The Claisen rearrangement approach to fused bicyclic medium-ring oxacycles

Article abstract of DOI:10.1039/b715354f

The synthesis of five fused-bicyclic medium-ring lactones carrying identical ring-fusion to that in the polyether toxins is described using an enolate hydroxylation, intramolecular hydrosilation, Claisen rearrangement sequence. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b715354f

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
The Claisen rearrangement approach to fused bicyclic medium-ring
oxacycles†‡§
a
Jonathan W. Burton,*a,b Edward A. Anderson,a Paul T. O’Sullivan,a Ian Collins,c John E. Davies,¶
a
a
Andrew D. Bond,¶ Neil Feeder¶ and Andrew B. Holmes*a,d
Received 5th October 2007, Accepted 30th November 2007
First published as an Advance Article on the web 4th January 2008
DOI: 10.1039/b715354f
The synthesis of five fused-bicyclic medium-ring lactones carrying identical ring-fusion to that in the
polyether toxins is described using an enolate hydroxylation, intramolecular hydrosilation, Claisen
rearrangement sequence.
Strategy
Introduction
Our strategy for the synthesis of fused bicyclic medium-ring
lactones is shown in Scheme 1. Thus, the first-generation mono-
cyclic medium-ring lactone 3 will be transformed into a 1,3-
diol 4 by a methylenation–hydrosilation sequence. Transformation
of the resultant 1,3-diol into a vinyl-substituted ketene acetal
5, via selenoxide elimination or carbonate methylenation,11 will
provide the desired fused bicyclic medium-ring lactone 6 after
Claisen rearrangement. The preparation of medium-ring lactones
by conversion of a selenide into a vinyl-substituted ketene acetal
followed by subsequent Claisen rearrangement was first reported
by Petrzilka12 for the preparation of a ten-membered lactone and
subsequently developed by us,8,9,13 and others,14,15 for the synthesis
of a number of medium-ring ether and lactone-containing natural
products.
The trans-fused polyether toxins, exemplified by the brevetoxins,
are a growing class of natural products of marine origin.1 Their
diverse and potent biological activities coupled with their unprece-
dented molecular architectures have caught the imagination of the
synthetic organic chemistry community. The total synthesis of
brevetoxins A (1) and B (2) by Nicolaou2,3 and co-workers stands
as a landmark in modern total synthesis. Since these ground-
breaking reports there have been a number of other total syntheses
of, and approaches to, the “ladder toxins” which are summarised
in a series of review articles.4 Perhaps the greatest challenge for the
synthesis of these molecules involves the construction of the fused
medium-ring ethers, often embedded in the natural product core,
and a large number of elegant methods have been invented and
developed to synthesise these structural motifs. Our own approach
to the synthesis of medium-ring ethers involves the synthesis of
a medium-ring lactone via Claisen rearrangement of a ketene
acetal,5,6 and subsequent conversion of these lactones into the cor-
responding medium-ring ethers by a methylenation–hydrosilation
sequence,7 a strategy which we have successfully employed in the
total synthesis of (+)-laurencin8 and (+)-obtusenyne.9 Herein we
report the full details10 of the extension of this methodology to
the synthesis of five fused-bicyclic medium-ring lactones carrying
identical ring-fusion to that found in the polyether toxins.
Results and discussion
Synthesis of three [6.6.0]-bicyclic lactones
The conversion of the medium-ring lactones 7, 8 and 9 into the cor-
responding [6.6.0]-bicyclic lactones was to follow a methylenation–
hydrosilation sequence which we had previously developed for the
synthesis of monocyclic medium-ring lactones.7–9 The first task
therefore involved the conversion of the medium-ring lactone into
the corresponding exo-cyclic enol ether. We have used both the
Tebbe reagent16,17 and Petasis reagent (dimethyltitanocene)18,19 to
effect this transformation,8,9 however, where possible, we favour
the use of the Petasis reagent for the methylenation of medium-
ring lactones because of its ease of preparation20 and extended
shelf-life.
aDepartment of Chemistry, University of Cambridge, Lensfield Road,
Cambridge, UK CB2 1EW
bChemistry Research Laboratory, University of Oxford, Mansfield Road,
Oxford, UK OX1 3TA. E-mail: jonathan.burton@chem.ox.ac.uk
cThe Institute of Cancer Research, 15 Cotswold Road, Sutton, UK SM2
5NG
Preparation of the [6.6.0]-bicyclic lactone 26
dSchool of Chemistry, Bio21 Institute, University of Melbourne, Victoria,
3010, Australia. E-mail: aholmes@unimelb.edu.au
The lactone 721 was efficiently converted into the exo-cyclic enol
ether 10 on exposure to dimethyltitanocene18 (71%) and the BOM
protecting group was removed on treatment of 10 with LiDBB22
giving 11 (94%) (Scheme 2). In our synthesis of (+)-laurencin8
we had converted a similar eight-membered lactone (ent-7 with
TBPDS in place of TIPS) into the corresponding a-hydroxy enol
ether using a four step procedure: replacement of the BOM group
by a TMS ether (2 steps), methylenation of the lactone, removal
of the TMS group.
