A formal total synthesis of (+)-apicularen A: Base-induced conversion of apicularen-derived intermediates into salicylihalamide-like products

Article abstract of DOI:10.1039/b209637b

A synthesis of apicularen precursor (-)-6 in 18 steps from D-glucal is reported. As (+)-6 has been converted into the potent, naturally occurring salicylate anti-cancer agent, (-)-apicularen A in 8 steps, this study constitutes a formal total synthesis of (+)-apicularen A. Key steps in the synthetic route include: (i) useful D-glucal elaboration processes. (ii) organometallic displacements at carbohydrate C-6 triflates using Knochel-type and related functionalised, aromatic Grignard reagents, (iii) stereoselective allyltrimethylsilane-acetal reactions generating C-allyl systems. (iv) stereocontrolled aldehyde allylation processes from both substrate and reagent, and (v) a novel Keck-type macrolactonisation. In addition, preliminary studies are reported in which a procedure has been devised to convert apicularen-derived intermediates into salicylihalamide-like products.

Full text of DOI:10.1039/b209637b

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A formal total synthesis of (؉)-apicularen A:
base-induced conversion of apicularen-derived intermediates into
salicylihalamide-like products
Arwel Lewis,a Ian Stefanuti,a Simon A. Swain,a Stephen A. Smithb and Richard J. K. Taylor*a
a Department of Chemistry, University of York, Heslington, York, UK YO10 5DD
b GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, UK SG1 2NY
Received 1st October 2002, Accepted 21st October 2002
First published as an Advance Article on the web 5th December 2002
A synthesis of apicularen precursor (Ϫ)-6 in 18 steps from -glucal is reported. As (ϩ)-6 has been converted into the
potent, naturally occurring salicylate anti-cancer agent, (Ϫ)-apicularen A in 8 steps, this study constitutes a formal
total synthesis of (ϩ)-apicularen A. Key steps in the synthetic route include: (i) useful -glucal elaboration processes,
(ii) organometallic displacements at carbohydrate C-6 triflates using Knochel-type and related functionalised,
aromatic Grignard reagents, (iii) stereoselective allyltrimethylsilane–acetal reactions generating C-allyl systems,
(iv) stereocontrolled aldehyde allylation processes from both substrate and reagent, and (v) a novel Keck-type
macrolactonisation. In addition, preliminary studies are reported in which a procedure has been devised to convert
apicularen-derived intermediates into salicylihalamide-like products.
cytostatic activity (IC50 values between 0.3 and 3 ng mlϪ1
Introduction
against nine different human cancer cell lines). Further-
Apicularen A (1) (Fig. 1) was originally isolated from the myxo-
more, Sasse2 observed several abnormal effects in tumour cells
bacterial genus Chondromyces by Jansen et al. in 1998.1 Apicu-
laren B (2), a glycosylated co-metabolite of apicularen A was
isolated from the same source. Biological screening indicated
that apicularen B showed weak antimicrobial activity against
suggesting a novel mode of action.
Other related salicylate anti-tumour natural products are
known,3 including salicylihalamide A (3),3a lobatamide C (4),3b
CJ-129503c and oximidine I (5).3d These families of compounds
some Gram-positive bacteria, e.g. Micrococcus luteus (MIC
were tested in the NCI 60 cell-line tumour screen and it was
found that as well as acting via a novel mode of action they all
12.5 µg mlϪ1), and moderate cytotoxic activity with IC50 values
ranging between 0.2 and 1.2 µg mlϪ1. Apicularen A did not
share the same (or similar) molecular target. Recent studies
show any antibiotic activity but exhibited remarkably high
have established that these compounds are selective inhibitors
of mammalian vacuolar (Hϩ)-ATPase.4
The potent biological activity, structural novelty and limited
availability of these salicylate anti-tumour natural products
has resulted in the development of numerous synthetic
approaches5 culminating in recent total syntheses of salicyli-
halamide A by De Brabander et al.,6a Fürstner et al.,6b Labrecque
et al.,6c Smith and Zheng6d and Snider and Song,6e of
lobatamide C by Porco et al.,6f and of apicularen A by De
Brabander’s group,6g together with a formal total synthesis of
the latter compound.7
This paper details the formal total synthesis of apicularen A
using a carbohydrate based route.7 -Glucal is used to prepare
the protected, side-chain truncated macrolide (Ϫ)-6 (Scheme 1);
(ϩ)-6 has been utilised by De Brabander et al. during their total
synthesis of apicularen A.5d,6g We also report our findings con-
cerning the base-induced ring opening of the tetrahydropyran
ring in an apicularen intermediate. This kind of process may be
Fig. 1
Scheme 1
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 0 4 – 1 1 6
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 3
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involved in the biosynthetic conversion of apicularens into
and organometallic reagent 8 (Scheme 2). We have previously
other members of the salicylate family (or vice versa).5p,r
described the preparation of reagent 8 (M = Cu) by a double
acetylene carbocupration process,8 and indeed this method-
ology has been successfully employed in the total syntheses
of salicylihalamide A reported by the groups of Smith6d
and Snider.6e Isocyanate 7 should be available by Curtius
rearrangement of the acyl azide derived from carboxylic acid
9, and again we carried out model studies5g,h to establish
the viability of this approach. Horner–Wadsworth–Emmons
alkene formation and functional group interconversion lead
back to the allylic intermediate 10, itself obtained by macro-
lactonisation of hydroxy-acid 11. Alternatively, functionalised
intermediates 12 and 13 were also considered viable at this
stage.
We envisaged two possible strategies for incorporation of the
appendage at C-1 of the tetrahydropyran (Routes A and B,
Scheme 2). The chiral alcohol could be produced by β-alkoxy-
or reagent-directed asymmetric reduction of a ketone 14. Side-
chains containing ketone functionalities have been introduced
at C-1 of sugar derivatives with good α-selectivity by reaction
of silyl enol ethers 15 with acetals of type 169 and we were
keen to establish whether functionalised silyl enol ethers were
(i) Formal total synthesis of (؉)-apicularen A
The absolute stereochemistry of apicularen A was mis-assigned
in the original publication1a and was subsequently revised to
the enantiomeric form.1c As we commenced our study before
the publication of the structural revision, we concentrated our
efforts on the synthesis of the enantiomer of the natural
product.
The unsaturated enamide side chains are characteristic struc-
tural features of the salicylate anti-tumour natural products,
and provide a significant synthetic challenge. We decided to
construct these side chains via vinyl organometallic addition
to unsaturated isocyanates, and in model studies successfully
developed this methodology for the preparation of enamide
side chains of the apicularen/salicylihalamide (hydrocarbon
terminated),5g and lobatamide/oximidine (oxime terminated)5h
types.
Retrosynthetic analysis of (ϩ)-apicularen A 1 therefore sug-
gested disconnection of the Z,Z-enamide to give isocyanate 7
Scheme 2
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 0 4 – 1 1 6
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applicable to this type of reaction (Route A). An alternative
methodology involved the use of an allyl group as a masked
aldehyde (Route B). In this second route, the asymmetric allyl-
ation of aldehyde 17 would be employed to install the secondary
alcohol in the side chain with the appropriate stereocontrol.
Lewis acid-promoted reactions of acetals of type 16 with
allyltrimethylsilane are well-established for the generation of
C-glycosides possessing the required α-stereochemistry.10
Construction of the sp2–sp3 bond of 16 at C-6 was con-
sidered possible by reaction of a functionalised organometallic
of type 18 with a suitable electrophile 19 (Scheme 2). Although
Grignard or organolithium reagents incorporating esters are
generally considered to be synthetically non-viable, recent work
by Knochel11 and Oshima12 and their co-workers indicates that
reagents 18 should be accessible. We were aware, however, that
β-oxygenated electrophiles such as 19 are known to possess
reduced electrophilicity.13 We therefore set out to explore the
synthesis of system 16 from precursors such as 18 and 19 as the
first part of this study.
Knochel et al. have shown that a range of functionalised aryl
iodides can be converted into the corresponding Grignard
reagents at low temperature by use of an iodine–magnesium
exchange reaction.11 As a model system, we initially examined
whether Grignard reagent 21 could be derived from ethyl
o-iodobenzoate 20 and then coupled with triflate 22 to produce
adduct 23 (Scheme 3).
Scheme 4
gave the unstable triflate derivative 28 which was used immedi-
ately in the subsequent coupling reaction.
Meanwhile, the aryl iodide coupling partner 30 was suc-
cessfully prepared from o-anisic acid 29 via o-lithiation and
iodination,16 followed by Mitsunobu esterification (Scheme 5).
Scheme 3
After generation of the Grignard reagent 21 using Knochel’s
conditions (iPrMgCl, THF, Ϫ40 ЊC), copper()-catalysed coup-
ling with triflate 22 at the same temperature failed to produce
adduct 23. However, by allowing the reaction temperature to
warm to 0 ЊC, the required coupling proceeded in reasonable
yield (51%) to produce 23. Encouraged by this result, we
embarked upon construction of the core tetrahydropyran-ring
system 28 required in our synthesis (Scheme 4). Derivatisation
of each hydroxy of -glucal 24 in a one-pot procedure using a
three reagent sequence (successively TBSCl, TPSCl then thio-
carbonyldiimidazole) gave the protected derivative 25 in 60%
overall yield after chromatography. The tri-protected -glucal
25 then underwent Bu3SnH-mediated deoxygenation via a
Barton–McCombie type process14 to give dihydropyran 26.
Acid-catalysed addition of methanol to the enol ether moiety,15
together with concomitant deprotection of the primary TBS
group, was then achieved using triphenylphosphine hydro-
bromideindichloromethane–methanolgivingprimaryalcohol27
as a mixture of anomers. Reaction with triflic anhydride then
Scheme 5
Disappointingly, none of the desired product 32 could be
isolated following treatment of iodide 30 with triflate 28 under
the previously-devised conditions for Grignard formation and
copper-catalysed coupling. Presumably the intermediate
Grignard reagent 31 was less stable than the model version 21
and failed to survive the elevated reaction temperatures
required for reaction with the relatively unreactive electrophile
28.
We therefore looked for a more stable alternative to Grignard
reagent 31 and examined Kotsuki’s benzofuryl reagent 34,
which has been designed as a masked nucleophilic o-hydroxy-
benzoic acid synthon: the latent functionality can be revealed
by oxidative furan cleavage (see later).17 The starting material
required for this procedure, 4-bromo-2-methylbenzofuran 33,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 0 4 – 1 1 6
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was prepared using the method published by Kotsuki et al.,17
and after some experimentation with reaction conditions, we
discovered that it was possible to couple Grignard reagent 34
to triflate 28 using Cu()-catalysis producing adduct 35 in 59%
yield (Scheme 6).
Scheme 6
Scheme 7
Having established a procedure for the introduction of the
C-6 substituent, we turned our attention towards the introduc-
tion of a suitably functionalised side-chain at the C-1 position.
