Synthesis of the anti-Helicobacter pylori agent (+)-spirolaxine methyl ether and the unnatural (2″S)-diastereomer

Article abstract of DOI:10.1039/b708265g

The first enantioselective synthesis of the anti-Heliocbacter pylori agent (+)-spirolaxine methyl ether 2b has been carried out in a convergent fashion establishing that the absolute stereochemistry of the natural product is in fact (3R, 2″R, 5″R, 7″R) after initial synthesis of the unnatural (2″S)-diastereomer 2a. The key step in the synthesis of (+)-spirolaxine methyl ether 2b involved a heterocycle-activated Julia-Kocienski olefination between benzothiazole-based spiroacetal sulfone 4b and phthalide aldehyde 3a. (2″R, 5″S, 7″S)-Spiroacetal sulfone 4b was prepared via cyclisation of protected dihydroxyketone 6b, which in turn was derived from the coupling of the acetylide derived from (R)-acetylene 24b with aldehyde 3a. Phthalide aldehyde 3a was prepared via intramolecular acylation of bromocarbamate 15, which was available via titanium tetrafluoride-(+)-BINOL- mediated allylation of 3,5-dimethoxybenzaldehyde 13. Union of the sulfone 4b and aldehyde 3a fragments successfully completed the enantioselective synthesis of (+)-spirolaxine methyl ether 2b. The synthesis of the unnatural (3R, 2″S, 5″R, 7″R)-diastereomer of spirolaxine methyl ether 2a was also undertaken in a similar manner by union of phthalide aldehyde 3a with (2″S, 5″S, 7″S)-spiroacetal sulfone 4a derived from (S)-acetylene 24a. The Royal Society of Chemistry.

Full text of DOI:10.1039/b708265g

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of the anti-Helicobacter pylori agent (+)-spirolaxine methyl ether
and the unnatural (2ꢀꢀS)-diastereomer†
James E. Robinson and Margaret A. Brimble*
Received 31st May 2007, Accepted 20th June 2007
First published as an Advance Article on the web 11th July 2007
DOI: 10.1039/b708265g
The first enantioselective synthesis of the anti-Heliocbacter pylori agent (+)-spirolaxine methyl ether 2b
has been carried out in a convergent fashion establishing that the absolute stereochemistry of the
natural product is in fact (3R, 2ꢀꢀR, 5ꢀꢀR, 7ꢀꢀR) after initial synthesis of the unnatural (2ꢀꢀS)-diastereomer
2a. The key step in the synthesis of (+)-spirolaxine methyl ether 2b involved a heterocycle-activated
Julia–Kocienski olefination between benzothiazole-based spiroacetal sulfone 4b and phthalide aldehyde
3a. (2ꢀꢀR, 5ꢀꢀS, 7ꢀꢀS)-Spiroacetal sulfone 4b was prepared via cyclisation of protected dihydroxyketone 6b,
which in turn was derived from the coupling of the acetylide derived from (R)-acetylene 24b with
aldehyde 3a. Phthalide aldehyde 3a was prepared via intramolecular acylation of bromocarbamate 15,
which was available via titanium tetrafluoride-(+)-BINOL-mediated allylation of 3,5-dimethoxy-
benzaldehyde 13. Union of the sulfone 4b and aldehyde 3a fragments successfully completed the
enantioselective synthesis of (+)-spirolaxine methyl ether 2b. The synthesis of the unnatural (3R, 2ꢀꢀS,
5ꢀꢀR, 7ꢀꢀR)-diastereomer of spirolaxine methyl ether 2a was also undertaken in a similar manner by union
of phthalide aldehyde 3a with (2ꢀꢀS, 5ꢀꢀS, 7ꢀꢀS)-spiroacetal sulfone 4a derived from (S)-acetylene 24a.
Introduction
Helicobacter pylori has been shown by epidemiologic studies to
have an etiological role in several diseases, including gastric and
duodenal ulcers, distal gastric cancer and mucosal-associated
lymphoid tissue (MALT) lymphoma (cancer of the B cell lym-
phocytes). It has been estimated that H. pylori was the cause
of 5.6% of all cancers worldwide in 2002.1 The microaerophilic,
Gram negative bacteria2 have been estimated to infect the stomach
of over half of the world’s population,3 and in most cases
infection will persist for the lifetime of an individual without
medical intervention.4 Therapy to eliminate H. pylori from the
gastroduodenal tract removes the primary cause of gastric and
duodenal ulcers, and eliminates the need for an ulcer patient to
continue long and costly treatment with H2 blockers. Current
treatment of H. pylori infection involves the prescription of one or
more antibiotics in combination with H2 blockers; however, none
of the existing treatments are capable of complete eradication of
H. pylori.5
Spirolaxine 1 and spirolaxine methyl ether 2 (Scheme 1) are pro-
duced by various strains of white rot fungi belonging to the genera
Sporotrichum and Phanerochaete.6 Spirolaxine 1 and spirolaxine
methyl ether 2 are potent helicobactericidal compounds and are
therefore useful compounds for the treatment of gastroduode-
nal disorders and the prevention of gastric cancer. Spirolaxine
Scheme 1
methyl ether 2 contains a 5,7-dimethoxyphthalide nucleus linked
through a polymethylene sidechain to a 6,5-spiroacetal group,
and belongs to the class of endecaketide derivatives that includes
phanerosporic and corticiolic acids.7 Several structurally related
phthalide-containing helicobactericidal compounds that contain
a 5,5-spiroacetal moiety have also been reported by Dekker
et al.,8 which also provide promising leads for the treatment
of H. pylori-related diseases. Spirolaxine has been reported to
exhibit cholesterol lowering activity9 and more recently studies
Department of Chemistry, University of Auckland, 23 Symonds St, Auckland,
New Zealand. E-mail: m.brimble@auckland.ac.nz; Fax: +64 9 3737422
† Electronic supplementary information (ESI) available: General experi-
1
mental details together with full experimental procedures, H NMR, 13C
NMR and mass spectral data for compounds 3, 6, 7, 12, 14–17 and 18–26.
See DOI: 10.1039/b708265g
2572 | Org. Biomol. Chem., 2007, 5, 2572–2582
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
have shown that it has cytotoxic activity toward endothelial cells
(BMEC and Huvec) as well as a variety of tumour cell lines (LoVo
and HL60).10
At the outset of this work the absolute and relative stereo-
chemistry of the four stereogenic centres present in spirolaxine
1 and spirolaxine methyl ether 2 had not been established, and a
synthesis of these unique helicobactericidal agents had not been
reported. We therefore herein report the full details11 of the first
enantioselective total synthesis of (+)-spirolaxine methyl ether 2
that established the absolute configuration of the natural product
to be (3R, 2ꢀꢀR, 5ꢀꢀR, 7ꢀꢀR). During the course of this work the rela-
tive stereochemistry of the four stereocentres of spirolaxine 1 was
determined through single-crystal X-ray analysis.12 A synthesis
of (+)-spirolaxine methyl ether 2 was also reported using a Prins
cyclisation to form a spiroacetal precursor, and a Wadsworth–
Emmons condensation to install the polymethylene chain on the
phthalide moiety. However, the absolute stereochemistry of the
phthalide moiety was not controlled, thus necessitating separation
of two diastereomers formed in the final reduction step.13
Scheme 2
converted to an amide group was next investigated. In this case
the allylboration of 11 using (−)-B-allyldiisopinocampheylborane
afforded benzylic alcohol 12 with a modest 30% ee. Catalytic asym-
metric allylation of benzaldehyde 11 using allyltrimethylsilane in
the presence of the catalyst15 generated from titanium tetrafluoride
and (R)−(+)-BINOL (10 mol%) afforded the desired (R)-benzylic
alcohol 12 also with a modest 51% ee.