† Electronic supplementary information (ESI) available: Experimental
procedures for the preparation of compounds: 10–54, 58–63 and 65–
79; selected 1H and 13C NMR spectra; X-ray crystal structure data for
compounds: 15, 17, 41, 61, 62 and 63. See 10.1039/b715354f
‡ CCDC reference numbers 655144–655146 and 655148–655150. For
crystallographic data in CIF or other electronic format see DOI:
10.1039/b715354f
§ The HTML version of this article has been enhanced with colour images.
¶ Authors to whom correspondence regarding the X-ray crystallography
should be addressed.
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readily converted into the silane 12 in readiness for the key
intramolecular hydrosilation reaction which would set the required
trans-stereochemistry of the ring fusion. We have previously
reported on the hydrosilation of a closely related silane (ent-12,
with TBDPS in place of TIPS)8 using platinum bis(1,3-divinyl-
1,1,3,3-tetramethylsiloxane)23 and had isolated the corresponding
diols in good yield (86%) but with poor diastereocontrol. More-
over, larger scale hydrosilation reactions under these conditions
had been capricious. We had also investigated the use of Wilkin-
son’s catalyst in the hydrosilation of the same substrate, which
had given the diols in low yield but with reasonable selectivity for
the trans-diol. We were pleased to find that exposure of the silane
12 to a catalytic quantity of (bicyclo[2.2.1]hepta-2,5-diene)[1,4-
(diphenylphosphino)butane]rhodium(I) tetrafluoroborate24 fol-
lowed by Tamao–Fleming oxidation,25,26 delivered the desired
trans-diol 13 as a single diastereomer in good yield. The stere-
ochemistry of the trans-diol 13 was assigned by comparison
with the spectroscopic data of a closely related trans-diol (ent-
13, with TBDPS instead of TIPS)8 and was proven by X-ray
crystallography of a later intermediate. Monoprotection of the
secondary alcohol in the diol 13 was achieved using a two step
procedure. Exposure of the diol 13 to p-anisaldehyde and PPTS
under Dean–Stark conditions in benzene at reflux provided the
corresponding benzylidene acetal 14 in excellent yield (85%). The
1H NMR coupling constant of the bridgehead protons Ha and
Hb (Ja,b = 8.5 Hz) confirmed that they were disposed trans to
one another. Reduction of the benzylidene acetal 14 with DIBAL-
H27 in dichloromethane and toluene provided the mono-protected
crystalline diol 15 in 80% yield. The advantages of using the robust
Scheme 1 Claisen rearrangement approach to bicyclic medium-ring
lactones.
We have frequently found that in order to completely remove
the titanium residues from the methylenation of a medium-ring
lactone with dimethyltitanocene, it is necessary to perform at
least two chromatographic separations. The use of LiDBB to
cleave the BOM group in 10 also acts to reduce any titanium
residues remaining from the previous reaction, thereby facilitating
purification of the a-hydroxy enol ether 11. This enol ether was
Scheme 2 Synthesis of the aldehyde 16. Reagents and conditions: (a) Cp2TiMe2, toluene, reflux, 71%; (b) LiDBB, THF, −78 ◦C, 94%; (c) (Me2SiH)2NH,
NH4Cl, 99%; (d) 3 mol% (bicyclo[2.2.1]hepta-2,5-diene)[1,4-bis(diphenylphosphino)butane]rhodium(I) tetrafluoroborate, THF, reflux, then H2O2, KOH,
THF, MeOH, 86%; (e) p-methoxybenzaldehyde, PPTS, benzene, reflux, 85%; (f) DIBAL-H, CH2Cl2, −50 → −30 ◦C, 80%; (g) IBX, Me2SO, RT. BOM =
benzyloxymethyl; TIPS = triisopropylsilyl; LiDBB = lithium di-tert-butylbiphenylide; IBX = o-iodoxybenzoic acid.
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TIPS group to protect the primary alcohol were again evident in
this transformation, as reduction of the corresponding TBDPS
protected acetal (ent-14, with TBDPS instead of TIPS)8 with
DIBAL-H had resulted in extensive loss of the silicon protecting
group with the desired product being isolated in only 51% yield.
Recrystallisation of the alcohol 15 from hot hexane provided
◦
crystals suitable for X-ray analysis (mp 121–121.5 C).‡ The X-
ray crystal structure established the relative stereochemistry of 1528
and confirmed that the hydrosilation had occurred in the desired
sense to provide the trans-diol 13 (Fig. 1). The primary alcohol
in 15 was readily oxidised to the corresponding aldehyde 16 using
IBX.29
Fig. 1 X-Ray crystal structure of the alcohol 15 showing 50% probability
ellipsoids.