Initial studies utilised the model compounds 36 (X = Cl, F) and
focused on the incorporation of a 4-carbon fragment by use of
silyl enol ether methodology (Scheme 2, Route A). Reactions
of simple silyl enol ethers with sugar-derived electrophiles are
well-documented,9 but extension of this technique to function-
alised nucleophiles has seen little attention to date. We required
a 4-carbon oxygenated silyl enol ether for later elaboration. To
this end we examined a series of functionalised silyl enol ethers
37a–e prepared by LDA deprotonation of the corresponding
ketones followed by enolate trapping using chlorotrimethyl-
silane.18 Unfortunately, this methodology gave a mixture of
regioisomeric enol ethers, despite the use of hindered alcohol
protecting groups, and all of the silyl enol ethers proved to be
unstable to the coupling conditions. However, the known bis-
silyl enol ether 3819 possesses higher stability, and reaction of
this with a model deoxyglycosyl chloride 36 (X = Cl), mediated
by silver triflate in dichloromethane, successfully generated the
C-glycoside 39, in good yield but with the undesired β-stereo-
chemistry predominating (Scheme 7). Efforts to bias the stereo-
selectivity of the reaction towards the α-anomer by use of
boron trifluoride–diethyl ether in acetonitrile20 gave a poor
yield of a mixture of anomers (<30%, α : β >5:1) which were
difficult to separate and purify.
Scheme 8
These disappointing results led us to examine the more stereo-
chemically reliable reactions of allyltrimethylsilane as outlined
in Scheme 2, Route B. We decided to retain the benzofuryl
group during the anomeric coupling procedure and therefore
investigated the allylation of methyl acetal 35 (Scheme 8).
Treatment of acetal 35 with allyltrimethylsilane–TMSOTf–
MeCN, conditions known10 to promote α-allylation, produced
exclusively the required C-allylated adduct 40, after resilylation
to restore the protection lost by partial cleavage during the
Lewis acid-mediated coupling conditions. Adduct 40 was iso-
lated in 84% yield over these two steps with complete α-stereo-
control (as deduced from anomeric coupling constants).
67% yield. Given the expected lower reactivity of the aromatic
aldehyde of 41, we had hoped to perform a regio- and stereo-
selective allylation reaction at the aliphatic aldehydic centre.
However, subjection of compound 41 to several allylation con-
ditions [allylmagnesium bromide, allyltrimethylsilane–dimethyl-
aluminium chloride,21 allyl(diisopinocampheyl)borane22] failed
to give any of the desired allyl compound 42.
The inability to discriminate between the two aldehydes
in compound 41 encouraged us to carry out these oxidative
cleavage processes in a sequential manner (Scheme 9). Thus,
intermediate 35, described earlier, was subjected to benzo-
furanyl ozonolytic cleavage to give mono-aldehyde 43. Sub-
sequent aldehyde oxidation and acetyl saponification followed
by concomitant methylation of both of the resultant benzoic
Subsequent ozonolysis of 40 resulted in the cleavage of both
the terminal alkene and the benzofuran giving dialdehyde 41 in
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 0 4 – 1 1 6
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Scheme 9
acid and phenol groups led us to the required salicylate core 44
(Scheme 9).
The use of reagent control was also successful (entry iii),
Brown’s allyl(diisopinocampheyl)borane22 reacting with alde-
hyde 46 to give a 90 : 10 predominance of the required 1,3-syn
addition product 47R in good yield.
Reaction of allyltrimethylsilane with acetal 44 using the allyl-
trimethylsilane–TMSOTf–MeCN conditions described above
again gave the desired α-C-allylated product, this time with a
significant amount of TPS group cleavage. Unfortunately, the
resultant secondary alcohol could not be reprotected using
TPSCl, presumably for steric reasons. Therefore, complete
removal of the TPS group was carried out using fluoride and
then the product was treated with the more reactive silylating
agent TBSOTf to give the TBS ether 45 in 81% yield over the
three steps (Scheme 9). The next step in this revised synthetic
strategy was the oxidative cleavage of the terminal double bond
of alkene 45. This was again achieved using ozone, with a
reductive work up, giving a quantitative yield of aldehyde 46
(Scheme 9).
We were then ready for a second attempt at stereoselective
allylation (cf. Scheme 8), this time without the problem of
regioselectivity. Initial attempts (Scheme 9, and Table 1) with
aldehyde 46, utilised allyltrimethylsilane in the presence of che-
lating Lewis acids, with a view to obtaining the 15S-diastereo-
mer of product 47 for subsequent Mitsunobu lactonisation.23
The best result (entry i) was obtained using dimethylaluminium
chloride giving the 1,3-anti and 1,3-syn addition products 47S
and 47R in a ratio of 85 : 15.21 The structure of the major
isomer was assigned with the help of Mosher ester studies.24
Interestingly (entry ii), the use of titanium() chloride in this
reaction lead to no diastereoselective bias at the C-15 centre,
which is unusual, although a similar result was reported by De
Brabander during his total synthesis of apicularen A.5d
Cleavage of the methyl ester in 47 was then attempted using
hydrolytic conditions [e.g. LiOH, Ba(OH)2] but without success.
However, we were pleased to find that lithium iodide-induced
O-alkyl ester cleavage allowed access to the macrocyclisation
precursors 48R and 48S (90 : 10) in good yield.
Several different lactonisation methods were assessed in
order to close the macrocyclic ring-system. Whilst the
procedures of Mitsunobu23 and Yamaguchi and co-workers25
gave none of the desired lactone, the DCC–DMAP pro-
cedure developed by Boden and Keck26 successfully afforded
the lactone 49, together with a small amount of the C-15
epimer 50, which was easily separated by chromatography
(Scheme 10).
Finally, silyl and methyl group deprotection of 49 with iodo-
9-BBN27 gave the diol 51, which was fully characterised and
found to have comparable spectroscopic/analytical data to
those reported by De Brabander et al. for the enantiomeric
compound.5d,6g For example, the 13C NMR data for 51 are com-
pared to published data5d in Table 2.
Silylation of both the phenolic and secondary hydroxy
groups then gave the corresponding bis-TBS ether (Ϫ)-6. The
enantiomeric compound, (ϩ)-6, has been converted into
(Ϫ)-apicularen A by De Brabander et al.5d,6g The chemistry
described herein, by preparation of the advanced apicularen
intermediate (Ϫ)-6, thus constitutes a formal total synthesis of
(ϩ)-apicularen A.
Table 1 Stereoselectivity in the conversion of 46 into 47R/S
Conditions
Yield 47(%)
Ratio of 15S : 15R
(i) Allyltrimethylsilane, Ϫ78 ЊC, Me2AlCl, 30 min
(ii) TiCl4, Ϫ78 ЊC, allyltrimethylsilane, 1 h
(iii) (Ϫ)-B-Allyl-β-(diisopinocampheyl)borane, Et2O, Ϫ78 ЊC, 3 h
85
35
77
85 : 15
50 : 50
10 : 90
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 0 4 – 1 1 6
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Scheme 10
Table 2 Key comparative data for apicularen precursor 51 (pub-
was treated with an excess of LDA a hydroxy-alkene was
lished5d values in brackets)a
formed in 20% yield. To our initial surprise, the product was not
enone 53, nor the regioisomeric enone, but the styrene 54. The
identity of compound 54 was confirmed unambiguously by
X-ray crystallography.28 It is possible that pyranone 52 is first
converted into enone 53 which subsequently undergoes isomer-
isation to give styrene 54: however, it seems more likely that
styrene 54 is generated directly from 52 by benzylic deproton-
ation. We next attempted to recyclise 54 by treatment with base,
but unfortunately without success. Lack of material precluded
further studies such as the base-mediated ring-opening of 49
and the acid-catalysed ring-closure of 54. Although further
research is obviously required, these preliminary experiments
demonstrate the first conversion of the apicularen nucleus into
a salicylihalamide-type product thus suggesting an altern-
ative synthetic approach to the salicylihalamides, and may be
instructive in terms of biosynthetic studies.
δC (125 MHz, acetone-d6): 169.28 (169.3), 154.31 (154.3), 140.23
(139.6), 135.32 (135.4), 130.38 (130.3), 125.47 (125.5),b 122.34 (122.4),
117.48 (117.5), 114.43 (114.4), 73.65 (73.7), 73.61 (73.6), 68.08 (68.1),
64.91 (64.9), 40.36 (40.4), 40.10 (40.1), 39.96 (40.0), 39.72 (39.8), 39.13
(39.1).
a Corrected for calibration at acetone, 29.84 (rather than 30.385d). b The
peak at δ 125.5 was not reported in the original paper5d where an
erroneous peak at δ 160.7 was included. In a personal communication
Professor De Brabander confirmed the revised data shown above.
(ii) Tetrahydropyran-ring cleavage: conversion of the apicu-
laren nucleus into salicylihalamide-type products
As a brief extension to our apicularen synthetic studies, we
decided to explore the ring-opening of the tetrahydropyran
ring, possibly leading to salicylihalamide-type products, and
then, if successful, the re-closure of the tetrahydroyran ring
system returning to the apicularen nucleus. We felt that such
studies would be valuable in terms of evaluating the possibility
of devising a unified approach to both types of natural prod-
ucts, and could provide information concerning possible
biosynthetic pathways.
We decided to attempt this interconversion via tetra-
hydropyranone 52, which we aimed to subject to ring-opening
conditions (Scheme 11). The regioselectivity in this proposed
enolate β-elimination process would obviously be of interest,
but we were hoping to observe at least partial conversion into
enone 53 which possesses a salicylihalamide-like nucleus. In
turn, we hoped to investigate the ring closure of hydroxy enone
53 to return to the apicularen nucleus 52 in what appears to be a
likely biosynthetic sequence.5p,r
Conclusions
Compound (ϩ)-6 has been converted into (Ϫ)-apicularen A in
8 steps (4% overall yield) by a published procedure.6a,5a The
synthetic studies described herein therefore constitute a formal
total synthesis of (ϩ)-apicularen A. Tetrahydropyran ring
opening has been achieved using pyranone 52, providing
interesting mechanistic and biosynthetic insights.
Experimental
General
All reactions were carried out under a nitrogen atmosphere.
THF and diethyl ether (Et2O) were dried over Na–benzophen-
one ketyl; CH2Cl2 was dried over CaH2 and distilled immedi-
ately before use. Where necessary, acetonitrile and toluene were
purchased in anhydrous form. Column chromatography was
carried out using 70–200 or 33–63 micron (60 Å) silica gel.
