Bioinspired Total Synthesis of Bussealin e

Article abstract of DOI:10.1021/acs.orglett.8b00340

The first total synthesis of bussealin E, a natural product with a unique cycloheptadibenzofuran scaffold, is reported. A strategy inspired by a proposed biosynthesis was employed whereby a diphenylpropane derivative underwent an oxidative phenolic coupling to forge the tetracyclic ring system. The synthesis of the diphenylpropane featured a key sp²-sp³ Hiyama coupling between a vinyldisiloxane and a benzylic bromide.

Full text of DOI:10.1021/acs.orglett.8b00340

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Bioinspired Total Synthesis of Bussealin E
David G. Twigg, Leonardo Baldassarre, Elizabeth C. Frye, Warren R. J. D. Galloway,
and David R. Spring*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
S
* Supporting Information
ABSTRACT: The first total synthesis of bussealin E, a natural product with a unique cycloheptadibenzofuran scaffold, is
reported. A strategy inspired by a proposed biosynthesis was employed whereby a diphenylpropane derivative underwent an
oxidative phenolic coupling to forge the tetracyclic ring system. The synthesis of the diphenylpropane featured a key sp2−sp3
Hiyama coupling between a vinyldisiloxane and a benzylic bromide.
irst isolated in 2007 from the roots of the endemic
Malagasy plant Bussea sakalava, the bussealin natural
products consist of four diphenylpropanes (A−D) and a
cycloheptadibenzofuran (E, 1, Figure 1) which display
With such a biomimetic approach deemed attractive, our
retrosynthetic analysis focused on diphenylpropane species 2.
Using disconnections analogous to those employed in the
synthesis of bussealin A,2 it was anticipated that 2 could be
generated from the corresponding protected olefin 3, which we
F
Scheme 1. Proposed Biosynthesis (A) and Retrosynthesis
(B) of Bussealin E (1)
Figure 1. Bussealin natural products.
moderate antiproliferative activity against the A2780 human
ovarian cancer cell line (IC50 24−45 μM).1 More thorough
biological assessment has been hampered by insufficient
material, and expedient synthetic routes are required to
investigate this natural product family further. In light of this,
the first total synthesis of bussealin A was reported in 2012,
with biological profiling indicating similar low micromolar
levels of activity against two other cancer cell lines.2 Of the
other family members, bussealin E is notable for its unique
carbon skeleton, with no other reported natural product
bearing the same tetracyclic core. This structural novelty,
alongside the potential biological applications of this unex-
plored system, suggested bussealin E as a target for total
synthesis.
Noting that bussealin E was found alongside several
diphenylpropanes, Pan et al. proposed a biosynthetic route
featuring the oxidative cyclization and subsequent dehydration
of an appropriately substituted intermediate 2 (Scheme 1A).1
Received: January 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00340
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
envisaged accessing via an sp2−sp3 Hiyama coupling of
disiloxane 4 with benzyl bromide 5, a reliable and atom-
economical methodology previously developed in these
laboratories (Scheme 1B).2,3 It was anticipated that the
sequence of bromination, Sonogashira coupling, and hydro-
silylation would deliver the disiloxane 4 from symmetrical
tetraether 6, itself accessible in multigram quantities from
readily available 2,3,4-trimethoxybenzaldehyde 7 using estab-
lished protocols. The synthesis of bromide 5 from methyl
gallate 8 has been described previously.2
Scheme 3. Synthesis of Key Diphenylpropane 2
Synthetic efforts began with a Baeyer−Villiger oxidation of
aldehyde 7, followed by hydrolysis of the crude formate ester.
Subsequent oxidation of the intermediate phenol using ceric
ammonium nitrate on silica provided 2,3-dimethoxy-1,4-
benzoquinone 9 (Scheme 2). Reduction with NaBH4 and bis-
Scheme 2. Synthesis of Alkyne Intermediate 12
oxidants have previously been used to effect similar intra-
molecular cyclizations.7 However, no examples featuring a 1,4-
hydroquinone have been reported. Nevertheless, diphenylpro-
pane 2 was subjected to a range of conditions, including metal
salts such as MoCl5,8 SnCl4,9 VOF3,10 Pb(OAc)4,11 FeCl3,12
and the TMEDA complex of CuCl(OH);13 hypervalent iodine
species PhI(OAc)2 and PhI(O2CCF3)2;14 and the organic
oxidant, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).15 In
all cases, a complex mixture of products was obtained, with the
predominant species consistently observed by NMR analysis to
be acyclic benzoquinone 13 (arising from oxidation of the
corresponding 1,4-hydroquinone moiety of 2) and the
spirocyclic species 14, which exists as a 3:1 mixture in solution
with its hemiacetal isomer 15 (Scheme 4). Desired product 1
Scheme 4. Synthesis and Proposed Mechanism of Formation
of Bussealin E (1)
protection of the resultant hydroquinone with benzyl bromide
proceeded smoothly to furnish tetraether intermediate 6.
Bromination was achieved in a near-quantitative yield using
the conditions of Krishna Mohan et al. (Oxone, NH4Br)4 to
yield 10, which then underwent Sonogashira cross-coupling
with trimethylsilylacetylene and subsequent deprotection of the