The next stage in the synthetic plan involved the addition
of a vinylmetal to the aldehyde 16. Due to the possibility of
epimerisation at C-2 in 16, coupled with the possibility of elim-
ination to provide the corresponding a,b-unsaturated aldehyde,
it was deemed necessary to use a vinylmetal of low basicity. We
had previously used Imamoto’s organocerium reagents30 to add
a vinyl unit to a base sensitive aldehyde,8 and this procedure
proved to be successful with the aldehyde 16. Thus, exposure of the
aldehyde to a mixture of vinylmagnesium bromide and thoroughly
dried cerium(III) chloride31 provided the desired allylic alcohols 17
and 18 as a 5 : 1 mixture of diastereomers (Scheme 3). The major
diastereomer 17 was readily crystallised from hot hexane and an
X-ray crystal structure established the relative stereochemistry28
(Fig. 2).‡ The X-ray structure of 17 (mp 99–100 ◦C) shows
that the vinylmetal addition to the aldehyde 16 had occurred
in accord with both the polar Felkin–Anh32,33 and Cornforth34,35
models for the addition of nucleophiles to a-chiral aldehydes,36
and not surprisingly, that the conformation of the medium-ring
was virtually identical to that of the primary alcohol 15 (Fig. 1).
Scheme 3 Formation of the allylic alcohols 19 and 20. Reagents and
conditions: (a) CH2 CHMgBr, CeCl3, THF, −78 ◦C → RT, 17 74%, 18
=
15%; (b) DDQ, CH2Cl2, water, 78%; (c) CAN, MeCN, water, 86%; (d) TFA,
CH2Cl2, −20 ◦C, 90%. DDQ = 2,3-dichloro-5,6-dicyano-p-benzoquinone;
CAN = ammonium cerium(IV) nitrate; TFA = trifluoroacetic acid.
in removal of the PMB group, even after prolonged reaction times,
but instead resulted in oxidation of the PMB group to provide the
benzylidene acetal 21 (78%). Finally it was found that exposure of
either of the pure diastereomers 17 or 18, or a mixture of the two,
to a solution of TFA in dichloromethane at −20 ◦C resulted in
clean removal of the PMB group, with the diols 19 and 20 being
isolated in excellent yield (90%) (Scheme 3).
Either of the diastereomeric diols 19 or 20 could be readily
transformed into the corresponding selenoacetals on treatment
with phenylselanylacetaldehyde diethyl acetal and catalytic PPTS
in toluene at reflux (Scheme 4). The diol 19 provided the selenides
23 as a 13 : 1 mixture of diastereomers at the centre indicated. The
major diastereomer 23maj was assigned as having the PhSeCH2
group in the less sterically demanding equatorial position on the
basis of the upfield shift of the proton H* (dH* = 4.83) compared
with the corresponding proton in the minor diastereomer (dH*
=
5.27); axial protons on six-membered rings generally come into res-
onance at lower chemical shifts than the corresponding equatorial
protons (Fig. 3).38 The corresponding selenide 24 synthesised from
the diol 20 was isolated as a single diastereomer, presumably with
the PhSeCH2 group in the thermodynamically more favourable
equatorial position.
Fig. 2 X-Ray crystal structure of the allylic alcohol 17 showing 50%
probability ellipsoids.
Oxidation of the selenides (23 or 24) with sodium periodate
furnished the corresponding selenoxides, which on pyrolysis under
reflux in xylene in the presence of DBU, provided the desired
[6.6.0]-bicyclic lactone 26 in excellent yield. The stereochemistry
at the ring fusion was readily confirmed to be trans by 1H NMR
coupling constant analysis (Scheme 4, Ja,b = 9.2 Hz). It also
proved possible to synthesise the bicyclic lactone 26 from the
carbonate 25, which was prepared by exposure of the diol 19 to
triphosgene in dichloromethane.11,39 Treatment of the carbonate 25
The next step required removal of the p-methoxybenzyl pro-
tecting group from 17. The use of standard reagents such as
DDQ or CAN to effect this transformation resulted in other
reaction pathways. Attempted removal of the PMB group from
the major diastereomer 17 using CAN resulted in isolation of the
diol 22 in 86% yield where the triisopropylsilyl group instead of
the PMB group had been removed.37 Similarly, exposure of the
allylic alcohol 17 to DDQ in wet dichloromethane did not result
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Fig. 3 Structures of the selenoacetals 23 and 24.
Scheme 5 Elaboration of the lactone 8. Reagents and conditions: (a)
KHMDS, toluene, −78 ◦C then ( )-2-(phenylsulfonyl)-3-phenyloxa-
ziridine, then ( )-camphor-10-sulfonic acid, 91%; (b) Me3SiCl, Et3N,
THF, 99%; (c) Cp2TiMe2, toluene, reflux, 2 h; (d) K2CO3, MeOH,
76% from 28; (e) (Me2SiH)2NH, NH4Cl, 98%; (f) 3 mol% (bicy-
clo[2.2.1]hepta-2,5-diene)[1,4-bis(diphenylphosphino)butane]rhodium(I)
tetrafluoroborate, THF, reflux, then H2O2, KOH, THF, MeOH, 32 33%,
33 24%; (g) p-methoxybenzaldehyde, PPTS, benzene, reflux, 34 100%, 35
100%.