NMR spectra were recorded using JEOL GX-270 or Bruker
The key pyranone 52 was readily prepared from silyl ether 49
in 94% overall yield by fluoride-mediated deprotection followed
by Dess–Martin oxidation. Initial attempts to ring-open the
tetrahydropyran moiety of 52 involved the use of weak acids
and bases but were not successful. However, when pyranone 52
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 0 4 – 1 1 6
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Scheme 11
AMX-500 instruments in the solvents indicated; chemical
shifts (δ) in ppm are given relative to Me4Si, coupling constants
(J) in Hz. Infra-red spectra were recorded on an API Mattson
Genesis FT-IR. Melting points were obtained using an Electro-
thermal IA9100 digital apparatus (uncorrected). Optical
rotations: JASCO DIP-370 digital polarimeter at 20 ЊC (Na-D
line, 589 nm). Mass spectra were obtained on a Fisons analyti-
cal (VG) autospec instrument. CuBr was purified by precipit-
ation from conc. HBr.29 Tf2O was re-distilled from P2O5 before
use. All other commercially available compounds were used as
received.
lowed by the slow addition of a solution of tert-butyl-
dimethylsilyl choride (9.53 g, 61.4 mmol) in THF (10 mL). After
4.5 h another portion of imidazole (4.60 g, 68.0 mmol) and a
solution of tert-butyldiphenylsilyl chloride (15.4 mL, 16.5 g,
58.9 mmol) in THF (10 mL) was added. The reaction mixture
was stirred for 24 h then filtered and thiocarbonyldiimidazole
(14.1 g, 71.8 mmol) added to the filtrate. After 20 h at rt the
solvent was evaporated under reduced pressure and the residue
purified by column chromatography (petroleum ether : EtOAc,
9 : 1) to give the title compound 25 (22.5 g, 60%) as a pale yellow
gum; Rf 0.56 (petroleum ether : EtOAc, 4 : 1); [α]D ϩ23.7
(c 2.50, CHCl3); νmax/cmϪ1 (thin film) 2953, 2932, 2858, 1646,
1391, 1247, 1112; δH (270 MHz, CDCl3): 8.20 (1 H, s), 7.72–7.66
(4 H, m), 7.51–7.32 (7 H, m), 7.00–6.98 (1 H, m), 6.40 (1 H,
d, J = 6.5 Hz), 5.94 (1 H, td, J = 4.0, 1.0 Hz), 4.63 (1 H, ddd,
J = 6.5, 4.5, 1.0 Hz), 4.41–4.34 (1 H, m), 4.24–4.21 (1 H, m),
4.14 (1 H, dd, J = 7.0, 11.5 Hz), 4.03 (1 H, dd, J = 4.5, 11.5 Hz),
1.08 (9 H, s), 0.93 (9 H, s), 0.11 (3 H, s), 0.09 (3 H, s); δC (67.9
MHz, CDCl3): 182.4, 143.5, 136.8, 135.8, 133.3, 132.5, 130.7,
130.0, 129.9, 127.8, 127.7, 117.9, 101.1, 78.5, 76.3, 63.4, 61.5,
26.8, 25.9, 19.1, 18.3, Ϫ5.3, Ϫ5.4. Found (CI): 609.2631 [MH]ϩ,
C32H45N2O4SSi2 requires 609.2639 (1.3 ppm error); m/z (CI) 609
(25%, [MH]ϩ), 69 (100).
Ethyl 2-(tetrahydro-2H-pyran-2-ylmethyl)benzoate (23)
To a stirred solution of ester 20 (750 mg, 2.66 mmol) in THF
(5 mL) at Ϫ40 ЊC was added isopropylmagnesium chloride
(1.5 mL, 3.0 mmol, 2 M in diethyl ether) dropwise. The mixture
was stirred at this temperature for 40 min then copper() brom-
ide (85 mg, 0.59 mmol) was added followed by a solution of
triflate 2213 (400 mg, 1.61 mmol) in THF (3 mL). The mixture
was warmed to 0 ЊC over 30 min, stirred at this temperature for
5 h then quenched with sat. NH4Cl(aq) and extracted with
diethyl ether. The organic extracts were dried (MgSO4), filtered
and evaporated under reduced pressure to give an oil which was
purified by flash chromatography (petroleum ether : EtOAc,
8 : 1) to give the title compound 23 (202 mg, 51%) as a colourless
oil; Rf 0.50 (petroleum ether : EtOAc, 7 : 1); νmax/cmϪ1 (thin
film) 2980, 2636, 2848, 1717, 1601, 1447, 1365, 1256, 1088,
1047; δH (270 MHz, CDCl3): 7.89 (dd, 1 H, J = 8.0, 1.5 Hz), 7.42
(ddd, 1 H, J = 8.0, 8.0, 1.5 Hz), 7.32–7.24 (m, 2 H), 4.37 (q, 2 H,
J = 7.0 Hz), 3.98–3.91 (m, 1 H), 3.58–3.48 (m, 1 H), 3.35 (ddd,
1 H, J 11.5, 11.5, 2.5 Hz), 3.17 (dd, 1 H, J = 13.0, 5.0 Hz), 3.09
(dd, 1 H, J = 13.0, 7.5 Hz), 1.85–1.79 (m, 1 H), 1.65–1.27 (m,
5 H), 1.41 (t, 3 H, J = 7.0 Hz); δC (67.9 MHz, CDCl3): 168.3,
140.8, 132.8, 131.9, 130.9, 130.8, 126.6, 79.0, 68.9, 61.2, 41.7,
32.2, 26.5, 24.0, 14.7. Found: C, 72.54; H, 8.37%. C15H20O3
requires C, 72.55; H, 8.12%. Found (CI): 249.1489 [MH]ϩ,
C15H20O3 requires 249.1491 (0.7 ppm error); m/z (CI) 249
(100%, [MH]ϩ), 203 (15).
2,6-Anhydro-1-O-[tert-butyl(dimethyl)silyl]-4-O-[tert-butyl-
(diphenyl)silyl]-3,5-dideoxy-D-threo-hex-5-enitol (26)
A stirred solution of -glucal derivative 25 (1.40 g, 2.23 mmol)
in toluene (40 mL) was degassed by the successive evacuation of
the reaction flask (water pump), then flushing with Ar (3 times).
The mixture was heated to reflux then a solution of tributyltin
hydride (1.26 mL, 1.36 g, 4.68 mmol) and AIBN (95 mg) in
toluene (10 mL) was added dropwise over 30 min. Heating was
continued for a further 30 min then the reaction was cooled to
rt and the solvent evaporated under reduced pressure to give an
orange oil. This was purified by column chromatography (petrol-
eum ether to petroleum ether : EtOAc, 9 : 1) to give the title
compound 26 (920 mg, 85%, containing a small amount of tri-
butyltin-derived impurity) as a pale yellow gum; Rf 0.83 (petrol-
eum ether : EtOAc, 4 : 1); νmax/cmϪ1 (thin film) 2957, 2931, 2856,
1644, 1471, 1427, 1251, 1110, 840, 701; δH (270 MHz, CDCl3):
7.70–7.62 (4 H, m), 7.47–7.34 (6 H, m), 6.28 (1 H, dd, J = 6.5,
1.0 Hz), 4.67 (1 H, ddd, J = 6.5, 2.5, 1.5 Hz), 4.44–4.38 (1 H, m),
3.92–3.80 (2 H, m), 3.64–3.59 (1 H, m), 1.98–1.90 (1 H, m),
1.81–1.75 (1 H, m), 1.07 (9 H, s), 0.89 (9 H, s), 0.05 (6 H, s);
1,5-Anhydro-6-O-[tert-butyl(dimethyl)silyl]-3-O-[tert-butyl-
(diphenyl)silyl]-2-deoxy-4-O-(1H-imidazol-1-ylthiocarbonyl-
oxy)-D-arabino-hex-1-enitol (25)
To a stirred solution of -glucal 24 (8.98 g, 61.4 mmol) in THF
(180 mL) at rt was added imidazole (4.60 g, 68.0 mmol) fol-
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 0 4 – 1 1 6
110

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δC (67.9 MHz, CDCl3): 144.3, 136.1, 136.1, 134.5, 134.4, 130.0,
127.9, 105.9, 75.5, 65.6, 63.9, 34.4, 27.3, 26.3, 19.4, 18.7, Ϫ4.3,
Ϫ5.0. Found (CI): 500.3016 [MNH4]ϩ, C28H42O3Si2 requires
500.3016 (0.1 ppm error); m/z (CI) 500 (<1%, [MNH4]ϩ), 483
(<1), 425 (1), 244 (6), 227 (100), 196 (6).
chromatography (petroleum ether : EtOAc, 30 : 1) to give the
title compound 30 (485 mg, 83%) as a colourless oil; Rf 0.84
(petroleum ether : EtOAc, 1 : 1); νmax/cmϪ1 (thin film) 2979,
2940, 1731, 1584, 1567, 1461, 1430, 1264, 1104; δH (270 MHz,
CDCl3): 7.37 (dd, 1 H, J = 8.0, 0.5 Hz), 7.03 (t, 1 H, J = 8.0 Hz),
6.87 (d, 1 H, J = 8.0 Hz), 4.41 (q, 2 H, J = 7.0 Hz), 3.79 (s, 3 H),
1.40 (t, 3 H, J = 7.0 Hz); δC (67.9 MHz, CDCl3): 167.7, 157.0,
131.7, 131.1, 130.6, 111.0, 92.7, 62.2, 56.7, 14.4. Found: C,
39.63; H, 3.55%. C10H11IO3 requires C, 39.24; H, 3.62%). Found
(EI): 305.9756 (Mϩ), C10H11IO3 requires 305.9753 (1.0 ppm
error); m/z (EI) 306 (40%, Mϩ), 261 (100), 218 (13), 203 (10),
151 (5).
Methyl 3-O-[tert-butyl(diphenyl)silyl]-2,4-dideoxy-D-threo-
hexopyranoside (27)
To an ice-cooled, stirred solution of compound 26 (3.04 g,
6.30 mmol) and methanol (300 mg, 9.4 mmol) in dichloro-
methane (25 mL) was added triphenylphosphine hydrobromide
(110 mg, 0.32 mmol). After 3 h at 0 ЊC, methanol (0.9 mL) and
triphenylphosphine hydrobromide (290 mg) were added and
the mixture was allowed to warm to rt then stirred for 2 h.
Sat. NaHCO3(aq) (15 mL) was then added and the mixture
extracted with dichloromethane. The organic layers were dried
(MgSO4), filtered and the solvent evaporated under reduced
pressure. The crude product was purified by column chromato-
graphy (petroleum ether : EtOAc, 4 : 1) to give the title com-
pound 27 (1.44 mg, 65%, mixture of anomers) as a colourless
gum; Rf 0.17 (petroleum ether : EtOAc, 4 : 1); νmax/cmϪ1 (thin
film) 3466, 2931, 1428, 1112, 1047, 703; δH (270 MHz, CDCl3):
7.69–7.63 (4 H, m), 7.45–7.33 (6 H, m), 4.78 (1 H, d, J = 3.5 Hz),
4.23–4.08 (1 H, m), 3.64–3.42 (3 H, m) 3.20 (3 H, s), 2.02–1.95
(1 H, m), 1.89 (1 H, dd, J = 7.5, 5.5 Hz), 1.67–1.57 (2 H, m),
1.49–1.36 (1 H, dt, J = 11.5. 11.5 Hz), 1.04 (9 H, s); δC (67.9
MHz, CDCl3): 136.0, 134.6, 134.5, 129.9, 127.9, 127.9, 99.5,
68.6, 65.9, 65.4, 54.2, 39.7, 37.0, 27.2, 19.4. Found (CI):
401.2157 [MH]ϩ, C23H32O4Si requires 401.2148 (2.1 ppm error);
m/z (CI) 401 (1%, [MH]ϩ), 386 (3), 291 (59), 207 (67), 187 (100),
133 (67).
