A palladium-mediated cascade cyclisation approach to the CDE cores of rubriflordilactone A and lancifodilactone G

Article abstract of DOI:10.1039/b814360a

Palladium-mediated cascade cyclisation reactions have been applied to the synthesis of the CDE-ring cores of two anti-HIV natural products, rubriflordilactone A and lancifodilactone G. The Royal Society of Chemistry.

Full text of DOI:10.1039/b814360a

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A palladium-mediated cascade cyclisation approach to the CDE cores
of rubriflordilactone A and lancifodilactone Gwz
Marie-Caroline A. Cordonnier,a S. B. Jennifer Kanb and Edward A. Anderson*ab
Received (in Cambridge, UK) 22nd August 2008, Accepted 17th September 2008
First published as an Advance Article on the web 2nd October 2008
DOI: 10.1039/b814360a
Palladium-mediated cascade cyclisation reactions have been
applied to the synthesis of the CDE-ring cores of two anti-HIV
natural products, rubriflordilactone A and lancifodilactone G.
steps, E : Z = 6.5 : 1). Although intramolecular bromoene-
diyne cyclisations have precedent in the elegant work of the
groups of Negishi and de Meijere,9 they have rarely been
applied to substrates containing a 7-membered tether, and
certainly not in natural product total synthesis.10 We were
therefore pleased to find that treatment of 9 with Pd(PPh3)4 in
acetonitrile in the presence of triethylamine (the conditions of
de Meijere)10 effected smooth cyclisation to the tricycle 5
(77%).
Lancifodilactone G1 (1, Fig. 1) and rubriflordilactone A2 (2)
are two members of a growing family of natural products
isolated by Sun and co-workers from Chinese herbal plants of
the Schisandra genus. They are characterised by highly oxyge-
nated, complex fused-ring architectures, and many have been
found to possess anti-HIV activity (e.g. EC50 = 95 mg mLꢀ1
for lancifodilactone G). This disease affects some 33 million
people worldwide, and causes around 3 million deaths each
year,3 yet there remains no cure. The discovery of new
candidates for drug development is thus of great importance.4
We recently reported a versatile palladium-mediated cascade
cyclisation5 which accesses bi- and tricyclic fused ring systems
using the combined efficiency of organopalladium and pericyclic
processes.6 This reaction was in fact inspired by consideration of
approaches to the challenging fused ring skeletons found in the
Schisandra natural products. We envisaged these could be
formed via a common strategy,7 involving single-step construc-
tion of the 7,8- or 7,6-fused CD rings, with simultaneous
appendage of a 5-membered E-ring. We report here the realisa-
tion of this strategy to prepare the CDE-cores of both natural
products (e.g. 3 and 4, Fig. 1), together with the observation of
unusual pericyclic cascades.
Satisfied that 7,6,5-fused ring formation could indeed be
achieved, we next examined installation of the D-ring oxygen
of rubriflordilactone A. It seemed that this might be intro-
duced through Tamao–Fleming oxidation11 of a suitable
arylsilane, which would in turn require the preparation of
the corresponding silyl alkyne. The dimethylisopropoxysilyl
group was selected, as it was anticipated to be sufficiently
stable for handling as the silyl alkyne, but also susceptible to
oxidation once it had been converted to the arylsilane.
This route commenced with oct-4-yn-1,8-diol 10, prepared in
three steps from 1,4-butynediol according to a literature pro-
cedure.12 10 was oxidised to give a dialdehyde, which was
prone to degradation under prolonged storage. However, if
used immediately and without purification, this aldehyde
underwent a moderate-yielding mono-olefination to the corres-
ponding enoate;8 subsequent addition of the lithium anion of
dimethylisopropoxysilyl acetylene13 to the remaining aldehyde
led to the allylic alcohol 11 (89%). To circumvent the problems
of the low yielding HWE, we were also able to employ an
alternative strategy involving mono-protection of diol 10,
which led to alcohol 11 in six steps.14
Our approach to the rubriflordilactone core targeted two
CDE-skeletons (4 and 5, Scheme 1), which would be formed
using a fully intramolecular cascade cyclisation of appropriate
bromoenediynes. The first of these (tricycle 5) was designed to
evaluate the efficiency of the cyclisation reaction to prepare
7,6,5-cores. The synthesis of 5 commenced with the mono-
silylation of 1,6-hexadiyne, followed by lithiation and addition
to aldehyde 6 to give alcohol 7. Following protecting group
and oxidation state manipulation,
a Ba(OH)2-mediated
Horner–Wadsworth–Emmons (HWE) olefination8 delivered
enoate 9, the cascade cyclisation substrate (81% over four
a Chemistry Research Laboratory, University of Oxford, 12 Mansfield
Road, Oxford, UK OX1 3TA.
E-mail: edward.anderson@chem.ox.ac.uk; Fax: +44 1865 285002;
Tel: +44 1865 285000
b Department of Chemistry, Lensfield Road, Cambridge, UK
CB2 1EW. Fax: +44 1223 336362; Tel: +44 1223 336300
w Dedicated to Prof. Andrew B. Holmes on the occasion of his 65th
birthday.
z Electronic supplementary information (ESI) available: Preparation
and characterisation of key intermediates and products, and selected
1H and 13C NMR spectra. See DOI: 10.1039/b814360a
Fig. 1
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Treatment of bromoenyne 14 with this stannane under our
standard reaction conditions (PdCl2(PPh3)2, toluene, reflux)
led not to the expected CDE rings, but to a mixture of two
compounds. The first was identified as the 7,6,4,5 tetracycle 15,
which had arisen from a cascade 8p/6p-electrocyclisation, a
rather surprising result given that the previously prepared
7,8-bicycles had not undergone this secondary 6p-process
(although we had observed a similar outcome from a related
