An efficient oxidative dearomatization-radical cyclization approach to symmetrically substituted bicyclic guttiferone natural products

Article abstract of DOI:10.1039/c0cc01419b

Detailed in this communication is an efficient synthetic approach towards the guttiferone family of natural products. Oxidatively unraveling a para-quinone monoketal followed by consecutive 5-exo radical cyclizations provides the bicyclic core. An additional strength of this approach is a late stage asymmetric desymmetrization of an advanced symmetric intermediate.

Full text of DOI:10.1039/c0cc01419b

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An efficient oxidative dearomatization–radical cyclization approach to
symmetrically substituted bicyclic guttiferone natural productswz
Nicholas A. McGrath, Joshua R. Binner, Georgios Markopoulos, Matthew Brichacek and
Jon T. Njardarson*
Received 14th May 2010, Accepted 18th June 2010
DOI: 10.1039/c0cc01419b
Detailed in this communication is an efficient synthetic approach
towards the guttiferone family of natural products. Oxidatively
unraveling a para-quinone monoketal followed by consecutive
5-exo radical cyclizations provides the bicyclic core. An addi-
tional strength of this approach is a late stage asymmetric
desymmetrization of an advanced symmetric intermediate.
[3.3.1] bridged bicyclic core had been reported in the last
twenty years since the first such member was reported (gutti-
ferone A).7 The only structural differences between members
of this remarkable family are the substitution of two adjacent
stereocenters (C5 and C6), minor variations with respect to the
degree of oxidation of the benzoyl group and the absolute
configuration of the desymmetrized core (Fig. 2).
A closer look at the published data for these eight com-
pounds reveals that although there are four possible arrange-
ments for each C5/C6 substitution pattern for each
enantiomeric series, it seems nature always prefers to place
the two large groups (geranyl and prenyl) trans to each other.
Guttiferone A is the only member of this natural product
stereochemical library whose absolute configuration has been
unambiguously established.8 The data suggest that guttiferone
A and I1 belong to the same enantiomeric series9 and that the
other six (guttiferones I2, J, K, L, G and garcicowin B) natural
products belong to the opposite one.10 The latter six structures
are remarkably similar, differing only in oxygenation of the
benzoyl group and whether there is a prenyl or geranyl group
at the C6-position.
In recent years a vast number of bridged bicyclic polypreny-
lated acylphloroglucinol natural products have been re-
ported.1 Perhaps the most famous member of this family of
natural products is hyperforin, which is one of the main
chemical constituents of the commonly used natural remedy
St. John’s wort and has in recent years shown promise as a
potential anticancer agent.2 We have in the last few years
established a research program focused on synthesizing and
evaluating unique bridged bicyclic natural product anti cancer
agents. The bridged phloroglucinol family drew our attention
early on, but the catalyst for launching a synthetic program
towards their synthesis was a report detailing the sirtuin
inhibitory activity of hyperforin and guttiferone G (Fig. 1).3
The sirtuins are considered high value targets for developing
new anticancer agents and gaining more insight into improv-
ing longevity.4 Not surprisingly, there is great interest in
finding small molecule inhibitors, which selectively block the
function of any of the seven known enzymes of the sirtuin
family (SIRT1-7).5
Although this unique natural product collection has never
been tested as one, each member has been shown to
exhibit promising anti-cancer activity ranging from general
cytotoxicity10,11 to potential as protease inhibitors,12
antiapoptotic13 or antiproliferative agents.10 In addition,
several studies have been reported on their various specific
biological functions beyond cancer.9,14 As stated above, we are
most excited about the sirtuin inhibitory activity of guttiferone
G3 and to learn how the other seven members of this family
compare. Such a study would provide important SAR clues on
the relative importance of the C5, C6 or benzoyl substitutions
on sirtuin inhibition.
Hyperforin and guttiferone G share many structural simila-
rities in addition to the common bridged bicyclic trione core,
neither natural product has been synthesized to date.6 In our
minds the most attractive difference is the bis-prenyl bridge-
head substitution of guttiferone G, which means that the fully
substituted trione part of the molecule is symmetrical.
This local symmetry opens the door for exciting synthetic
designs and more importantly for late introduction of chir-
ality. By inspecting the literature for other such structures we
chose to limit our search only to compounds containing
stereocenters at both C5 and C6, similar to that found in both
guttiferone G and hyperforin. In doing so we excluded a fair
number of symmetrically substituted compounds containing
the more common C5 gem-dimethyl substitution pattern. Our
search revealed that eight guttiferones sharing a symmetrical
Our retrosynthetic analysis is presented in Scheme 1. It relies
