A two-directional synthesis of the C58-C71 fragment of palytoxin

Article abstract of DOI:10.1039/b307950c

A two directional approach, in which asymmetric dihydroxylation and reduction reactions were used to control absolute configuration, was exploited in the preparation of a C₂-symmetrical dipyranone. The homotopic dihydropyran (DHP) rings of this precursor were differentiated statistically using by a Prevost reaction and further functionalisation. A second Prevost reaction was used to functionalise the other DHP; global deprotection and peracetylation gave a protected version of the C₅₈-C₇₁ fragment of palytoxin. Methods which might be of value in future synthetic work were developed for the stereoselective functionalisation of THP rings similar to those found in this fragment.

Full text of DOI:10.1039/b307950c

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A two-directional synthesis of the C58–C71 fragment of palytoxin
Robert Hodgson and Adam Nelson*
Department of Chemistry, University of Leeds, Leeds, UK LS2 9JT
Received 14th July 2003, Accepted 18th November 2003
First published as an Advance Article on the web 5th January 2004
A two directional approach, in which asymmetric dihydroxylation and reduction reactions were used to control
absolute configuration, was exploited in the preparation of a C2-symmetrical dipyranone. The homotopic
dihydropyran (DHP) rings of this precursor were differentiated statistically using by a Prévost reaction and further
functionalisation. A second Prévost reaction was used to functionalise the other DHP; global deprotection and
peracetylation gave a protected version of the C58–C71 fragment of palytoxin. Methods which might be of value in
future synthetic work were developed for the stereoselective functionalisation of THP rings similar to those found in
this fragment.
Table 1 Deprotection of the bis silyl ether 7
Introduction
Yielda (%)
Palytoxin, 1, was isolated from marine soft corals of the genus
Palythoa.1 Palytoxin acts by interacting with sodium-potas-
sium-activated APTase2 and its toxicity is rivalled only by a few
naturally occurring proteins.1 The connectivity of palytoxin was
determined in 1981,3 and its complete structure elucidated a
year later.4 A total synthesis of palytoxin was reported in 1989.5
Palytoxin remains one of the most complex molecules to have
succumbed to total synthesis, both in terms of its molecular size
and its structural and stereochemical complexity.
Entry
Conditions
Product
b
c
c
1
2
3
4
5
TBAF, THF, 20 ЊC
NH4F, MeOH, 60 ЊC
AcOH–H2O, 20 ЊC
TBAF, AcOH, 20 ЊC
HFؒpyridine, 20 ЊC
—
—
—
43
20
12
12
a Yield of purified product. b Analysis of the crude reaction mixture by
300 MHz 1H spectroscopy indicated that elimination had occurred.
c No reaction.
Our goals were more modest. The C58–C71 fragment (2) of
palytoxin is tantalizingly close to being C2-symmetric. The only
features which break its symmetry are (a) the absence of a
hydroxyl group from C59, and (b) different (2,6) relative con-
figurations of the two tetrahydropyran rings. We sought to
exploit this hidden symmetry for the first time in a two-
directional synthesis of the fragment 2. We have previously
described some methods for the synthesis of diastereomeric
polyhydroxylated tetrahydropyrans (THPs).6 Some of these
methods might be used to differentiate between the termini of a
C2-symmetric template and to control the configuration of the
two THP rings of 2.
Our synthetic plan is outlined in Scheme 1. It was envisaged
that a C2-symmetric template, 3, would be prepared using a
two-directional7 approach. At this stage, the dihydropyran
rings of 3 would be functionalised stereoselectively and the C59
hydroxyl group removed ( 4).
Having differentiated between the homotopic termini of 3,
this information would be exploited in the stepwise and stereo-
selective introduction of the C58 and C71 side chains. The C58
acetal does not have a neighbouring deactivating substituent;8
reaction at C58 was, therefore, expected to occur first and to
allow the introduction of an axial side chain. In contrast, the
acyloxy substituent on C70 was expected to act as both a
deactivating8 and a participating group:9 subsequent substi-
tution would, therefore, introduce an equatorial side chain at
C71.
The dilactone12 8a and the diester 8b were investigated as
alternative acylating reagents: these compounds were prepared
as racemates from the sodium salt of trans-β-hydromuconic
acid, either by treatment of the corresponding silver salt with
iodine ( 8a),12 or by Upjohn dihydroxylation followed by
acid-catalysed reaction with 2,2-dimethoxypropane ( 8b). The
acylating agents 8 were treated with 2-lithio furan in THF at
Ϫ78 ЊC; analysis of the crude reaction mixtures by 300 MHz 1H
NMR spectroscopy revealed, however, complex mixtures of
products.
We have previously investigated the substrate-controlled
reduction of a racemic sample of the diketone 7 with a range of
reagents.10 However, these reactions were either unselective or
were 1,3syn-diastereoselective. In an attempt to develop an
1,3anti-selective method, we investigated the addition of 2-lithio
furan to a 3-silyloxy aldehyde (Scheme 3). Hence, reduction of
the diamide 9 with DIBAL gave the aldehyde 10 in 64% yield.
Unfortunately, addition of 2-lithio furan to 10 was not
diastereoselective, and gave the hydroxy ketone 11 as a 50 : 50
mixture of diastereoisomers.
An alternative approach involved delivery of a reducing
agent to the carbonyl groups. The deprotection of 7, however,
proved problematic (Scheme 4). Treatment of 7 with TBAF in
THF resulted in elimination (entry 1, Table 1), and the use of
milder reagents13 resulted in no reaction at all (entries 2–3). The
use of a buffered fluoride source resulted in less competing
elimination,14 and low yields of the diol 12 could be obtained
(entries 4–5).15 Treatment of the diol 12 with tetramethyl-
ammonium triacetoxyborohydride16 in acetic acid resulted only
in decomposition of the starting material. The diol 12 was,
therefore, treated with chlorodiisopropylsilane, pyridine and
catalytic DMAP, and the bis silyl ether 13 was obtained in 34%
yield. In view of the low yield of 13, Lewis acid-17 and base-18
mediated intramolecular hydride delivery was not studied in
detail.
Two-directional synthesis of a C2-symmetrical template
The reaction of the enediamide10 5, prepared from trans-β-
hydromuconic acid, with commercially available AD-mix11
β was extremely slow. However, addition of 1 mol% potassium
osmate and 5 mol% hydroquinidine 1,4-phthalazinediyl diether
(DHQD2-PHAL) enabled efficient dihydroxylation; the result-
ing diol was, however, rather water soluble, and was, therefore,
silylated in situ to give the corresponding silyl diether 6 in 67%
overall yield (Scheme 2). Addition of 2-lithio furan to the
diamide 6 gave the diketone 7 in >95% yield.10
Our failure to identify substrate-controlled methods for
the 1,3anti-selective synthesis of diketones such as 7 lead us to
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 7 3 – 3 8 6
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Scheme 1
Scheme 2
Scheme 3
investigate reagent-controlled methods instead (Scheme 5).
Treatment of the diketone (R,R)-7 with 10 mol% of the
CBS reagent19 17 gave a 90 : 10 mixture of the diols 14 and 16
(entry 1, Table 2). There was no trace of the unsymmetrical
diastereoisomer 15. The diols 14 and 16, whose relative con-
figuration had previously been determined, were readily
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 7 3 – 3 8 6
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Table 2 Asymmetric reduction of the diketone 7
Entry
Starting material
Ratio of productsa 14 : 15 : 16
Yield 14b (%)
ee 14c (%)
Yield 16b (%)
1
2
7d
rac-7
90 : 0 : 10
49.7 : 0.6 : 49.7
82
41
>98
>98
7
42
a Determined by analytical HPLC. b Yield of purified diastereoisomer. c Determined by chiral analytical HPLC. d Synthesised from enantiomerically
enriched 6, prepared by asymmetric dihydroxylation of the diamide 5.
Scheme 4
Scheme 5
the reaction mixture in >98% yield as a 63 : 37 mixture of C2-
symmetrical and unsymmetrical anomers (Scheme 6). Careful
purification by flash chromatography gave the required C2-
symmetrical dipyranone 20 in 52% yield. It was possible to
re-equilibrate the mixture of diastereoisomers isolated from the
mother liquors by treatment with trimethyl orthoformate and
boron trifluoride: the C2-symmetrical dipyranone 20 was
obtained in 76% yield after three recycles.
Stereoselective Luche25 reduction of the meso dipyranone 20
was highly stereoselective, and gave the diol 21 as a >95 : 5
mixture of diastereoisomers. The selectivity of the reaction
20 21 is remarkable, and reflects >97 : 3 stereo- and regio-
selectivity for each of the individual reduction steps. The con-
figuration of the diol 21 was assigned by analysis of the vicinal
separable by column chromatography.10 Analysis of the diol 14
coupling constant (8.7 Hz) between the protons at C-2 and C-3.
by chiral analytical HPLC revealed it to have >98% ee.
Similar stereoselective Luche reductions of dihydropyrans have
Given these favourable results, we probed the asymmetric
been exploited by us6,10,26,27 and others;28 the fundamental pref-
reduction reaction further. Thus, asymmetric reduction of a
erence for axial attack on six-membered ketones (in the absence
racemic sample of the diketone 7 under the same conditions
of strong steric effects) has previously been rationalized theor-
gave a 49.7 : 0.6 : 49.7 mixture of the diols 14–16 (entry 2,
etically.29 The diol 21 was converted into the corresponding
Table 2). Separation of the diols 14 and 16 by column chrom-
p-methoxybenzoyl diester 22.
atography, and analysis by chiral HPLC, revealed that the
diol 14 had >98% ee. In the light of this result, we propose that
Development of methods for the stereoselective functionalisation
the asymmetric dihydroxylation of 5 was only moderately
of tetrahydropyran rings
enantioselective, and gave, after silylation, the diamide 6 with
ca. 80% ee. The asymmetric reduction of 7 was, however, highly
enantioselective: a ca. 90 : 10 mixture of the enantiomeric
diketones 7 was, therefore, converted into a 90 : 10 mixture of
diastereomeric diols 14 and 16.
Efficient methods were required for the functionalisation of
the two tetrahydropyran rings of the di-THP 22. In view of the
complexity of this compound, we decided to develop the
required methods using a model system (see Schemes 7–9). Pre-
viously, we have investigated the use of a Prévost reaction in the
stereoselective functionalisation of compounds such as 23.6
Treatment of the allylic p-methoxybenzoate 23 with iodine and
silver benzoate in rigorously dry carbon tetrachloride gave a ca.
4 : 1 mixture of stereoisomers from which the hydroxy iodide 24
could be obtained in 74% yield6 (Scheme 7). Hydrolysis of the
hydroxy iodide 24 with aqueous potassium hydroxide solution,
and peracetylation, gave the triacetate 25 in 74% yield. The
triacetate 25 has the relative configuration found in one of
the THPs (C67–C71) of the required fragment 2.
An alternative approach was to control the ‘outside’
stereogenic centres before dihydroxylating a central double
bond. Homo-metathesis of the allylic alcohol 18, prepared by
Barbier-type coupling of allyl bromide with furfural, gave the
diol20 19 as a mixture of isomers, from which the centro-
symmetric (E)-(R*,S*) isomer could be recrystallised in 19%
yield. Having established that a metathesis approach was viable,
the allylic alcohol (R)-18 was prepared by Sharpless kinetic
resolution;21,22 homo-metathesis of (R)-18 gave 19 as a 4 : 1
mixture of E and Z geometric isomers from which the required
C2-symmetric isomer (E)-(R,R)-19 could be isolated in 63%
yield by column chromatography. This approach was not
pursued further.