5-membered ring substrate).6 This process is likely driven by
rearomatisation of the furan ring upon 6p-electrocyclisation of
the intermediate cyclooctatriene,15,17 despite the inevitable
increase in ring strain. The second product was identified as
the isomeric triene 1618 which, in keeping with our previous
observations, seemed to have arisen from isomerisation of an
intermediate palladium species. The ratio of 15 and 16
varied,19 but was typically around 1 : 1 (60% yield).
We next examined the cyclisation of enone 17, which
contains functionality more relevant to our strategy towards
lancifodilactone G. Again, varying ratios of tetracycle 18 and
tetraenylfuran 19 were isolated (typically ratios of 18 : 19,
1 : 1–3 : 1), with the nature of the catalyst seeming to play an
important role.
The degree of isomerisation (to give 19) was rather surprising
given the rate of reaction (o2 h) and relative ease with which
furanylstannanes undergo transmetallation, which we would
have predicted to lead to little isomerisation based on our
previous work. Theorising that the bulk of the palladium
ligand sphere and/or the rate of transmetallation might affect
the degree of isomerisation, we repeated the reaction using
ligand-free conditions (Pd(OAc)2). This resulted in almost
exclusive formation of the tetracycle 18 (55%), with very little
of the isomer 19 being detected.
Scheme 1
With 11 in hand, the key cascade cyclisation was attempted.
Pleasingly, the use of identical cyclisation conditions gave the
pentasubstituted 7,6,5-core 12 in 66% yield. In addition, we
were able to validate the use of the dimethylisopropoxysilyl
group as a masked phenol, as it was smoothly oxidised to the
fully functionalised CDE core 4 of rubriflordilactone A under
standard Tamao conditions (74%).
On several occasions, 19 could be isolated as the sole
product (70–92%). Although this was also not a consistent
result, it permitted a definitive confirmation of the undesired
geometry of the tetrasubstituted olefin using NOE experi-
ments.18 Further heating of this tetraene in toluene (in the
presence or absence of Pd catalyst) led to no further reaction.
However, a report by van Leusen on electrocyclisations of
4-nitropyrroles20 prompted us to test higher boiling solvents,
and we were pleased to find that heating pure tetraene 19 in
triglyme at 205 1C for 2 h led to complete consumption of
Our approach to the 7,8,5-CDE core of lancifodilactone
G
called for a cascade cyclisation terminating in an
8p-electrocyclisation.15 In the course of methodology
development, we had already prepared 7,8-fused bicyclic ring
systems via cascade cyclisation,6 and now sought to annulate an
additional ring through coupling with a cyclic (furanyl) stannane.
Towards this end, stannane 13 (Scheme 2) was prepared in two
steps from commercially available 3-furaldehyde, via directed
lithiation/stannylation using Comins’ protocol,16 and Wittig
olefination (65%, 2 steps).
Scheme 2
Scheme 3
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starting material (Scheme 3). Three inseparable products were
isolated (85%, 1 : 1 : 1): tetracycle 18, the remarkable hexa-
cycle 20, and the 7,8,5-tricycle 21. Hexacycle 20 likely arises
from an initial 6p-electrocyclisation to form a spirocyclic
7,6-ring system 22, which then undergoes an intramolecular
Diels–Alder reaction with the proximal exo-methylene group,
again driven by restoration of aromaticity to the furan. This
mode of cascade cyclisation was initially discovered by
Marvell et al.,21 and has undergone a revival in the context
of the pyrone-polypropionate natural products.22 The forma-
tion of tetracycle 18 and tricycle 21 (the latter containing the
targeted lancifodilactone CDE core) can be rationalised by an
initial thermal isomerisation of 19, followed by 8p-cyclisation;
the intermediate cyclooctatriene then undergoes either
6p-cyclisation to give 18, or a 1,5-hydride shift to tricycle 21.23
Although interesting from the viewpoint of construction of
unusual molecular skeletons, these side reactions are not pro-
ductive in terms of efficient synthesis of the natural product core.
We recognised that their driving force (rearomatisation of the
furan) could be removed through use of the dihydrofuran
analogue of stannane 13. To this end, stannane 23 (Scheme 4)
was prepared in three steps from the known methyl ester 24,24
via DIBALH reduction, reoxidation (TPAP/NMO)25 and Wittig
olefination (60%). With 23 in hand, the crucial cyclisation was
re-examined. This time, to our delight, the desired 7,8,5-tricycle
25 could be isolated cleanly (62%), although transmetallation of
the dihydrofuranyl stannane 23 was markedly slower than 13,
requiring catalytic copper(I) iodide. This reaction completes the
7,8,5-CDE core of lancifodilactone G for the first time.
Notes and references
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Scheme 4
In conclusion, we have prepared the highly functionalised
CDE cores of the natural products rubriflordilactone A and
lancifodilactone G, the latter featuring a 7,8,5-fused ring
system ripe for further functionalisation. In the course of this
work, we also observed three remarkable rearomatisation-
driven pericyclic processes, leading to the formation of poly-
cylic ring systems. Ongoing studies towards advanced syn-
thetic intermediates and total syntheses of these intruiging
natural products will be reported in due course.
We thank the EPSRC (Advanced Research Fellowship to
E. A. A.; EP/E055273/1) and the Royal Society for financial
support. We also thank Prof. Ian Paterson (University of
Cambridge) for helpful discussions and the generous provision
of laboratory space and chemicals for preliminary experiments.
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