At this stage it was postulated that the steric bulkiness of either a
diethyl amide or bromide substituent was preventing the formation
of the desired benzylic alcohols in high enantiomeric excess. A
new synthetic route was therefore proposed wherein introduction
of the stereochemistry at the benzylic position took place to
allow functionalisation at the ortho position. Gratifyingly, tita-
nium tetrafluoride-(R)−(+)-BINOL-derived Lewis acid-catalysed
addition of allyltrimethylsilane to 3,5-dimethoxybenzaldehdye 13
provided homoallylic alcohol 14 in 76% yield and in 86% ee.
(Scheme 3). Regioselective bromination of the aromatic ring
using NBS afforded bromide 12 in preparation for subsequent
installation of the phthalide functionality at this position.
Results and discussion
In planning our synthesis of spirolaxine methyl ether it was
necessary to consider the stereochemistry of the four stereogenic
centres, the relative and absolute configuration of which had not
been established at the outset of this work. It was anticipated that
the [6,5]-spiroacetal ring system would adopt the anomerically-
stabilised bis-axial conformation and that the polymethylene side
chain at C7ꢀꢀ would occupy the thermodynamically preferred
equatorial position. The stereochemistry of the remaining two
stereogenic centres however, could not be predicted. Therefore
a convergent and flexible synthetic strategy was developed that
would allow the stereochemistry at C3 of the phthalide and C2ꢀꢀ
of the spiroacetal ring to be varied.
The retrosynthesis adopted (Scheme 1) involves heterocycle-
activated Julia–Kocienski olefination of phthalide aldehyde 3
with sulfonyl spiroacetal 4. Phthalide aldehyde 3 is available
via lactonisation of alcohol 5. Both enantiomers of alcohol 5
are available via asymmetric allylation, thus providing access to
both enantiomers of phthalide aldehyde 3. Sulfonyl spiroacetal
4 can be prepared via acid-catalysed cyclisation of protected
dihydroxyketone 6 with the addition of the lithium acetylide
of 8 to aldehyde 7 providing the dihydroxyketone precursor 6.
Both enantiomers of acetylene 8 are commercially available, thus
facilitating the synthesis of the spiroacetal ring system with either
(R)- or (S)-stereochemistry at C2ꢀꢀ. In turn, aldehyde 7, would be
accessible in both enantiomeric forms from the chiral pool reagent
(S)-aspartic acid 9.
Initial attention focused on the synthesis of (3R, 2ꢀꢀS, 5ꢀꢀR,
7ꢀꢀR)-spirolaxine methyl ether 2a based on the availability of the
chiral starting materials (S)-aspartic acid 9 and (R)-3-butyn-2-ol
8a. The synthesis of this diasteromer 2a as the initial synthetic
target then rested on a successful synthesis of (3R)-phthalide
aldehyde 3a from (R)-homoallylic alcohol 5a (Scheme 2). Towards
this end, the asymmetric allylation of benzaldehyde 10 was
investigated following the procedure of Brown et al.14 Disappoint-
ingly, allylation using the allylboron reagent derived from (−)-B-
allyldiisopinocampheylborane failed to take place. Allylboration
of bromobenzaldehyde 11 where the bromide could later be
Scheme 3
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 2572–2582 | 2573
©

View Article Online
Attempts to effect direct carboxylation of bromide 12 proved
fruitless. However, Castedo et al.16 have prepared a number of ph-
thalides via internal trapping of carbamates derived from benzylic
alcohols. With this precedent in mind, alcohol 12 was converted
to diethyl carbamate 15 by treatment with sodium hydride and
diethyl carbamoyl chloride. Lithium–halogen exchange of 15,
method used by Frick et al.19 (R)-epoxide 2020,21 was prepared
in 82% yield by one-pot intramolecular cyclisation of bromodiol
19 and subsequent protection of the primary alcohol as a silyl
ether.
Subsequent allylation of epoxide 20 proved difficult, with initial
attempts using allylmagnesium bromide leading to the formation
of an inseparable bromohydrin by-product. Treatment of epoxide
20 with allylmagnesium bromide in the presence of copper iodide
(15 mol%) or copper bromide dimethyl sulfide complex (15 mol%)
at −78 ◦C also led to the exclusive formation of the bromohydrin.
Lipshutz et al.22 have opened epoxides with higher-order diallyl-
cyanocuprates. Diallylcyanocuprate was therefore prepared from
lithium chloride, copper(I) cyanide and allyllithium (formed in situ
by the transmetallation of allyltributyltin and methyllithium), and
added v◦ia cannula to a solution of epoxide 20 in tetrahydrofuran
at −78 C.23 Gratifyingly, the reaction proceeded to furnish the
desired alcohol 21 in 90% yield.
The enantiomeric excess of alcohol 21 was determined to be 94%
by examination of the 19F NMR spectrum of the corresponding
Mosher ester. After protection as a tert-butyldimethylsilyl ether
22 hydroboration of the alkene, using borane dimethylsulfide
complex in tetrahydrofuran at 0 ◦C afforded alcohol 23 in 83%
yield. Dess–Martin periodinane oxidation of the primary alcohol
to the corresponding aldehyde 7 then proceeded in 86% yield.
With aldehyde 7 in hand, subsequent union with the acetylide
derived from (S)-acetylene 24a17 was investigated. Accordingly,
the lithium acetylide was generated from (S)-acetylene 24a using
◦
with tert-butyllithium (2.2 equiv.) in tetrahydrofuran at −78 C,
provided a mixture of the desired phthalide 16 and diethyl amide
5a. Direct treatment of this mixture with p-toluenesulfonic acid
for 12 h provided phthalide 16 in 76% yield over two steps.
Hydroboration of 17 then furnished the desired phthalide alcohol
17 that underwent smooth PCC oxidation to the desired (3R)-
phthalide aldehyde 3a.
With (3R)-phthalide aldehyde 3a in hand, attention next focused
on the synthesis of (2R, 7R)-spiroacetal sulfone 4a in preparation
for the synthesis of (3R, 2ꢀꢀS, 5ꢀꢀR, 7ꢀꢀR)-spirolaxine methyl ether
2a (Scheme 4) via the intermediacy of aldehyde 7. It was envisaged
that aldehyde 7 would be available from (R)-epoxide 20, which
could in turn be prepared from (S)-aspartic acid 9. Additionally,
the lithium acetylide generated from (S)-acetylene 24a17 can
be used to form C-2 of the spiroacetal ring with the desired
stereochemistry.
Bromodiol 19 was initially prepared by treatment of (S)-aspartic
acid 9 with sodium nitrite in the presence of potassium bromide
to afford bromosuccinic acid 1818 in 92% yield. Reduction of the
two carboxylic acid groups using borane dimethylsulfide complex
afforded bromodiol 19 in 93% yield. In an adaptation of the
Scheme 4
2574 | Org. Biomol. Chem., 2007, 5, 2572–2582
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
n-butyllithium and treated with aldehyde 7 at −78 ◦C and at
−100 ◦C. Unfortunately, this procedure only afforded a complex
mixture of products. The addition of lithium alkynyltrifluorobo-
rates to anhydrides and esters for the synthesis of a,b-acetylenic
ketones, has been reported by Brown et al.24 and Yamaguchi
et al.,25 hence it was hoped that the use of this less basic nucleophile
would favour the desired coupling of 24a with 7. Disappointingly,
sequential treatment of acetylene 24a with n-butyllithium and
boron trifluoride etherate, followed by the addition of aldehyde
7, also resulted in the formation of a complex mixture of
products.
It was postulated that enolate formation was occurring in
preference to the desired nucleophilic addition reaction. This
postulate was supported by the observations of Brandsma et al.,26
who had encountered a similar problem during the preparation
of propargylic alcohols from lithium acetylides and ketones.