The other THP (C58–C62) in the fragment 22 lacks a hydroxyl
group at C59. The model compound 24 was, therefore, treated
with tributyltin hydride30 and AIBN in refluxing benzene for
one hour (Scheme 8). Unfortunately, a 50 : 50 mixture of the
regioisomeric hydroxy esters 26 and 30 was obtained, whose
Double oxidative ring expansion23,24 of the difuryl diol 14
using tert-butyl hydroperoxide and catalytic vanadyl() acetyl-
acetonate, was followed by protection as the corresponding bis
methyl acetal. The dipyranone 20 was isolated by filtration of
1
configuration was determined by careful analysis of their H
NMR spectra (for 26, 3-H had J = 10.1 and 3.0 Hz). Given that
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 7 3 – 3 8 6
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Scheme 6
Scheme 7
Scheme 8
Scheme 9
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 7 3 – 3 8 6
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Table 3 Diastereoselective acetal substitution reactions involving carbon nucleophiles
Starting
material
Yielda
Product (%)
Entry
Reagents
Dias.b 2,6-trans : cis
J (H5H6) 2,6-trans J (H5H6) 2,6-cis
1
29
37
37
34
34
propargyl-SiMe3, BF3ؒOEt2, CH2Cl2
propargyl-SiMe3, BF3ؒOEt2, CH2Cl2
allyl-SiMe3, BF3ؒOEt2, CH2Cl2
allyl–SiMe3, BF3ؒOEt2, CH2Cl2
Me3SiCN, BF3ؒOEt2, MeNO2
33
—
—
35
36
78c
>95 : 5
—
—
75 : 25
25 : 75
5.6, 1.8
—
—
5.8
3.4
—
d
2a
2b
3a
3b
—
—
—
9.8
d
84
76
a Yield of mixture of diastereoisomers. b Determined by analysis of the 300 MHz 1H NMR spectrum of the crude reaction mixture. c Yield of single
diastereoisomer. d No reaction.
much shorter reaction times did not prevent the intramolecular
transfer of the p-methoxybenzoyl group, it is likely that a
thermodynamic mixture of the esters 26 and 30 had been
obtained. The susceptibility of the initial product 26 to
rearrangement was thought to stem from the Lewis acidity of
the tributyltin iodide by-product. The use of tris(trimethyl-
silyl)silane31 gave superior results, and the required alcohol 26
was obtained as a single regioisomer in >98% yield provided
that the reaction was quenched after ten minutes.† It has been
previously been shown that (Me3Si)3SiI is less Lewis acidic than
tributyltin iodide.32
intermediate oxonium ion 38 (Fig. 1).36 The THP 2,6-trans-33
has the same relative configuration as the C58–C62 THP of
palytoxin.
Fig. 1
In contrast, no reaction was observed when the methyl acetal
37 was treated with either propargyl trimethylsilane or allyl tri-
methylsilane under similar conditions (entries 2a–b, Table 3).‡
This difference in reactivity is synthetically useful since selective
reaction of one of the acetals of 4 would be required in our
approach to the palytoxin fragment 2; however, the reactivity
difference is not surprising since neighbouring electron with-
drawing acyloxy substituents are well known to destabilise
oxonium ions strongly.8 However, the acetal of 37 was easily
activated by transformation into the corresponding anomeric
acetate:37 treatment of 37 with catalytic sulfuric acid in acetic
anhydride gave the pentacetate 34 in >98% yield as a 7 : 3
mixture of anomers.
Unsurprisingly, subjection of the iodo alcohol 24 to Mitsu-
nobu’s reaction conditions33 resulted only in reversion to the
allylic ester 23. However, treatment of the alcohol 26 with tri-
phenylphosphine, p-nitrobenzoic acid and diisopropyl azodi-
carboxylate (DIAD) gave the required diester 27 in 64% yield,
as well as the elimination product 23 (12% yield). Methanolysis
of the diester 27 gave the diol 28 which, after acetylation,
provided the diacetate 29 in 96% yield over the two steps.
An alternative approach for inverting the configuration of
the alcohol 26 would involve oxidation to the corresponding
ketone 31, followed by stereoselective reduction. Treatment of
the alcohol 26 with pyridinium chlorochromate34 buffered with
sodium acetate gave the ketone 31 in 89% yield. Unfortunately,
reduction of the ketone 31 with sodium borohydride ( 80 : 20
26 : 32) and K-selectride ( >95 : 5 26 : 32) resulted in mainly
equatorial attack of the reagent; this trajectory avoids an
unfavourable 1,3-diaxial interaction with the axial methoxy
group.23 In addition, both of these reactions were further
complicated by migration23 of the acyl group of 26 to give its
regioisomer 30.
The reaction of the pentacetate 34 with carbon nucleophiles
was straightforward (entries 3a–b, Table 3). Treatment of 34
with allyl trimethylsilane and boron trifluoride etherate gave the
THP38 35 as a 75 : 25 mixture of 2,6-trans and 2,6-cis
diastereoisomers 35. In contrast, reaction of 34 with trimethyl-
silyl cyanide and boron trifluoride etherate in nitromethane
proceeded in the opposite diastereoselective sense: a 75 : 25
mixture of 2,6-cis and 2,6-trans tetrahydropyrans39 36 was
obtained. In each case, the ratio and configurations of the
products were determined by careful analysis of the 300 MHz
1H NMR spectra of the crude reaction mixtures (see Table 3).
The complementary reactions of the pentacetate 34 ( 35 or
36) are remarkable and deserve further comment. Activation of
34 must initially give the oxonium ion 39 which may close to
give the dioxolenium ion 40 (Fig. 2). It appears that carbon
nucleophiles strike a more delicate balance between reaction40
with the dioxolenium ion 40 (with clean inversion of configur-
ation) and direct attack on the less stable oxonium ion 39 (with
axial attack). The sp2-hybridised nucleophile—allyl trimethyl-
silane—is believed to have attacked the oxonium ion 39 prefer-
entially, leading to a 75 : 25 mixture of diastereoisomers in
favour of the THP 2,6-trans-35. In contrast, the trimethylsilyl
cyanide may have undergone preferential reaction with 40 to
Methods were developed for the diastereoselective reaction
of six-membered acetals using carbon nucleophiles (see Scheme
9 and Table 3). Treatment of the methyl acetal 29 with pro-
pargyl trimethylsilane35 and boron trifluoride etherate in
dichloromethane was highly diastereoselective, and gave the
allene 33 in 78% yield as a >95 : 5 mixture of diastereoisomers.
The 2,6-trans configuration of the product was determined by
1
careful analysis of its 300 MHz H NMR spectrum (entry 1,
Table 3). The highly stereoselective reaction of 29 is believed
to stem from axial attack of the propargyl silane on the
‡ Perbenzylated methyl glycosides are much more reactive and undergo
clean reaction with propargyl trimethylsilane in the presence of
trimethylsilyl trifluorosulfonate (ref. 35).
† After four hours, the alcohols 26 and 30 were isolated as an 80 : 20
mixture of regioisomers.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 7 3 – 3 8 6
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Fig. 2
give mainly the THP 2,6-cis-36. Alternatively, it is possible that
the configuration of the cyanide-substituted THPs 36 was
thermodynamically controlled.
our model studies have shown that similar Prévost reactions are
only moderately (ca. 80 : 20) regioselective.6 Treatment of
the template 22 with one equivalent of both iodine and silver
benzoate in dry carbon tetrachloride gave a mixture of the
regioisomeric hydroxy esters 42 and 48, together with recovered
starting material. Separation, and two successive recycles of the
recovered starting material, gave the required hydroxy esters 42
in 54% overall yield.
Synthesis of a protected version of the C58–C71 fragment of
palytoxin
The C2-symmetrical intermediate 22 is a highly functionalised
template for further functionalisation (Schemes 10 and 11).
Hence, treatment of 22 with catalytic osmium tetraoxide
and NMO in acetone–water was followed by hydrolysis with
aqueous potassium hydroxide solution and peracetylation:
the octaacetate 41 was obtained in 87% yield as a single
diastereoisomer (Scheme 10). The level of stereoselectivity
observed in the two-directional functionalisation 22 41 is
remarkable, and we have previously exploited this approach in
the synthesis of some C-linked disaccharide mimetics.26,41 How-
ever, despite the stereochemical complexity of the octaacetate
41, this approach does not directly tackle the critical issue of
differentiation between the homotopic termini of 22: consider-
able functional group manipulation would be required to
convert 41 into the protected fragment 2.
The iodo alcohol 42 was treated with tris(trimethylsilyl)silane
and AIBN in benzene at 60 ЊC, and the required hydroxy ester
43 was obtained in >98% yield. There was no trace of the regio-
isomeric hydroxy ester which would have resulted from Lewis
acid-catalysed migration of the acyl substituent. Unfortunately,
attempted Mitsunobu inversion of the alcohol of 43 resulted
only in elimination to return the template 22. Alternative
reaction conditions, including reversing the order of reagent
addition and using DIAD in place of DEAD, did not suppress
the elimination. The presence of a proton which is anti-
periplanar to the leaving group may well promote the unwanted
elimination pathway; however, in view of the similarity between
43 and the model alcohol 26, in which only substituents which
are remote from the reacting THP rings are different, this result
was highly surprising.
Despite having found this approach fruitless in a model
system, we explored the use of an oxidation, followed by a
stereoselective reduction, to correct the configuration of the
alcohol of 43. Oxidation of the alcohol 43 with pyridinium
chlorochromate, in the presence of sodium acetate, gave the
corresponding ketone 44. As we had observed with the ketone
31, however, reduction with sodium borohydride in ethanol
gave mainly the equatorial alcohol: analysis of the crude
reaction mixture by 300 MHz 1H NMR spectroscopy revealed a
90 : 10 mixture of the alcohols 43 and 45, together with signifi-
cant quantities of the rearrangement product in which the
neighbouring p-methoxybenzoyl group had migrated to the
alcohol of 43. Remarkably, the sense of induction was reversed
by treating the ketone 44 with sodium borohydride in THF at
50 ЊC. Under these conditions, the required alcohol 45 was
Scheme 10
1
obtained in 54% yield. Careful analysis of the 500 MHz H
We investigated the use of a Prévost reaction to differentiate
between the homotopic termini of 22 (Scheme 11). The two
dihydropyran rings of 22 are sufficiently remote that an essen-
tially statistical functionalisation was expected. Furthermore,
NMR spectra of 43 and 45 revealed the hydroxyl group to be
axial [3J(H3H4): 2.8 Hz] and equatorial [3J(H3H4): 10.0 Hz]
respectively. The alcohol 45 was acetylated to give 46 in >98%
yield.
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Scheme 11
The Prévost reaction of 46 provided a valuable means for
Summary
functionalising the remaining THP ring. Reaction of the allylic
p-methoxybenzoate 46 with iodine and silver benzoate in rigor-
ously dry carbon tetrachloride gave a crude product which
was treated with potassium hydroxide in water–THF and
peracetylated. Under these conditions, the epoxide 49 was
obtained as a single diastereoisomer in 74% yield. Although we
had expected that ring-opening of the epoxide by hydroxide ion
would have occurred under these conditions, the isolation of
the epoxide 49 did, at least, provide direct evidence for a mech-
anism proposed for the transformation 24 25.6 Furthermore,
in view of the hydrolysis of the tert-butyldimethylsilyl ethers of
22 ( 41) under remarkably similar conditions, the survival
of the silyl ethers in 49 was surprising. It appears that the use of
THF as a co-solvent in hydrolysis of the Prévost product is
important: under biphasic conditions, the substrate may remain
in the organic layer and, therefore, be physically separated from
the aqueous base.
We have shown that the Prévost reaction is a reliable reaction
for the functionalisation of allylic p-methoxybenzoates. This
reaction was used to functionalise both of the THP rings of the
di-THP 47. In the first instance, treatment of the C2-sym-
metrical template 22 with iodine and silver benzoate gave the
iodo alcohol 42 in which the homotopic termini had been dif-
ferentiated. The participation of the neighbouring p-methoxy-
benzoyloxy group ensured that the iodine atom was introduced
to (and could subsequently be removed from) the atom (C59)
of palytoxin which lacks a hydroxyl group. At a later stage,
a Prévost reaction was used once more to the functionalise
the other THP ring; after hydrolysis, and peracetylation, a
protected C58–C71 fragment, 47, of palytoxin was isolated.
Using a model system, methods have been developed for the
reaction of the two acetals of 47 with carbon nucleophiles.
However, due to a lack of material, the fragment 47 was not
further functionalised. We have shown that the C58 acetal of 47
is likely to be the more reactive, and reaction of this acetal with
carbon nucleophiles would probably lead to a 2,6-anti THP, as
required. The C71 acetal has a neighbouring participating
group, and in a model system, this feature could be exploited in
the synthesis of a 2,6-syn THP ring.
In summary, a two-directional synthetic strategy has been
applied in the synthesis of a protected version of the C58–C71
fragment of palytoxin. This fragment is almost C2-symmetrical,
and this hidden symmetry was exploited in the synthesis of the
C2-symmetrical template 22. Further stereoselective function-
alisation gave the required fragment 47.