{(4S,6R)-2-Methoxy-6-[(2-methyl-1-benzofuran-4-yl)methyl]-
tetrahydro-2H-pyran-4-yloxy}(tert-butyl)diphenylsilane (35)
(a) Formation of Grignard reagent 34: to a suspension of mag-
nesium turnings (180 mg, 7.40 mmol) in THF (2 mL) was added
catalytic iodine and the mixture stirred at rt, under N2 until the
iodine colour had been consumed. A solution of 4-bromo-2-
methylbenzofuran 3317 (1.04 g, 4.91 mmol) in THF (5 mL) was
then added over 6 h via syringe pump and the mixture stirred
for a further 1 h giving the Grignard reagent 34 as a grey–green
cloudy solution which was used immediately.
(b) Synthesis of triflate 28: to a stirred solution of alcohol 27
(1.12 g, 2.80 mmol) and pyridine (0.68 mL, 660 mg, 8.4 mmol)
in dichloromethane (10 mL) at Ϫ12 ЊC (ice–salt) under N2 was
added triflic anhydride (0.60 mL, 1.0 g, 3.6 mmol) in dichloro-
methane (2 mL) over 2 min. After a further 15 min at this
temperature the mixture was diluted with dichloromethane
(5 mL) and washed with sat. NaHCO3(aq) (5 mL). The aqueous
layer was then extracted with dichloromethane (2 × 5 mL). The
organic layers were washed with brine (10 mL), dried (MgSO4),
and filtered through a short plug of silica, eluting with di-
chloromethane (15 mL). The solvent was evaporated under
reduced pressure (below 20 ЊC), azeotroping the remaining
pyridine with toluene (1 mL), at 0.1 mmHg to give triflate 28
(1.07 g, 96%, mixture of anomers) as a colourless oil. (This
material darkened in colour upon standing and was dried for
no more than 30 min at rt, then used immediately.) Rf 0.37
(dichloromethane : petroleum ether, 1 : 1); δH (270 MHz, C6D6):
7.75–7.69 (4 H, m), 7.26–7.19 (6 H, m), 4.39 (1 H, d, J = 3.0 Hz),
4.28–4.15 (1 H, m), 3.81 (1 H, dd, J = 7.5, 10.5 Hz), 3.55 (1 H,
dd, J = 2.5, 10.5 Hz), 3.23 (1 H, ddt, J = 12.0, 7.5, 2.5 Hz), 1.91
(1 H, ddt, J = 13.0, 5.0, 1.5 Hz), 1.44 (1 H, ddd, J = 13.0, 10.5,
3.0 Hz), 1.34–1.27 (1 H, m), 1.16 (10 H, m).
(c) The Grignard reagent 34, freshly prepared, was cooled to
0 ЊC, then copper() bromide (140 mg, 1.00 mmol) was added
and the mixture stirred for 2 min under N2. Triflate 28 was then
dissolved in THF (10 mL) and added to the Grignard reagent
dropwise over 5 min. The resultant mixture was stirred over-
night at 0 ЊC then quenched with sat. NH4Cl(aq) : NH4OH(aq)
(10 : 1, 2 mL) and the mixture filtered through Celite and the
filtrate extracted with EtOAc. The organic extract was then
dried (MgSO4), filtered and the solvent evaporated under
reduced pressure. Flash chromatography (petroleum ether : di-
chloromethane, 2 : 1) gave the title compound 35 (852 mg, 59%
from alcohol 27, mixture of anomers) as a pale brown oil; Rf
0.26 (dichloromethane : petroleum ether, 1 : 1); νmax/cmϪ1 (thin
film) 2932, 1428, 1113, 1070, 1048, 702; δH (270 MHz, CDCl3):
7.63–7.57 (4 H, m), 7.41–7.23 (7 H, m), 7.08 (1 H, t, J = 8.0 Hz),
6.91 (1 H, dd, J = 8.0, 0.5 Hz), 6.30 (1 H, t, J = 1.0 Hz), 4.72
(1 H, d, J = 2.5 Hz), 4.12–4.01 (1 H, m), 3.69–3.79 (1 H, m), 2.99
(3 H, s), 2.97 (1 H, dd, J = 13.5, 6.5 Hz), 2.76 (1 H, dd, J = 13.5,
6.5 Hz), 2.44 (3 H, d, J = 1.0 Hz), 1.95 (1 H, ddt, J = 13.0, 4.5,
1.5 Hz), 1.63–1.71 (2 H, m), 1.35 (1 H, dt, J = 11.5, 11.5 Hz),
1.02 (9 H, s); δC (67.9 MHz, CDCl3): 155.0, 154.8, 136.1, 134.5,
129.9, 129.8, 128.0, 127.9, 127.7, 155.0, 154.8, 130.7, 129.2,
123.4, 123.1, 108.9, 101.7, 99.5, 68.3, 66.0, 54.5, 41.3, 39.8, 39.7,
27.2, 19.3, 14.4. Found (CI): 532.2878 [MNH4]ϩ, C32H38O4Si
Ethyl 2-iodo-6-methoxybenzoate (30)
(a) To a stirred solution of TMEDA (3.40 mL, 22.5 mmol) in
THF (50 mL) was added sec-butyllithium (1.4 M in cyclo-
hexane, 16.0 mL, 22.4 mmol) at ca. Ϫ60 ЊC under N2. The
resultant yellow solution was cooled to ca. Ϫ100 ЊC (EtOH/liq.
N2 cooling bath) and a solution of 2-methoxybenzoic acid 29
(1.45 g, 9.53 mmol) in THF (10 mL) was added dropwise over
30 min. The orange–yellow mixture was stirred for a further 30
min at this temperature then warmed to Ϫ78 ЊC over 30 min. A
solution of iodine (9.00 g, 35.4 mmol) in THF (10 mL) was then
added until the brown colour persisted and the mixture was
warmed to Ϫ60 ЊC then stirred at this temperature for a further
1 h. Sat. NH4Cl(aq) (5 mL) was then added slowly followed by
sat. Na2SO3(aq) until the brown colour had dissipated. The
solution was then extracted with diethyl ether (100 mL) and the
organic extract washed with 1 M NaOH (10 mL). The aqueous
layers were then combined and acidified (10% HCl) and
extracted with dichloromethane (4 × 100 mL), these organic
extracts were dried (MgSO4), filtered and the solvent evapor-
ated under reduced pressure to give the crude product as a
yellow oil containing unreacted 2-methoxybenzoic acid. This
mixture was re-dissolved in methanol (15 mL) and conc. H2SO4
(0.75 mL), then stirred at reflux for 4 h. After cooling to rt,
water (50 mL), then diethyl ether (50 mL) were added and the
mixture was made alkaline with 1 M NaOH. The organic layer
was separated and the aqueous phase further extracted with
diethyl ether (50 mL). The aqueous layer was then acidified
(10% HCl) and extracted with dichloromethane (3 × 50 mL).
These organic extracts were dried (MgSO4), filtered and the
solvent evaporated under reduced pressure to give 2-iodo-6-
methoxybenzoic acid (1.01 g, 39%) as colourless crystals; Rf
0.22 (EtOAc); mp 128–130 ЊC (lit.30 mp 131.5–132 ЊC).
(b) To a stirred solution of the acid from (a) (526 mg, 1.91
mmol), triphenylphosphine (650 mg, 2.48 mmol) and ethanol
(0.17 mL, 2.90 mmol) in THF (15 mL) at 0 ЊC was added drop-
wise diethyl azodicarboxylate (0.39 mL, 2.48 mmol). After 4 h,
the solvent was evaporated and the residue purified by flash
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 0 4 – 1 1 6
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requires 532.2883 (1.0 ppm error); m/z (CI) 532 (3%,
[MNH4]ϩ), 500 (2), 483 (9), 457 (3), 405 (4), 274 (17), 227 (100),
216 (30), 196 (42), 183 (17).
3-{(2R,4S )-4-[tert-Butyl(diphenyl)silyloxy]-6-methoxytetra-
hydro-2H-pyran-2-ylmethyl}-2-formylphenyl acetate (43)
Oxygen was bubbled through a stirred solution of benzofuran
35 (403 mg, 0.783 mmol) in dichloromethane (15 mL) for
10 min, with cooling to Ϫ78 ЊC. Ozone in oxygen was then
bubbled through the solution for ca. 30 min until a pale blue
colour appeared. Oxygen was then bubbled through the solu-
tion for a further 10 min after which time triphenylphosphine
(637 mg, 2.43 mmol) was added. The cooling bath was then
removed and the reaction mixture allowed to warm to rt over
3 h. The solvent was evaporated under reduced pressure and the
residue purified by flash chromatography (petroleum ether :
EtOAc, 9 : 1) to give the title compound 43 (280 mg, 68%, mix-
ture of anomers) as a yellowish gum; Rf 0.18 (petroleum ether :
EtOAc, 9 : 1); νmax/cmϪ1 (thin film) 2933, 1773, 1697, 1197,
1112; δH (270 MHz, CDCl3): 10.34 (1 H, s), 7.75–7.65 (4 H, m),
7.51–7.34 (7 H, m), 7.14 (1 H, d, J = 7.0 Hz), 7.03 (1 H, dd,
J = 8.0, 1.0 Hz), 4.68 (1 H, d, J = 3.0 Hz), 4.20–4.08 (1 H, m),
3.68–3.55 (1 H, m), 3.18 (1 H, dd, J = 14.0, 8.0 Hz), 3.01 (1 H,
dd, J = 14.0, 4.5 Hz), 2.87 (3 H, s), 2.38 (3 H, s), 2.00–1.94 (1 H,
m), 1.89–1.82 (1 H, m), 1.64 (1 H, ddd, J = 13.0, 11.0, 3.5 Hz),
1.45 (1 H, dd, J =11.5, 11.5 Hz), 1.09 (9 H, s); δC (67.9 MHz,
CDCl3): 190.0, 169.5, 151.9, 143.0, 135.8, 134.5, 134.4, 133.8,
129.7, 127.7, 126.8, 121.9, 99.0, 68.3, 65.6, 54.2, 41.1, 39.4, 38.6,
27.0, 21.0, 19.2. Found (CI): 564.2790 [MNH4]ϩ, C32H38O6Si
requires 564.2781 (1.5 ppm error); m/z (CI) 564 (12%,
[MNH4]ϩ), 529 (6), 515 (100), 473 (10), 259 (25), 196 (8).
