Biomimetic photocycloaddition of 3-hydroxyflavones: Synthesis and evaluation of rocaglate derivatives as inhibitors of eukaryotic translation

Article abstract of DOI:10.1002/anie.201003212

Shedding light on translation: A light-driven, biomimetic [3+2] cycloaddition has been achieved with the synthesis of a series of rocaglate derivatives. Mechanistic data suggest the possibility for donor-acceptor interactions and the involvement of triple

Full text of DOI:10.1002/anie.201003212

Angewandte
Chemie
DOI: 10.1002/anie.201003212
Photochemical Synthesis
Biomimetic Photocycloaddition of 3-Hydroxyflavones: Synthesis and
Evaluation of Rocaglate Derivatives as Inhibitors of Eukaryotic
Translation**
Stꢀphane P. Roche, Regina Cencic, Jerry Pelletier, and John A. Porco, Jr.*
In memory of Pierre Potier and Christian Marazano
The plant genus Aglaia produces a number of secondary
metabolites including the cyclopenta[b]benzofurans[1] roca-
glamide (1), silvestrol (2), and cyclopenta[b,c]benzopyrans[2]
(aglains) including ponapensin (3; Figure 1). Cyclopenta[b]-
biological activity, rocaglamide (1) has been targeted by many
research groups and has inspired a number of elegant
synthetic strategies.[4] We have previously reported a bio-
mimetic approach to the cyclopenta[b]benzofuran natural
products involving a photocycloaddition/ketol shift rear-
rangement/reduction sequence using 3-hydroxyflavone (3-
HF) derivatives such as 4 and methyl cinnamate (5a). This
strategy enabled total syntheses of both 1 and 2 (Figure 1 and
Scheme 1)[5] utilizing excited-state intramolecular proton
Figure 1. Representative aglain and rocaglate metabolites from Aglaia.
benzofuran natural products possess potent anticancer prop-
erties due to the modulation of the activity of the RNA
helicase eukaryotic initiation factor 4A (eIF4A) which is
involved in loading ribosomes onto mRNA templates during
Scheme 1. [3+2] Photocycloaddition approach to the cyclopenta[b]benzo-
furans.
translation initiation,
a step frequently deregulated in
cancer.[3] As a result of its unusual structure and important
transfer (ESIPT) of 3-HFꢀs. Photoirradiation of 4 affords
[*] Dr. S. P. Roche, Prof. Dr. J. A. Porco, Jr.
Department of Chemistry, Center for Chemical Methodology and
Library Development (CMLD-BU), Boston University
590 Commonwealth Avenue, Boston MA, 02215 (USA)
Fax: (+1)617-358-2847
the oxidopyrylium intermediate
6
which undergoes
[3+2] photocycloaddition with 5a to provide the correspond-
ing aglain core 7a which was converted into methyl rocaglate
(8a) in two steps (Scheme 1). Herein, we describe the scope
of the photocycloaddition with various dipolarophiles, mech-
anistic and photophysical studies, and evaluation of the
rocaglates produced as inhibitors of eukaryotic translation.
Although extensive photophysical studies concerning
ESIPT of 3-HF derivatives have been conducted,[6] the
reactivity of the resulting oxidopyrylium species (e.g., 6)
still remains largely unexplored.[7] We first examined achiral
photocycloadditions between 4 and 5a to study the role of
proton transfer in the ESIPT process. We initiated an
extensive screening of hydrogen-bond donors, Brønsted
acids, and additives to optimize the cycloaddition of 4 and
5a (08C, 12 h, l > 330 nm to avoid photodimerization[8] of 5a;
E-mail: porco@bu.edu
Dr. R. Cencic, Prof. Dr. J. Pelletier
McGill University, Department of Biochemistry and
The Rosalind and Morris Goodman Cancer Research Centre
Room 810, 3655 Drummond St., Montreal, QC, H3G 1Y6 (Canada)
Fax: (+1)514-398-7384
[**] Financial support from the National Institutes of Health (R01
GM073855) is gratefully acknowledged. We thank Professors R.
Johnson (UNH), F. D. Lewis (Northwestern University), and Dr.
Baudouin Gerard (Broad Institute) for extremely helpful and
stimulating discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003212.