Brandsma et al. successfully circumvented this problem by the
inclusion of lithium bromide in the reaction. Lithium bromide has
also been employed by Carreira and Du Bois27 to improve the
problematic coupling of an aldehyde and acetylide. Encouraged
by these reports, the union of the acetylide of 24a with aldehyde 7
in the presence of lithium bromide (50 mol%) was undertaken in
tetrahydrofuran at −78 ◦C. Gratifyingly, this procedure furnished
acetylenic alcohol 25a in 86% yield.
Oxidation of acetylenic alcohol 25a using tetrapropylammo-
nium perruthenate and N-methylmorpholine N-oxide proceeded
smoothly to give the corresponding ynone 26a in near quantitative
yield. Hydrogenation of the alkyne 26a over 10% Pd/C for 48 h
furnished the protected dihydroxyketone 6a in 86% yield. Selective
removal of the tert-butyldimethylsilyl ethers with camphorsulfonic
acid and concomitant acid-catalysed cyclisation, afforded spiroac-
etal 27a in 86% yield. Finally removal of the tert-butyldiphenylsilyl
ether, with tetrabutylammonium fluoride provided the desired
volatile spiroacetal alcohol 28a.
sulfide 29a in 74% yield. Oxidation to the corresponding sulfone
proceeded smoothly in 90% yield using m-chloroperoxybenzoic
acid in dichloromethane.
Finally it remained to perform the modified Julia–Kocienski
olefination of sulfone 4a and aldehyde 3a. Accordingly, sulfone
4a was metallated with lithium diisopropylamide at −78 ◦C in
tetrahydrofuran, and the resultant anion was treated with aldehyde
3a providing olefin 30a in a modest 37% yield. Resonances in
1
the H NMR‡ spectrum at d 5.43–5.58, corresponding to H3ꢀ,
H3ꢀ*, H4ꢀ and H4ꢀ*, supported the formation of olefin 30a, as did
resonances at d 127.9, 128.8, 128.9 and 130.0 in the 13C NMR‡
spectrum, corresponding to C3ꢀ, C3ꢀ*, C4ꢀ and C4ꢀ*, respectively.
Although the 13C NMR spectrum clearly indicated the presence
of both the (E)- and (Z)-alkenes, the relative ratio of these two
diastereomers could not be determined.
Having finally effected the successful coupling of the spiroacetal
and phthalide fragments, it next remained to simply hydrogenate
alkenes 30a to furnish the (3R,2ꢀꢀS,5ꢀꢀR,7ꢀꢀR)-diastereomer of
spirolaxine methyl ether 2a. Use of 10% palladium on charcoal as
the catalyst afforded a complex mixture of products. Gratifyingly,
hydrogenation over Adams’ catalyst in tetrahydrofuran proceeded
smoothly to provide the (3R,2ꢀꢀS,5ꢀꢀR,7ꢀꢀR)-diastereomer of spiro-
laxine methyl ether 2a§ in 90% yield.
Comparison of the 1H NMR and 13C NMR data obtained
for 2a with that reported for the natural product,6,29 however,
revealed that the (3R, 2ꢀꢀS, 5ꢀꢀR, 7ꢀꢀR)-diastereomer 2a was in fact
an unnatural stereoisomer. Significant differences in the chemical
shifts for the (3R, 2ꢀꢀS, 5ꢀꢀR, 7ꢀꢀR)-diastereomer of spirolaxine
methyl ether 2a and those reported for the natural product, were
observed in the 1H NMR spectrum for the methyl group (d 1.22 for
natural product and 1.27 for 2a) and H2ꢀꢀ of the spiroacetal ring (d
4.13 for natural product and 4.22 for 2a). Similarly, differences
were also observed in the 13C NMR spectrum for the methyl
group (d 21.3 for natural product and 23.3 for 2a) and C2ꢀꢀꢀ of
the spiroacetal ring (d 73.6 for natural product and 76.6 for 2a).
This, coupled with the fact that the remaining signals were closely
matched with those of the natural product, led to the conclusion
that the stereochemistry at C2ꢀꢀ was of the wrong configuration.
It was therefore proposed that the relative stereochemistry of the
natural product was in fact (3R, 2ꢀꢀR, 5ꢀꢀR, 7ꢀꢀR).
The structure of spiroacetal alcohol 28a was assigned on the
1
basis of NMR evidence (Fig. 1). Resonances in the H NMR
spectrum at d 4.10 and 4.24, assigned to H7 and H2 respectively,
exhibited multiplicities that were indicative of carbocyclic ring
formation. In addition, a quaternary carbon resonance in the 13
C
NMR spectrum at d 105.9, assigned to C5, was characteristic
of a spiroacetal carbon. Due to the thermodynamic stabilisation
by the anomeric effect,28 it was predicted that the acid-catalysed
cyclisation of protected dihydroxyketone 6a would lead to forma-
tion of spiroacetal alcohol 28a where both oxygen atoms of the
spiroacetal adopt an axial orientation. This was confirmed by the
NOE observed between H7 and the protons of the methyl group
at C2.
Having proposed the stereochemistry at C2ꢀꢀ of the natural
product to be of (R)-configuration and not (S), it next remained
to synthesise (3R, 2ꢀꢀS, 5ꢀꢀR, 7ꢀꢀR)-spirolaxine methyl ether 2b. It
was envisaged that a strategy similar to that developed for the
synthesis of (3R, 2ꢀꢀS, 5ꢀꢀR, 7ꢀꢀR)-spirolaxine methyl ether 2a could
be used to achieve this goal (Scheme 5). The convergent and
flexible nature of the synthetic route adopted herein meant that
the only change necessary for the synthesis of (3R, 2ꢀꢀR, 5ꢀꢀR, 7ꢀꢀR)-
spirolaxine methyl ether 2b, is the substitution of (R)-acetylene
24b for (S)-acetylene 24a.
Using the conditions developed previously for the synthesis
of alcohol 25a, the lithium acetylide of 24b, generated with n-
butyllithium, in the presence of lithium bromide (0.5 equiv.) was
Fig. 1 NMR evidence supporting the structure of spiroacetal alcohol 28.
‡ The symbol * is used here to denote the presence of (E)- and (Z)- isomers.
§ It was expected that spirolaxine methyl ether 2a would be obtained as
a 93 : 7 mixture of diastereomers however, advantageous removal of the
minor isomer by flash column chromatography provided 2a as the sole
product.
In preparation for the Julia–Kocienski olefination of spiroacetal
sulfone 4a with phthalide aldehyde 3a, alcohol 28a was treated with
2-mercaptobenzothiazole under Mitsunobu conditions to provide
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 2572–2582 | 2575
©

View Article Online
Scheme 5
treated with aldehyde 7 in tetrahydrofuran at −78 ◦C (Scheme 5).
After stirring for 5 h, alcohol 25b was furnished in 76% yield. Oxi-
dation of acetylenic alcohol 25b to corresponding ynone 26b with
tetrapropylammonium perruthenate and N-methylmorpholine N-
oxide proceeded smoothly in 87% yield. Hydrogenation of the
alkyne using Adamsꢀ catalyst provided protected dihydroxyketone
6b in 95% yield after only 6 h, in contrast to the use of palladium on
carbon previously for the synthesis of protected dihydroxyketone
6a in 86% yield, which took 48 h. Selective deprotection of the tert-
butyldimethylsilyl ethers and concomitant cyclisation of protected
dihydroxyketone 6b to spiroacetal 27b using camphorsulfonic acid
in dichloromethane at 0 ◦C proceeded in 86% yield. Removal of the
tert-butyldiphenylsilyl ether using tetrabutylammonium fluoride
gave the volatile spiroacetal alcohol 28b in 83% yield.