Indeed, treatment of the crude Prévost product with reflux-
ing aqueous potassium hydroxide in the absence of THF, and
peracetylation, provided the required intermediate 47; the
relative configuration of 47 was established by comparison of
its 1H NMR spectrum with those of the model compounds 256
and 29. We have previously shown, in related systems, that
similar epoxides are also opened to give trans-diequatorial
products; this unusual42 observation has been rationalized
elsewhere.6 The heptaacetate 47 is a protected version of the
C58–C71 fragment of palytoxin.
Experimental
General experimental methods have been previously described.6
All non-aqueous reactions were performed under an atmos-
phere of nitrogen. Analytical HPLC was conducted on a
Gynkotek HPLC system with diode array detection; unless
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otherwise stated, the column oven was set at 24 ЊC. An Econosil
column (silica particle size: 10 µm) was used for analytical
(4.6 × 250 mm) work, and a Chiracel OD column (4.6 ×
250 mm) was used for chiral analytical HPLC; samples were
calibrated against external standard samples dissolved in
methanol. Semi-preparative HPLC was conducted with a
Waters 2525 binary gradient pump with detection by a Micro-
mass ZQ mass spectrometer; an XTerra® preparative HPLC
column (19 × 50 mm) was used. Microanalyses were carried out
by staff of the Department of Chemistry using a Carlo Erba
1106 automatic analyser.
and purified by flash chromatograph, eluting with EtOAc, to
give the aldehyde 10 (205 mg, 64%) as a colourless oil, Rf 0.19
(EtOAc); (Found: MNaϩ 456.2577; C20H43NO5Si2 requires
MNa, 456.2577); νmax/cmϪ1 (CHCl3 solution) 3447, 2939 (C–H),
2857, 1715, 1664, 1472, 1413, 1388, 1256 and 1096; δH (300
MHz; CDCl ) 9.72 (1H, dd, J 2.9 and 1.7, HC᎐O), 4.32–4.14
᎐
3
(2H, m, 3-H and 4-H), 3.62 (3H, s, OCH3), 3.11 (3H, s, NCH3),
2.65–2.43 (4H, m, CH2), 0.79 (9H, s,tBu), 0.77 (9H, s,tBu), 0.05
(3H, s, SiCH3), 0.03 (3H, s, SiCH3), 0.00 (3H, s, SiCH3) and
Ϫ0.04 (3H, s, SiCH ); δ (75 MHz; CDCl ) 201.9 (C᎐O), 71.5,
᎐
3
C
3
70.1, 61.7, 46.2, 33.3, 32.4, 26.1, 26.1, 18.3, Ϫ4.1, Ϫ4.5 and
Ϫ4.5; m/z (ES) 456.2 (100%, MNaϩ).
(3R,4R)-3,4-Di-(tert-butyl-dimethyl-silyloxy)-1,6-di-morpholin-
4-yl-hexane-1,6-dione 6
Addition of 2-lithio furan to the aldehyde 10
The amide 5 (300 mg, 1.056 mmol) was added to a stirred suspen-
sion of AD-mix β (1.479 g, 1.4 g per mmol), methanesulfonamide
(100 mg, 1.056 mmol), potassium osmate dihydrate (4 mg,
1 mol%) and ligand DHQD2-PHAL (41 mg, 5 mol%) in 1 : 1
t-butanol-water (3 ml) at 0 ЊC. This solution was stirred vigor-
ously for 48 h before quenching with a saturated aqueous solu-
tion of sodium sulfite (3 ml). After stirring for a further 30 min
the solution was evaporated to dryness and the thoroughly dried
residue stirred in dry DMF (5 ml). The solution was filtered and
the residue washed with a further portion of DMF (1.0 ml). The
solution was stirred for 24 h at room temperature under N2 after
the addition of imidazole (433 mg, 6.37 mmol) and t-butyl-
dimethylsilyl chloride (637 mg, 4.22 mmol). The solvent was
removed by evaporation under reduced pressure at 80 ЊC and the
residue partitioned between EtOAc (10 ml) and saturated aque-
ous sodium bicarbonate (5 ml). The organic layer was washed
with water (2 × 5 ml) and brine (5 ml) before drying (MgSO4).
Solvent was removed under reduced pressure to give the silyl
diether10 6 (386 mg, 67%) as a colourless oil.
Butyllithium (535 µl of a 1.52 M solution in hexanes, 0.813
mmol) was added slowly to a stirred solution of furan (64 µl,
0.890 mmol) in dry tetrahydrofuran (3 ml) at Ϫ78 ЊC. The solu-
tion was allowed to warm to 0 ЊC, stirred for a further 30 min,
rapidly cooled to Ϫ40 ЊC and the aldehyde 10 (74 mg, 0.171
mmol) added as a solution in THF (0.5 ml). The solution was
stirred for a further 6 h, quenched by addition of a saturated
aqueous solution of ammonium chloride (5 ml), warmed to
room temperature and the aqueous layer extracted with EtOAc
(3 × 50 ml). The combined organic layers were dried (MgSO4)
and evaporated under reduced pressure to give the alcohol 11
(81 mg, 93%) as a colourless oil. Analysis of the crude reaction
1
mixture by 300 MHz H NMR revealed a 1 : 1 mixture of
diastereoisomers.
(3R*,4R*)-1,6-Di-furan-2-yl-3,4-dihydroxy-hexane-1,6-dione 12
A solution of hydrogen fluoride–pyridine complex was pre-
pared by dissolving commercial HF pyridine complex (3.8 ml)
and pyridine (14 ml) in tetrahydrofuran (40 ml). The diketone 7
(1.35 g, 2.66 mmol) was dissolved in 10 ml of this solution and
stirred at room temperature under N2 for 4 days before the
solution was cautiously dropped into a saturated aqueous solu-
tion of sodium bicarbonate (20 ml). The aqueous layer was
extracted with EtOAc (4 × 20 ml) and the combined extracts
dried (MgSO4), solvent was removed under reduced pressure
and the residue pre-absorbed on silica gel. Purification by
flash chromatography, eluting with 6 : 4 EtOAc–petrol, gave
the difuryl diol 12 (148 mg, 20%) as colourless prisms, mp
127.4–128.7 ЊC; Rf 0.12 (6 : 4 EtOAc–petrol); (Found: MNaϩ
301.0678; C14H14O6 requires MNa, 301.0688); νmax/cmϪ1 (CHCl3
(4R*,5R*)-Di-(5-methoxycarbonylmethyl)-2,2-dimethyl-[1,3]-
dioxolane 8b
trans-Hydromuconic acid (1.00 g, 6.94 mmol was added slowly
in small portions to a stirred solution of potassium carbonate
(958 mg, 6.94 mmol) in water (5 ml). N-methylmorpholine-
N-oxide (1.62 g, 13.88 mmol) and osmium tetroxide (10 mg,
catalytic) were added and the solution stirred at room temper-
ature for 4 h. The solution was acidified to pH 1 with p-toluene-
sulfonic acid and evaporated to dryness under reduced pressure.
The residue was dissolved in a 1 : 1 mixture of acetone–2,2-
dimethoxypropane (15 ml) and stirred at room temperature for
a further 12 h. The solution was neutralized with triethyl-
amine (2 ml) and the solvent removed under reduced pressure.
The residue was partitioned between EtOAc (20 ml) and water
(20 ml) and the aqueous layer extracted with a further portion
of EtOAc (10 ml). The combined extracts were dried (MgSO4)
and the solvent removed under reduced pressure to give the
diester 8b (634 mg, 35%) as a colourless oil, νmax/cmϪ1 (CHCl3
solution) 3307 (O–H), 3115, 1664 (C᎐O), 1563, 1469, 1398,
᎐
1282, 1162, 1051 and 1024; δH (300 MHz; DMSO-d6) 8.03 (2H,
dd, J 1.5 and 0.6, furyl 5-H), 7.50 (2H, dd, J 2.9 and 0.6, furyl
4-H), 6.76 (2H, dd, J 2.9 and 1.5, furyl 3-H), 4.95 (2H, d, J 5.5),
4.09 (2H, broad s, 3-H and 4-H), 3.46 (2H, s, OH), 3.05 (2H, dd,
J 15.4 and 9.0, CHaHb), 2.92 (2H, dd, J 15.4 and 2.6, CHaHb);
δC (75 MHz; DMSO-d ) 187.9 (C᎐O), 152.8 (furyl 2-C), 147.9
᎐
6
(furyl 5-C), 119.0 (furyl), 112.8 (furyl), 70.2 (C–O) and 41.4
solution) 2989 (C–H), 2955, 1741 (C᎐O), 1439, 1382, 1204, 1172
(CH2); m/z (ES) 301.1 (100%, MNaϩ).
᎐
and 1061; δH (300 MHz; CDCl3) 4.17 (2H, t, J 4.0), 3.71 (6H, s,
CH3), 2.67 (4H, d, J 5.0) and 1.40 (6H, s, CH3); δC (75 MHz;
(1R,3R,4R,6R)-3,4-Di-(tert-butyl-dimethyl-silyloxy)-1,6-di-
furan-2-yl-hexane-1,6-diol 14
CDCl ) 171.4 (C᎐O), 109.6, 77.1, 52.2, 38.0 and 27.5.
᎐
3
A stock solution of the CBS reagent (0.2 M solution) was
freshly prepared by stirring a solution of (S)-diphenylprolinol
(506 mg, 2 mmol) and n-butylboronic acid (204 mg, 2 mmol) in
sodium dried toluene (10 ml) over 4 Å molecular sieves for 2 h.
An aliquot of the stock solution of the CBS reagent (197 µl,
39.4 µmol, 10 mol%) was added to a stirred solution of the
diketone 7 (200 mg, 0.39 mmol) in toluene (3.2 ml) at room
temperature under N2. To the stirred solution borane dimethyl
sulfide complex (0.39 ml, 0.78 mmol, 2 M solution in THF) was
added slowly over 1 h. The solution was stirred for a further 5 h
and then quenched with a saturated aqueous solution of
ammonium chloride (3 ml). The organic layer was dried
(3R*,4R*)-3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-6-oxo-6-
[methoxy(methyl)amino]hexan-1-al 10
DIBAL (2.95 ml, 2.95 mmol, as a 1 M solution in toluene) was
added to a stirred solution of the Weinreb diamide10 9 (363 mg,
0.738 mmol) in dry THF (10 ml) at Ϫ78 ЊC. The solution was
stirred for a further 6 h and quenched with methanol (0.5 ml).
The solution was allowed to warm to room temperature,
saturated aqueous sodium potassium tartrate solution added
(10 ml), stirred vigorously until the two layers separated and the
aqueous layer extracted with EtOAc (2 × 10 ml). The combined
organic layers were dried (MgSO4), pre-absorbed on silica gel
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 7 3 – 3 8 6
380

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(MgSO4) and solvent removed by evaporation under reduced
pressure to give a crude product. Analysis by analytical HPLC
1.14 mmol) and vanadyl acetylacetonate (5 mg) in dichloro-
methane (4 ml) at room temperature under N2. The solution
was stirred for 6 h before the solution was evaporated to half its
original volume with a steady stream of nitrogen. The floccu-
lent white needles were filtered and washed with petrol ether
(2 ml). A second crop was procured by evaporating under
reduced pressure at room temperature, trituration with petrol
(4 ml) and filtration. The dipyranone 20 (R = H; 594 mg, 96%;
65 : 35 mixture of anomers) was obtained as flocculent colour-
less needles, [α]D = ϩ24.2 (c = 0.57, MeOH); Rf 0.34 (1 : 1
EtOAc–petrol); (Found: MNaϩ, 565.2622; C26H46O8Si2 requires
MNa, 565.2629); νmax/cmϪ1 (thin film) 3341, 2927, 2853, 1684,
1470, 1259, 1204, 1091 and 1044; δH (300 MHz; DMSO-d6) 7.14
(2H, d, J 8.5, O–Hmin), 6.97 (2H, dd, J 10.2 and 3.6, 5-Hmaj),
6.93 (2H, d, J 10.2, 5-Hmin), 6.84 (2H, d, J 7.4, O–Hmaj), 6.00
(2H, d, J 10.2, 4-Hmin), 5.93 (2H, d, J 10.2, 4-Hmaj), 5.38 (2H, d,
J 8.5, 6-Hmin), 5.33 (2H, dd, J 7.4 and 3.6, 6-Hmaj), 4.38 (2H, d,
J 11.0, 2-Hmaj), 3.93 (2H, d, J 10.2, 2-Hmin), 3.84 (2H, m,
2-HЈ and 3-HЈ), 1.80–1.50 (4H, m, CH2majϩmin), 0.74 (18H, s,tBu,
Hmajϩmin) and 0.00 (12H, s, SiCH3, Hmajϩmin); δC (75 MHz;
DMSO-d6) 197.9 (3-Cmaj), 197.4 (3-Cmin), 148.4 (5-Cmajϩmin),
127.9 (4-Cmin), 125.8 (4-Cmaj) 91.0 (6-Cmin), 86.7 (6-Cmaj) 74.5
(Cmin), 70.4 (Cmaj), 69.6 (Cmaj), 69.2 (Cmin), 26.1 (tBu), 18.0,
Ϫ4.3, Ϫ4.4 and Ϫ4.5; m/z (ES) 565.9 (100%, MNaϩ).