Scheme 4 Formation of the fused bicyclic lactone 26. Reagents and
conditions: (a) PhSeCH2CH(OEt)2, PPTS, toluene, reflux, 90% from 19,
60% from 20; (b) NaIO4, CH2Cl2, MeOH, water, 100%; (c) DBU, xylene,
reflux, 90% from 23 or 24; (d) (Cl3CO)2CO, pyridine, Et3N, CH2Cl2,
−78 ◦C → RT, 89%; (e) Cp2TiMe2, toluene, reflux, 63%. DBU =
1,8-diazabicyclo[5.4.0]undec-7-ene.
the diols 32 and 33 was disappointing. Attempts to improve the
proportion of the desired trans-diol 32 proved fruitless: conducting
the hydrosilation in the presence of tetramethyldisilazane (which
had previously been used to increase the proportion of trans-
diol)7 merely increased the proportion of the undesired cis-diol 33,
and using platinum bis(1,3-divinyl-1,1,3,3-tetramethylsiloxane)23
gave the cis-diol 33 as the sole product after Tamao–Fleming
oxidation.25,26
Conversion of both diols 32 and 33 into the corresponding p-
methoxybenzylidene acetals 34 and 35 was readily achieved in
quantitative yields and the stereochemistry of the ring junctions
of the acetals 34 and 35 was determined using 1H NMR coupling
constant analysis (34, Ja,b = 9.5 Hz; 35, Ja,b = 1.5 Hz). The
trans-acetal 34 was elaborated to the [6.6.0]-bicyclic lactone 39
as illustrated in Scheme 6. Exposure of the acetal to DIBAL-
H delivered the primary alcohol 3627 which was readily oxidised
to the corresponding aldehyde 37 using IBX.29 Exposure of the
aldehyde 37 to vinylmagnesium bromide gave a complex mixture
of degradation products. Disappointingly the use of the less basic
organocerium reagent only returned the alcohol 36. There is
some precedent for the reduction of carbonyl substrates with
certain organocerium reagents,30 although in those examples, the
organocerium compound is more usually aliphatic and contains
with dimethyltitanocene in toluene at reflux11 provided the desired
bicyclic lactone 26 in 63% yield.
Having established an efficient method for the annulation of an
eight-membered lactone onto an existing medium-ring lactone, we
sought to verify the generality of the method with the synthesis of
a number of other bicyclic medium-ring lactones.
Preparation of the [6.6.0]-bicyclic lactone 40
The synthesis of the remaining [6.6.0]-bicyclic lactones followed
synthetic routes analogous to the one described above for the
synthesis of 26 (Scheme 5). Thus, the lactone 811 was converted
into the a-hydroxy lactone 27 in excellent yield and as a single
diastereomer, by oxidation of the derived potassium enolate with
the Davis oxaziridine.40 The a-hydroxy lactone was protected,
methylenated, deprotected and silylated to give the dimethylsilane
31. Hydrosilation of the enol ether 31 using the same catalyst as for
the enol ether 12 delivered the diols (1.34 : 1, 32 : 33) in reasonable
yield (57%). The poor diastereoselectivity in the formation of
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The allylic alcohols 38 were readily converted into the corre-
sponding cyclic carbonates 39 by deprotection (TFA) followed
by exposure of the resultant diols to triphosgene.39 The relative
1
stereochemistry of the two carbonates 39 was determined by H
NMR coupling constant analysis (Fig. 4) which consequently
allowed the assignment of the relative stereochemistry of the allylic
alcohols 38. Exposure of the carbonates 39 to dimethyltitanocene
in toluene at reflux11 in the absence of light effected methylenation
of the carbonyl group and subsequent Claisen rearrangement to
afford the bicyclic lactone 40 in 46% yield. As before the ring-
1
fusion stereochemistry was confirmed to be trans by H NMR
coupling constant analysis (Scheme 6, Ja,b = 9.5 Hz).
Fig. 4 Structures of the carbonates 39.
Scheme 6 Synthesis of the fused bicyclic lactone 40. Reagents and
conditions: (a) DIBAL-H, toluene, CH2Cl2, −78 → −5 ◦C, 90%; (b) IBX,
Me2SO, RT, 90%; (c) vinyl iodide, CrCl2 (1% NiCl2), Me2SO, RT, 40%;
(d) TFA, CH2Cl2, −20 ◦C, 75%; (e) triphosgene, Et3N, pyridine, CH2Cl2,
−78 → −10 ◦C, 90%; (f) Cp2TiMe2, toluene, reflux, 46%.