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see the Supporting Information). Results of additive screen-
stabilization at the b position of the a,b-unsaturated ester (see
below). As the use of TFE as a cosolvent significantly
increases the population of oxidopyrylium species 6/6’ (see
Figure 2), less reactive dipolarophiles such as 5b–g were
found to participate in the photocycloaddition. Accordingly,
we were able to obtain novel cycloadducts including thioester
7b, imide 7d, Weinreb amide 7e, amide 7 f, and cyanide 7g in
moderate to good yields (Scheme 2). The use of
electron-withdrawing groups for LUMO (lowest unoc-
cupied molecular orbital) lowering of dipolarophiles
5b–g appears to impact the yield of the reaction (e.g.,
26% for 7d; 59% for 7g). Different reactivity was
observed for ethyl and phenyl thioesters 5b and 5c (7b
(40%) and 7c (0%), respectively, which was in
agreement with fluorescence quenching experiments;
see the Supporting Information), thus indicating that
steric factors may greatly influence photocycloaddi-
tions. Steric hindrance at the terminus of a,a-disub-
stituted dipolarophiles 5s–t may also be responsible
for their lack of reactivity in photocycloadditions
(Scheme 2, see inset). In contrast, the substitution
pattern of the aryl substituents (5h–r) appears to be
very flexible. Interestingly, the ortho substituent pres-
ent in 5j did not lead to favorable cycloaddition,
whereas the para-substituted dipolarophile 5k
afforded the desired aglain cycloadduct 7k (71%).
Other electronic effects for reaction partners (5k–r)
ing indicated that trifluoroethanol (TFE) improved both the
yield of the isolated cycloadduct 7a (55%) and endo/exo
diastereoselectivity (5:1 d.r.).[9] Protic polar solvents may
facilitate proton tunneling of the 3-HF excited state (N*),
thereby stabilizing and increasing the population of the
oxidopyrylium phototautomers (T*) 6/6’ (Figure 2).[6b–e]
Figure 2. Fluorescence emission of 3-HF (4) and 3-MF (9) indicating both
ESICT and ESIPT processes with presumed charge transfer (CT) in both excited
states from phototautomers 6/6’ and 6’’/6’’’. Light blue: 4 in CHCl3, orange: 4
in CHCl3/TFE (95:05), red: 4 in CHCl3/TFE (70:30), green: 4 in TFE, purple: 9
in TFE.
did not affect the course of the reaction, leading to
isolation of cycloadducts 8i–r.
Comparison of dipolarophile reactivity also
revealed new insights concerning the photocycloaddi-
tion diastereoselection. Unexpectedly, reaction of
cinnamate 5r bearing a free phenol gave an inverse
Indeed, excitation of 4 in the presence of TFE resulted in a
large ESIPT fluorescence emission band (l(T*) = 530 nm)
corresponding to oxidopyrylium phototautomers 6/6’. The
presence of a shoulder emission band (l(N*) = 440 nm) may
be attributed to excited-state intramolecular charge transfer
(ESICT) of 4 by superposition with the emission band of the
corresponding 3-methoxyflavone (3-MF; 9; Figure 2). After
excitation of 4, the normal excited form (N*) may undergo
charge transfer to stabilize the dipole moment developed
through ESICT, resulting in phototautomers 6’’/6’’’ and a
second l(N*) emission.[10] Our photophysical data indicates
that both excited-state phototautomers 6/6’ and 6’’/6’’’ gen-
erated by ESICT and ESIPT, respectively, are present upon
irradiation and may be of relevance in the photocycloaddi-
tion.
endo/exo diastereoselectivity (1:2 d.r.) of rocaglate 8r. In
comparison, cinnamate 5q lacking a free phenol led to the
formation of rocaglate 8q (2:1 d.r.) favoring the endo dias-
tereomer. Interestingly, reaction of dienoate 5h resulted in
complete chemo- and regioselectivity in the [3+2] photo-
cycloaddition for the a,b-unsaturated moiety with moderate
endo/exo diastereoselectivity (3:1 d.r.) to afford cycloadduct
7h (38%). Examination of the diastereoselectivity outcome
of rocaglate adducts 8k–m (from 2:1 to 5:1 to 10:1 d.r.)
revealed an interesting trend for the dipolarophiles. These
results suggest that electron-poor aryl substituents at the
b position of the cinnamate (Figure 3, 5m) may be involved in
donor–acceptor (p-stacking) interactions[12] with the electron-
rich aromatic ring of the oxidopyrylium 6 in the excited state,
thereby reinforcing substrate interactions in the endo transi-
Using the optimum reaction conditions (CHCl3/TFE =
70:30), we next turned our attention to evaluation of over
40 dipolarophiles (5) for their reactivity in the [3+2] photo-
cycloaddition. The set of dipolarophiles tested contained
cinnamate derivatives modified at both termini (commer-
cially available or readily prepared)[11] and unactivated
alkenes. We were pleased to find that a broad range of
dipolarophiles were workable in the photocycloadditions.