(gradient elution: 99 : 1
98 : 2 hexane : IPA over 30 min,
with detection at 220 nm) revealed a 90 : 10 mixture of the
diastereoisomers 14 and 16. The crude product was pre-
absorbed onto silica gel and separated by flash chromatography
to give the difuryl diol10 14 (165.6 mg, 82%) as colourless
needles, mp 105–106 ЊC; [α]D = ϩ31.7 (c = 1.69, CHCl3). Analy-
sis of the diol 14 by chiral analytical HPLC revealed it to have
>98% ee and >99% purity (gradient elution: 99.6 : 0.4
97.5 :
2.5 hexane–isopropanol over 30 min; flow: 1.0 ml minϪ1; obser-
vation at λmax, 219 nm; retention times, 24.4 and 26.2 min).
Also obtained was the difuryl diol10 16 (13.9 mg, 7%) as
colourless needles, mp 95–96 ЊC; [α]D = Ϫ19.6 (c = 1.43, CHCl3).
Asymmetric reduction of the racemic diketone 7
By the same general method, the racemic diketone 7 (200 mg,
0.39 mmol) gave a crude product Analysis by analytical HPLC
revealed a 49.7 : 0.6 : 49.7 mixture of the diols 14, 15 and 16.
Pre-absorption of the crude mixture onto silica gel and separ-
ation by flash chromatography gave the diol10 14 (82 mg, 41%),
mp 105–106 ЊC, [α]D = ϩ29.4 (c = 0.14, CHCl3), and the diol10
16 (83 mg, 42%), mp 95–97 ЊC, [α]D = Ϫ18.2 (c = 0.11, CHCl3).
Analysis of the diol 14 by chiral analytical HPLC revealed it to
have >98% ee.
(2R)-2-[(2R,3R)-2,3-Bis-(tert-butyl-dimethyl-silanyloxy)-4-
((R)-3-oxo-6-methoxy-3,6-dihydro-2H-pyran-2-yl)-butyl]-6-
methoxy-6H-pyran-3-one 20 (R ؍ Me)
(E )-(1R,6R)-1,6-Difuran-2-yl-hex-3-ene-1,6-diol 19
The furyl alcohol21 (R)-18 (1.00 g, 7.30 mmol) and bis(tricyclo-
hexylphosphine)benzylideneruthenium() dichloride (300 mg,
0.36 mmol, 5 mol%) in dichloromethane (4 ml) were refluxed
under N2 for 4 days. The solvent was evaporated under reduced
pressure to give a crude product. Analysis by 300 MHz 1H NMR
spectroscopy revealed a 4 : 1 ratio of E : Z isomers. Flash chro-
Boron trifluoride diethyl etherate complex (5 µl, 39 µmmol) was
added to a stirred solution of (R)-2-[(2R,3R)-2,3-bis-(tert-
butyl-dimethyl-silanyloxy)-4-((R)-3-oxo-6-hydroxy-3,6-dihydro-
2H-pyran-2-yl)-butyl]-6-hydroxy-6H-pyran-3-one 20 (R = H)
(427 mg, 0.78 mmol) and trimethyl orthoformate (258 µl,
2.35 mmol) in dichloromethane (5 ml) at room temperature
under N2. Stirring was continued for a further 30 min before
the solution was quenched with saturated aqueous sodium
bicarbonate (10 ml). The aqueous layer was extracted with di-
chloromethane (2 × 5 ml) and the combined organic extracts
dried (MgSO4). Solvent was removed under reduced pressure
to give the acetal 20 (R = Me; 446 mg, >98%; 63 : 37 mixture of
matography (gradient elution: 2 : 8
1 : 1 EtOAc–petrol) gave
the alkene (E)-(1R,6R)-19 (570 mg, 63%) as a colourless oil, Rf
0.09 (2 : 8 EtOAc–petrol); νmax/cmϪ1 (CHCl3 solution) 3255, 2917,
1504, 1437, 1353, 1298, 1228, 1216, 1151, 1009 and 907; δH (300
MHz; CDCl3) 7.11 (2H, dd, J 1.8 and 0.9, furyl 5-H), 6.15 (2H,
dd, J 3.0 and 1.8, furyl 3-H), 6.04 (2H, dd, J 3.0 and 0.9, furyl
4-H), 5.36 (2H, br s, HC᎐C), 4.50 (2H, t, J 6.3, HC–O), 2.60 (2H,
᎐
anomers), a colourless oil, Rf 0.28 (2 : 8 EtOAc–petrol); (Found:
broad s, OH) and 2.38 (4H, broad, CH2); δC (75 MHz; CDCl3)
156.5 (furyl 2-C), 142.3 (furyl 5-C), 129.8, 110.5 (furyl), 106.4
(furyl), 67.3 (C–O) and 39.4 (CH2); m/z (ES) 270.8 (100%,
MNaϩ).
ϩ
MNH4
, 588.3384. C28H50Si2O8 requires MNH4 588.3388);
νmax/cmϪ1 (CHCl solution) 2957 (C–H), 2931 2859, 1699 (C᎐O),
᎐
3
1472, 1390, 1259, 1101 and 1053; δH (300 MHz; CDCl3) 6.77 (2H,
d, J 10.3, 5-Hmin), 6.71 (2H, dd, J 10.2 and 3.3, 5-Hmaj), 6.07 (2H,
d, J 10.3, 4-Hmin), 6.00 (2H, d, J 10.2, 4-Hmaj), 5.18 (2H, s, 6-Hmin),
4.97 (2H, d, J 3.3, 6-Hmaj), 4.39 (2H, dd, J 10.5 and 1.8, 2-Hmaj),
4.05 (2H, d, J 11.0, 2-Hmin), 3.92 (2H, t, J 11.0, 2,3-Hmin), 3.56
(6H, s, OMemajϩmin), 2.08 (2H, d, J 12.0 CHaHbmaj), 1.96 (2H, d,
J 12.0, CHaHbmin), 1.85 (2H, d, J 13.8, CHaHbmin), 1.78 (2H, d,
J 13.8, CHaHbmin), 0.77 (18H, s,tBu, Hmin), 0.77 (18H, s,tBu, Hmaj),
0.03 (6H, s, SiCH3, Hmin), 0.02 (6H, s, SiCH3, Hmaj), 0.00 (6H, s,
SiCH3, Hmin), Ϫ0.03 (6H, s, SiCH3, Hmaj); δC (75 MHz; CDCl3)
195.5 (3-Cmaj), 195.4 (3-Cmin), 146.3 (5-Cmin), 141.9 (5-Cmaj),
128.5 (4-Cmin), 126.6 (4-Cmaj), 96.0 (6-Cmin), 93.3 (6-Cmaj), 74.0
(Cmin), 70.9 (Cmaj), 69.8 (Cmaj), 69.6 (Cmin), 55.9 (OMemaj), 54.8
(OMemin), 30.2 (CH2maj), 29.4 (CH2min), 24.7 (tBumajϩmin), 17.0,
Ϫ4.8 (SiMe), Ϫ4.9 (SiMe), Ϫ5.9 (SiMe) and Ϫ5.7 (SiMe); m/z
(ES) 593.7 (100%, MNaϩ).
E-(1R*,6S*)-1,6-Difuran-2-yl-hex-3-ene-1,6-diol 19
By the same general method, the racemic alcohol 18 (1.00 g,
7.30 mmol) and bis(tricyclohexylphosphine)benzylidene-
ruthenium() dichloride (300 mg, 0.36 mmol, 5 mol%) in di-
chloromethane (4 ml), gave a crude product. Analysis by 300
1
MHz H NMR spectroscopy revealed a 4 : 1 mixture of E : Z
isomers. Recrystallization from chloroform gave the alkene
(E)-(1R*,6S*)-19 (171 mg, 19%) as colourless needles, mp
112.7–114.2 ЊC; Rf 0.12 (2 : 8 EtOAc–petrol); νmax/cmϪ1 (CHCl3
solution) 3255 (O–H), 2917, 1504, 1437, 1353, 1298, 1228, 1216,
1151, 1009 and 907; δH (300 MHz; CDCl3) 7.53 (2H, dd, J 1.6
and 0.7, furyl 5-H), 6.35 (2H, dd, J 3.0 and 1.6, furyl 3-H), 6.04
(2H, dd, J 3.0 and 0.7, furyl 4-H), 5.40 (2H, dd, J 7.3 and 3.7,
HC᎐C), 5.25 (2H, d, J 5.3), 4.44 (2H, m), 3.36 (2H, s, OH) and
In a separate experiment, the dipyranone C2-20 (R = Me),
spectroscopically identical to the major isomer obtained
previously, was isolated in 52% yield by careful flash column
chromatography (eluting with 2 : 8 EtOAc–petrol).
᎐
2.50–2.34 (4H, broad, CH2); δC (75 MHz; CDCl3) 157.9 (furyl
2-C), 141.9 (furyl 5-C), 128.8, 110.4 (furyl), 105.8 (furyl), 66.5
(C–O) and 39.4 (CH2); m/z (ES) 270.8 (100%, MNaϩ).
(R)-2-[(2R,3R)-2,3-Bis-(tert-butyl-dimethyl-silanyloxy)-4-((R)-
3-oxo-6-hydroxy-3,6-dihydro-2H-pyran-2-yl)-butyl]-6-hydroxy-
6H-pyran-3-one 20 (R ؍ H)
(2R,3R,6R)-2-[(2R,3R)-2,3-Bis-(tert-butyl-dimethyl-silany-
loxy)-4-((2R,3R,6R)-3-hydroxy-6-methoxy-3,6-dihydro-2H-
pyran-2-yl)-butyl]-6-methoxy-3,6-dihydro-2H-pyran-3-ol 21
t-Butyl hydroperoxide (570 µl, 2.85 mmol, 5 M solution in
decanes) was added to a stirred solution of the diol 14 (586 mg,
The diacetal 20 (421 mg, 0.736 mmol; 63 : 37 mixture of
anomers) and cerium chloride heptahydrate (686 mg, 1.84
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 7 3 – 3 8 6
381

View Article Online
mmol) were stirred under nitrogen at Ϫ40 ЊC in ethanol (5 ml)
while sodium borohydride (62 mg, 1.62 mmol) was added
slowly in small portions. The solution was stirred for 6 h,
quenched with water (1.0 ml) and evaporated under reduced
pressure to give a crude product which was pre-absorbed onto
silica gel and purified by careful flash chromatography (gradient
1168, 1090 and 1026; δH (500 MHz; CDCl3) 7.90 (2H, d, J 9.0,
Ar), 6.79 (2H, d, J 9.0, Ar), 4.72 (1H, d, J 3.0, 6-H), 4.67 (1H,
dd, J 10.1 and 3.0, 3-H), 4.11 (1H, br, td, J 3.5 and 3.0, 4-H),
4.02 (1H, td, J 10.1 and 2.6, 2-H), 3.73 (3H, s, OMe), 3.37 (1H,
d, J 9.4, OH), 3.28 (3H, s, OMe), 2.03 (1H, dd, J 14.8 and 3.0,
CHaHb), 1.90 (1H, td, J 14.8 and 3.0, CHaHb), 1.75–1.20 (6H,
m, butyl CH2) and 0.87 (3H, t, J7.4, CH3); δC (75 MHz; CDCl3)
elution: 15 : 85
25 : 75 EtOAc–petrol) to give the diol 21 (173
mg, 41%) as a colourless oil, [α]D = ϩ19.4 (c = 0.12, CHCl3);
166.4 (C᎐O), 162.5 (Ar), 130.8 (Ar), 121.2 (Ar), 112.6 (Ar), 97.4
᎐
Rf 0.32 (3 : 7 EtOAc–petrol); (Found: MNH4ϩ, 592.3707.