Having synthesised spiroacetal alcohol 28b, preparation of
the modified Julia olefination precursor sulfone 4b was under-
taken. Accordingly, alcohol 28b was treated with 2-mercapto-
benzothiazole under Mitsunobu conditions to provide the cor-
responding sulfide in 62% yield, and the oxidation of which with
m-chloroperoxybenzoic acid, provided spiroacetal sulfone 4b in
82% yield. The structure of spiroacetal sulfone 4b was assigned on
the basis of NMR evidence (Fig. 2). Resonances in the 1H NMR
spectrum at d 3.89 and 4.09, assigned to H7ꢀꢀ and H2ꢀꢀ respectively,
both exhibited multiplicities that were indicative of carbocyclic
ring formation. The chemical non-equivalence of geminal protons
at C3, C4, C8, and C9 was also consistent with ring formation. In
addition, the 13C NMR spectrum exhibited a quaternary carbon
resonance at d 106.1, which is characteristic of the spiroacetal
carbon C5ꢀꢀ.
Similar to spiroacetal sulfone 4a, the influence of the anomeric
effect was also expected to produce a spiroacetal ring system in
which the two oxygen atoms would adopt an axial orientation.
This prediction was confirmed by the NOE correlation observed
between H7ꢀꢀ and H2ꢀꢀ, which would be unlikely for the correspond-
ing epimer 4c in which the oxygen atom of the five-membered ring
occupies an equatorial position.
With spiroacetal sulfone 4b and aldehyde 3a in hand, it next
remained to couple the two fragments in a modified Julia–
Kocienski olefination. Accordingly, sulfone 4b was metallated with
lithium diisopropylamide, and the resultant anion treated with
◦
aldehyde 3a in tetrahydrofuran at −78 C. After 4 h the desired
alkene 30b was isolated in a modest 40% yield.
1
Resonances in the H NMR‡ spectrum at d 5.41–5.55, corre-
sponding to H3ꢀ, H3ꢀ*, H4ꢀ and H4ꢀ*, supported the formation of
alkene 30b. Signals in the 13C NMR‡ at d 127.9, 128.8, 129.0 and
129.9, corresponding to C3ꢀ, C3ꢀ*, C4ꢀ and C4ꢀ* respectively, were
also consistent with olefination and indicated the presence of both
the (E)- and (Z)- isomers, the relative ratios of which were unable
to be determined.
Hydrogenation of olefin 30b over Adamsꢀ catalyst in tetrahydro-
furan afforded (3R, 2ꢀꢀR, 5ꢀꢀR, 7ꢀꢀR)-spirolaxine methyl ether 2b¶ in
quantitative yield. The 1H NMR and 13C NMR data for 2b were
identical to that reported for the natural product.6,29 Gratifyingly,
comparison of the optical rotation {[a]2D0 +63.7◦ (c 0.85, CHCl3)}
◦
29
with that reported in the literature {[a]3D0 +62 (c 0.22 in CHCl3)}
¶ It was expected that spirolaxine methyl ether 2b would be obtained as
a 93 : 7 mixture of diastereomers however, advantageous partial removal
of the minor isomer by flash column chromatography provided a 95 : 5
mixture of diastereomers.
Fig. 2 NMR evidence supporting the structure of spiroacetal sulfone 4
2576 | Org. Biomol. Chem., 2007, 5, 2572–2582
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
confirmed unequivocally that the absolute stereochemistry of the
natural product is in fact (3R, 2ꢀꢀR, 5ꢀꢀR, 7ꢀꢀR).
v
max(film)/cm−1 3435br (OH), 2939, 2871, 1456, 1439, 1377, 1221,
1159, 1115, 1069, 1027, 972, 947, 876 and 862; dH (300 MHz,
CDCl3): 1.15–1.29 (1 H, m, H8a), 1.25 (3 H, d, J 6.3 Hz, Me),
1.43–1.51 (1 H, m, H8b), 1.52–1.68 (7 H, m, H3a, H4a, H9a, H10
and H1ꢀ), 1.68–1.85 (1 H, m, H9b), 1.88–2.03 (2 H, m, H3b and
H4b), 3.68–3.72 (2 H, m, H2ꢀ), 4.10 (1 H, dddd, J 11.4, 8.8, 4.1
and 2.2 Hz, H7) and 4.24 (1 H, qdd, J 6.3, 6.3 and 1.8 Hz, H2);
dC (75 MHz, CDCl3): 20.0 (CH2, C9), 23.1 (CH3, Me), 31.0 (CH2,
C8), 31.8 (CH2, C3), 33.3 (CH2, C10), 37.9 (CH2, C1ꢀ), 39.3 (CH2,
C4), 61.7 (CH2, C2ꢀ), 71.0 (CH, C7), 76.9 (CH, C2) and 105.9
(quat., C5); m/z (EI): 185 (M−Me, 3%), 149 (7), 137 (14), 129
(17), 95 (18), 81 (52), 69 (100), 57 (37), 55 (36) and 41 (49);
HRMS (CI, NH3): Found MH+, 201.14858. C11H21O3 requires M,
201.14907.
In summary, a convergent enantioselective total synthesis of the
anti-Helicobacter pylori agent (+)-spirolaxine methyl ether 2b has
been achieved (Scheme 5). The key step of the synthesis involved a
modified Julia–Kocienski olefination between spiroacetal sulfone
4b and phthalide aldehyde 3a. The synthesis of (+)-(3R, 2ꢀꢀR, 5ꢀꢀR,
7ꢀꢀR)-spirolaxine methyl ether 2b together with the (3R, 2ꢀꢀS, 5ꢀꢀR,
7ꢀꢀR)-diastereomer 2a established the absolute configuration of the
four stereogenic centres in the natural product to be (3R, 2ꢀꢀR, 5ꢀꢀR,
7ꢀꢀR). The modular nature of the present synthesis based on union
of two moieties of predefined stereochemistry also provides an
opportunity for the synthesis of other diastereomers of spirolaxine
methyl ether, thus providing a potential source of analogues of the
natural product for structure–activity studies.
(2ꢀꢀS, 5ꢀꢀR, 7ꢀꢀS)-2-[2ꢀ-(2ꢀꢀ-Methyl-1ꢀꢀ,6ꢀꢀ-dioxaspiro[4.5]dec-7ꢀꢀ-yl)-
ethylsulfanyl]benzothiazole (29a)
Experimental
Triphenylphosphine (701 mg, 2.67 mmol) and mercaptobenzoth-
iazole (596 mg, 3.56 mmol) were dissolved in tetrahydrofuran
(15 cm3) and cooled to 0 ◦C under an atmosphere of nitrogen. To
this stirred solution was added alcohol 28a (357 mg, 1.78 mmol)
in tetrahydrofuran (5 cm3). After stirring for 0.25 h, diethyl
azodicarboxylate (0.53 cm3, 3.21 mmol) was added dropwise via
syringe. The resultant bright yellow solution was allowed to stir at
0 ◦C for 2 h. The reaction was quenched by the addition of brine
(10 cm3) and the mixture extracted with diethyl ether (3 × 40 cm3).