silyl group to give the desired terminal alkyne 12 in a combined
63% yield. The Sonogashira coupling required relatively high
catalyst loadings (10 mol % Pd(PPh3)2Cl2 and CuI) and an
elevated temperature, possibly due to the electron-rich nature
of the aryl bromide 10. Intermediate purification of the
trimethylsilyl-protected alkyne 11 was also found to improve
the overall yield compared to a one-pot procedure which only
gave the desired product 12 in 44% yield from bromide 10.
Pt-catalyzed hydrosilylation of alkyne 12, as per the
conditions of Denmark et al.,5 generated the desired (E,E)
isomer of disiloxane 4 in excellent yield and geometric purity
(Scheme 3). Pleasingly, the key sp2−sp3 Hiyama coupling of
disiloxane 4 and benzyl bromide 5 (prepared in four steps from
readily available methyl gallate 8, see ref 2) proceeded in 80%
yield and with complete retention of the olefin stereochemistry,
with no evidence of the α isomer occasionally formed in such
reactions.6 Catalytic hydrogenation of 3 over palladium on
carbon then served to reduce the olefin and remove the four
benzyl ether protecting groups, generating the desired
tetraphenol species 2.
was only observed in trace amounts in some of these reactions,
as assessed by comparing the analytical HPLC traces of the
crude reaction mixtures against a reference sample of natural
bussealin E (kindly provided for analysis by Prof. D. Kingston,
Virginia Polytechnic Institute and State University). Of the
reagents evaluated, FeCl3 gave the most promising result in this
regard; further exploration of this oxidant was carried out by
varying temperature and reagent stoichiometry and including or
excluding an acidic additive. Gratifyingly, the use of FeCl3
adsorbed onto silica gel, as employed by Jempty et al.,16
With 2 in hand, investigation of the proposed oxidative
phenolic coupling toward bussealin E commenced. A range of
B
DOI: 10.1021/acs.orglett.8b00340
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
followed by heating with para-toluenesulfonic acid produced a
sufficient amount of bussealin E 1 to isolate an analytically pure
sample, albeit in a low yield. While further attempts to improve
this result were not successful, the 1H and 13C NMR spectra of
the synthetic material closely matched those previously
reported for the natural sample (see the SI), confirming its
identity.
ACKNOWLEDGMENTS
■
This research was supported by the EPSRC, BBSRC, MRC,
Wellcome Trust, and ERC (FP7/2007-2013; 279337/DOS).
D.G.T. thanks AstraZeneca for funding. D.R.S. acknowledges
support from a Royal Society Wolfson Research Merit award.
We thank Prof. D. Kingston (Virginia Polytechnic Institute and
State University) for providing a sample of authentic bussealin
E. Data accessibility: all data supporting this study are provided
as Supporting Information accompanying this paper.
The concomitant observation of the previously mentioned
byproducts 13 and 14 provides new insights into the possible
biosynthesis of bussealin E (1). These results suggest a
mechanism for the formation of 1 from 2 that proceeds via
intramolecular Michael addition of initially generated benzo-
quinone 13, with formation of the smaller 6-membered
spirocyclic ring (path b, Scheme 4) favored over that of the
7-membered carbocycle (path a, Scheme 4), as evidenced by
the reactions in this report. One previous publication
demonstrates a similar result for an analogous diphenylethane
system.17 When heated strongly in an acidic solution, an
isolated sample of compound 14 did not undergo any change,
with no observed rearrangement or retro-Michael reaction,
suggesting 14 exists as a thermodynamically stable species.
Alongside this observation, the low isolated yield of 1 may
suggest that the reaction relies on an enzyme-catalyzed process
when formed naturally in order to generate appreciable
quantities of the natural product.
In conclusion, we have completed the first reported synthesis
of the unique cycloheptadibenzofuran natural product,
bussealin E. The final intermediate in the synthesis,
diphenylpropane 2, was prepared in 11 steps, in its longest
linear sequence, in an overall 14% yield, featuring a key sp2−sp3
Hiyama coupling between a vinyldisiloxane and a benzylic
bromide. The final bioinspired cyclization to deliver bussealin E
only proceeded in low yield, with the observed byproducts
suggesting a mechanism that proceeds via Michael addition of
the initially formed 1,4-benzoquinone 13 with selectivity for the
undesired 6-membered ring as seen in compound 14. This low
yield could suggest that the reaction relies on an enzyme-
catalyzed process when formed naturally. With a route to
bussealin E determined, further synthetic studies and biological
evaluation of this novel scaffold are underway and will be
reported in due course.
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* Supporting Information
The Supporting Information is available free of charge on the
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Experimental details and characterization data for all
1
products including H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: spring@ch.cam.ac.uk.
ORCID
David R. Spring: 0000-0001-7355-2824
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.8b00340
Org. Lett. XXXX, XXX, XXX−XXX