(6-H), 72.6, 64.9, 63.9, 54.2, 31.4, 28.0, 22.8 and 14.4; m/z (ES)
ϩ
C28H54Si2O8 requires MNH4 592.3701); νmax/cmϪ1 (CHCl3
360.8 (100%, MNaϩ).
solution) 3436, 2956, 2929, 2856, 1472, 1260, 1054 835; δH (500
MHz; CDCl3) 5.85 (2H, d, J 10.2, 5-H), 5.60 (2H, dt, J 10.2 and
1.8, 4-H), 4.65 (2H, s, 6-H), 3.72 (2H, br m, 3-H), 3.46 (2H, td,
J 8.7 and 1.8, 2-H), 3.32 (6H, s, OMe), 1.80–1.50 (4H, m, CH2),
0.77 (18H, s,tBu), 0.01 (6H, s, SiCH3) and 0.00 (6H, s, SiCH3);
δC (125 MHz; CDCl3) 134.1, 126.7, 96.0, 71.7, 69.8, 68.5, 56.9,
34.0, 26.3, 18.4, Ϫ3.6 and Ϫ4.2; m/z (ES) 574.3 (100%,
MNH4ϩ).
4-Methoxy-benzoic acid (2R*,3S*,4R*,6S*)-2-butyl-4-
(4-nitrobenzoyl)-6-methoxy-tetrahydro pyran-3-yl ester 27
Diisopropyl azodicarboxylate (108 mg, 103 µl, 0.534 mmol) was
added slowly to a stirred solution of triphenylphoshine (140.0
mg, 0.534 mmol) in THF (3 ml) at 0 ЊC under nitrogen. The
resulting slurry was stirred for a further 20 min, the hydroxy
ester 26 (93 mg, 0.276 mmol) was added as a solution in THF
(1.2 ml), p-nitrobenzoic acid (89.2 mg, 0.534 mmol) added
immediately and the solution was allowed to warm to room
temperature and stirred for a further 48 h before solvent was
removed and the residue pre-absorbed onto silica. Purification
by flash chromatography, eluting with 15 : 85 EtOAc-petrol
gave the diester 27 (85.8 mg, 64%), a colourless crystalline solid,
mp 180–181 ЊC; Rf 0.24 (1 : 9 EtOAc-petrol); νmax/cmϪ1 (CHCl3
solution) 2932, 1721, 1712, 1606, 1526, 1263, 1172, 1119, 1049;
δH (300 MHz; CDCl3) 8.20 (2H, d, J 9.0, Ar), 8.08 (2H, d, J 9.0,
Ar), 7.92 (2H, d, J 9.0, Ar), 6.85 (2H, d, J 9.0, Ar), 5.62 (1H,
ddd, J 12.9, 9.6 and 5.4, 4-H), 5.22 (1H, t, J9.6, 3-H), 4.90 (1H,
d, J 3.4, 6-H), 3.92 (1H, td, J 9.6 and 2.3, 2-H), 3.82 (3H, s,
OMe), 3.42 (3H, s, OMe), 2.47 (1H, dd, J 12.9 and 5.4, CHaHb),
1.95 (1H, td, J 12.9 and 3.4, CHaHb), 1.80–1.10 (6H, m, butyl
CH2) and 0.87 (3H, t, J7.4, CH3); δC (75 MHz; CDCl3) 165.9,
164.4, 164.1, 150.9, 135.6, 132.2, 131.2, 123.9, 122.0, 114.1,
98.2, 73.5, 72.0, 69.7, 55.9, 55.3, 35.7, 31.5, 27.9, 23.0 and 14.4;
m/z (ES) 509.7 (100%, MNaϩ).
In a separate experiment, the dipyranone C2-20 was reduced
under identical conditions to give the diol 21 in >98% yield.
4-Methoxybenzoic acid (2R,3R,6R)-2-[(2R,3R)-2,3-bis-(tert-
butyl-dimethyl-silanyloxy)-4-((2R,3R,6R)-6-methoxy-3-
(4-methoxybenzoyloxy)-3,6-dihydro-2H-pyran-2-yl)-butyl]-6-
methoxy-3,6-dihydro-2H-pyran-3-yl ester 22
The diol 21 (273 mg, 0.474 mmol) and triethylamine (237 µl,
1.71 mmol) were stirred at room temperature under nitrogen in
dichloromethane (5 ml, 0.095 M in the diol) while p-anisoyl
chloride (142 µl, 1.04 mmol) was added by syringe. The result-
ing solution was treated with DMAP (2.9 mg, 23.7 µmol) and
stirred for 18 hours. The solution was quenched with saturated
aqueous sodium bicarbonate (5 ml) and diluted with chloro-
form (10 ml). The organic layer was separated and washed with
saturated aqueous sodium bicarbonate (2 × 5 ml) and brine
(5 ml) and was dried (MgSO4) and evaporated under reduced
pressure to give a crude product which was purified by flash
chromatography, after pre-absorption onto silica gel (gradient
Also obtained was allylic p-methoxybenzoate 23 (10.6 mg,
12%).
elution: 1 : 9
2 : 8 EtOAc–petrol) to give the diester 22
(389 mg, 97%) as a colourless crystalline solid, mp 191–192 ЊC;
[α]D = ϩ17.3 (c = 0.31, CHCl3); Rf 0.32 (15 : 85 EtOAc–petrol);
(Found: MNaϩ, 865.3394. C44H66Si2O12 requires MNa
865.3991); νmax/cmϪ1 (CHCl3 solution) 2931 (C–H), 2857, 1718
(2R*,3S*,4R*,6S*)-2-Butyl-6-methoxy-tetrahydro-pyran-3,4-
diol 28
Potassium carbonate (144.5 mg, 1.047 mmol) was added to a
stirred solution of the diester 27 (102 mg, 0.209 mmol) in
methanol (2 ml), at room temperature under nitrogen. The solu-
tion was stirred for 3 days, the solvent was removed under
reduced pressure and the residue pre-absorbed onto silica.
Purification by flash chromatography (gradient elution: 4 : 6
(C᎐O), 1604, 1512, 1464, 1325, 1257, 1105, 1051; δ (300 MHz;
᎐
H
CDCl3) 7.75 (4H, d, J 8.7, Ar), 6.69 (4H, d, J 8.7, Ar), 5.80 (2H,
d, J 10.3, 5-H), 5.61 (2H, dt, J 10.3 and 1.8, 4-H), 4.93 (2H, dd,
J 9.5 and 1.8, 3-H), 4.64 (2H, s, 6-H), 3.86 (2H, t, J 9.5, 2-H),
3.70 (2H, dd, J 9.5 and 7.2, 2-HЈ and 3-HЈ), 3.68 (6H, s, OMe),
3.29 (6H, s, OMe), 1.61 (2H, dd, J 13.8 and 9.5, CHaHb), 1.26
(2H, dd, J 13.8 and 7.2, CHaHb), 0.76 (18H, s,tBu), 0.00 (6H, s,
SiCH3) and Ϫ0.03 (6H, s, SiCH3); δC (75 MHz; CDCl3) 164.0,
132.2, 130.6, 127.8, 122.7, 114.0, 96.1, 71.6, 69.9, 66.7, 57.1,
55.9, 34.2, 26.2, 18.4, Ϫ3.6 and Ϫ4.2; m/z (ES) 883.4 (100%,
MNaϩ).
8 : 2 EtOAc–petrol) gave the diol 28 (41.0 mg, 96%), as a
colourless oil, Rf 0.21 (1 : 1 EtOAc–petrol); (Found: MNH4
ϩ
,
222.1704. C10H24NO4 requires MNH4 222.1705); νmax/cmϪ1
(CHCl3 solution) 3400 (O–H), 2933 (C–H), 1443, 1209, 1128,
1050, 951, 900; δH (300 MHz; CDCl3) 4.75 (1H, d, J 3.2, 6-H),
3.87 (1H, ddd, J 11.6, 9.2 and 5.0, 4-H), 3.55 (2H, br, OH), 3.44
(1H, td, J 9.2 and 2.0, 2-H), 3.31 (3H, s, OMe), 3.13 (1H, t,
J 9.2, 3-H), 2.11 (1H, ddd, J 12.7, 5.0 and 0.9, CHaHb), 1.65
(1H, ddd, J 12.7, 11.6 and 3.2, CHaHb), 1.55–1.25 (6H, m, CH2)
and 0.92 (3H, t, J6.8, CH3); δC (75 MHz; CDCl3) 98.6, 76.7,
71.5, 69.9, 54.9, 38.0, 31.6, 28.1, 23.2 and 14.5; m/z (ES) 222.1
(100%, MNH4ϩ).
4-Methoxybenzoic acid (2R*,3S*,4S*,6S*)-2-butyl-4-hydroxy-
6-methoxy-tetrahydropyran-3-yl ester 26
A solution of iodo alcohol 24 (104 mg, 0.224 mmol) in benzene
(3.0 ml) was deoxygenated by bubbling through a steady stream
of nitrogen for 30 seconds. Tris-(trimethylsilyl)silane (150 µl)
was added while the solution was stirred under nitrogen at
65 ЊC, and azobiisobutyronitrile (5 mg) was added. The reac-
tion was stirred at 65 ЊC for a further 30 min or until TLC
indicated completion, cooled in an ice bath and loaded directly
without pre-absorption or concentration onto a short column
of silica. Elution first with 1 : 9 EtOAc–petrol and then 4 : 6
EtOAc–petrol gave the hydroxy ester 26 (74.9 mg, >98%; 26 : 30
>98 : 2) as a colourless oil, Rf 0.36 (3 : 7 EtOAc–petrol);
(Found: MHϩ, 339.1804. C18H26O6 requires MH 339.1807);
νmax/cmϪ1 (CHCl3 solution) 3522, 2955, 1713, 1606, 1512, 1257,
Acetic acid (2R*,3S*,4R*,6S*)-3-acetoxy-2-butyl-6-methoxy-
tetrahydropyran-4-yl ester 29
The diol 28 (54.6 mg, 0.268 mmol) was stirred in a mixture of
acetic anhydride (2 ml) and pyridine (1 ml) at room temperature
under nitrogen for 12 h. Solvent was removed under reduced
pressure and the residue dissolved in chloroform (5 ml) and
washed with a saturated aqueous sodium bicarbonate solution
(2 ml) and brine (2 ml), dried (MgSO4) and evaporated under
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 7 3 – 3 8 6
382

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reduced pressure to give the diacetate 29 (76.9 mg, >98%) as a
Acetic acid (2R*, 3R*, 4R*, 5S*, 6R*)-3,5-diacetoxy-2-
acetoxymethyl-6-allyl-tetrahydro-pyran-4-yl ester 2,6-cis-35
ϩ
colorless oil, Rf 0.34 (3 : 7 EtOAc–petrol); (Found: MNH4
,
306.1917. C14H28NO6 requires MNH4 306.1917); νmax/cmϪ1
(CHCl3 solution) 2955 (C–H), 1443, 1369, 1244, 1226, 1128,
1092, 1048; δH (300 MHz; CDCl3) 5.24 (1H, ddd, J 11.7, 9.4
and 5.4, 4-H), 4.78 (1H, dd, J 3.7 and 1.2, 6-H), 4.77 (1H, t,
J 9.4, 3-H), 3.69 (1H, td, J 9.4 and 2.8, 2-H), 3.33 (3H, s, OMe),
2.22 (1H, ddd, J 12.8, 5.4 and 1.2, CHaHb), 2.05 (3H, s, OAc),
2.01 (3H, s, OAc), 1.77 (1H, ddd, J 12.8, 11.7 and 3.7, CHaHb),
1.55–1.15 (6H, m, CH2) and 0.90 (3H, t, J 7.4, CH3);
δC (75 MHz; CDCl3) 170.7, 170.7, 98.0, 73.7, 69.8, 69.4, 55.1,
35.5, 31.4, 27.8, 23.0, 21.4, 21.3, 14.4; m/z (ES) 306.2 (100%,
MNH4ϩ).