The combined extracts were dried over magnesium sulfate, filtered
and the solvent removed under reduced pressure. Purification of
the resultant oil by flash column chromatography using hexane–
diethyl ether (98 : 2 to 7 : 3) as eluent gave the title compound
29a (461 mg,. 74%) as a yellow oil; [a]D +76.3 (c 1.00 in CHCl3);
(2S, 5R, 7S)-7-[2ꢀ-(tert-Butyldiphenylsilyloxy)ethyl]-
2-methyl-1,6-dioxaspiro[4.5]decane (27a)
To a stirred solution of ke◦tone 6a (4.48 g, 6.54 mmol) in
dichloromethane (65 cm3) at 0 C under an atmosphere of nitrogen
was added camphorsulfonic acid (3.60 g, 14.38 mmol). After
stirring for 2 h, the mixture was filtered through a pad of Celiteꢀ,
R
and the solvent removed under reduced pressure. Flash column
chromatography using hexane–diethyl ether (8 : 2 to 6 : 4) as eluent
afforded the title compound 27a (2.47 g, 86%) as a yellow oil; [a]D
+117.1 (c 0.50 in CHCl3); vmax(film)/cm−1 2934, 2858, 1472, 1428,
1219, 1112, 823, 736 and 702; dH (300 MHz, CDCl3): 1.05 (9 H, s,
SitBuPh2), 1.13–1.19 (1 H, m, H8a), 1.22 (3 H, d, J 6.2 Hz, Me),
1.52–1.59 (1 H, m, H8b), 1.59–1.76 (7 H, m, H3a, H4a, H9a, H10
and H1ꢀ), 1.76–1.88 (1 H, m, H9b), 1.88–2.00 (2 H, m, H3b and
H4b), 3.75 (2 H, t, J 6.8 Hz, H2ꢀ), 4.00 (1 H, dddd, J 11.5, 7.5, 5.3
and 2.2 Hz, H7), 4.20 (1 H, qdd, J 6.2, 6.2 and 1.9 Hz, H2), 7.33–
7.44 (6 H, m, SitBuPh2, m and p) and 7.65–7.69 (4 H, m, SitBuPh2,
o); dC (75 MHz, CDCl3): 19.2 (quat., SitBuPh2), 20.4 (CH2, C9),
23.4 (CH3, Me), 26.9 (CH3, SitBuPh2), 31.1 (CH2, C8), 31.8 (CH2,
C3), 33.5 (CH2, C10), 39.4 (CH2, C4 or C1ꢀ), 39.5 (CH2, C1ꢀ or C4),
60.9 (CH2, C2ꢀ), 66.9 (CH, C7), 76.6 (CH, C2), 105.7 (quat., C5),
127.5 (CH, SitBuPh2, m), 129.5 (CH, SitBuPh2, p), 134.1 (quat.,
SitBuPh2), 135.6 (CH, SitBuPh2, o) and 135.6 (CH, SitBuPh2, o*);
v
max(film)/cm−1 2936, 2868, 1459, 1427, 1309, 1237, 1221, 1158,
1113, 1072, 994, 976, 876, 854, 755 and 726; dH (400 MHz, CDCl3):
1.18–1.28 (1 H, m, H8ꢀꢀ ), 1.30 (3 H, d, J 6.2 Hz, Me), 1.56–1.69
a
(4 H, m, H8ꢀꢀ , H9ꢀꢀa and H10ꢀꢀ), 1.70–1.90 (3 H, m, H3ꢀꢀ , H4ꢀꢀa and
b
a
H9ꢀꢀ ), 1.91–2.03 (4 H, m, H3ꢀꢀ , H4ꢀꢀb and H2ꢀ), 3.32–3.39 (1 H, m,
b
H1ꢀa), 3.43–3.50 (1 H, m, H1ꢀbb), 4.00 (1 H, dddd, J 11.3, 9.0, 3.8
and 2.3 Hz, H7ꢀꢀ), 4.23 (1 H, qdd, J 6.2, 6.2 and 1.9 Hz, H2ꢀꢀ), 7.27
(1 H, td, J 7.9 and 1.0 Hz, H6), 7.39 (1 H, td, J 7.9 and 1.0 Hz, H5),
7.74 (1 H, dd, J 7.9 and 1.0 Hz, H7) and 7.85 (1 H, dd, J 7.9 and
1.0 Hz, H4); dC (100 MHz, CDCl3): 20.2 (CH2, C9ꢀꢀ), 23.4 (CH3,
Me), 30.1 (CH2, C1ꢀ), 30.9 (CH2, C8ꢀꢀ), 32.0 (CH2, C3ꢀꢀ), 33.6 (CH2,
C10ꢀꢀ), 36.0 (CH2, C2ꢀ), 39.4 (CH2, C4ꢀꢀ), 68.5 (CH, C7ꢀꢀ), 76.9 (CH,
C2ꢀꢀ), 105.9 (quat., C5ꢀꢀ), 120.9 (CH, C7), 121.5 (CH, C4), 124.0
(CH, C6), 125.9 (CH, C5), 135.2 (quat., C7a), 153.4 (quat., C3a)
and 167.4 (quat., C2); m/z (EI): 349 (M+, 17%), 334 (M−Me, 4),
182 (M−C7H5NS, 63), 167 (C7H5NS, 100), 125 (29), 111 (68), 98
(69), 83 (14), 55 (25), 43 (26) and 41 (26); HRMS (EI): Found M+,
349.11669. C18H23NO2S2 requires M, 349.11702.
t
m/z (EI): 381 (M− Bu, 46%), 303 (4), 295 (5), 281 (8), 199 (51),
165 (25), 111 (100), 98 (18), 83 (17) and 55 (19); HRMS (CI, NH3):
Found MH+, 439.26654. C27H39O3Si requires M, 439.26685.
(2S, 5R, 7S)-7-(2ꢀ-Hydroxyethyl)-2-methyl-1,
6-dioxaspiro[4.5]decane (28a)
To a stirred solution of silyl ether 27a (2.46 g, 5.60 mmol) in
tetrahydrofuran (30 cm3) was added tetrabutylammonium fluoride
(8.40 cm3, 8.40 mmol, 1 mol dm−3). After stirring for 2 h, brine
(10 cm3) was added and the mixture extracted with diethyl ether
(4 × 40 cm3). The combined extracts were dried over magnesium
sulfate, filtered and the solvent removed under reduced pressure.
Flash column chromatography using hexane–diethyl ether (9 :
1 to 6 : 4) as eluent gave the title compound 28a (0.76 g,
68%) as a volatile pale yellow oil; [a]D +60.6 (c 1.03 in CHCl3);
(2ꢀꢀS, 5ꢀꢀR, 7ꢀꢀS)-2-[2ꢀ-(2ꢀꢀ-Methyl-1ꢀꢀ,6ꢀꢀ-dioxaspiro[4.5]dec-7ꢀꢀ-yl)-
ethylsulfonyl]benzothiazole (4a)
To a solution of thioethe◦r 29a (461 mg, 1.32 mmol) in
dichloromethane (5 cm3) at 0 C under an atmosphere of nitrogen
was added sodium bicarbonate (554 mg, 6.59 mmol) and a
solution of m-chloroperoxybenzoic acid (569 mg, 3.30 mmol) in
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 2572–2582 | 2577
©

View Article Online
dichloromethane (5 cm3). After stirring the solution for 12 h,
saturated aqueous sodium bicarbonate (2 cm3) and saturated
aqueous sodium thiosulfate (2 cm3) were added. The aqueous layer
was extracted with dichloromethane (3 × 10 cm3). The combined
extracts were dried over magnesium sulfate, filtered and the solvent
removed under reduced pressure. The resultant oil was purified by
flash column chromatography using hexane–diethyl ether (8 : 2 to
6 : 4) as eluent to afford the title compound 4a (453 mg, 90%)
as a white solid; m.p. 74–77 ◦C; [a]D +24.8 (c 0.40 in CHCl3);
dd, J 7.7 and 3.5 Hz, H3*), 5.43–5.58 (4 H, m, H3ꢀ, H3ꢀ*, H4ꢀ
and H4ꢀ*), 6.38–6.39 (2 H, m, H6 and H6*) and 6.40–6.41 (2 H,
m, H4 and H4*); dC (75 MHz, CDCl3)‡: 20.3 (CH2, C9ꢀꢀ), 22.8
[CH2, (Z)-C2ꢀ], 23.3 (CH3, Me), 23.4 (CH3, Me*), 27.9 [CH2, (E)-
C2ꢀ*], 30.6 (CH2, C8ꢀꢀ), 31.7 (CH2, C3ꢀꢀ), 31.7 (CH2, C3ꢀꢀ*), 33.3
(CH2, C10ꢀꢀ), 33.4 (CH2, C10ꢀꢀ*), 34.1 [CH2, (Z)-C5ꢀ], 34.8 (CH2,
C1ꢀ), 39.3 (CH2, C4ꢀꢀ), 39.6 [CH2, (E)-C5ꢀ], 55.9 (CH3, OMe), 56.0
(CH3, OMe), 69.7 (CH, C7ꢀꢀ), 69.8 (CH, C7ꢀꢀ*), 76.6 (CH, C2ꢀꢀ),
79.1 (CH, C3), 79.3 (CH, C3*), 97.3 (CH, C6), 98.7 (CH, C4),
105.9 (quat., C5ꢀꢀ), 106.8 (quat., C7a), 106.9 (quat., C7a*), 127.9
(CH, C3ꢀ), 128.8 (CH, C3ꢀ*), 128.9 (CH, C4ꢀ), 130.0 (CH, C4ꢀ*),
155.1 (quat., C3a), 155.1 (quat., C3a*), 159.6 (quat., C7), 166.6
(quat., C5) and 168.5 (quat., C1); m/z (EI): 416 (M+, 2%), 398 (5),
316 (6), 262 (6), 207 (26), 193 (34), 155 (100), 137 (27), 111 (51),
97 (33), 83 (40), 71 (52), 57 (85), 55 (69) and 43 (70); HRMS (EI):
Found M+, 416.22012. C24H32O6 requires M, 416.21989.