Unfortunately, all b-alkylacrylate derivatives proved to be
unreactive under the reaction conditions (yield < 10%),
likely as a result of the lack of positive charge or radical
Figure 3. Proposed endo transition-state arrangements from phototau-
tomers 6/6’ in the excited state with dipolarophiles 5m and 5o.
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Scheme 2. Scope of the [3+2] photocycloaddition to produce aglains 7a–r and rocaglates 8a–r (major diastereomer shown, d.r. obtained by
1H NMR). See the Supporting Information for details. TMS=trimethylsilyl, Tf=trifluoromethanesulfonyl.
tion state. The corresponding acceptor–donor interactions
may also be considered wherein the charged delocalized
oxidopyrylium phototautomer 6’ may interact with electron-
rich cinnamates (Figure 3, 5o).[12] An equilibrium between
phototautomers 6 and 6’ may explain the high diastereose-
lectivity observed for both electron-deficient (5l–m, 5–
10:1 d.r.) and electron-rich cinnamates (5i, 5o–p, 10:1 d.r.).
During our study, aglain derivative 7a was isolated as a
solid material, encouraging us to separate the major endo
diastereomer by crystallization.[13] Interestingly, the aglain
core was found to exist preferentially as a hydrated bridge-
head ketone (also observed for other aglain derivatives)
which may result from double hydrogen-bond stabilization of
the hydrate with the benzopyran ether oxygen atom and
tertiary hydroxyl (Figure 4).[14] Such stabilization highlights
the high degree of electrophilicity of the bridgehead ketone
and may be of importance for additional manipulations such
as stereocontrolled reduction to access aglain natural prod-
ucts including ponapensin 3.[2]
All aglain cycloadducts bearing a methyl ester moiety 7h–
r were readily converted into the corresponding rearranged
cyclopenta[b,c]benzofurans and additionally reduced to
afford the desired rocaglates 8h–r according to Method A
Figure 4. X-ray structure showing the hydrated form of aglain deriva-
tive 7a.
Scheme 3. Base versus Lewis acid mediated ketol rearrangements.
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(Schemes 2 and 3). As shown in Scheme 3 [Eq. (1)], alkaline
conditions[5] may be used to convert aglain 7a into alkoxide
11a which may undergo a-ketol rearrangement to afford
b-ketoester enolate 12a prior to workup and reprotonation to
afford cyclopenta[b]benzofuran 10a. Further reduction pro-
duced the desired rocaglates 8a in 62% yield (two steps).
Unfortunately, upon similar treatment aglain thioester 7b,
imide 7d, and amides 7e–f were found to undergo retro-
cycloaddition leading to regeneration of 3-HF 4 and the
corresponding dipolarophiles 5b–f [Scheme 2 and Scheme 3,
Eq. (2)]. Apparently the electron-poor thioester, amide, and
imide moieties of aglains 7b–f favored retro-cycloaddition
rather than the expected ketol rearrangement. Accordingly,
we evaluated alternative conditions for ketol rearrangement
and found that Lewis acids such as trimethylsilyltrifluorome-
thanesulfonate (TMSOTf) mediated the desired transforma-
tion and afforded the cyclopenta[b]benzofuran 8b after
protodesilylation and hydroxy-directed reduction [Scheme 2
and Scheme 3, Eq. (3)]. A Lewis acid mediated ketol shift
may occur through a concerted mechanism, thereby avoiding
retro-cycloaddition.[15] Hydrated ketone 7b may be silylated
by TMSOTf to afford hemiketal 13b, which may undergo
pinacol-type rearrangement[16] involving a [1,2]-aryl shift to
deliver the corresponding b-ketothioester. Using the
TMSOTf protocol, aglain thioester 7b, Weinreb amide 7e,
and amide 7 f were successfully rearranged and transformed
into rocaglates 8b, 8e, and 8 f, respectively (Scheme 2,
Method B). Notably, the Weinreb amide derivative 8d
could be prepared using both methods (Scheme 2, Meth-
od A: 20% yield (two steps); Method B: 46% (three steps)).
Despite our efforts, aglain imide 7d could not be rearranged
in a satisfactory manner. Finally, the aglain nitrile derivative
7g was readily converted into the desired rocaglate 8g by
treatment under alkaline conditions and subsequent reduc-
tion (Scheme 2, Method A).