Boron trifluoride diethyl etherate complex (100 µl, 0.769 mmol)
was added slowly to a stirred solution of glucose pentaacetate
34 (100 mg, 0.256 mmol) and allyl trimethylsilane (400 µl, 2.56
mmol) in dry nitromethane (2.0 ml) at 0 ЊC. The solution was
allowed to warm to room temperature and stirred for 3 days,
diluted with dichloromethane (5 ml) and quenched with satur-
ated aqueous sodium bicarbonate solution (4 ml). The aqueous
layer was extracted with chloroform (2 × 3 ml) and the combined
organic extracts were dried (MgSO4). The solvent was removed
under reduced pressure and the residue pre-absorbed onto silica.
Purification by flash chromatography (gradient elution: 3 : 7
1 : 1 EtOAc–petrol) gave the THP38 35 (80.0 mg, 84%; 75 : 25 2,6-
cis : trans) as a colourless oil, δH (500 MHz; CDCl3) 5.78 (1H,
dddd, J 17.1, 10.0, 7.5 and 6.0, allyl), 5.34 (1H, t, J 9.0, 4-H), 5.17
(1H, dq, J 17.1 and 1.0, allyl), 5.12 (1H, dq, J 10.0 and 1.0, allyl),
5.09 (1H, dd, J 9.0 and 5.8, 5-H), 4.98 (1H, t, J 9.0, 3-H), 4.28
(1H, ddd, J 10.5, 5.8 and 4.8, 6-H), 4.21 (1H, dd, J 12.0 and 5.2,
CHaHbOAc), 4.08 (1H, dd, J 12.0 and 2.8, CHaHbOAc), 3.87
(1H, ddd, J 9.0, 5.2 and 2.8, 2-H), 2.56 (1H, dddt,2JHH 15.5,
4-Methoxybenzoic acid (2R*,3S*,6S*)-2-butyl-4-oxo-6-
methoxy-tetrahydropyran-3-yl ester 31
A solution of the alcohol 26 (24.2 mg, 71.6 µmol) in dichloro-
methane (4 ml) was added to a stirred suspension of anhydrous
sodium acetate (59 mg, 0.72 mmol), pyridinium chloro-
chromate (62 mg, 0.288 mmol) and powdered 3 Å molecular
sieves (50 mg) in dichloromethane (16 ml). The solution was
stirred at 0 ЊC for 6 h, filtered through a plug of celite and the
filtrate was washed with saturated aqueous sodium bicarbonate
(2 × 5 ml) and water (5 ml), dried (MgSO4) and evaporated
under reduced pressure. The crude product was pre-absorbed
on silica and purified by flash chromatography, eluting with
15 : 85 EtOAc–petrol to give the ketone 31 (21.5 mg, 89%)
as a colourless oil, Rf 0.27 (15 : 85 EtOAc–petrol); (Found:
MNaϩ, 359.1470. C18H24O6 requires MNa 359.1471); νmax/cmϪ1
4
J 10.5 and 7.5, JHH 1.0), 2.33 (1H, dddt,2JHH 15.5, J 6.0 and
4.8,4JHH 1.0), 2.08 (3H, s, OAc), 2.05 (3H, s, OAc), 2.04 (3H, s,
OAc) and 2.03 (3H, s, OAc) (data for major isomer only); δC (125
MHz; CDCl ) 171.1 (C᎐O), 170.6 (C᎐O), 170.1 (C᎐O), 170.0
᎐
᎐
᎐
3
(C᎐O), 133.4 (C᎐C), 118.3 (C᎐C), 77.6, 76.0, 74.8, 72.3, 72.0,
᎐
᎐
᎐
70.7, 70.6, 69.2, 62.6, 30.9 and 21.1 (data for major isomer only).
Acetic acid (2R*,3R*,4R*,5S*,6S*)-3,5-diacetoxy-2-acetoxy-
methyl-6-cyano-tetrahydro-pyran-4-yl ester 2,6-trans-36
(CHCl solution) 2924 (C–H), 2854, 1745 (C᎐O), 1720 (C᎐O),
᎐
᎐
3
1606, 1512, 1257, 1169, 1104, 1044; δH (300 MHz; CDCl3)
7.96 (2H, d, J 9.0, Ar), 6.87 (2H, d, J 9.0, Ar), 5.14 (1H, d,
J 10.2, 3-H), 5.07 (1H, dd, J 3.2 and 1.0, 6-H), 4.06 (1H, ddd,
J 10.2, 8.6 and 2.6, 2-H), 3.80 (3H, s, OMe), 3.32 (3H, s,
OMe), 2.80 (1H, dd, J 14.1 and 3.2, CHaHb), 2.61 (1H, dd,
J 14.1 and 1.0, CHaHb), 1.80–1.10 (6H, m, butyl CH2) and 0.84
Boron trifluoride diethyl etherate complex (100 µl, 0.769 mmol)
was added slowly to a stirred solution of glucose pentaacetate
34 (100 mg, 0.256 mmol) and trimethylsilyl cyanide (170 µl,
1.28 mmol) in dry nitromethane (2.0 ml) at 0 ЊC under nitrogen.
The solution was allowed to warm to room temperature, stirred
for 3 days, diluted with dichloromethane (5 ml) and quenched
with a saturated aqueous solution of sodium bicarbonate
(4 ml). The aqueous layer was further extracted with chloro-
form (2 × 3 ml) and the combined organic extracts dried
(MgSO4). The solvent was removed under reduced pressure and
the residue pre-absorbed onto silica. Purification by flash
(3H, t, J 7.4, CH3); δC (75 MHz; CDCl ) 199.1 (C᎐O), 165.4,
᎐
3
164.2, 132.5, 122.0, 114.1, 99.9 (6-C), 77.7, 71.7, 55.9, 55.3,
49.8, 32.6, 30.1, 27.7, 23.0 and 14.4; m/z (ES) 359.1 (100%,
MNaϩ).
Acetic acid (2R*,3R*,4R*,6S*)-3-acetoxy-2-butyl-6-propa-1,2-
dienyl-tetrahydro-pyran-4-yl ester 2,6-trans-33
chromatography, (gradient elution: 2 : 8
4 : 6 EtOAc–petrol)
gave the cyanide39 36 (69.6 mg, 76%; 75 : 25 2,6-trans : cis) as a
colourless oil, δH (500 MHz; CDCl3) 5.41 (1H, t, J 9.6, 4-Hmin),
5.24 (1H, t, J 9.6, 4-Hmaj), 5.11 (1H, t, J9.6, 3-Hmaj), 5.03 (1H, t,
J 9.6, 5-Hmaj), 5.00 (1H, t, J 9.6, 3-Hmin), 4.89 (1H, d, J 3.4,
6-Hmin), 4.83 (1H, dd, J 9.6 and 3.4, 5-Hmin), 4.26 (1H, dd, J 9.6,
6-Hmaj), 4.19 (1H, dd, J 12.8 and 4.7, CHaHbOAcmin), 4.17 (1H,
dd, J 12.8 and 5.1, CHaHbOAcmaj), 4.07 (1H, dd, J 12.8 and 2.1,
CHaHbOAcmaj), 4.05 (1H, dd, J 12.8 and 2.1, CHaHbOAcmin),
3.92 (1H, ddd, J 9.6, 4.7 and 2.1, 2-Hmin), 3.65 (1H, ddd, J 9.6,
5.1 and 2.1, 2-Hmaj), 2.04 (6H, s, OAcmaj), 2.03 (3H, s, OAcmin),
2.01 (3H, s, OAcmin), 1.97 (3H, s, OAcmaj), 1.96 (3H, s, OAcmin),
1.95 (3H, s, OAcmaj) and 1.94 (3H, s, OAcmin); δC (125 MHz;
A solution of boron trifluoride diethyl etherate complex (3.2 µl,
25.6 µmol) in dry dichloromethane (100 µl) was added slowly to
a stirred solution of diacetate 29 (36.8 mg, 127.8 µmol) and
propargyl trimethylsilane (48 µl, 0.639 mmol) in dry dichloro-
methane (1.2 ml) at 0 ЊC under nitrogen. The solution was
allowed to warm to room temperature and stirred for a further
16 h, diluted with dichloromethane (5 ml), quenched with sat-
urated aqueous sodium bicarbonate solution (2 ml). The aque-
ous layer was further extracted with chloroform (2 × 3 ml)
and the combined organic extracts were dried (MgSO4). The
solvent was removed under reduced pressure and the residue
pre-absorbed onto silica. Purification by flash chromatography
CDCl ) 170.5 (C᎐O), 170.1 (C᎐O), 169.6 (C᎐O), 169.2 (C᎐O),
᎐
᎐
᎐
᎐
3
114.6 (CN), 97.2 (6-C), 73.2, 69.3, 67.6, 66.8, 61.8, 21.2 (Me),
21.1 (Me), 20.9 (Me) and 20.8 (Me) (data for 2,6-trans-36 only).
(gradient elution: 1 : 9
3 : 7 EtOAc–petrol) gradient gave
the allene 2,6-trans-33 (29.5 mg, 78%; >95 : 5 mixture of
diastereoisomers) as a colourless oil, Rf 0.37 (4 : 6 EtOAc–
petrol); (Found: MNaϩ, 309.1521. C16H24O5 requires MNa
309.1521); νmax/cmϪ1 (CHCl3 solution) 2957 (C–H), 2872, 1957,
1749, 1368, 1243, 1225, 1049; δH (300 MHz; CDCl3) 5.19 (1H,
dd, J 5.6 and 3.6), 5.16 (1H, ddd, J 11.1, 9.2 and 5.1, 4-H), 4.97
(2H, m), 4.77 (1H, t, J 9.2, 3-H), 4.69 (1H, m, 6-H), 3.66 (3H,
td, J 9.2 and 3.1, 2-H), 2.25 (1H, ddd, J 13.1, 5.1 and 1.8,
CHaHb), 2.05 (3H, s, OAc), 2.03 (3H, s, OAc), 1.89 (1H, dddd,
J 13.1, 11.1, 5.6 and 0.8, CHaHb), 1.45–1.20 (6H, m, butyl CH2)
and 0.89 (3H, t, J 6.8, CH3); δC (75 MHz; CDCl3) 208.2, 170.8,
170.6, 91.3, 78.3, 74.0, 72.1, 70.0, 69.8, 32.7, 31.4, 27.8, 23.0,
21.5, 21.4 and 14.4; m/z (ES) 309.1 (100%, MNaϩ).