Preparation of the [6.6.0]-bicyclic lactone 54
The final [6.6.0]-bicyclic lactone was synthesised in an analogous
manner to the previous two, beginning from the lactone 9.11
Formation of the potassium enolate of the lactone 9 (KHMDS)
in toluene followed by the addition of three equivalents of the
Davis oxaziridine40 delivered the desired a-hydroxy lactone 41 in
b-hydrogens which can eliminate with release of hydride (the
reducing agent). This pathway is less likely for a vinylcerium
reagent, and reduction in these cases may occur via a single
electron transfer process.30 Addition of a vinyl nucleophile to the
aldehyde 37 was eventually achieved using the Nozaki–Hiyama–
Kishi reaction.41 Thus, exposure of a mixture of the aldehyde 37
and vinyl iodide to excess chromium(II) chloride (1% nickel(II)
chloride) in dimethylsulfoxide, provided the desired allylic alcohols
38 in 40% yield as a 2 : 1 mixture of diastereoisomers. The
1
88% yield as a 20 : 1 mixture of diastereomers as judged by H
NMR (Scheme 7). After extensive purification by repeated flash
chromatography the major diastereomeric a-hydroxy lactone 41
was isolated pure as a white crystalline solid (mp 102–104 ◦C). The
relative stereochemistry of the major diastereomer was proven by
X-ray crystal structure analysis and the X-ray structure is shown
in Fig. 5.28‡ The a-hydroxy lactone 41 was converted into the
dimethylsilane 44 in readiness for the hydrosilation reaction.
Treatment of the silane 44 with the previously used cationic
rhodium catalyst followed by Tamao–Fleming oxidation25,26 de-
livered the corresponding diols 45 and 46 isolated as a 6.4 : 1
mixture of inseparable diastereomers. The mixture of diols was
readily converted into the corresponding p-methoxybenzylidene
1
stereochemistry of the diastereomers was assigned by H NMR
coupling constant analysis of later intermediates (the carbonates
39). The major diastereomer has the (R)-stereochemistry at the
newly installed stereocentre, which is consistent with both the
polar Felkin–Anh32,33 and Cornforth34 models for the addition of
nucleophiles to a-chiral aldehydes.
Scheme 7 Preparation of the diols 45 and 46. Reagents and conditions: (a) KHMDS, toluene, −78 ◦C then ( )-2-(phenylsulfonyl)-3-phenyloxaziridine,
then ( )-camphor-10-sulfonic acid, 88%; (b) Me3SiCl, Et3N, THF, 86%; (c) Cp2TiMe2, toluene, reflux, 98%; (d) K2CO3, MeOH, 87%; (e) (Me2SiH)2NH,
NH4Cl, 99%; (f) 3 mol% (bicyclo[2.2.1]hepta-2,5-diene)[1,4-bis(diphenylphosphino)butane]rhodium(I) tetrafluoroborate, THF, reflux, then H2O2, KOH,
THF, MeOH, 61%, 6.4 : 1 mixture of 45 : 46; (g) p-methoxybenzaldehyde, PPTS, benzene, reflux, 81% from mixture of 45 and 46.
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1
in the above synthetic sequence, the H NMR spectrum of 54
measured at 27 ◦C contained many broad unidentifiable peaks,
while the 13C NMR spectrum was found to be missing several
carbon peaks. This problem was again easily solved by measuring
both spectra above 50 ◦C, affording mostly distinct sharp peaks in
the 1H NMR spectrum and all of the expected carbon resonances
in the 13C NMR spectrum (see ESI†). The cis-ring fusion of 54
1
was confirmed by H NMR nOe and coupling constant analysis
(Scheme 8, Ja,b = 2.4 Hz).
Fig. 5 X-Ray crystal structure of the a-hydroxy lactone 41 showing
disorder in the benzyl group (50% probability ellipsoids).
Synthesis of the [7.6.0]-bicyclic lactones
Synthesis of the dilactone 63
acetals from which the major diastereomer 47 could be isolated in
81% yield.
1
The room temperature H NMR spectrum (400 MHz) of 47
contained a number of broad peaks, while the room temperature
13C NMR spectrum (100 MHz) of 47 was missing a number
of key resonances. This indicated that the acetal existed as an
interconverting mixture of conformers which were in intermediate
exchange on the NMR timescale. A number of spectra were taken
at varying temperatures (see ESI†) and the stereochemistry of
the bridgehead protons could be assigned as cis on the basis of
The synthesis of the first of the two [7.6.0]-bicyclic lactones began
with the nine-membered lactone 55, a literature compound that
is readily available from 2-deoxy-D-ribose.11,42 Monodeprotection
of the lactone 55 using the conditions initially described by
Congreve42 (HF·pyridine, pyridine, THF in glassware) proved
capricious. However, when the reaction was executed in a
polypropylene vessel a reproducibly high yield of the alcohol 56
could be obtained (80%) (Scheme 9). Oxidation of the alcohol
56 was readily achieved using the procedure of Swern et al.43 to
provide 57. For the next step in the synthetic sequence it was
necessary to introduce a vinylmetal equivalent which would react
chemoselectively with the aldehyde in the presence of the lactone,
and we elected to use the Nozaki–Hiyama–Kishi reaction41 for
this purpose. Addition of vinyl bromide to the aldehyde 57 in
the presence of CrCl2 containing 1% NiCl2 provided the desired
allylic alcohols 58 and 59 as a 1 : 2 mixture of diastereomers. X-Ray
crystal structure analysis of later intermediates (the lactone 61 and
the carbonate 62) indicated that the addition of the vinylchromium
species onto the aldehyde 57 had occurred according to both the
polar Felkin–Anh32,33 and Cornforth34 models. Vinyl iodide could
also be used in the above addition process with no detriment to
the yield.