Given the effectiveness of dipolarophiles bearing b-aryl
and related substituents, we next investigated trans-methyl-
styrene (5u) and trans-stilbene (5v) in the photocycloaddition
with 4 (see the Supporting Information for details). Use of 5u
as dipolarophile afforded a complex mixture of regioisomeric
and diastereoisomeric products. In contrast, when 5v was
employed in the [3+2] photocycloaddition, a clean reaction
was observed providing the aglain cycloadduct 7v in 40%
yield (Scheme 4). The structure of 7v was determined by
single-crystal X-ray structure analysis and indicated the
presence of a bridgehead ketone moiety.[13] The utility of
stilbene as dipolarophile and our results from the overall
dipolarophile screening suggest the involvement of the triplet
biradicaloid[17] form of phototautomer 6 in the photocycload-
dition.[18] Indeed, photocycloaddition of methyl cinnamate 5a
and 4 in the presence of the triplet quencher 9,10-dibromoan-
thracene did not lead to cycloadduct formation.[19] In another
experiment, addition of benzophenone (triplet sensitizer,
ET= 68.8 kcalmolÀ1) to the reaction between trans-stilbene
(5v) and 4 significantly increased the yield (from 40 to 56%)
of the cycloadduct 7v (see the Supporting Information), thus
supporting involvement of the photoexcited triplet biradical
14.[20] Based on our current studies, a radical ion mechanism
involving photoinduced electron transfer (PET) from the
Scheme 4. Use of stilbene 5v as dipolarophile in the [3+2] photo-
cycloaddition.
triplet excited state 14 to the dipolaraphile cannot be
excluded.[21] Treatment of aglain 7v under alkaline conditions
(Method A) did not effect ketol rearrangement. Under
TMSOTf conditions (Scheme 4, Method B), derivative 7v
smoothly rearranged to
a
mixture of cyclopenta-
[b,c]benzofuran isomers and silylated products. Protodesily-
lation of this mixture afforded an oxidized enone product
which was further reduced to rocaglate 8v.
Having an efficient access to various rocaglate derivatives
in racemic form, we evaluated their potencies as inhibitors of
eukaryotic translation in comparison to enantiopure silvestrol
2.[3b] When tested for potency in vitro, 6 out of 25 compounds
showed greater than 50% inhibition of translation at 10 mm,
all endo cycloaddition diastereomers (for a complete list of
derivatives tested and% inhibition see the Supporting
information). Titration of the six compounds (Figure 5a)
revealed that 8e and 8 f were the most potent inhibitors with
IC50 values within the range of 300–400 nm. Silvestrol 2
showed an IC50 value of approximately 100 nm in the same
experiment (Figure 5a). We further tested the potency of
these analogues for their ability to inhibit protein synthesis
in vivo (Figure 5b). In this case, hydroxymate 8e[22] was the
most potent analogue, inhibiting 85% of protein synthesis
over the course of an hour, similar to silvestrol 2.
Figure 5. Evaluation of rocaglate derivatives as inhibitors of eukaryotic
translation. a) Dose-dependent inhibition of in vitro translation.
b) In vivo inhibition of protein synthesis in HeLa cells by rocaglate
derivatives. See the Supporting Information for details.
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b) M. El Sous, M. L. Khoo, G. Holloway, D. Owen, P. J.
In conclusion, we have expanded the biomimetic ESIPT
photocycloaddition methodology to a broad range of dipolar-
ophiles and additionally validated the [3+2] photocycloaddi-
tion pathway for concise access to a range of aglain and
rocaglate structures. Evaluation of dipolarophiles revealed
that donor–acceptor interactions of phototautomers 6/6’ may
result in increased diastereocontrol. Our results also strongly
support that photocycloadditions may proceed via a photo-
excited triplet biradicaloid derived from 3-hydroxyflavone 4.
A pinacol-type rearrangement provided an alternative to the
base-mediated ketol shift protocol and enabled expedient
access to hitherto inaccessible rocaglate derivatives. Finally,
evaluation of rocaglates as inhibitors of eukaryotic translation
led to the identification of a modified rocaglate derivative
with potency similar to silvestrol 2 in vitro and in vivo.
Additional studies regarding ESIPT-mediated photocycload-
ditions and applications to complex molecule synthesis are
currently in progress and will be reported in due course.
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Received: May 27, 2010
Published online: August 4, 2010
Keywords: antitumor agents · biomimetic synthesis ·
.
cycloaddition · natural products · photochemistry
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