Acetic acid (2R,3R,4R,5S,6R)-3,5-diacetoxy-2-[(2R,3R)-2,3-
diacetoxy-4-{(2R,3R,4R,5S,6R)-3,4,5-triacetoxy-6-methoxy-
tetrahydro-pyran-2-yl}-butyl]-6-methoxy-tetrahydro-pyran-4-yl
ester 41
Osmium tetroxide (1 mg, catalytic) was added to a stirred solu-
tion of the diester 22 (10.2 mg, 12.1 µmmol) and NMO (14 mg,
120 µmol) in 1 : 1 acetone–water (1.5 ml). The solution was
stirred for a further 2 days before the solvent was removed
under reduced pressure. A solution of potassium hydroxide
(100 mg) in water (1 ml) was added to the residue and the
solution refluxed under nitrogen for 2 days. The solvent was
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 7 3 – 3 8 6
383

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removed under reduced pressure and the residue stirred in a
mixture of acetic anhydride (4 ml) and pyridine (2 ml) for
4 hours. The solvent was removed under reduced pressure and
the residue partitioned between chloroform (5 ml) and water
(5 ml). The organic layer was washed with saturated aqueous
sodium bicarbonate solution (2 × 3 ml) and brine (3 ml). The
organic layer was dried (MgSO4) and evaporated under reduced
pressure to give a crude product which was pre-absorbed onto
silica gel and purified by flash chromatography (gradient elu-
and the solution was stirred under nitrogen at 70 ЊC and azobiiso-
butyronitrile (10 mg) added. The reaction was stirred at 70 ЊC for
30 min, cooled and loaded directly without pre-absorption or
concentration onto a short column of silica. Elution with 1 : 9
EtOAc–petrol and then 4 : 6 EtOAc–petrol gave the alcohol 43
(83 mg, >98%) as a colourless oil, Rf 0.34 (4 : 6 EtOAc–petrol);
(Found: MNaϩ, 883.4095. C44H68O13Si2 requires MNa, 883.4096);
νmax/cmϪ1 (CHCl solution) 3535 (O–H), 2930, 2856, 1716 (C᎐O),
1607, 1512, 1257, 1168, 1108, 1051, 1031; δH (300 MHz; CDCl3)
7.83 (2H, d, J 9.0, Ar), 7.78 (2H, d, J 9.0, Ar), 6.71 (2H, d, J 9.0,
Ar), 6.69 (2H, d, J 9.0, Ar), 5.82 (1H, d, J 10.2, 5-HЈ), 5.62 (1H,
dt, J 10.2 and 2.1, 4-HЈ), 4.93 (1H, dd, J 9.5 and 2.1, 3-HЈ), 4.68
(1H, s, 6-HЈ), 4.56 (1H, d, J 3.3, 6-H), 4.44 (1H, dd, J 10.0 and
2.8, 3-H), 4.08 (1H, t, J 10.0, 2-H), 4.08 (1H, m, 4-H), 3.86 (1H, t,
J 9.5, 2-HЈ), 3.73 (2H, m, CHOTBS), 3.69 (3H, s, OMe), 3.69
(3H, s, OMe), 3.32 (3H, s, OMe), 3.27 (3H, s, OMe), 3.11 (1H, d,
J 9.5, OH), 1.97 (1H, dd, J 14.8 and 3.3, 5-HaHb), 1.81 (1H, dt,
J 14.8 and 3.3, 5-HaHb), 1.59 (2H, dd, J 14.1 and 10.2, CHaHb),
1.30 (2H, m, CHaHb), 0.80 (9H, s,tBu), 0.76 (9H, s,tBu), 0.01 (3H,
s, SiMe), 0.00 (3H, s, SiMe), Ϫ0.02 (3H, s, SiMe) and Ϫ0.04 (3H,
s, SiMe); δC (75 MHz; CDCl3) 166.1, 163.9, 163.9, 132.4, 132.2,
130.6, 127.8, 122.7, 114.0, 114.0, 99.0, 96.0, 77.6, 73.9, 72.4, 71.7,
69.9, 66.8, 65.7, 63.6, 57.1, 56.4, 55.9, 55.8, 35.6, 33.9, 33.7, 30.1,
26.2, 18.5, 18.4, Ϫ3.5, Ϫ3.5, Ϫ3.9 and Ϫ4.2; m/z (ES) 883.4
(100%, MNaϩ).
᎐
3
tion: 3 : 7
4 : 7 EtOAc–petrol) to give the octaacetate 41 (7.9
mg, 87%) as a colourless oil, Rf 0.36 (3 : 7 EtOAc–petrol);
(Found: MNaϩ, 773.2481. C32H46O20 requires MNa 773.2480);
νmax/cmϪ1 (CHCl solution) 2925, 1748 (C᎐O), 1371, 1222, 1162,
᎐
3
1131, 1085, 1046; δH (500 MHz; CDCl3) 5.29 (2H, dd, J 10.2
and 3.4, 4-H), 5.26 (2H, br, d, J 8.6, CHOAc), 5.20 (2H, dd,
J 3.4 and 1.7, 5-H), 5.06 (2H, t, J 10.2, 3-H), 4.60 (2H, d, J 1.7,
6-H), 3.70 (2H, td, J 9.8 and 2.1, 2-H), 3.35 (6H, s, OMe), 2.16
(6H, s, OAc), 2.08 (6H, s, OAc), 2.07 (6H, s, OAc), 1.99 (6H, s,
OAc), 1.73 (4H, m, CH2); m/z (ES) 773.0 (100%, MNaϩ).
(2R,3R,4S,5R,6R)-2-[(2R,3R)-2,3-Bis-(tert-butyl-dimethyl-
silanyloxy)-4-((2RЈ,3RЈ,6RЈ)-6Ј-methoxy-3Ј-(4-methoxybenzoyl-
oxy)-3,6-dihydro-2H-pyran-2-yl)-butyl]-5-iodo-6-methoxy-3-
(4-methoxybenzoyloxy)-tetrahydro-pyran-4-ol 42
A mixture of the diester 22 (105 mg, 0.124 mmol) and freshly
prepared silver benzoate (28.5 mg, 0.124 mmol, 1.0 mol eq) were
dried azeotropically using toluene and the residue dissolved in
dry CCl4 (2.7 ml). Iodine (31.5 mg, 0.124 mmol, 1.0 mol eq) was
added to the stirred suspension and the mixture stirred for a
24 days with protection from light. The suspension was diluted
with chloroform (10 ml) and the silver salts removed by centri-
fugation. The organic filtrate was washed with 10% aqueous
sodium sulfite solution (2 × 2 ml) and saturated sodium bicarbon-
ate (2 × 2 ml), dried (MgSO4) and evaporated under reduced
pressure. The crude residue was purified by flash chromatography
after pre-absorption onto silica gel (gradient elution: 1 : 9
25 : 75 EtOAc : petrol) to give the iodo alcohol 42 (48.2 mg, 39%,
>98 : 2 mixture of regioisomers) as a colourless oil, Rf 0.24
(15 : 85 EtOAc–petrol); (Found: MNH4ϩ, 1004.3515. C44H67I-
Si2O13 requires MNH4, 1004.3509); νmax/cmϪ1 (CHCl3 solution)
(2R,3R,6R)-2-[(2R,3R)-2,3-Bis-(tert-butyl-dimethyl-silanyl-
oxy)-4-((2RЈ,3RЈ,6RЈ)-3Ј-(4-methoxybenzoyloxy)-6Ј-methoxy-
3,6-dihydro-2H-pyran-2-yl)-butyl]-6-methoxy-3-(4-methoxy-
benzoyloxy)-tetrahydro-pyran-4-one 44
A solution of the alcohol 43 (12.3 mg, 14.3 µmol) in dichloro-
methane (1.2 ml) was added to a stirred suspension of anhydrous
sodium acetate (11.8 mg, 143 µmol), pyridinium chlorochromate
(12.3 mg, 57.2 µmol, 4 mol%) and powdered 3 Å molecular sieves
(50 mg) in dichloromethane (5 ml). The solution was stirred
under nitrogen and the temperature maintained at 0 ЊC for 2 h.
The reaction mixture was filtered through a plug of celite, washed
with saturated aqueous sodium bicarbonate solution (2 × 3 ml)
and water (3 ml), and the organic layer dried (MgSO4) and
evaporated under reduced pressure. The crude product was
pre-absorbed onto silica gel and purified by flash chromato-
graphy, eluting with 2 : 8 EtOAc–petrol, to give the ketone 44
(10.8 mg, 88%) as a colourless oil, Rf 0.42 (3 : 7 EtOAc–petrol);
(Found: MNaϩ, 881.3940. C44H66O13Si2 requires MNa, 881.3940);
νmax/cmϪ1 (CHCl solution) 2928, 2856, 1721 (C᎐O), 1606, 1512,
3422 (O–H), 2955 (C–H), 2930, 2856, 1717 (C᎐O), 1607, 1512,
᎐
1257, 1168, 1103, 1053; δH (500 MHz; CDCl3) 7.84 (2H, d, J 9.0,
Ar), 7.83 (2H, d, J 9.0, Ar), 6.78 (2H, d, J 9.0, Ar), 6.76 (2H, d,
J 9.0, Ar), 5.86 (1H, d, J 10.5, 5-HЈ), 5.68 (1H, dt, J 10.5 and 2.3,
4-HЈ), 5.16 (1H, dd, J 9.4 and 2.3, 3-H), 5.03 (1H, dd, J 9.2 and
1.5, 3-HЈ), 4.78 (1H, d, J 2.8, 6-H), 4.72 (1H, s, 6-HЈ), 4.15 (3H,
m, 5-H, 4-H and 2-H), 3.98 (1H, td, J 7.2 and 3.6, CHOTBS),
3.91 (1H, t, J 9.2, 2-HЈ), 3.79 (1H, m, CHOTBS), 3.74 (3H, s,
OMe), 3.73 (3H, s, OMe), 3.37 (3H, s, OMe), 3.36 (3H, s, OMe),
3.02 (1H, br, OH), 1.84 (1H, ddd, J 13.8, 10.5 and 4.1, CHaHb),
1.69 (1H, dd, J 13.8 and 10.5, CHaHb), 1.34 (2H, dd, J 14.1 and
9.7, CHaHb), 0.83 (9H, s,tBu), 0.81 (9H, s,tBu), 0.07 (3H, s, SiMe),
0.02 (3H, s, SiMe), 0.01 (3H, s, SiMe) and 0.00 (3H, s, SiMe);
δC (125 MHz; CDCl3) 166.2, 166.0, 164.0, 164.0, 132.4, 132.3,
130.6, 128.9, 127.8, 122.6, 122.4, 114.1, 102.7, 96.1, 71.6, 71.4,
71.1, 70.9, 69.9, 66.6, 66.5, 57.2, 57.0, 55.9, 34.1, 32.7, 31.4, 30.1,
27.1, 26.3, 26.2, 18.5, 18.4, Ϫ3.5, Ϫ3.5, Ϫ4.1 and Ϫ4.2; m/z (ES)
1009.6 (100%, MNaϩ).
᎐
3
1463, 1259, 1168, 1104, 1051; δH (500 MHz; CDCl3) 7.83 (2H, d,
J 9.0, Ar), 7.79 (2H, d, J 9.0, Ar), 6.74 (2H, d, J 9.0, Ar), 6.73 (2H,
d, J 9.0, Ar), 5.83 (1H, d, J 10.2, 5-HЈ), 5.65 (1H, dt, J 10.2 and
2.1, 4-HЈ), 4.98 (1H, dd, J 9.4 and 2.1, 3-HЈ), 4.89 (1H, d, J 4.3,
6-H), 4.89 (1H, d, J 9.8, 3-H), 4.69 (1H, s, 6-HЈ), 4.08 (1H, t,
J 9.4, 2-HЈ), 3.90 (1H, t, J 9.8, 2-H), 3.78 (1H, dd, J 7.7 and 4.3,
CHOTBS), 3.77 (1H, dd, J 7.7 and 4.3, CHOTBS), 3.71 (6H, s,
OMe), 3.34 (3H, s, OMe), 3.26 (3H, s, OMe), 2.69 (1H, dd, J 13.7
and 4.3, 5-HaHb), 2.50 (1H, d, J 13.7, 5-HaHb), 1.85 (1H, dd,
J 14.1 and 9.8, CHaHb), 1.64 (1H, dd, J 14.1 and 10.3), 1.43 (1H,
dd, J 14.1 and 9.4), 1.31 (1H, dd, J 14.1 and 9.8), 0.81 (9H, s,tBu),
0.79 (9H, s,tBu), 0.05 (3H, s, SiMe), 0.00 (3H, s, SiMe), 0.00 (3H,
s, SiMe) and Ϫ0.02 (3H, s, SiMe); δC (75 MHz; CDCl3) 133.4,
133.0, 131.3, 128.6, 123.5, 123.1, 115.6, 114.7, 100.9, 96.7, 72.7,
72.0, 71.0, 70.6, 67.0, 57.5, 56.5, 56.2, 54.0, 47.0, 35.5, 34.2, 26.4,
26.3, 18.5, Ϫ3.4, Ϫ3.4, Ϫ4.1 and Ϫ4.2; m/z (ES) 881.4 (100%,
MNaϩ).
Also obtained was recovered starting material (24 mg, 23%).
The recovered starting material was recycled twice to give an
overall 54% yield of 42.