{(2S,4R,6R)-2-Allyl-6-[(2-methyl-1-benzofuran-4-yl)methyl]-
tetrahydro-2H-pyran-4-yloxy}(tert-butyl)diphenylsilane (40)
To a stirred solution of acetal 35 (420 mg, 0.760 mmol) and
allyltrimethylsilane (0.43 mL, 2.7 mmol) in acetonitrile (4 mL)
at Ϫ35 ЊC was added trimethylsilyl triflate (60 µL, 0.34 mmol)
dropwise. The reaction mixture was warmed to ca. Ϫ25 ЊC,
stirred for 40 min then sat. NaHCO3 (6 mL) was added and the
mixture extracted with EtOAc. The organic extracts were
washed with brine, dried (MgSO4), filtered and the solvent
removed under reduced pressure to give an oil which was
re-dissolved in DMF (3 mL).
The resultant solution was cooled to 0 ЊC then imidazole
(50 mg, 0.73 mmol) and tert-butyldiphenylsilyl chloride
(200 mg, 0.73 mmol) were added. The mixture was allowed to
warm to rt and stirred for 15 h. The solvent was then evapor-
ated under reduced pressure and the residue purified by flash
chromatography (petroleum ether : EtOAc, 30 : 1) to give the
title compound 40 (337 mg, 84%) as a colourless gum; Rf 0.52
(petroleum ether : EtOAc, 9 : 1); [α]D ϩ59.3 (c 0.750, CHCl3);
νmax/cmϪ1 (thin film) 3071, 2932, 2857, 1589, 1428, 1251, 1111,
1073; δH (270 MHz, CDCl3): 7.67–7.60 (m, 4 H), 7.44–7.26
(m, 7 H), 7.11 (t, 1 H, J = 8.0 Hz), 6.96 (d, 1 H, J = 8.0 Hz), 6.35
(s, 1 H), 5.60–5.47 (m, 1 H), 4.92 (dd, 1 H, J = 10.0, 2.0 Hz), 4.85
(dd, 1 H, J = 17.0, 1.5 Hz), 4.10–3.90 (m, 2 H), 3.81–3.70 (m,
1 H), 3.18 (dd, 1 H, J = 13.5, 6.5 Hz), 2.86 (dd, 1 H, J = 13.5, 7.0
Hz), 2.46 (s, 3 H), 2.25–2.14 (m, 1 H), 2.20 (ddd, 1 H, J = 14.0,
7.0, 7.0 Hz), 1.99–1.88 (ddd, 1 H, J = 14.0, 7.0, 7.0 Hz), 1.79–
1.72 (m, 1 H), 1.70–1.58 (m, 2 H), 1.51–1.40 (m, 1 H), 1.07 (s, 9
H); δC (67.9 MHz, CDCl3): 154.9, 154.7, 136.1, 135.3, 134.5,
131.1, 130.0, 129.2, 127.9, 123.4, 123.2, 116.9, 109.0, 101.7,
71.7, 70.3, 66.4, 40.4, 40.0, 37.6, 37.1, 27.3, 19.4, 14.5. Found:
C, 77.92; H, 7.37%. C34H40O3Si requires C, 77.82; H, 7.68%.
Found (CI): 542.3097 [MNH4]ϩ, C34H40O3Si requires 542.3090
(1.2 ppm error); m/z (CI) 542 (12%, [MNH4]ϩ), 525 (2, [MH]ϩ),
467 (15), 447 (18), 379 (15), 269 (50), 251 (30), 227 (20), 199
(100), 185 (24), 145 (30).
Methyl 2-{(2R,4S )-4-[tert-butyl(diphenyl)silyloxy]-6-methoxy-
tetrahydro-2H-pyran-2-ylmethyl}-6-methoxybenzoate (44)
(a) To a solution of sodium chlorite (83 mg, 0.91 mmol),
sodium dihydrogen orthophosphate (176 mg, 1.47 mmol) and
hydrogen peroxide (30% v/v in water, 75 mg) in water (2 mL) at
0 ЊC was added sodium hydrogen sulfite (48 mg, 0.40 mmol)
portion-wise. This mixture was slowly added to a stirred solu-
tion of aldehyde 43 (230 mg, 0.409 mmol) in acetonitrile (5 mL)
at rt. After 1.5 h a mixture of sodium chlorite (40 mg),
sodium dihydrogen orthophosphate (85 mg), hydrogen peroxide
(30% v/v in water, 35 mg) and sodium hydrogen sulfite (25 mg)
was again prepared and added to the aldehyde mixture. After a
further 2 h, sat. sodium sulfite (2 mL) was added cautiously and
the reaction mixture extracted with EtOAc (4 × 20 mL). The
organic extracts were dried (MgSO4), filtered and the solvent
evaporated under reduced pressure to give 2-(acetyloxy)-6-
{(2R,4S)-4-[tert-butyl(diphenyl)silyloxy]-6-methoxytetrahydro-
2H-pyran-2-ylmethyl}benzoic acid (222 mg, 94%, mixture of
anomers) as a colourless oil; Rf 0.19 (petroleum ether : EtOAc,
2 : 1); νmax/cmϪ1 (thin film) 3070, 2930, 2858, 1771, 1730, 1702,
1472, 1427, 1371, 1198, 1112; δH (270 MHz, CDCl3): 8.50
(1 H, br s), 7.70–7.62 (4 H, m), 7.48–7.33 (7 H, m), 7.05 (1 H,
d, J = 8.0 Hz), 7.00 (1 H, dd, J = 8.0, 1.0 Hz), 4.71 (1 H, d,
J = 3.5 Hz), 4.20–4.07 (1 H, m), 3.80–3.68 (1 H, m), 2.93 (1 H,
dd, J = 14.0, 9.0 Hz), 2.81 (1 H, dd, J = 14.0, 4.0 Hz), 2.77 (3 H,
s), 2.27 (3 H, s), 1.99–1.84 (2 H, m), 1.65 (1 H, ddd, J = 12.0,
11.0, 4.0 Hz), 1.53 (1 H, dt, J = 12.0, 12.0 Hz), 1.05 (9 H, s);
δC (67.9 MHz, CDCl3): 169.6, 167.0, 148.7, 135.8, 134.3, 134.1,
131.2, 129.8, 127.9, 127.7, 121.8, 99.4, 69.8, 65.1, 54.5, 40.9,
40.6, 39.2, 27.0, 21.0, 19.2. Found (CI): 580.2726 [MNH4]ϩ,
C32H38O7Si requires 580.2731 (0.8 ppm error); m/z (CI) 580
(22%, [MNH4]ϩ), 453 (75), 247 (75), 196 (100).
3-{(2R,4S,6R)-4-[tert-Butyl(diphenyl)silyloxy]-6-(2-oxoethyl)-
tetrahydro-2H-pyran-2-ylmethyl}-2-formylphenyl acetate (41)
Ozone was bubbled through a stirred solution of benzofuran 40
(195 mg, 0.372 mmol) in dichloromethane (6.5 mL) at Ϫ78 ЊC
for ca. 20 min, until a pale blue colour appeared. Oxygen was
then bubbled through the solution for a further 5 min and tri-
phenylphosphine (420 mg, 1.60 mmol) was added. The reaction
mixture was allowed to warm to 4 ЊC then stirred for a further
15 h. The solvent was evaporated under reduced pressure and
the residue purified by flash chromatography (petroleum ether :
EtOAc, 3 : 1) to give the title compound 41 (140 mg, 67%) as a
colourless gum; Rf 0.12 (petroleum ether : EtOAc, 4 : 1); [α]D
ϩ54.6 (c 1.00, CHCl3); νmax/cmϪ1 (thin film) 2930, 2857, 1768,
1723, 1695, 1603, 1468, 1427, 1368, 1188, 1110, 1059; δH (270
MHz, CDCl3): 10.31 (s, 1 H), 9.38 (t, 1 H, J = 3.0 Hz), 7.69–7.60
(m, 4 H), 7.51–7.35 (m, 7 H), 7.13 (d, 1 H, J = 7.5 Hz), 7.03 (d, 1
H, J = 7.5 Hz), 4.63–4.53 (m, 1 H), 4.02–3.92 (m, 1 H), 3.73–
3.65 (m, 1 H), 3.33 (dd, 1 H, J = 14.0, 8.5 Hz), 3.17 (dd, 1 H,
J = 14.0, 4.0 Hz), 2.41 (ddd, 1 H, J = 16.0, 9.0, 3.0 Hz), 2.37 (s, 3
H), 2.06 (ddd, 1 H, J = 16.0, 5.5, 3.0 Hz), 1.95–1.87 (m, 1 H),
1.74–1.50 (m, 2 H), 1.50–1.41 (m, 1 H), 1.09 (s, 9 H); δC (67.9
MHz, CDCl3): 200.9, 190.3, 169.7, 152.9, 143.2, 136.0, 136.0,
134.2, 134.1, 130.2, 130.1, 128.0, 126.6, 122.0, 71.2, 66.3,
66.0, 46.5, 39.6, 38.7, 38.2, 27.2, 19.3. Found (CI): 576.2772
[MNH4]ϩ, C33H38O6Si requires 576.2784 (1.6 ppm error); m/z
(CI) 576 (80%, [MNH4]ϩ), 559 (25, [MH]ϩ), 517 (65), 303 (37),
274 (35), 261 (30), 216 (37), 196 (100).
(b) To a stirred solution of the acid from (a) (222 mg, 0.395
mmol) in methanol (6 mL) was added potassium carbonate
(290 mg, 2.10 mmol) at rt. After 1 h, the basic reaction mix-
ture was neutralised with 1 M HCl and extracted with EtOAc.
