A biomimetic approach towards phorone sesterterpenoids

Article abstract of DOI:10.1039/c9ob00745h

We report an investigation towards a unified total synthesis of the Korean sponge derived sesterterpenoids, phorones A (1) and B (2), via a biomimetic strategy. This work has established a new synthetic strategy to the parent ansellane sesterterpenoid ske

Full text of DOI:10.1039/c9ob00745h

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A biomimetic approach towards phorone
sesterterpenoids†
Cite this: DOI: 10.1039/c9ob00745h
Harry J. Shirley
and Christopher D. Bray
*
Received 1st April 2019,
Accepted 15th May 2019
DOI: 10.1039/c9ob00745h
rsc.li/obc
We report an investigation towards a unified total synthesis of the further signifies trapping of the putative tertiary carbocation
Korean sponge derived sesterterpenoids, phorones A (1) and B (2), with either a γ-hydroxycyclohexenone or exogenous acetate.
via a biomimetic strategy. This work has established a new syn- The parent ansellane skeleton is devoid of the C8-19 bridge
thetic strategy to the parent ansellane sesterterpenoid skeleton and so alternative nomenclature for the phorane skeleton is
with unanticipated diversion to a biogenetically related pathway.
8β-19-cycloansellane.
In the present work we have investigated a biomimetic syn-
thesis of the phorone isoprenoids in order to elucidate key
events in their biogenesis, confirm their assigned relative
stereochemistry and assist future structure–activity relation-
ship studies.
Introduction
Phorones A (1) and B (2) are isoprenoid natural products and
constitutional isomers which bear the unprecedented tetra-
cyclic phorane carbon skeleton. Phorone A (1) was extracted
from a sample of the marine sponge Phorbas sp. collected off
the coast of Korea, and reported in 2012 by Nam, Kang and
their co-workers.1 More recently, the isolation of phorone B
(2), which exhibits anti-cancer activity, was reported in 2015 by
Woo et al.2 from the Korean marine sponge Clathria gomba-
wuiensis. While isolated from two distinct genera of sponge,
the phorones are likely derived from a common biogenesis
related to that of a large family of bioactive sesterterpenoids:
encompassing the phorbaketals (6),3 alotaketals (7)4 and ansel-
lones (8, 9)5 (Scheme 1) as well as the gombaspiroketals,6 phor-
basones7 and isophorbasones1 whose isolations have spawned
multiple total synthesis efforts over recent years.8
Results and discussion
In light of their proposed biogeneses, our retrosynthetic ana-
lysis of phorones A (1) and B (2) (Scheme 2) began with discon-
nection of the key C8–C19 bond bridging the decalin and aro-
matic systems.
A key proposed biogenetic step in the formation of the
phorane skeleton from geranylfarnesyl pyrophosphate (3)
involves intramolecular cyclization of the ansellane tertiary
carbocation 5 via electrophilic aromatic substitution of the
tethered phenol to give para- and ortho-adducts, as 1 and 2
respectively. Of note is the resulting stereochemical relation-
ship between the seven-membered ring and drimane bicycle,
since cis-annulation has not previously been reported. The iso-
lation and structural assignments of ansellones B (8) and C (9)
The School of Biological and Chemical Sciences, Queen Mary University of London,
Mile End Road, London, E1 4NS, UK. E-mail: c.bray@qmul.ac.uk
†Electronic supplementary information (ESI) available. CCDC 1043793 and
1043794. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c9ob00745h
Scheme 1 Proposed biogeneses of phorones and ansellones (OPP =
pyrophosphate).
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unfavourable steric interactions between the axial methyl
groups and the peracid. Following this, the epoxide 19 was
reductively ring-opened using Red-Al in refluxing PhMe, to
allow regiospecific formation of the desired 1,3-diol in quanti-
tative yield (1,2-diol product was not observed) to give the triol
20. The primary alcohol of triol 20 was selectively oxidised, in
preference to the secondary and tertiary alcohols, using PhI
(OAc)2 with catalytic TEMPO, to the aldehyde 21. The structure
of the aldehyde 21 was confirmed by X-ray crystallographic
analysis (Fig. 1, see ESI†) revealing the syn-relationship
between the tertiary alchohol and the potentially epimerizable
aldehyde, with the remaining secondary alcohol on the oppo-
site face of the decalin system.
Scheme 2 Retrosynthetic analysis of phorones A (1) and B (2).
Following 8 synthetic steps without the need for protecting
groups, silylation of the secondary and tertiary alcohols using
standard silyl chloride and base combinations returned start-
ing material only, perhaps reflective of a sterically demanding
environment. However, rapid trimethylsilylation of both alco-
hols was achieved using TMSOTf to give the aldehyde 22 (cf.
14) which was used to probe the envisaged coupling with the
appropriate vinyl metal species.
This gave synthon 10 which would enable trapping of the
tertiary carbocation via electrophilic aromatic substitution of
the phenol at the ortho- or para-positions to give 1 or 2 respect-
ively. We anticipated that a mixture of regioisomers may form
from this step. The formation of such a carbocation intermedi-
ate 10 could be achieved by treatment of a tertiary alcohol or
acetate 11 with Lewis- or Brønsted acid. Construction of the
ansellane skeleton 12 was planned to proceed via coupling of
the (Z)-haloalkene 13 with the drimane aldehyde 14 by way of
a halogen-metal exchange/electrophile trapping process.9 The
(Z)-haloalkene 13 would in turn be accessed by halo-olefina-
tion of a suitable acetophenone.
The synthesis of a drimane aldehyde such as 14 com-
menced by treatment of commercially available β-ionone with
NaH in the presence of dimethylcarbonate to give the ester 15,
which could be accessed in >20 g. Photochemically-mediated