(2R,3R,4S,6R)-2-[(2R,3R)-2,3-Bis-(tert-butyl-dimethyl-silanyl-
oxy)-4-((2RЈ,3RЈ,6RЈ)-6Ј-methoxy-3Ј-(4-methoxybenzoyloxy)-
3,6-dihydro-2H-pyran-2-yl)-butyl]-6-methoxy-3-(4-methoxyben-
zoyloxy)-tetrahydro-pyran-4-ol 43
(2R,3R,4R,6R)-2-[(2R,3R)-2,3-Bis-(tert-butyl-dimethyl-silanyl-
oxy)-4-((2RЈ,3RЈ,6RЈ)-3Ј-(4-methoxybenzoyloxy)-6Ј-methoxy-
3,6-dihydro-2H-pyran-2-yl)-butyl]-6-methoxy-3-(4-methoxy-
benzoyloxy)-tetrahydro-pyran-4-ol 45
A solution of iodo alcohol 42 (95.6 mg, 96.8 µmol) in benzene
(3.5 ml) was deoxygenated by a steady stream of nitrogen for
30 seconds. Tris-(trimethylsilyl)silane (0.484 mmol) was added
Sodium borohydride (30 mg, 0.789 mmol) was added to a
stirred solution of the ketone 44 (12.4 mg, 14.5 µmol) in THF
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 7 3 – 3 8 6
384

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(1.5 ml) at 50 ЊC. The solution was stirred for 30 min, cooled
to room temperature and quenched with water (0.2 ml). The
solvent was evaporated under reduced pressure and the residue
pre-absorbed onto silica gel, purified by flash chromatography
hydroxide solution (2.0 M, 1.5 ml) added, and the reaction mix-
ture was stirred at room temperature for 2 h and refluxed for
2 days, evaporated under reduced pressure and the residue dis-
solved in 2 : 1 acetic anhydride–pyridine (3 ml). The reaction
was stirred for 6 h and evaporated under reduced pressure to
give a crude product which was dissolved in chloroform (5 ml),
washed with saturated aqueous sodium bicarbonate solution
(1.0 M, 2 × 3 ml) and brine (3 ml), dried (MgSO4) and evapor-
ated under reduced pressure to give the epoxide 49 (6.5 mg,
90%) as a colourless oil, Rf 0.42 (3 : 7 EtOAc–petrol); (Found:
MNH4ϩ, 752.4073. C33H66O13Si2 requires MNH4, 752.4073);
νmax/cmϪ1 (CHCl3 solution) 2926, 2855, 1743, 1654, 1463, 1371,
1259, 1072, 1047; δH (500 MHz; C6D6) 5.45 (1H, ddd, J 11.7, 9.4
and 4.9, 4-H), 4.93 (1H, t, J 9.4, 3-H), 4.70 (1H, dd, J 9.4 and
1.6, 3-HЈ), 4.27 (1H, d, J 2.6, 6-HЈ), 4.21 (1H, d, J 2.6, 6-H),
4.17 (1H, t, J 9.4, 2-H), 3.95 (1H, dd, J 9.5 and 7.7, CHOTBS),
3.90 (1H, dd, J 9.5 and 4.3, CHOTBS), 3.84 (1H, td, J 9.4 and
3.0, 2-HЈ), 3.19 (3H, s, OMe), 3.08 (3H, s, OMe), 3.02 (1H, dd,
J 4.3 and 1.6, 4-HЈ), 2.73 (1H, dd, J 4.3 and 2.6, 5-HЈ), 2.12–
1.98 (5H, m, CH2 and 5-HaHb), 1.80 (1H, ddd, J 14.1, 11.7 and
2.6, 5-HaHb), 1.52 (3H, s, OAc), 1.45 (3H, s, OAc), 1.42 (3H, s,
OAc), 0.95 (9H, s,tBu), 0.93 (9H, s,tBu), 0.20 (3H, s, SiMe), 0.14
(3H, s, SiMe), 0.12 (3H, s, SiMe) and 0.09 (3H, s, SiMe);
m/z (ES) 752.2 (100%, MNH4ϩ).
(gradient elution: 15 : 85
4 : 6 EtOAc–petrol) to give
the alcohol 45 (6.6 mg, 54%) as a colourless oil, Rf 0.46 (3 : 7
EtOAc–petrol); (Found: MNaϩ, 883.4095. C44H68O13Si2
requires MNa, 883.4096); νmax/cmϪ1 (CHCl3 solution) 3468
(O–H), 2928, 2855, 1716 (C᎐O), 1606, 1512, 1463, 1258, 1168,
᎐
1104, 1051; δH (300 MHz; CDCl3) 7.84 (2H, d, J 9.0, Ar), 7.81
(2H, d, J 9.0, Ar), 6.75 (2H, d, J 9.0, Ar), 6.75 (2H, d, J 9.0, Ar),
6.02 (1H, d, J 10.2, 5-HЈ), 5.82 (1H, dd, J 10.2 and 2.1, 4-HЈ),
5.26 (1H, m, 3-H), 5.22 (1H, dd, J 9.5 and 2.1, 3-HЈ), 4.86 (1H,
s, 6-HЈ), 4.71 (1H, d, J 3.0, 6-H), 4.07 (1H, t, J 9.5, 2-HЈ), 3.91
(2H, m, CHOTBS), 3.87 (3H, s, OMe), 3.86 (3H, s, OMe), 3.69
(1H, td, J 10.0 and 2.8, 4-H), 3.49 (3H, s, OMe), 3.36 (3H, s,
OMe), 3.36 (1H, t, J 9.3, 2-H), 2.26 (1H, dd, J 14.0 and 5.4,
5-HaHb), 1.87 (1H, ddd, J 14.0, 10.0 and 3.0, 5-HaHb), 1.82–
1.73 (3H, m, CH2), 1.65 (1H, dd, J 13.8 and 8.7, CHaHb), 0.81
t
t
(9H, s, Bu), 0.78 (9H, s, Bu), 0.05 (3H, s, SiMe), 0.01 (3H, s,
SiMe), 0.00 (3H, s, SiMe) and Ϫ0.01 (3H, s, SiMe); m/z (ES)
883.4 (100%, MNaϩ).
(2R,3R,4R,6R)-2-[(2R,3R)-2,3-Bis-(tert-butyl-dimethyl-silanyl-
oxy)-4-((2RЈ,3RЈ,6RЈ)-3Ј-(4-methoxybenzoyloxy)-6Ј-methoxy-
3,6-dihydro-2H-pyran-2-yl)-butyl]-4-acetoxy-6-methoxy-3-
(4-methoxybenzoyloxy)-tetrahydropyran 46
Acetic acid (1R,2R)-2-acetoxy-3-((2ЉR,3ЉR,4ЉR,6ЉS )-3Љ,4Љ-
diacetoxy-6Љ-methoxy-tetrahydro-pyran-2-yl)-1-((2ЈR,3ЈR,4ЈS,
5ЈR,6ЈS )-3Ј,4Ј,5Ј-triacetoxy-6Ј-methoxy-tetrahydro-pyran-2Ј-
ylmethyl)-propyl ester 47
The alcohol 45 (10.2 mg, 11.7 µmol) was dissolved in a mixture
of acetic anhydride (2 ml) and pyridine (1 ml). The mixture was
stirred under nitrogen at room temperature for 2 hours before
the solvent was removed under reduced pressure. The solid resi-
due was dissolved in chloroform (5 ml), washed with saturated
aqueous sodium bicarbonate solution (2 × 3 ml) and water
(3 ml), dried (MgSO4) and evaporated under reduced pressure
to give the acetate 46 (10.4 mg, >98%) as a colourless oil,
Rf 0.37 (2 : 8 EtOAc–petrol); (Found: MNaϩ, 925.4200.
C46H70O14Si2 requires MNa, 925.4202); νmax/cmϪ1 (CHCl3 solu-
By the same general method, using aqueous potassium hydrox-
ide solution (2.0 M, 1.5 ml) as the solvent in the hydrolysis step,
the allylic ester 46 (4.0 mg, 4.4 µmol) gave a crude product
which was purified by semi-preparative HPLC-MS (20 : 80
MeCN–water for 1 min, then ramp to 35 : 65 MeCN–water over
30 s, then ramp to 65 : 35 MeCN–water over 4 min, then ramp
to 95 : 5 MeCN–water over 30 s, then 95 : 5 MeCN–water
over 3 min, 24 ЊC) to give the heptaacetate 47 (1.5 mg, 48%)
as a colourless viscous oil, retention time 4.6 min, [α]D = Ϫ10
(c = 0.1, CHCl3); Rf 0.2 (3 : 7 EtOAc–petrol); (Found: 715.2421;
C30H44O18 requires MNa, 715.2426); νmax/cmϪ1 2940, 1750
tion) 2928, 2856, 1746, (C᎐O), 1718 (C᎐O), 1606, 1512, 1464,
᎐
᎐
1257, 1168, 1103, 1049; δH (500 MHz; CDCl3) 7.98 (2H, d, J 9.0,
Ar), 7.91 (2H, d, J 9.0, Ar), 6.90 (2H, d, J 9.0, Ar), 6.88 (2H, d,
J 9.0, Ar), 6.02 (1H, d, J 10.3, 3-HЈ), 5.82 (1H, dt, J 10.3 and
2.1, 4-HЈ), 5.33 (1H, ddd, J 11.5, 9.4 and 5.1, 4-H), 5.20 (1H,
dd, J 9.4 and 2.1, 3-HЈ), 4.88 (1H, t, J 9.4, 3-H), 4.85 (1H, s,
6-HЈ), 4.71 (1H, dd, J 3.0 and 1.2, 6-H), 4.06 (1H, t, J 9.8), 3.88
(1H, dd, J 9.8 and 4.7), 3.87 (3H, s, OMe), 3.84 (1H, td, J 9.8
and 5.1), 3.83 (3H, s, OMe), 3.49 (3H, s, OMe), 3.38 (3H, s,
OMe), 2.38 (1H, ddd, J 12.7, 5.1 and 1.2, 5-HaHb), 2.12–1.76
(5H, m, 5-HaHb, 1-H and 4-HЈ), 0.94 (9H, s,tBu), 0.91 (9H,
s,tBu), 0.18 (3H, s, SiMe), 0.13 (3H, s, SiMe), 0.12 (3H, s, SiMe)
and 0.12 (3H, s, SiMe); m/z (ES) 925.1 (100%, MNaϩ).
(C᎐O), 1442, 1371, 1246, 1224, 1043; δ (500 MHz; CDCl ) 5.43
᎐
H
3
(1H, t, J 9.5, 4Љ-H), 5.26–5.22 (3H, m, 1-, 2- and 4Ј-H), 4.88
(1H, d, J 9.5, 5Љ-H), 4.87 (1H, s, 6Љ-H), 4.85 (1H, t, J 9.5, 3Љ-H),
4.78–4.75 (2H, m, 3Ј- and 6Ј-H), 3.73–3.68 (2H, m, 2Ј and
2Љ-H), 3.35 (3H, s, OCH3), 3.28 (3H, s, OMe), 2.2–1.8 (2H, m,
5Ј-H2), 2.08 (3H, s, OAc), 2.05 (6H, s, OAc × 2), 2.01 (3H, s,
OAc), 2.00 (3H, s, OAc), 1.6–1.2 (4H, m, CH2 × 2); m/z (ES) 715
(100, MNaϩ).
Acknowledgements
(2R,3R,4R,6R)-2-[(2R,3R)-2,3-Bis-(tert-butyl-dimethyl-silanyl-
oxy)-4-((2RЈ,3RЈ,4SЈ,5RЈ,6RЈ)-3Ј-acetoxy-4Ј,5Ј-epoxy-6Ј-
methoxy-tetrahydro-pyran)-butyl]-3,4-diacetoxy-6-methoxy-
tetrahydropyran 49
We thank EPSRC and Aventis for providing funds under the
CASE scheme for new appointees, the Royal Society for a grant
and Pfizer for an academic award. The EPSRC National Mass
Spectrometry Centre (Swansea) is acknowledged for perform-
ing accurate mass measurements. We are extremely grateful to
Dr Stuart Warriner for the purification of the final product and
to Dr Tahir Majid for helpful discussions.
The allylic ester 46 (8.9 mg, 9.8 µmol) was dried azeotropically
from toluene and dissolved in dry carbon tetrachloride (1.5 ml).
To the stirred solution under N2 freshly prepared and azeo-
tropically dried silver benzoate (30.7 mg, 96.0 µmol) was added,
followed by iodine (25.0 mg, 96.0 µmol). The suspension was
stirred at room temperature with protection from light for
4 days. The suspension was diluted with chloroform (5 ml)
and the silver residues removed by centrifugation. The resi-
due was washed with chloroform (3 ml) and the combined
organic extracts were washed with saturated aqueous sodium
bicarbonate solution (2 × 3 ml), 10% aqueous sodium sulfite
solution (2 × 3 ml) and brine (3 ml). The organic layer was dried
(MgSO4) and the solvent removed under reduced pressure. The
residue was dissolved in THF (1.2 ml), aqueous potassium
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