The aqueous layer was then acidified to pH 2.0 and again
extracted with EtOAc. The organic extracts were combined,
dried (MgSO4), filtered and the solvent evaporated under
reduced pressure to give crude hydroxy-acid as a pale brown
gum (203 mg). This was re-dissolved in acetone (5 mL) and
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112

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potassium carbonate (216 mg, 1.56 mmol) added, followed by
methyl iodide (0.49 mL, 1.1 g, 7.8 mmol). The mixture was
stirred under N2 at reflux for 2 d. After cooling to rt the reaction
mixture was filtered, the solvent evaporated under reduced
pressure and the crude product purified by flash chromato-
graphy (petroleum ether : EtOAc, 6 : 1) to give the title com-
pound 44 (161 mg, 75%, mixture of anomers) as a yellowish
gum; Rf 0.26 (petroleum ether : EtOAc, 6 : 1); νmax/cmϪ1 (thin
film) 2932, 1726, 1472, 1279, 1113; δH (270 MHz, CDCl3): 7.77–
7.60 (4 H, m), 7.43–7.30 (6 H, m), 7.22 (1 H, t, J = 8.0 Hz), 6.77
(1 H, d, J = 8.0 Hz), 6.76 (1 H, d, J = 8.0 Hz), 4.68 (1 H, d,
J = 3.0 Hz), 4.05–4.14 (1 H, m), 3.81 (3 H, s), 3.80 (3 H, s), 3.67–
3.57 (1 H, m), 2.99 (3 H, s), 2.77 (1 H, dd, J = 14.0, 7.5 Hz), 2.57
(1 H, dd, J = 14.0, 6.0 Hz), 1.96 (1 H, dd, J = 12.5, 5.0 Hz), 1.73–
1.56 (2 H, m), 1.32 (1 H, dt, J = 11.5, 11.5 Hz), 1.04 (9 H, s);
δC (67.9 MHz, CDCl3): 168.7, 156.5, 137.3, 135.8, 134.6, 134.5,
130.1, 129.8, 129.6, 127.6, 127.0, 122.8, 109.1, 99.2, 67.9, 65.7,
56.0, 56.3, 52.1, 41.1, 39.5, 39.5, 27.0, 19.2. Found (CI):
566.2963 [MNH4]ϩ, C32H40O6Si requires 566.2938 (4.4 ppm
error); m/z (CI) 566 (3%, [MNH4]ϩ), 517 (95), 491 (100), 261
(95).
phenylphosphine (246 mg, 0.939 mmol) was added. The cooling
bath was then removed and the reaction mixture allowed to
warm to rt over 3 h. The solvent was evaporated under reduced
pressure and the residue purified by flash chromatography
(petroleum ether : EtOAc, 4 : 1) to give the title compound 46
(133 mg, 98%) as a colourless gum; Rf 0.52 (petroleum ether :
EtOAc, 2 : 1); [α]D ϩ36.3 (c 2.20, CHCl3); νmax/cmϪ1 (thin film)
2951, 2935, 2856, 1738, 1585, 1471, 1267, 1247, 1074; δH (270
MHz, C6D6): 9.36 (1 H, dd, J = 3.0, 2.0 Hz), 7.05 (1 H, t, J = 8.0
Hz), 6.87 (1 H, dd, J = 8.0, 1.0 Hz), 6.64 (1 H, dd, J = 8.0, 1.0
Hz), 4.40 (1 H, m), 4.01–3.85 (1 H, m), 3.73 (1 H, m), 3.65 (3 H,
s), 3.25–3.15 (4 H, m), 2.76 (1 H, dd, J = 14.0, 5.0 Hz), 2.37 (1
H, ddd, J = 16.0, 9.0, 3.0 Hz), 1.81 (1 H, ddd, J = 16.0, 5.5, 2.0
Hz), 1.85–1.72 (1 H, m), 1.53 (1 H, ddd, J = 13.0, 8.5, 5.0 Hz),
1.40–1.30 (2 H, m), 0.94 (9 H, s), 0.00 (3 H, s), Ϫ0.01 (3 H, s);
δC (67.9 MHz, C6D6): 199.7, 168.6, 157.0, 138.1, 130.1, 125.2,
122.9, 109.3, 71.0, 65.9, 65.3, 55.3, 51.8, 46.7, 39.9, 39.5,
38.7, 26.1, 18.2, Ϫ4.5, Ϫ4.6. Found (CI): 437.2374 [MH]ϩ,
C23H36O6Si requires 437.2359 (3.2 ppm error); m/z (CI) 437 (1,
[MH]ϩ), 401 (6), 379 (100), 257 (46).
Methyl 2-{(2R,4S,6R)-4-[tert-butyl(dimethyl)silyloxy]-6-[(2S )-
2-hydroxypent-4-enyl]tetrahydro-2H-pyran-2-ylmethyl}-6-
methoxybenzoate (47)
Methyl 2-{(2R,4R,6S )-6-allyl-4-[tert-butyl(dimethyl)silyloxy]-
tetrahydro-2H-pyran-2-ylmethyl}-6-methoxybenzoate (45)
To a stirred solution of acetal 44 (139 mg, 0.253 mmol) in
acetonitrile (1.5 mL) at Ϫ20 ЊC, under N2, was added allyl-
trimethylsilane (0.20 mL, 150 mg, 1.3 mmol) followed by tri-
methylsilyl triflate (46 µL 57 mg, 0.26 mmol) dropwise over
10 min. The reaction mixture was warmed to 0 ЊC over 45 min
then quenched with sat. NaHCO3(aq) and extracted with
EtOAc (2 × 10 mL). The organic extracts were dried (MgSO4),
filtered and evaporated under reduced pressure to give a colour-
less gum. This was re-dissolved in THF (1.0 mL) and TBAF
(1 M in THF ϩ 5 wt% water, 0.75 mL, 0.75 mmol) added. This
was stirred overnight at rt. The solvent was then evaporated
under reduced pressure and the residue purified by flash
chromatography (petroleum ether : EtOAc, 1 : 1) to give the
corresponding alcohol (83 mg) as a colourless gum. This was
re-dissolved in dichloromethane (2.0 mL), cooled to 0 ЊC and
2,6-lutidine (56 µL, 51 mg, 0.48 mmol) followed by tert-butyl-
(dimethyl)silyl triflate (52 µL, 61 mg, 0.23 mmol) were added
with stirring. After 45 min, a further portion of tert-butyl-
(dimethyl)silyl triflate (5 µL, 6 mg, 0.02 mmol) was added and
stirring continued for a further 45 min. The solvent was then
evaporated under reduced pressure and the residue purified by
flash chromatography (petroleum ether : EtOAc, 6 : 1) to give
the title compound 45 (89 mg, 81%) as a colourless gum; Rf 0.69
(petroleum ether : EtOAc, 2 : 1); [α]D ϩ35.2 (c 1.34, CHCl3);
νmax/cmϪ1 (thin film) 2950, 2855, 1733, 1585, 1472, 1268, 1114,
1073; δH (270 MHz, CDCl3): 7.27 (1 H, t, J = 8.0 Hz), 6.90 (1 H,
d, J = 8.0 Hz), 6.80 (1 H, d, J = 8.0 Hz), 5.70 (1 H, dddd,
J = 17.0, 10.0, 7.5, 6.5 Hz), 5.08–4.98 (2 H, m), 4.05–3.98 (1 H,
m), 3.97–3.90 (1 H), 3.91 (3 H, s), 3.91–3.84 (1 H, m), 3.82 (3 H,
s), 3.00 (1 H, dd, J = 14.0, 7.5 Hz), 2.67 (1 H, dd, J = 14.0, 6.0
Hz), 2.45–2.33 (1 H, m), 2.23–2.13 (1 H, m), 1.87–1.78 (1 H, m),
1.76–1.54 (2 H, m), 1.34 (1 H, dt, J = 13.0, 9.0 Hz), 0.89 (9 H, s),
0.05 (6 H, s); δC (67.9 MHz, CDCl3): 168.9, 156.5, 137.7, 135.2,
130.2, 124.1, 123.0, 116.8, 109.0, 70.8, 70.4, 65.1, 56.0, 52.3,
40.1, 39.5, 37.8, 37.3, 25.9, 18.2, Ϫ4.5, Ϫ4.6. Found (CI):
435.2568 [MH]ϩ, C24H38O5Si requires 435.2567 (0.3 ppm error);
m/z (CI) 435 (100%, [MH]ϩ), 403 (50), 377 (18), 255 (20).
(a) To a solution of aldehyde 46 (334 mg, 0.765 mmol) in di-
chloromethane (15 mL) at Ϫ78 ЊC was added allyltrimethyl-
silane (0.36 mL, 2.3 mmol) followed by dimethylaluminium
chloride (1 M in hexane, 4.59 mL, 4.59 mmol) with stirring
under N2. After 30 min, sat. NH4Cl(aq) (0.5 mL) was added
and the reaction allowed to warm to rt. Brine (5 mL) was added
and the mixture extracted with dichloromethane (4 × 10 mL).
The organic extracts were dried (MgSO4), filtered and the
solvent evaporated under reduced pressure to give the crude
product as a cloudy gum. Flash chromatography (petroleum
ether : EtOAc, 2 : 1) gave the title compound 47 (310 mg, 85%,
15S : 15R = 85 : 15) as a colourless oil; Rf 0.34 (petroleum ether :
EtOAc, 2 : 1); [α]D ϩ18.0 (c 1.50, CHCl3); νmax/cmϪ1 (thin film)
3460, 2927, 2853, 1721, 1583, 1468, 1433, 1264, 1104, 1070;
δH (270 MHz, CDCl3): 7.28 (1 H, t, J = 8.0 Hz), 6.87 (1 H, d,
J = 8.0 Hz), 6.80 (1 H, d, J = 8.0 Hz), 5.76–5.61 (1 H, m), 5.05–
4.96 (2 H, m), 4.34–4.25 (1 H, m), 4.02–3.93 (1 H, m), 3.89 (3 H,
s), 3.82 (3 H, s), 3.82–3.73 (1 H, m), 3.43–3.34 (1 H, m), 3.06
(1 H, dd, J = 14.0, 8.5), 2.66 (1 H, dd, J = 14.0, 4.5), 2.09 (2 H, t,
J = 7.0 Hz), 1.84 (1 H, dt, J = 13.0, 3.5 Hz), 1.75 (1 H, ddd,
J = 14.0, 11.0, 3.0 Hz), 1.62 (2 H, t, J = 5.0 Hz), 1.45–1.26 (2 H,
m), 0.89 (9 H, s), 0.05 (6 H, 2 × s); δC (67.9 MHz, CDCl3): 168.9,
156.6, 138.2, 135.3, 130.2, 124.0, 122.7, 117.0, 109.2, 70.6, 67.0,
66.8, 65.2, 55.9, 52.2, 41.6, 39.8, 39.2, 38.8, 38.7, 25.8, 18.1,
Ϫ4.7, Ϫ4.7. Found (CI): 479.2825 [MH]ϩ, C26H42O6Si requires
479.2829 (0.9 ppm error); m/z (CI) 479 (100%, [MH]ϩ), 447
(42), 429 (47), 167 (33).
(b) To a stirred solution of (ϩ)-B-methoxydiisopino-
campheylborane(475mg,1.50mmol)inEt2O(10mL)wasadded
allylmagnesium bromide (1 M in Et2O, 1.5 mL, 1.50 mmol) at
Ϫ78 ЊC under N2. After 15 min, the mixture was allowed to
warm to rt and stirred for 2 h. The mixture was again cooled to
Ϫ78 ЊC and aldehyde 46 (437 mg, 1.5 mmol) in Et2O (5 mL) was
added dropwise. After 3 h at Ϫ78 ЊC, the mixture was allowed
to warm to rt and 1 M NaOH (5 mL) then 30% H2O2 (5 mL)
was added; stirring was continued for a further 45 min. Sat.