v
max(film)/cm−1 2930, 2870, 1472, 1458, 1328s (SO), 1236, 1221,
1148s (SO), 1072, 1026, 977, 877, 855, 763 and 730; dH (400 MHz,
CDCl3): 1.12–1.24 (1 H, m, H8ꢀꢀ ), 1.24 (3 H, d, J 6.2 Hz, Me),
a
1.50–1.58 (3 H, m, H8ꢀꢀb and H10ꢀꢀ), 1.59–1.72 (3 H, m, H3ꢀꢀ , H4ꢀꢀ
a
a
and H9ꢀꢀ ), 1.72–1.84 (1 H, m, H9ꢀꢀ ), 1.84–2.03 (4 H, m, H3ꢀꢀ ,
a
b
b
H4ꢀꢀb and H2ꢀ), 3.47 (1 H, ddd, J 14.4, 11.3 and 4.8 Hz, H1ꢀa), 3.74
(1 H, ddd, J 14.4, 11.3 and 4.8 Hz, H1ꢀb), 3.86–3.92 (1 H, m, H7ꢀꢀ),
4.19 (1 H, qdd, J 6.2, 6.2 and 1.9 Hz, H2ꢀꢀ), 7.57 (1 H, td, J 7.3 and
1.5 Hz, H6), 7.64 (1 H, td, J 7.3 and 1.5 Hz, H5), 8.01 (1 H, dd, J
7.3 and 1.5 Hz, H7) and 8.22 (1 H, dd, J 7.3 and 1.5 Hz, H4); dC
(100 MHz, CDCl3): 20.0 (CH2, C9ꢀꢀ), 23.4 (CH3, Me), 29.1 (CH2,
C2ꢀ), 30.8 (CH2, C8ꢀꢀ), 31.9 (CH2, C3ꢀꢀ), 33.4 (CH2, C10ꢀꢀ), 39.3
(CH2, C4ꢀꢀ), 51.9 (CH2, C1ꢀ), 68.0 (CH, C7ꢀꢀ), 76.9 (CH, C2ꢀꢀ), 106.0
(quat., C5ꢀꢀ), 122.3 (CH, C7), 125.5 (CH, C4), 127.6 (CH, C5),
128.0 (CH, C6), 136.8 (quat., C7a), 152.8 (quat., C3a) and 165.7
(quat., C2); m/z (EI): 381 (M+, 2%), 366 (M−Me, 3), 282 (18),
217 (15), 189 (34), 149 (30), 135 (52), 98 (100), 55 (40) and 41 (34);
HRMS (EI): Found M+, 381.10540. C18H23NO4S2 requires M,
381.10685.
(3R, 2ꢀꢀS, 5ꢀꢀR, 7ꢀꢀR)-5,7-Dimethoxy-3-[5ꢀ-(2ꢀꢀ-methyl-1ꢀꢀ,6ꢀꢀ-
dioxaspiro[4.5]dec-7ꢀꢀ-yl)pent-1ꢀ-yl]-3H-isobenzofuran-1-one (2a)
Alkene 30a (12 mg, 0.03 mmol) was dissolved in tetrahydrofuran
(10 cm3) and hydrogenated using a hydrogen-filled double balloon
in the presence of platinum(IV) oxide (1.5 mg) for 6 h. The catalyst
R
was removed by filtration through a pad of Celiteꢀ, and the solvent
removed under reduced pressure. Purification of the resultant oil
by flash column chromatography using hexane–ethyl acetate (8 :
2 to 6 : 4) as eluent gave the title compound 2a (11 mg, 90%) as a
yellow oil; [a]D +51.1 (c 1.44 in CHCl3); vmax(film)/cm−1 2934, 2861,
1755s (CO), 1605s, 1494, 1456, 1435, 1337, 1219, 1158, 1051, 1027
and 975; dH (300 MHz, CDCl3): 1.14 (1 H, dddd, J 13.1, 13.1, 11.5
(3ꢀE, 3R, 2ꢀꢀS, 5ꢀꢀR, 7ꢀꢀR)- and (3ꢀZ, 3R, 2ꢀꢀS, 5ꢀꢀR, 7ꢀꢀR)-5,7-
Dimethoxy-3-[5ꢀ-(2ꢀꢀ-methyl-1ꢀꢀ,6ꢀꢀ-dioxaspiro[4.5]dec-7ꢀꢀ-yl)pent-
3ꢀ-en-1ꢀ-yl]-3H-isobenzofuran-1-one (30a)
and 3.9 Hz, H8ꢀꢀ ), 1.27 (3 H, d, J 6.2 Hz, Me), 1.28–1.48 (8 H, m,
a
H2ꢀ, H3ꢀ, H4ꢀ and H5ꢀ), 1.52–1.80 (7 H, m, H1ꢀa, H3ꢀꢀ , H4ꢀꢀ , H8ꢀꢀ ,
a
a
H9ꢀꢀa and H10ꢀꢀ), 1.81–1.87 (1 H, m, H9ꢀꢀ ), 1.94–2.04 (3 H, m, H1ꢀbb,
H3ꢀꢀb and H4ꢀꢀ ), 3.74–3.82 (1 H, m, H7ꢀbꢀ), 3.89 (3 H, s, OMe), 3.95
b
Sulfone 4a (181 mg, 0.47 mmol) was dissolved in tetrahydrofuran
(9 cm3) and cooled to −78 ◦C under an atmosphere of nitrogen. To
this stirred solution was added dropwise lithium diisopropylamide
(0.52 cm3, 0.52 mmol, 1 mol dm−3). The resultant deep yellow
solution was stirred for 0.75 h before a solution of aldehyde
3a (119 mg, 0.47 mmol) in tetrahydrofuran (3 cm3) was added
dropwise. After stirring at −78 ◦C for 4 h, the solution was allowed
to slowly warm to room temperature then stirred for 0.5 h. The
reaction was quenched by the addition of brine (4 cm3) and the
aqueous layer was extracted with ethyl acetate (3 × 20 cm3). The
combined extracts were dried over magnesium sulfate, filtered, and
the solvent removed in vacuo. Purification of the resultant oil by
flash column chromatography using hexane–ethyl acetate (9 : 1
to 1 : 1) as eluent gave the title compound 30a (73 mg, 37%) as
a yellow oil; [a]D +52.9 (c 1.38 in CHCl3); vmax(film)/cm−1 2923,
2850, 1755s (CO), 1605s, 1456, 1337, 1219, 1158, 1059, 1027 and
(3 H, s, OMe), 4.22 (1 H, qdd, J 6.2, 6.2 and 1.6 Hz, H2ꢀꢀ), 5.30
(1 H, dd, J 7.7 and 3.8 Hz, H3), 6.40 (1 H, apparent s, H6) and 6.42
(1 H, d, J 1.6 Hz, H4); dC (75 MHz, CDCl3): 20.4 (CH2, C9ꢀꢀ), 23.3
(CH3, Me), 24.5 (CH2, C2ꢀ), 25.5 (CH2, C4ꢀ), 29.4 (CH2, C3ꢀ), 31.1
(CH2, C8ꢀꢀ), 31.8 (CH2, C3ꢀꢀ), 33.5 (CH2, C10ꢀꢀ), 34.8 (CH2, C1ꢀ),
36.3 (CH2, C5ꢀ), 39.4 (CH2, C4ꢀꢀ), 55.9 (CH3, OMe), 55.9 (CH3,
OMe), 69.6 (CH, C7ꢀꢀ), 76.6 (CH, C2ꢀꢀ), 79.9 (CH,C3), 97.3 (CH,
C6), 98.6 (CH, C4), 105.8 (quat., C5ꢀꢀ), 106.9 (quat., C7a), 155.1
(quat., C3a), 159.5 (quat., C7), 166.6 (quat., C5) and 168.5 (quat.,
C1); m/z (EI): 418 (M+, 8%), 400 (7), 361 (11), 318 (59), 293 (24),
290 (23), 261 (25), 207 (54), 193 (72), 155 (63), 111 (28), 98 (100),
55 (25), 43 (22) and 41 (24); HRMS (EI): Found M+, 418.23519.
