Stereospecificity in the Au-catalysed cyclisation of monoallylic diols. Synthesis of (+)-isoaltholactone

Article abstract of DOI:10.1039/c1cc11805f

We describe a concise synthesis of (+)-isoaltholactone via a Au-catalysed cyclisation of a monoallylic diol to form the tetrahydrofuranyl ring. Analogous cyclisations show that the stereochemical outcome is dictated by the stereochemistry of the diol substrate.

Full text of DOI:10.1039/c1cc11805f

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Stereospecificity in the Au-catalysed cyclisation of monoallylic diols.
Synthesis of (+)-isoaltholactonew
William P. Unsworth,a Kiri Stevens,a Scott G. Lamontb and Jeremy Robertson*a
Received 30th March 2011, Accepted 25th May 2011
DOI: 10.1039/c1cc11805f
We describe a concise synthesis of (+)-isoaltholactone via
a Au-catalysed cyclisation of a monoallylic diol to form the
tetrahydrofuranyl ring. Analogous cyclisations show that the
stereochemical outcome is dictated by the stereochemistry of
the diol substrate.
towards P388 cells.2 Thirteen years after the first report of
(+)-altholactone, the diastereomer (+)-isoaltholactone 5 was
described as an isolate from combined extracts of Goniothalamus
malayanus, G. montanus, and G. tapis.6 Both compounds may be
considered6 to be biosynthesised by 5-endo cyclisation7 of the
epoxides 2 and 3 which, in turn, could arise from oxidation of
either face of 5-hydroxygoniothalamin (1). With one exception8i
the syntheses8 of (+)-isoaltholactone rely on exactly this strategy
in order to construct the THF ring although there are variations
in the relative timing of the ring-forming steps.
(+)-Altholactone1 (a.k.a. goniothalenol)2 4, Scheme 1, was
originally isolated from a specimen of an unnamed Polyalthia
species, its gross structure established by chemical degradation,
and its stereochemistry proposed on the basis of NMR and
CD spectroscopy, later confirmed by total synthesis of the
enantiomers.3 Subsequently, interesting biological activity was
found, including an antiproliferative effect on breast cancer
cells,4 induction of apoptosis in HL-60 cells,5 and toxicity
Our interest in this area arose out of a research programme
based on the cyclisation of alcohols of the form 6 (Scheme 2)
onto alkenes, following electrophilic activation, to provide
functionalised tetrahydrofuran cores 7 and 8 stereoselectively.9
In this context, we assessed Aponick’s Au-catalysed cyclisation
of monoallylic diols that appeared in the literature whilst
our study was underway.10,11 At the time we had in hand
ketone 10 (Scheme 3), available from D-ribonolactone
acetonide (9) in four steps,12 and conceived a short synthesis
of (+)-isoaltholactone from this compound based on
cyclisation under Aponick’s conditions. The synthesis initiated
with cross metathesis of racemic alkene 1113 and, following
diastereoselective reduction with L-Selectride,12 monoallylic
diol 13 was obtained as an epimeric mixture at the allylic
alcohol centre. Application of Aponick’s conditions afforded
three diastereomers of the cyclisation products (14–16). Such
compounds have been shown to cyclise to (iso)altholactone8g–i,14
and, initially, separated diastereomer 14 was elaborated to
(+)-isoaltholactone by sequential acetonide and ester hydro-
lysis then lactonisation15 of the Z-enoic acid formed in situ. In
parallel, the inseparable diastereomers 15 and 16 were taken
through an efficient one-pot process consisting of acetonide
deprotection then lactonisation following a solvent swap from
methanol to benzene; the diol derived from acetonide 15 was
converted back into the acetonide in situ in order to allow
isolation of (+)-isoaltholactone.
Scheme 1 Key steps in the proposed biogenesis of styryl lactones
altholactone and isoaltholactone.
a Department of Chemistry, Chemistry Research Laboratory,
University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
E-mail: jeremy.robertson@chem.ox.ac.uk; Tel: +44 1865 275660
b AstraZeneca Global R&D, Alderley Park, Macclesfield, Cheshire
SK10 4TG, UK
w Electronic supplementary information (ESI) available: Experimental
procedures, spectroscopic data, and support for the stereochemistry of
cyclisation products. See DOI: 10.1039/c1cc11805f
Scheme 2 Allylic stereoinduction accompanying electrophilic cyclo-
etherification.
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Scheme 3 Reagents and conditions. (a) (ꢀ)-11, cat. Grubbs II, CH2Cl2, reflux, 2 h; (b) L-Selectride, THF, ꢁ78 1C, 0.5 h; (c) cat. Ph3PAuCl,