Na2SO3(aq) (2 mL) was then added and the reaction mixture
extracted with EtOAc (3 × 100 mL). The organic extracts
were combined and dried (MgSO4), filtered and evaporated
under reduced pressure. Flash chromatography (petroleum
ether : EtOAc, 4 : 1) gave the title compound 47 (416 mg, 77%,
15R : 15S = 90 : 10) as a colourless oil; Rf 0.35 (petroleum ether :
EtOAc, 2 : 1); [α]D ϩ28.0 (c 0.95, CHCl3); νmax/cmϪ1 (thin film)
3496, 2949, 2929, 2856, 1732, 1585, 1471, 1267, 1074; δH (270
MHz, CDCl3): 7.28 (1 H, t, J = 8.0 Hz), 6.87 (1 H, d, J = 8.0
Methyl 2-{(2R,4S,6S )-4-[tert-butyl(dimethyl)silyloxy]-6-(2-oxo-
ethyl)tetrahydro-2H-pyran-2-ylmethyl}-6-methoxybenzoate (46)
Oxygen was bubbled through a stirred solution of ester 45 (136
mg, 0.313 mmol) in dichloromethane (10 mL) at Ϫ78 ЊC for 10
min. Ozone in oxygen was then bubbled through the solution
for ca. 25 min until a pale blue colour appeared. Oxygen was
bubbled through the solution for a further 10 min then tri-
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 0 4 – 1 1 6
113

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Hz), 6.80 (1 H, d, J = 8.0 Hz), 5.86–5.70 (1 H, m), 5.10–5.00
(2 H, m), 4.30–4.19 (1 H, m), 4.04–3.94 (2 H, m), 3.89 (3 H, s),
3.81 (3 H, s), 3.80–3.68 (1 H, m), 3.10 (1 H, dd, J = 14.0,
8.0 Hz), 2.75 (1 H, dd, J = 14.0, 5.5 Hz), 2.20–2.13 (2 H, m),
1.82 (1 H, dt, J = 13.0, 4.0 Hz), 1.75–1.66 (1 H, m), 1.59 (2 H, t,
J = 6.0 Hz), 1.43–1.36 (2 H, m), 0.88 (9 H, s), 0.05 (3 H, s), 0.04
(3 H, s); δC (67.9 MHz, CDCl3): 168.9, 156.7, 137.6, 135.2,
130.4, 124.1, 122.8, 117.3, 109.4, 71.1, 71.0, 69.8, 64.9, 56.1,
52.4, 41.7, 39.7, 39.4, 38.9, 38.6, 26.0, 18.2, Ϫ4.5, Ϫ4.6. Found
(CI): 479.2818 [MH]ϩ, C26H42O6Si requires 479.2829 (2.2 ppm
error); m/z (CI) 479 (100%, [MH]ϩ), 447 (15), 421 (10), 180 (15),
167 (18).
39.11, 39.44, 25.97, 18.18, Ϫ4.74. Found (CI): 447.2566 [MH]ϩ,
C25H38O5Si requires 447.2567 (0.1 ppm error); m/z (FAB) 469
(100%, [MNa]ϩ), 176 (45), 149 (17).
Further elution gave a trace of diastereomer 50 (2 mg, 2%) as
a white solid; Rf 0.31 (petroleum ether : EtOAc, 4 : 1); mp 93–95
ЊC; [α]D ϩ7.9 (c 0.20, CHCl3); νmax/cmϪ1 (thin film) 2951, 2924,
2856, 1718, 1585, 1471, 1458, 1263, 1110, 1070; δH (500 MHz,
CDCl3): 7.29 (1 H, t, J = 8.0 Hz), 6.82 (1 H, d, J = 8.0 Hz), 6.74
(1 H, d, J = 8.0 Hz), 5.83–5.74 (1 H, m), 5.06 (1 H, dd, J = 17.0,
1.5 Hz), 5.05 (1 H, d, J = 11.0 Hz), 4.66 (1 H, m), 4.24 (1 H, t,
J = 10.5 Hz), 4.14 (1 H, m), 3.99–3.92 (1 H, m), 3.81 (3 H, s),
3.61 (1 H, t, J = 13.0 Hz), 2.56–2.50 (2 H, m), 2.44 (1 H, dt,
J = 7.5, 7.5 Hz), 1.95 (1 H, ddd, J = 13.5, 6.5, 4.0 Hz), 1.67–1.60
(3 H, m), 1.55–1.50 (1 H, m), 1.47 (1 H, dt, J = 9.5, 3.5 Hz), 0.92
(9 H, s), 0.06 (6 H, s); δC (125 MHz, CDCl3): 170.22, 155.64,
140.23, 133.80, 130.64, 124.52, 122.66, 117.75, 108.28, 74.20,
74.06, 65.72, 60.67, 55.71, 39.77, 38.98, 37.37, 36.73, 25.95,
18.11, Ϫ4.64, Ϫ4.78. Found (CI): 447.2565 [MH]ϩ, C25H38O5Si
requires 447.2567 (0.3 ppm error); m/z (CI) 447 (100%, [MH]ϩ),
429 (32), 389 (13), 297 (10), 148 (10).
2-{(2R,4S,6R)-4-[tert-Butyl(dimethyl)silyloxy]-6-[(2R)-2-
hydroxypent-4-enyl]tetrahydro-2H-pyran-2-ylmethyl}-6-
methoxybenzoic acid (48)
To a stirred solution of ester 47 (15R : 15S = 90 : 10, 32 mg,
0.067 mmol) in pyridine (2 mL) was added lithium iodide
(105 mg, 0.784 mmol), and the solution was heated at 100 ЊC
under N2 for 24 h. The mixture was cooled to rt and diluted
with EtOAc (5 mL) and 0.5 M HCl (1 mL). This was extracted
with EtOAc (6 × 5 mL) and the organic extracts dried (MgSO4),
filtered and the solvent evaporated under reduced pressure.
Flash chromatography (petroleum ether : EtOAc, 2 : 1 to
EtOAc ϩ 1% AcOH) gave first, recovered starting material 47
(12 mg) and then the title compound 48 (17 mg, 55%, 88% with
respect to the recovered starting material, 15R : 15S = 90 : 10) as
a yellowish gum; Rf 0.45 (EtOAc ϩ 1% AcOH); [α]D ϩ64.4
(c 1.00, CHCl3); νmax/cmϪ1 (thin film) 3440, 2951, 2929, 2856,
1726, 1585, 1471, 1263, 1074; δH (270 MHz, CDCl3): 7.29 (1 H,
dd, J = 7.5, 8.5 Hz), 6.84 (1 H, d, J = 8.5 Hz), 6.82 (1 H, d,
J = 7.5 Hz), 5.76–5.59 (1 H, m), 5.08–5.00 (2 H, m), 4.28–4.18
(1 H, m), 4.11–4.01 (1 H, m), 4.01–3.88 (1 H, m), 3.85 (3 H, s),
3.67–3.58 (1 H, m), 3.07 (1 H, dd, J = 14.0, 4.0 Hz), 2.86 (1 H,
dd, J = 14.0, 10.0 Hz), 2.20–2.10 (2 H, m), 2.00–1.62 (2 H, m),
1.69–1.63 (2 H, m), 1.47–1.26 (2 H, m), 0.88 (9 H, s), 0.06 (3 H,
s), 0.05 (3 H, s); δC (67.9 MHz, CDCl3): 156.7, 137.0, 134.3,
130.7, 123.6, 117.8, 109.8, 72.3, 71.8, 70.1, 64.6, 56.1, 41.2, 40.5,
39.9, 39.6, 37.3, 25.9, 18.1, Ϫ4.8, Ϫ4.9. Found (CI): 465.2664
[MHϩ], C25H40O6Si requires 465.2672 (1.8 ppm); m/z (CI) 465
(100%, [MH]ϩ), 447 (30), 421 (25), 184 (30), 167 (35).
(1R,11R ,13R,15S )-11-Allyl-7,15-dihydroxy-10,17-dioxa-
tricyclo[11.3.1.03,8]heptadeca-3,5,7-trien-9-one (51)
To a stirred solution of methyl ether 49 (8 mg, 0.018 mmol) in
dichloromethane (1 mL) was added 9-iodo-9-BBN (1 M in hex-
anes, 40 µL, 0.040 mmol) at 0 ЊC under N2. After 1 h a further
portion of 9-iodo-9-BBN (1 M in hexanes, 10 µL, 0.010 mmol)
was added and the reaction was stirred for a further 1 h. Water
(2 drops) was added, stirring continued for 15 min, then the
mixture extracted with EtOAc. The organic extracts were dried
(MgSO4), filtered and the solvent evaporated under reduced
pressure. The residue was purified by flash chromatography
(dichloromethane : EtOH, 20 : 1) to give the title compound 51
(4 mg, 70%) as a pale brown gum; Rf 0.30 (dichloromethane :
EtOH, 20 : 1); [α]D Ϫ4.5 (c 0.15, MeOH); lit. (enantiomer)5d [α]D
ϩ6.8 (c 0.16, MeOH); νmax/cmϪ1 (thin film) 3262, 2924, 1716,
1583, 1464, 1294; δH (500 MHz, acetone-d6) 8.39 (1 H, s), 7.11
(1 H, dd, J = 8.0, 7.7 Hz), 6.77 (1 H, d, J = 8.0 Hz), 6.69 (1 H, d,
J = 7.7 Hz), 5.92 (1 H, dddd, J = 6.4, 7.6, 10.2, 17.2 Hz), 5.48
(1 H, dddd, J = 2.4, 5.6, 5.6, 10.0 Hz), 5.13 (1 H, dddd, J = 1.6,
1.6, 2.4, 17.2 Hz), 5.03 (1 H, dddd, J = 1.6, 1.6, 2.4, 10.2 Hz),
4.24–4.30 (1 H, m), 3.96–4.03 (1 H, m), 3.85–3.91 (1 H, m),
3.77–3.81 (1 H, m), 3.34 (1 H, dd, J = 9.8, 15.0 Hz), 2.44 (1 H,
dd, J = 1.0, 15.0 Hz), 2.30–2.41 (2 H, m), 1.93 (1 H, ddd, J = 4.5,
4.5, 12.7 Hz), 1.77–1.86 (1 H, m), 1.40–1.71 (4 H, m); δC (125
MHz, acetone-d6) 169.28, 154.31, 140.23, 135.32, 130.38,
125.47, 122.34, 117.48, 114.43, 73.65, 73.61, 68.08, 64.91, 40.36,
40.10, 39.96, 39.72, 39.13. Found (CI): 319.1545 [MH]ϩ,
C18H22O5 requires 319.1546 (0.1 ppm error); m/z (CI) 336 (20%,
[MNH4]ϩ), 319 (100, [MH]ϩ), 301 (70), 283 (20), 162 (20), 134
(25).