C24H34O6 requires M, 418.23554.
(2R, 5R, 9S)- and (2R, 5S, 9S)-2,9-Bis-(tert-butyldimethyl-
silyloxy)-11-(tert-butyldiphenylsilyloxy)undec-3-yn-5-ol (25b)
976; dH (300 MHz, CDCl3)‡: 1.09–1.28 (2 H, m, H8ꢀꢀa and H8ꢀꢀ *),
a
1.25 (6 H, d, J 6.4 Hz, Me and Me*), 1.55–1.66 (8 H, m, H8ꢀꢀ ,
H8ꢀꢀ *, H9ꢀꢀ , H9ꢀꢀ *, H10ꢀꢀ and H10ꢀꢀ*), 1.66–1.83 (8 H, m, H1ꢀba,
n-Butyllithium (7.71 cm3, 12.33 mmol, 1.6 mol dm−3) was added
to a stirred solution of (R)-silyl ether 24b (2.08 g, 11.30 mmol)
in tetrahydrofuran (30 cm3) at −78 ◦C under an atmosphere
of nitrogen and the resultant pale yellow solution stirred for
0.5 h before the addition of anhydrous lithium bromide (0.45 g,
5.14 mmol) in tetrahydrofuran (5 cm3). After 0.25 h, a solution of
aldehyde 7 (5.13 g, 10.27 mmol) in tetrahydrofuran (20 cm3) was
b
a
a
H1ꢀa*, H3ꢀꢀ , H3ꢀꢀ *, H4ꢀꢀ , H4ꢀꢀ *, H9ꢀꢀb and H9ꢀꢀ *), 1.89–2.07 (6 H,
a
a
a
a
b
m, H1ꢀb, H1ꢀb*, H3ꢀꢀ , H3ꢀꢀ *, H4ꢀꢀb and H4ꢀꢀ *), 2.07–2.18 [4 H, m,
b
b
b
(E)-H5ꢀ and (Z)-H5ꢀ], 2.18–2.46 [4 H, m, (E)-H2ꢀ and (Z)-H2ꢀ],
3.78–3.84 (2 H, m, H7ꢀꢀ and H7ꢀꢀ*), 3.88 (6 H, s, OMe and OMe*),
3.94 (6 H, s, OMe and OMe*), 4.20 (2 H, qd, J 6.4 and 6.4 Hz,
H2ꢀꢀ and H2ꢀꢀ*), 5.29 (1 H, dd, J 7.7 and 3.5 Hz, H3), 5.30 (1 H,
2578 | Org. Biomol. Chem., 2007, 5, 2572–2582
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
added dropwise and the solution stirred for 5 h. Saturated aqueous
ammonium chloride (30 cm3) was added and the mixture extracted
with diethyl ether (3 × 100 cm3). The combined extracts were dried
over magnesium sulfate, filtered and the solvent removed under
reduced pressure. Flash column chromatography using pentane–
diethyl ether (95 : 5 to 70 : 30) as eluent afforded the title compound
25b (5.34 g, 76%) as a yellow oil; [a]D +19.5 (c 4.38 in CHCl3);
SitBuPh2, p), 129.6 (CH, SitBuPh2, p*), 133.9 (quat., SitBuPh2),
135.5 (CH, SitBuPh2, o) and 187.4 (quat., C5); m/z (FAB): 623
t
(M− Bu+, 1%), 549 (3), 491 (2), 471 (2), 413 (2), 293 (3), 271 (3),
239 (4), 209 (7), 197 (15), 135 (38) and 73 (100); HRMS (FAB):
Found MH+, 681.41812. C39H65O4Si3 requires M, 681.41907.
v
max(film)/cm−1 3400br (OH), 2954, 2930, 2857, 1472, 1463, 1428,
(2R, 9S)-2,9-Bis-(tert-butyldimethylsilyloxy)-11-
(tert-butyldiphenylsilyloxy)undecan-5-one 6b
1255, 1152, 1104, 835, 775, 738 and 701; dH (300 MHz, CDCl3):
0.02 (3 H, s, SitBuMe2), 0.05 (3 H, s, SitBuMe2), 0.16 (3 H, s,
SitBuMe2), 0.17 (3 H, s, SitBuMe2), 0.90 (9 H, s, SitBuMe2), 0.95
(9 H, s, SitBuMe2), 1.10 (9 H, s, SitBuPh2), 1.44 (3 H, d, J 6.5 Hz,
H1), 1.46–1.55 (4 H, m, H7 and H8), 1.68–1.77 (4 H, m, H6
and H10), 3.77 (2 H, t, J 5.9 Hz, H11), 3.92 (1 H, m, H9), 4.40
(1 H, t, J 6.3 Hz, H5), 4.59 (1 H, q, J 6.5 Hz, H2), 7.38–7.47
(6 H, m, SitBuPh2, m and p) and 7.69–7.72 (4 H, m, SitBuPh2,
o); dC (75 MHz, CDCl3): −4.9 (CH3, SitBuMe2), −4.6 (CH3,
SitBuMe2), −4.5 (CH3, SitBuMe2), −4.4 (CH3, SitBuMe2), 18.0
(quat., SitBuMe2), 18.2 (quat., SitBuMe2), 19.1 (quat., SitBuPh2),
20.8 (CH2, C7), 25.4 (CH3, C1), 25.8 (CH3, SitBuMe2), 25.9 (CH3,
SitBuMe2), 26.9 (CH3, SitBuPh2), 36.9 (CH2, C8), 37.9 (CH2, C6),
39.8 (CH2, C10), 58.9 (CH, C2), 60.9 (CH2, C11), 62.3 (CH, C5),
69.1 (CH, C9), 84.2 (quat., C4), 87.3 (quat., C3), 127.6 (CH,
SitBuPh2, m), 129.5 (CH, SitBuPh2, p), 133.9 (quat., SitBuPh2)
Ynone 26b (3.48 g, 5.11 mmol) was dissolved in a solution of
methanol and tetrahydrofuran (10 cm3, 1 : 1), and hydrogenated
using a hydrogen-filled double balloon in the presence of PtO2
(0.17 g) for 6 h. The catalyst was removed by filtration through a
R
pad of Celiteꢀ, and the solvent removed under reduced pressure.