cyclisation of the ester 15 gave enone 16 (Scheme 3).10
Enone 16 was then readily converted to the diol 18 in three
steps by reduction with LiAlH4, allylic alcohol oxidation and
then nucleophilic addition using an excess MeLi.9 Diol 18 was
then oxidised with m-CPBA to give the epoxide 19 as a single
diastereomer. The stereochemistry of the epoxide 19 was con-
firmed by X-ray crystallographic analysis (see ESI†). The
observed non-chelation controlled diastereofacial selectivity
anti to the pendant tertiary alcohol may be a consequence of
The synthesis of a (Z)-haloalkene fragment such as 13
began with aromatic nitration of commercially purchased
4-methylacetophenone using HNO3/H2SO4 to nitro compound
23 and hydrogenolysis of the nitro group to an aniline inter-
mediate, before diazotisation and in situ hydrolysis finally gave
phenol 24.11 O-Protection of 24 as the tert-butyldimethlsilyl
ether using TBSCl in the presence of imidazole gave the silox-
yacetophenone 25 (Scheme 4). There are scarcely any methods
for the halo-olefination of acetophenones. Indeed, the use of
standard halogenated Wittig and Horner–Wadsworth–
Emmons reagents in combination with a range of bases was
initially investigated but this resulted in either the return of
starting materials or the observed formation of only traces of
suspected alkenes. Of the few known methods for such a trans-
formation we investigated a three-step process firstly reported
by Barluenga12 and later modified by Ando.13 Treatment of
acetophenone 25 with dibromomethyl lithium, formed
through deprotonation of CH2Br2 with LiNi-Pr2, facilitated con-
version to alcohol 26. The tertiary alcohol of 26 was then pro-
tected as the trimethylsilyl ether using TMSCl in the presence
Scheme 3 Synthesis of drimane aldehyde 21.
Fig. 1 ORTEP image of aldehyde 21.
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Scheme 6 Attempted oxidation of allylic alcohol 29.
temp for 72 hours we observed that alcohol 29 degraded to a
complex mixture. Isolation of the major degradation product
was achieved and after thorough spectroscopic analysis identi-
fied as ansellane diene 30, bearing a 1,3-diene motif. This see-
mingly labile transformation involved elimination of the sec-
ondary alcohol. It was suggested that this process may reflect a
sterically demanding environment of the alcohol, whose elim-
ination is thermodynamically favoured, furthermore with
extended π-conjugation. It was interesting to observe a similar
1,3-diene moiety in the biosynthetically related ansellone C (9)
(which was reported five months after our synthesis of 30). We
hypothesise that the 1,3-diene moiety may be acquired in
nature through an analogous deoxygenative elimination process.
After this set-back, storage of the ansellane alcohol in a
−30 °C freezer and using within 3/4 days allowed a short inter-
val for probing of oxidation of the allylic alcohol 29 to enone
31. To our surprise the oxidation of the secondary alcohol
could not be achieved using any conventional methods (Dess-
Martin’s periodinane, MnO2, IBX and PhI(OAc)2/TEMPO),
returning starting material only. It was found that Swern oxi-
dation assisted degradation to a mixture of products of a vir-
tually identical composition to that previously observed upon
storage of 29 at room temperature (Scheme 6).
Scheme 4 Synthesis of (Z)-bromoalkene 28.
of imidazole, to give gem-dibromide 27. Finally, treatment of
27 with n-BuLi gave an isomeric mixture of bromoalkenes (Z)
and (E)-28 in a 1.3 : 1.0 ratio respectively. These apolar bro-
moalkenes were separated by careful column chromatography
on standard silica gel, although this essential separation
(which could not be achieved using basic alumina or other
non-acidic stationary phases) resulted in apparent loss of large
amounts of material through degradation during elution. The
stereochemistry of each isolated alkene isomer was determined
by NOESY experiments (see ESI†).
Having achieved the synthesis of drimane aldehyde 22 and
(Z)-bromoalkene 28, work was focused upon their convergence
(Scheme 5). Treatment of (Z)-28 with t-BuLi at −78 °C caused
bromine–lithium exchange to form an organolithium species,
to which drimane aldehyde 22 was added. The ansellane
alcohol 29 was isolated as a single diastereomer. The stereo-
chemistry of the secondary alcohol was not determined as it
would be oxidised to a ketone in the next step. Retention of
the crucial Z-alkene was confirmed through a NOESY experi-
ment (see ESI†). This point denotes a new chemical synthesis
of the novel ansellane skeleton. Following storage at room
Conclusions
These synthetic accomplishments leading to ansellane alcohol
29 and ansellane diene 30 provide novel chemical syntheses of
the important ansellane sesterterpenoid skeleton. Key steps
include diastereofacial selective epoxide installation to 19 and
subsequent reductive epoxide opening to 20, before t-BuLi-
mediated addition of (Z)-bromoalkene 28 to aldehyde 22. This
work will provide valuable guidance for future total synthesis
endeavours of phorone, ansellone and related natural pro-
ducts, in which we anticipate sustained interest. The labile
transformation of ansellane alcohol 29 into ansellane diene 30
has shed some light on the biogenesis of this family of sester-
terpenoids, and may provide guidance to related future syn-
thetic endeavours.
Conflicts of interest
Scheme 5 Synthesis of ansellane alcohol 29 and diene 30.
The authors have no conflicts to declare.
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Acknowledgements
We thank Queen Mary University of London and the
Engineering & Physical Sciences Research Council for a DTA
studentship (EP/J50029X/1) (HJS). We thank the Engineering &
Physical Sciences Research Council UK National Crystallography
Service at the University of Southampton for the collection of
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