(1R,11R,13R,15S )-11-Allyl-15-[tert-butyl(dimethyl)silyloxy]-7-
methoxy-10,17-dioxatricyclo[11.3.1.03,8]heptadeca-3,5,7-trien-9-
one (49)
To a solution of DCC (365 mg, 1.77 mmol), DMAP (252 mg,
2.07 mmol) and DMAPؒHCl (280 mg, 1.77 mmol) in CHCl3
(spectrophotometric grade 99.8%, 105 mL) at reflux with stir-
ring under N2 was added carboxylic acid 48 (15R : 15S = 90 : 10,
137 mg, 0.295 mmol) via syringe pump over 5 h. This was
stirred for a further 16 h at reflux then cooled to rt and
methanol (2 mL) and acetic acid (0.2 mL) were added. After
stirring for a further 30 min at rt the solvent was evaporated
under reduced pressure and the residue purified by flash chrom-
atography (petroleum ether : EtOAc, 6 : 1) giving first the
cyclised compound 49 (50 mg, 38%) as a white solid; Rf 0.40
(petroleum ether : EtOAc, 4 : 1); mp 149–150 ЊC (EtOAc); [α]D
Ϫ6.3 (c 0.50, CHCl3); νmax/cmϪ1 (thin film) 2928, 2913, 1719,
1583, 1471, 1276, 1252, 1117; δH (500 MHz, CHCl3): 7.22 (1 H,
t, J = 8.0 Hz), 6.76 (1 H, d, J = 8.0 Hz), 6.73 (1 H, d, J = 8.0 Hz),
5.87 (1 H, dddd, J = 16.0, 10.0, 6.0, 6.0 Hz), 5.61–5.55 (1 H, m),
5.13 (1 H, dd, J = 16.0, 2.0), 5.09 (1 H, d, J = 10.0), 4.56–4.49
(1 H, m), 4.08–4.01 (1 H, m), 4.00–3.93 (1 H, m), 3.78 (3 H, s),
3.54 (1 H, dd, J = 15.0, 10.5 Hz), 2.37 (1 H, dd, J = 15.0, 1.5 Hz),
2.47–2.43 (1 H, m), 2.36–2.28 (1 H, m), 1.87 (1 H, ddd, J = 13.5,
5.5, 4.0 Hz), 1.82 (1 H, ddd, J = 11.0, 11.0, 14.5), 1.66–1.48
(4 H, m), 0.91 (9 H, s), 0.06 (6 H, s); δC (125 MHz, CHCl3):
169.59, 156.01, 139.31, 133.92, 130.02, 125.92, 122.90, 117.66,
109.50, 74.06, 73.12, 65.87, 65.69, 55.98, 39.77, 39.43, 39.32,
1H NMR, 13C NMR and IR spectroscopic data were in
agreement with published values (see Table 2).5d
(1R,11R,13R,15S )-11-Allyl-7,15-bis[tert-butyl(dimethyl)-
silyloxy]-10,17-dioxatricyclo[11.3.1.03,8]heptadeca-3,5,7-trien-9-
one [(؊)-6]
To a solution of diol 51 (3 mg, 0.009 mmol) in dichloromethane
(0.5 mL) was added 2,6-lutidine (0.2 mL) and tert-butyl-
(dimethyl)silyl triflate (10 µL 12 mg, 0.044 mmol) with stirring
at 0 ЊC under N2. After 2 h a further portion of tert-butyl-
(dimethyl)silyl triflate (10 µL, 12 mg, 0.044 mmol) was added
and stirring was continued for a further 2 h. The solvent was
evaporated under reduced pressure and the residue purified by
flash chromatography (petroleum ether : EtOAc, 9 : 1) to give
the title compound (Ϫ)-6 (3 mg, 80%) as a colourless oil; Rf 0.71
(petroleum ether : EtOAc, 2 : 1); [α]D Ϫ20 (c 0.10, CHCl3);
νmax/cmϪ1 (thin film) 2927, 2856, 1722, 1579, 1463, 1285, 1255,
1106; δH (500 MHz, acetone-d6): 7.18 (1 H, t, J = 8.0 Hz), 6.83
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 0 4 – 1 1 6
114

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(1 H, d, J = 8.0 Hz), 6.79 (1 H, d, J = 8.0 Hz), 5.90 (1 H, dddd,
J = 17.0, 10.0, 7.0, 7.0 Hz), 5.58–5.52 (1 H, m), 5.14 (1 H, dd,
J = 17.0, 1.0 Hz), 5.07 (1 H, dt, J = 10.0, 1.0 Hz), 4.33–5.28
(1 H, m), 4.18–4.13 (1 H, m), 3.93–3.88 (1 H, m), 3.46 (1 H, dd,
J = 15.0, 10.5 Hz), 2.44 (1 H, J = 15.0, 1.5 Hz), 2.48–2.35 (2 H,
m), 1.92 (1 H, ddd, J = 13.5, 5.0, 5.0 Hz), 1.81 (1 H, dt, J = 14.5,
10.5 Hz), 1.65–1.58 (1 H, m), 1.60 (1 H, dt, J = 14.5, 2.0 Hz),
1.56–1.47 (2 H, m), 0.99 (9 H, s), 0.92 (9 H, s), 0.26 (3 H, s), 0.20
(3 H, s), 0.10 (3 H, s), 0.09 (3 H, s); δC (125 MHz, acetone-d6):
169.54, 152.45, 140.94, 134.98, 130.17, 129.85, 124.08, 117.98,
117.67, 74.20, 73.75, 66.75, 66.55, 40.22, 40.10, 39.97, 39.47,
38.87, 26.25, 26.16, 18.88, 18.55, Ϫ3.79, Ϫ4.22, Ϫ4.61, Ϫ4.64.
Found (CI): 547.3275 [MH]ϩ, C30H50O5Si2 requires 547.3275
(0.0 ppm error); m/z (CI) 564 (12%, [MNH4]ϩ), 547 (85,
[MH]ϩ), 529 (100), 489 (14), 428 (30), 261 (25), 137 (30).
After 15 min the reaction mixture had darkened considerably.
Sat. NH4Cl(aq) (0.1 mL) was then added, the mixture stirred at
Ϫ10 ЊC for a further 10 min, then the solvent evaporated under
reduced pressure. Flash chromatography (petroleum ether:
EtOAc, 3 : 1 to 1 : 1) gave first recovered starting material 52
(2 mg, 20%), then the title compound 54 (2 mg, 20%) as a yellow-
ish oil, which was recrystallised from ether to give a yellowish
solid; Rf 0.27 (petroleum ether : EtOAc, 1 : 1); mp 123–124 ЊC;
[α]D Ϫ110 (c 0.20, MeOH); νmax/cmϪ1 (thin deposit): 3448, 2941,
1707, 1644, 1575, 1467, 1268, 1110; δH (500 MHz, acetone-d6):
7.37 (1 H, t, J = 8.0 Hz), 7.01 (1 H, d, J = 8.0 Hz), 6.86 (1 H, d,
J = 8.0 Hz), 6.71 (1 H, d, J = 16.0 Hz), 6.00 (1 H, ddd, J = 16.0,
8.0, 6.5 Hz), 5.87 (1 H, dddd, J = 16.0, 10.0, 6.5, 6.5 Hz),
5.31 (1 H, m), 5.11 (1 H, dq, J = 17.0, 1.5 Hz), 5.08 (1 H, ddt,
J = 10.0, 2.5, 1.0 Hz), 4.46 (1 H, m), 3.81 (1 H, d, J = 6.0 Hz),
3.23 (2 H, m), 2.99 (1 H, dd, J = 13.5, 3.5 Hz), 2.43 (2 H, tq,
J = 6.0, 1.5 Hz), 2.26 (1 H, dd, J = 13.5, 9.5 Hz), 1.99 (1 H, ddd,
J = 14.0, 11.0, 5.0 Hz), 1.76 (1 H, ddd, J = 14.0, 9.5, 3.5 Hz);
δC (125 MHz, acetone-d6): 206.75, 167.87, 157.29, 136.96,
134.60, 134.04, 131.06, 128.85, 124.16, 121.23, 118.05, 111.13,
71.78, 65.21, 56.33, 50.15, 47.93, 41.77, 40.36. Found (CI):
348.1812 [MNH4]ϩ, C19H22O5 requires 348.1811 (0.2 ppm
error); m/z (CI) 348 (10%, [MNH4]ϩ), 331 (100, [MH]ϩ), 313
(85), 295 (15), 234 (15), 217 (35), 174 (20), 148 (15).
(1R,11R,13R)-11-Allyl-7-methoxy-10,17-dioxatricyclo-
[11.3.1.03,8]heptadeca-3,5,7-triene-9,15-dione (52)
(a) To a solution of lactone 49 (50 mg, 0.11 mmol) in THF
(2 mL) was added TBAF (1 M in THF, 0.22 mL, 0.22 mmol)
with stirring at rt. After 5 h the solvent was evaporated under
reduced pressure and the residue purified by flash chromato-
graphy (petroleum ether : EtOAc, 4 : 1 to EtOAc) to give
(1R,11R,13R,15S)-11-allyl-15-hydroxy-7-methoxy-10,17-di-
oxatricyclo[11.3.1.03,8]heptadeca-3,5,7-trien-9-one (36 mg,
97%) as a colourless oil; Rf 0.50 (EtOAc); [α]D Ϫ10.6 (c 1.50,
CHCl3); νmax/cmϪ1 (thin film) 3460, 2946, 2923, 2841, 1732,
1598, 1581, 1470, 1272, 1119, 1089, 1071; δH (270 MHz,
CDCl3): 7.21 (1 H, t, J = 8.0 Hz), 6.77 (1 H, d, J = 8.0 Hz), 6.72
(1 H, d, J = 8.0 Hz), 5.86 (1 H, dddd, J = 17.0, 10.0, 7.0, 7.0 Hz),
5.62–5.52 (1 H, m), 5.18–5.08 (2 H, m), 4.34–4.25 (1 H, m),
4.05–3.93 (2 H, m, 9-H), 3.77 (3 H, s), 3.37 (1 H, dd, J = 15.0,
10.0 Hz), 2.50–2.27 (2 H, m), 2.44 (1 H, d, J = 14.5 Hz), 2.08
(1 H, broad s), 2.00–182 (2 H, m), 1.77–1.70 (1 H, dt, J = 13.0,
6.0 Hz), 1.58–1.46 (3 H, m); δC (67.9 MHz, CDCl3): 169.2,
156.1, 138.5, 133.7, 130.0, 125.5, 122.9, 117.8, 109.5, 73.0, 72.7,
67.6, 65.1, 55.9, 39.7, 39.5, 38.9, 38.7, 38.2. Found (CI):
333.1701 [MH]ϩ, C19H24O5 requires 333.1702 (0.4 ppm error);
m/z (CI) 350 (10%, [MNH4]ϩ), 333 (100, [MH]ϩ), 315 (63), 245
(10), 148 (25).
Acknowledgements
We thank the BBSRC and GlaxoSmithKline for a CASE
studentship (I. S.) and Elsevier Science for additional financial
support (A. L. and S. A. S.).
References
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