2 h), the 3-HF was
consumed and a mixture of products was observed resulting from
presumed [3+2] cycloaddition (Scheme 1). According to spectro-
scopic data and X-ray analysis of a crystalline derivative,14 the major
compound (56%) was confirmed to be endo cycloadduct 15 in
which the phenyl ring of the dipolarophile is anti to the oxido
bridge.10b Interestingly, an equilibrium between 15 and the benzo-
We next proceeded to evaluate conditions for conversion of
aglain core structure 15 to both the rocaglamide and forbaglin ring
9
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J. AM. CHEM. SOC. 2004, 126, 13620-13621
10.1021/ja044798o CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Conversion of the Aglain to the Forbaglin and
Rocaglamide Ring Systems
droxyflavones. Methodology has been developed to transform the
initially formed aglain structures to rocaglamide derivatives using
a base-mediated R-ketol rearrangement. Further studies, including
asymmetric synthesis of the rocaglamides and further applications
of the photocycloaddition process, are in progress and will be
reported in due course.
Acknowledgment. We thank Dr. John Beutler (NCI) and Profs.
Scott Schaus and John Snyder (Boston University) for helpful
discussions, Drs. Emil Lobkovsky (Cornell) and Richard Staples
(Harvard) for X-ray crystal structure analyses, Prof. Jonathan Lee
(Boston University) for assistance with NMR experiments, and
Bristol-Myers Squibb for an Unrestricted Grant in Synthetic Organic
Chemistry (J.A.P, Jr.).
Scheme 4. Synthesis of (()-Methyl Rocaglate
Supporting Information Available: Experimental procedures and
characterization data for all new compounds (PDF), including X-ray
crystal structure coordinates and files in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
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In conclusion, we have developed a biomimetic approach to the
aglain/rocaglamide/forbaglin classes of natural products. The key
strategy involves dipolar cycloaddition of oxidopyrylium ylides
derived from excited-state intramolecular proton transfer of 3-hy-
JA044798O
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