cat. AgOTf, 4 A MS, CH2Cl2, 20 1C, 2 h (dr E 1 : 1 : 1); (d) from 14: 1. cat. TsOH, MeOH, reflux, 18 h; 2. aq. NaOH, i-PrOH, 20 1C, 15 min
(85% from 14); 3. 2,4,6-trichlorobenzoyl chloride, pyridine, 20 1C, 18 h (40%); (e) from 15 & 16: cat. TsOH, MeOH, 50 1C, 18 h; replace solvent
with C6H6, ))), 20 1C, 2 h; replace solvent with (MeO)2CH2, acetone, MeOH, 20 1C, 10 min [one-pot].
Our synthesis, at nine steps overall from D-ribonolactone,
compares favourably with the shortest of those so far published.
Interestingly, during the key step of this synthesis, the 2 : 1
diastereomeric ratio of alcohols 13 was carried through into
the products; that is, the ratio of E-:Z- a,b-unsaturated
esters (14/15 : 16) was ca. 2 : 1, as was the ratio of products
in which the enoate side chain is located endo- or exo- on the
trioxabicyclo[3.3.0]octane ring (14/16 : 15 respectively).
(Scheme 4) by cross metathesis.18,19 The L-Selectride reduction
of ketone 17 gave a 7.2 : 1 mixture of diols 19 and 21, epimeric
at the benzylic alcohol; the corresponding reduction of ketone
18 gave a single diastereomer (20) but in lower yield.
The results from the cyclisation reactions are summarised in
Scheme 5. Comparing first the benzylic (S)-alcohols 19 and 20:
the allylic (S)-alcohol (19) led to the endo-Z- product (24) and
the exo-E- product (25) in ca. 2 : 1 ratio respectively whereas
the allylic (R)-alcohol (20) gave the endo-E- product (26)
exclusively. Diastereomer 27 was the only product that could
be traced back to the minor benzylic (R)-alcohol 21. With
these results we can infer that in the (+)-isoaltholactone
synthesis, tetrahydrofuran derivative 14 arose from the diol
with the (R)-configured allylic alcohol (‘13R’) and diastereo-
mers 15 and 16 arose from cyclisation of diol 13S (which is
therefore the major component in 13).
On this basis we wondered if these cyclisations are stereo-
specific to the extent that correct choice of monoallylic diol
configuration would yield a single product diastereomer. This
point had not arisen in Aponick’s original publications nor in
reported applications of the methodology.16 Very recently,
Aponick showed that in the synthesis of tetrahydropyrans the
configuration at the newly-formed allylic centre is determined
by both the alkene and the allylic alcohol configurations;
however, no results were reported concerning the formation
of tetrahydrofurans.17 This information was not available to
us at the time,9 and the allylic alcohol stereochemistry in
isomers 13 was not assigned; therefore, we could not draw
any conclusions on the stereospecificity based on the results
presented in Scheme 3. Alkene 11 had not been reported as a
single enantiomer so, in order to probe this further, we
prepared the stereodefined epimeric ketones 17 and 18
In general, these results fit Aponick’s recent stereochemical
model17 but some key differences are evident that augment the
emerging stereochemical picture. Specifically, (i) our results
include the first examples of the formation of Z-olefins in this
system; (ii) the stereochemical outcome does not depend
exclusively on the alkene+allylic alcohol configuration;
and (iii) the configuration at the incoming hydroxyl centre is
important.
Scheme 4 Reagents and conditions. (a) cat. Hoveyda–Grubbs II, CH2Cl2, 50 1C, 1.5–3 h; (b) L-Selectride, THF, ꢁ78 1C - 0 1C, 1 h; (c) TBSCl,
imidazole, DMF, 0 1C - 20 1C, 2 h; (d) Me3S+Iꢁ, BuLi, THF, ꢁ10 1C - 20 1C, 2.5 h.
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Notes and references
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Fig. 1 A syn-SN20 hydroxyl displacement model to relate substrate
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20 For experimental and theoretical evidence that analogous
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and product diastereomers.
Our model (Fig. 1) places the Au(I)-centre loosely
co-ordinated to both hydroxyls, mediating an overall syn-SN20
displacement. We stress that this is merely a rule-of-thumb
mnemonic and a stereochemically equivalent anti-alkoxyauration/
anti-elimination process has been advocated.17,20
In conclusion, application of the Au(I)-mediated cyclo-
etherification of monoallylic diols to the synthesis of
(+)-isoaltholactone, and a follow-up study, have revealed
further elements of stereocontrol in this reaction. In particular,
secondary structural elements temper predictions based upon
strict control by the allylic alcohol configuration.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 7659–7661 7661