◦
1H NMR (55 C, CDCl3) coupling constant analysis (Scheme 7,
Ja,b = 1.6 Hz). The cis ring fusion in 47 was further verified by
1
the observation of a large H NMR nOe between these protons.
As before the p-methoxybenzylidene acetal 47 was cleaved with
DIBAL-H27 and the released primary alcohol 48 was oxidised29
to the corresponding aldehyde 49 (Scheme 8). Addition of the
vinylcerium reagent30 derived from vinylmagnesium bromide and
thoroughly dried cerium(III) chloride31 to the aldehyde 49 gave
the allylic alcohols 50 as a 3 : 1 mixture of diastereomers. The p-
methoxybenzyl protecting group was then cleaved as before using
TFA. The resultant diols 51 were converted into the corresponding
selenoacetals 52 as a mixture of one major and two minor
diastereomers; the full stereochemistry of the selenoacetals was not
assigned. The selenoacetals 52 were oxidised to the corresponding
selenoxides, which were heated in xylene in the presence of DBU
to deliver the bicyclic lactone 54 in 60% yield. The diols 51 could
also be converted into the corresponding carbonates,39 which on
heating with dimethyltitanocene11 in toluene delivered the same
bicyclic lactone 54 in 47% yield. Akin to several intermediates
Desilylation of the lactone 58 using HF·pyridine occurred in
reasonable yield to provide the nine-membered diol 60 (71%)
(Scheme 10). The quenching procedure for this reaction proved
to be important for the attainment of high yields of 60. Quenching
Scheme 8 Synthesis of the bicyclic lactone 54. Reagents and conditions: (a) DIBAL-H, CH2Cl2, −78 → −5 ◦C, 97%; (b) IBX, Me2SO, RT, 100%; (c)
◦
◦
=
CH2 CHMgBr, CeCl3, THF, −78 C → RT, 80%, 3 : 1 mixture of diastereomers; (d) TFA, CH2Cl2, −15 C, 86%; (e) PhSeCH2CH(OEt)2, PPTS, toluene,
reflux, 97%; (f) NaIO4, CH2Cl2, MeOH, water, 100%; (g) DBU, xylene, reflux, 60%; (h) triphosgene, Et3N, pyridine, CH2Cl2, −78 → −10 ◦C, 81%; (i)
Cp2TiMe2, toluene, reflux, 47%.
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Scheme 9 Synthesis of the allylic alcohols 58 and 59. Reagents and conditions: (a) HF·pyridine, pyridine, THF, 80%; (b) (COCl)2, Me2SO, 55, −78 ◦
then Et3N, −78 ◦C → RT, 78%; (c) vinyl bromide, CrCl2 (1% NiCl2), Me2SO, RT, 63%.
C
concern. In the event, exposure of the diol 60 to triphosgene,
triethylamine and pyridine provided the desired carbonate 62
in good yield (78%). The carbonate 62 was isolated as a white
crystalline solid which was recrystallised from hexane (mp 126–
127 ◦C) and provided crystals suitable for X-ray analysis. The
X-ray crystal structure confirmed the relative stereochemistry of
62 (Fig. 7)28 and established that no undesired ring expansion had
occurred under the reaction conditions.‡
Scheme 10 Synthesis of the bicyclic dilactone 63. Reagents and conditions:
(a) HF·pyridine, pyridine, THF, 71%; (b) HF MeCN; (c) triphosgene, Et3N,
pyridine, CH2Cl2, −78 ◦C → RT, 78%; (d) Cp2TiMe2, toluene, reflux, 31%.
the reaction with either aqueous sodium bicarbonate or aqueous
hydrochloric acid resulted in the isolation of significant quantities
of the ten-membered lactone 61. However, quenching the reaction
with water followed by washing with aqueous copper(II) sulfate
provided solely the nine-membered diol 60 in acceptable yield.
When the deprotection of the silylether 58 was attempted with
aqueous HF in acetonitrile the ten-membered diol 61 was the sole
product.
The ten-membered diol 61 was isolated as a white crystalline
solid that provided crystals suitable for X-ray analysis after re-
crystallisation from hexane and ether (mp 112–114 ◦C). The X-ray
crystal structure (Fig. 6) established the relative stereochemistry
of 6128 and confirmed that the addition of the vinylmetal species
to the aldehyde 57 had occurred in accord with both the polar
Felkin–Anh and Cornforth models.32–35‡ We have noted this ring
expansion previously,13,42 and it is likely driven by the release
of strain when moving from a nine-membered lactone to a ten-
membered lactone.44 Due to the ease of this ring expansion,
the formation of the carbonate 62 was approached with some
Fig. 7 X-Ray crystal structure of the carbonate 62 showing disorder in
the medium ring (50% probability ellipsoids).