on the late stage desymmetrization of 2, which we envision
could be converted to all eight targeted natural products by
proper choice of reagents. This intermediate is rapidly
accessed via tandem 5-exo radical cyclizations (3) enabled by
Department of Chemistry and Chemical Biology, Baker Laboratory,
Cornell University, Ithaca, NY, USA. E-mail: jn96@cornell.edu;
Fax: +1 607 255 4137; Tel: +1 607 254 5035
w Electronic supplementary information (ESI) available: Experimental
section and spectroscopic data. See DOI: 10.1039/c0cc01419b
z This article is part of the ‘Emerging Investigators’ themed issue for
ChemComm
Fig. 1 Guttiferone G and hyperforin.
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Fig. 2 Guttiferones containing locally symmetrical bicyclic cores.
Scheme 2 Synthesis of the bridged bicyclic core of the guttiferones.
would force the two radicals to be on the same face, which is
critical for accessing the bicyclic motif. This logic flows well
with our synthetic design because an oxygenated phenacyl
group happens to reside in this exact position on the
guttiferones. Towards that end, diester 6 was alkylated (11)
and reduced to diol 12. Bromination of the bis-neopentyl
alcohols was accomplished in two steps to give 13. Selective
deprotection of the methyl ether was eventually accomplished
using B(C6F5)3 in the presence of triethylsilane.17
Scheme 1 Guttiferone G retrosynthesis.
oxidative dearomatization of a strategically functionalized
para-hydroquinone, which in turn is assembled from phenol
415 and malonate derivative 5.
Our synthetic efforts commenced with known diallyl ether 4,
which is readily accessible from 4-methoxy phenol (Scheme 2).
The free phenol was alkylated with diethyl 2-bromomalonate
(5) to afford 6. The esters were converted into bromomethyl
groups (7) following standard procedures. Selective deprotec-
tion of the methyl capped phenol was accomplished using BCl3
and hypervalent iodine mediated oxidative dearomatization
yielded the desired dienone acetal radical cyclization precursor
8. Despite discouraging literature precedents,16 which sug-
gested preferential formation of 9 over 10 we decided to test
the tandem 5-exo/5-exo radical cyclization thesis. Cyclization
proceeded smoothly and selectively, affording only ketal 9 and
not even trace amounts of bridged bicyclic ketal 10. We argued
that placing a large group in between the two radical sites
Dearomatization proceeded uneventfully to produce ketal
15, which gratifyingly cyclized to form the desired symmetrical
bridged bicyclic product 16 as the only product. Cross meta-
thesis of 16 with 2-methyl propene gave bis-prenylated 17.18
To test the facial selectivity in the alkylation of the bicyclic
ketone 17, the enolate generated with LHMDS was trapped as
the silyl ether. Treatment with MeLi and MeI resulted in
exclusive methylation from the exo-face (18). This stereoselective
alkylation lends promise to our stated goal of being able to
access any member of this natural product class by changing
the order of the alkylation sequence.
In order to explain the profound reversal of selectivity in the
cyclization of 8 and 15, we performed density functional
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Notes and references
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Scheme 3 Rationalization of stereochemical outcome.
Table 1 Asymmetric desymmetrization of ketone 17
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Base
Additive
Temp (1C)
Yield (%)
dr
LHMDS
—
—
LiCl
LiCl
LiCl
ꢁ78
ꢁ78
85
87
83
75
72
1.1 : 1
3 : 1
10 : 1
1 : 6
3 : 1
(R,R)-Amide
(R,R)-Amide
(S,S)-Amide
(R,R)-Amide
ꢁ78
ꢁ78
ꢁ100
theory calculations (UB3LYP 6-31G(d)). The two possible
transition states for the first radical cyclization were found and
the more stable in each case (21 and 23) is depicted in
Scheme 3. We see that in the case of R = H, the transition
state having the methylene bromide on the exo face is pre-
ferred by 2.8 kcal molꢁ1. Alternatively with R = Bn, steric
interactions with the benzyl group force it to the less hindered
exo face and the methylene bromide to the endo which is
competent for further cyclization.
In order to assess our ability to carry out a late-stage
desymmetrization to access either enantiomeric series of the
guttiferone family, we employed chiral amide bases (Table 1).
The asymmetry in the deprotonation was determined by
trapping the enolate as a Mosher ester. Both enantiomers of
the enolate were trapped to give the corresponding diastereo-
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In conclusion, we have developed an efficient approach to
this exciting class of natural products that takes advantage of
the inherent local symmetry present in the bicyclic structure.
The complex core was accessed by employing a unique double
radical cyclization of a p-quinone ketal derived from a simple
aromatic precursor. The shape of the molecule controls the
facial selectivity during the ketone alkylation and the use of a
chiral amide base provides access to either enantiomeric series.
We gratefully acknowledge the NIH for a CBI training
grant (T32GM008500 to NAM and MB), NIH-NIGMS
(RO1 GM086584) and most recently an ARRA administrative
supplement to RO1 GM086584.
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Chem. Commun., 2011, 47, 209–211 | 211