Exposure of the carbonate 62 to dimethyltitanocene in toluene
at reflux11 provided the dilactone 63 as a white crystalline solid
(31%, mp 109–111 ◦C). The mass-balance from this reaction
was made up of material possessing the [7.6.0]-bicyclic skeleton
with either one of the lactone carbonyl groups having been
competitively methylenated. Recrystallisation of the dilactone
63 from hot hexane provided crystals suitable for X-ray anal-
ysis which established the relative stereochemistry (Fig. 8).28‡
Attempted synthesis of the corresponding selenoacetals from
the nine-membered lactone 60 under our standard conditions
[PhSeCH2CH(OEt)2, PPTS] resulted in the formation of a myriad
of products most probably due to translactonisation of 60 under
the reaction conditions and subsequent formation of acetals from
both the nine- and ten-membered lactones 60 and 61.
Fig. 6 X-Ray crystal structure of the lactone 61 showing 50% probability
Fig. 8 X-Ray crystal structure of the dilactone 63 showing 50% proba-
ellipsoids.
bility ellipsoids.
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Synthesis of the [7.6.0]-bicyclic lactone 79
oxidative cross-coupling of the silane 69 with loss of dihydrogen
followed by deprotection of the so formed disilane on work up; a
known side reaction in hydrosilation reactions.45 The structure of
the diol 70 was established by using the latent C2 symmetry of the
molecule. Deprotection of the silyl group in 70, giving 71, followed
by hydrogenolysis of the benzyl group and hydrogenation of the
alkene provided the tetrol 72 in excellent yield. The 13C NMR
spectrum of 72 contained only five resonances indicating that it
was either C2 or CS-symmetric. However, the tetrol 72 had a non-
zero optical rotation {[a]2D0 +26 (c 0.05 in EtOH)} and therefore
must be C2-symmetric having the structure indicated. The diol
70 was converted into the corresponding p-methoxybenzylidene
acetal 73, which was reduced with DIBAL-H27 to provide the
desired primary alcohol 74 in low yield (45%) along with the diol
corresponding to loss of the silyl group from 74 (Scheme 12). This
side reaction has been noted in other systems8 and may be avoided
by the use of the TIPS protecting group (see above). The primary
alcohol 74 was oxidised (IBX)29 to the corresponding aldehyde
75 and addition of vinylmagnesium bromide provided the allylic
alcohols 76 as a 6 : 1 mixture of diastereomers in excellent yield.
Deprotection of the mixture of diastereomers with TFA provided
a separable mixture of diols 77 (88%). The major diastereomer
was converted into the selenides 78 which were oxidised with
sodium periodate to the corresponding selenoxides. Pyrolysis of
the selenoxides in toluene at reflux provided the bicyclic lactone 79
in good yield. The stereochemistry across the ring fusion was once
The second [7.6.0]-bicyclic lactone was synthesised beginning with
the related nine-membered lactone 64 prepared in a similar manner
from 2-deoxy-D-ribose.11,42 The lactone 64 was converted into the
a-hydroxy lactone 65 by oxidation of the derived potassium enolate
with the Davis oxaziridine40 to give the product 65 in good yield
as a single diastereomer (Scheme 11). The stereochemistry of
the newly introduced hydroxy group was confirmed on a later
intermediate and was in keeping with the selectivity observed for
the a-oxidation of a closely related nine-membered lactone which
we used in our recent synthesis of obtusenyne.9 Surprisingly the
enolate oxidation was very sensitive to the nature of the protecting
groups on the hydroxy and hydroxymethyl groups adorning the
nine-membered lactone. The bis-TBDPS-protected lactone 55 was
completely unreactive under these reaction conditions whereas the
corresponding bis-TES-protected lactone (55 with TES in place of
TBDPS) was readily hydroxylated under the same conditions as
for the lactone 64.
1
again confirmed as being trans by H NMR coupling constant
analysis (Scheme 12, Ja,b = 9.3 Hz).
Scheme 11 Synthesis of the diol 70. Reagents and conditions: (a)
KHMDS, toluene, −78 ◦C then ( )-2-(phenylsulfonyl)-3-phenyloxazi-
ridine, then ( )-camphor-10-sulfonic acid, 78%; (b) Me3SiCl, Et3N, THF,
87%; (c) Cp2TiMe2, toluene, reflux; (d) K2CO3, MeOH, 60% from 65;
(e) (Me2SiH)2NH, NH4Cl, 100%; (f) 3 mol% (bicyclo[2.2.1]hepta-2,5-
diene)[1,4-bis(diphenylphosphino)butane]rhodium(I) tetrafluoroborate,
THF, reflux, then H2O2, KOH, THF, MeOH, 61%; (g) HF·pyridine,
pyridine, THF, 97%; (h) H2, Pd/C, EtOH, 88%.
The a-hydroxy lactone 65 was converted into the silane
69 in readiness for the intramolecular hydrosilation reaction.
Exposure of the silane 69 to catalytic (bicyclo[2.2.1]hepta-2,5-
diene)[1,4(diphenylphosphino)butane]rhodium(I) tetrafluorobo-
rate followed by Tamao–Fleming oxidation25,26 gave the trans-diol
70 exclusively after oxidation as well as returning some of the
enol ether 68 (Scheme 11). All efforts to improve this yield have
so far failed. The enol ether 68 is most probably formed from
Scheme 12 Synthesis of the bicyclic lactone 79. Reagents and conditions:
(a) p-methoxybenzaldehyde, PPTS, benzene, reflux, 80%; (b) DIBAL-H,
CH2Cl2, −78 → −30 ◦C, 45%; (c) IBX, Me2SO, RT, 100%; (d)
◦
=
CH2 CHMgBr, THF, 0 C, 94%, 6 : 1 mixture of diastereomers; (e) TFA,
CH2Cl2, −20 ◦C, 88%; (f) PhSeCH2CH(OEt)2, PPTS, toluene, reflux, 91%;
(g) NaIO4, CH2Cl2, MeOH, water; (h) DBU, toluene, reflux, 73% from 77.
700 | Org. Biomol. Chem., 2008, 6, 693–702
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Discussion
Conclusion
We have developed a procedure for the annulation of an eight-
membered lactone onto an existing medium-ring lactone which
utilises an enolate oxidation, enol ether hydrosilation, Claisen
rearrangement sequence. The preparation of five fused-bicyclic
medium-ring lactones containing the precise structural features
present in the medium-ring fused polyether segments of brevetoxin
A and ciguatoxin has been achieved.
The general procedure for the annulation of an eight-membered
lactone onto a medium-ring lactone follows an enolate oxidation,
hydrosilation, Claisen rearrangement route. During the course of
these studies and in the synthesis of both (+)-obtusenyne9 and
(+)-laurencin8 we have investigated the intramolecular hydrosila-
tion of a number of medium-ring exo-cyclic enol ethers. Due to
the complexity of the systems, we are currently unable to predict
with any certainty what the diastereoselectivity of this process
will be. Nevertheless, it is generally the case that either the cis-
or the trans diol can be selected as the major product from the
reaction after screening a number of catalysts and reaction cond-
itions.
Acknowledgements
We thank the Royal Society for the award of a University
Research Fellowship, and Corpus Christi College (JWB); Merck
Sharp & Dohme (CASE award to EAA); the University of
Cambridge (Robert Gardiner Memorial Scholarship), the Cam-
bridge European Trust (awards to PTO’S); and the EPSRC for
generous financial support, including financial assistance towards
the purchase of the Nonius CCD diffractometer, and provision of
the Swansea National Mass Spectrometry Service. We thank the
ARC, VESKI and CSIRO for support.
The annulated medium-ring lactones are all formed by Claisen
rearrangement of the corresponding ketene acetals, which, in turn,
are prepared by selenoxide elimination or methylenation of a cyclic
carbonate. We,11 and others,46–48 have previously demonstrated
that it is possible to perform chemoselective methylenations of
carbonyl groups using titanium-based reagents. The yields for
the synthesis of the bicyclic lactones via methylenation of a
carbonate and subsequent Claisen rearrangement, and for the
formation of monocyclic medium-ring lactones via an analogous
route, demonstrate that methylenation of a cyclic carbonate with
dimethyltitanocene is frequently faster than methylenation of an
ester13 or a medium-ring lactone. The methylenation of carbonyl
groups with the Petasis reagent has been demonstrated to occur
via formation of a titanium carbene.49,50 The chemoselectivity
observed in the preferential methylenation of a six- or seven-
membered ring cyclic carbonate over an acetate or medium-ring
lactone, may relate to the nucleophilicity of the lone pairs of the
carbonyl group oxygen atom, which presumably coordinate to the
titanium carbene to initiate the methylenation process. Wiberg
and Waldron51 have studied the basicities of a number of esters
and lactones as well as that of diethyl carbonate. Furthermore,
they have shown that the rate of reaction of a set of carbonyl com-
pounds with triethyloxonium tetrafluoroborate follows the order:
valerolactone (fastest), butyrolactone, diethyl carbonate and ethyl
acetate (slowest), which mirrors the basicities of these compounds
towards triethyloxonium tetrafluoroborate.51 They conclude that
(E)-esters are more basic than (Z)-esters from dipole–dipole
interaction arguments. From their work it is reasonable to assume
that six- and seven-membered cyclic carbonates would be more
basic than diethyl carbonate. Huisgen and Ott52 have reported that
eight- and nine-membered lactones exist as an equilibrium mixture
of (Z)- and (E)-forms whereas ten-membered lactones adopt the
(Z)-configuration; a search of the Cambridge Crystallographic
Data Centre (CCDC) confirms that eight- and nine-membered lac-
tones can exist in either (E)- or (Z)-forms whereas ten-membered
lactones invariably adopt the (Z)-form. Since diethyl carbonate
is more basic than (Z)-esters51 the chemoselective methylenation
of a carbonate in the presence of an enol-acetate13 is readily
accounted for. The chemoselectivity in the methylenation of a
carbonate in the presence of a medium-ring lactone may be related
to the (E) : (Z)-conformer ratio of the lactone, and may therefore
account for the moderate yields sometimes encountered in the
formation of medium-ring lactones derived from methylenation
and subsequent Claisen rearrangement of the corresponding cyclic
carbonates.
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