Purification of the resultant oil by flash column chromatography
using hexane–diethyl ether (9 : 1) as eluent gave the title compound
6b (3.32 g, 95%) as a yellow oil; [a]D −1.0 (c 3.60 in CHCl3);
v
max(film)/cm−1 2955, 2929, 2857, 1716s (CO), 1472, 1428, 1255,
1111, 1005, 836, 774, 738 and 701; dH (300 MHz, CDCl3): 0.01 (6 H,
s, SitBuMe2), 0.04 (6 H, s, SitBuMe2), 0.86 (9 H, s, SitBuMe2), 0.89
(9 H, s, SitBuMe2), 1.06 (9 H, s, SitBuPh2), 1.13 (3 H, d, J 6.1 Hz,
H1), 1.36–1.45 (2 H, m, H8), 1.53–1.62 (2 H, m, H7), 1.63–1.76
(4 H, m, H3 and H10), 2.34–2.55 (4 H, m, H4 and H6), 3.72 (2 H,
td, J 6.5 Hz, Jw 1.7 Hz, H11), 3.66–3.92 (2 H, m, H2 and H9),
7.35–7.44 (6 H, m, SitBuPh2, m and p) and 7.65–7.69 (4 H, m,
SitBuPh2, o); dC (75 MHz, CDCl3): −4.8 (CH3, SitBuMe2), −4.6
(CH3, SitBuMe2), −4.4 (CH3, SitBuMe2), −3.9 (CH3, SitBuMe2),
18.0 (quat., 2 × SitBuMe2), 19.2 (quat., SitBuPh2), 19.6 (CH2, C7),
23.7 (CH3, C1), 25.9 (CH3, SitBuMe2), 26.0 (CH3, SitBuMe2), 26.9
(CH3, SitBuPh2), 33.2 (CH2, C3), 36.8 (CH2, C8), 38.6 (CH2, C4),
39.7 (CH2, C10), 42.9 (CH2, C6), 42.9 (CH2, C6*), 60.8 (CH2,
C11), 67.6 (CH, C9), 69.0 (CH, C2), 127.6 (CH, SitBuPh2, m),
129.5 (CH, SitBuPh2, p), 129.5 (CH, SitBuPh2, p*), 133.9 (quat.,
SitBuPh2), 135.5 (CH, SitBuPh2, o) and 210.9 (quat., C5); m/z
(FAB): 685 (MH+, 2%), 627 (M-tBu, 2), 553 (3), 495 (3), 421 (6),
239 (8), 197 (16), 135 (39) and 73 (100); HRMS (FAB): Found
MH+, 685.44720. C39H69O4Si3 requires M, 685.45037.
t
and 135.5 (CH, SitBuPh2, o); m/z (EI): 625 (M− Bu+, 2%), 493
(9), 401 (8), 361 (15), 313 (12), 271 (17), 209 (23), 197 (32), 159
(21), 145 (42), 135 (69), 91 (35) and 73 (100); HRMS (FAB): Found
MH+, 683.43464. C39H67O4Si3 requires M, 683.43472.
(2R, 9S)-2,9-Bis-(tert-butyldimethylsilyloxy)-11-
(tert-butyldiphenylsilyloxy)undec-3-yn-5-one (26b)
Alcohol 25b (4.02 g, 5.88 mmol) was dissolved in dichloromethane
◦
3
˚
(15 cm ) with 4 A molecular sieves and cooled to 0 C under an
atmosphere of nitrogen. To this stirred solution was added N-
methylmorpholine-N-oxide (1.03 g, 8.82 mmol) and tetrapropy-
lammonium perruthenate (0.10 g, 0.29 mmol). After stirring at
room temperature for 2 h the solvent was removed under reduced
pressure. Purification of the resultant residue by flash column
chromatography using hexane–diethyl ether (9 : 1 to 7 : 3) as eluent
gave the title compound 26b (3.49 g, 87%) as a yellow oil; [a]D
+18.6 (c 1.78 in CHCl3); vmax(film)/cm−1 2955, 2930, 2857, 2213
(C≡C), 1680s (CO), 1472, 1428, 1255, 1156, 1111, 836, 776, 738
and 701; dH (300 MHz, CDCl3): 0.02 (3 H, s, SitBuMe2), 0.05 (3 H,
s, SitBuMe2), 0.13 (3 H, s, SitBuMe2), 0.16 (3 H, s, SitBuMe2), 0.87
(9 H, s, SitBuMe2), 0.92 (9 H, s, SitBuMe2), 1.06 (9 H, s, SitBuPh2),
1.39–1.47 (2 H, m, H8), 1.47 (3 H, d, J 6.6 Hz, H1), 1.62–1.76
(4 H, m, H7 and H10), 2.53 (2 H, t, J 7.4 Hz, H6), 3.73 (2 H, td,
J 6.4 Hz, Jw 2.1 Hz, H11), 3.90 (1 H, quintet, J 5.8 Hz, H9), 4.66
(1 H, q, J 6.6 Hz, H2), 7.35–7.45 (6 H, m, SitBuPh2, m and p) and
7.65–7.69 (4 H, m, SitBuPh2, o); dC (75 MHz, CDCl3): −5.0 (CH3,
SitBuMe2), −4.6 (CH3, SitBuMe2), −4.6 (CH3, SitBuMe2), −4.4
(CH3, SitBuMe2), 18.0 (quat., SitBuMe2), 18.1 (quat., SitBuMe2),
19.1 (quat., SitBuPh2), 19.6 (CH2, C7), 24.5 (CH3, C1), 25.7
(CH3, SitBuMe2), 25.9 (CH3, SitBuMe2), 26.9 (CH3, SitBuPh2),
36.4 (CH2, C8), 39.7 (CH2, C10), 45.5 (CH2, C6), 58.8 (CH, C2),
60.8 (CH2, C11), 68.9 (CH, C9), 82.3 (quat., C4), 93.5 (quat., C3),
127.6 (CH, SitBuPh2, m), 127.6 (CH, SitBuPh2, m*), 129.5 (CH,
(2R, 5S, 7S)-7-[2ꢀ-(tert-Butyldiphenylsilyloxy)ethyl]-2-methyl-1,
6-dioxaspiro[4.5]decane (27b)
To a stirred solution of ke◦tone 6b (3.32 g, 4.85 mmol) in
dichloromethane (50 cm3) at 0 C under an atmosphere of nitrogen
was added camphorsulfonic acid (2.67 g, 10.67 mmol). After
R
stirring for 2 h the solution was filtered through a pad of Celiteꢀ,
and the solvent removed under reduced pressure. Flash column
chromatography using hexane–diethyl ether (8 : 2 to 6 : 4) as
eluent afforded the title compound 27b (1.83 g, 86%) as a yellow
oil; [a]D +22.5 (c 1.21 in CHCl3); vmax(film)/cm−1 2933, 2857, 1472,
1428, 1219, 1111, 823, 736 and 701; dH (300 MHz, CDCl3): 1.06
(9 H, s, SitBuPh2), 1.11–1.17 (1 H, m, H8a), 1.20 (3 H, d, J 6.6 Hz,
Me), 1.28–1.42 (1 H, m, H3a), 1.51–1.59 (1 H, m, H8b), 1.60–1.68
(5 H, m, H9a, H10 and H1ꢀ), 1.69–1.78 (1 H, m, H4a), 1.80–1.90
(2 H, m, H4b and H9b), 2.04 (1 H, dddd, J 11.8, 8.8, 6.6 and 6.6 Hz,
H3b), 3.67 (1 H, ddd, J 10.1, 6.4 and 6.4 Hz, H2ꢀa), 3.85 (1 H, ddd,
J 10.1, 6.4 and 6.4 Hz, H2ꢀb), 4.00 (1 H, dddd, J 11.4, 6.5, 6.5
and 2.1 Hz, H7), 4.13 (1 H, qd, J 6.6 and 6.6 Hz, H2), 7.34–7.45
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 2572–2582 | 2579
©

View Article Online
(6 H, m, SitBuPh2, m and p) and 7.65–7.71 (4 H, m, SitBuPh2,
o); dC (75 MHz, CDCl3): 19.2 (quat., SitBuPh2), 20.4 (CH2, C9),
21.1 (CH3, Me), 26.8 (CH3, SitBuPh2), 31.1 (CH2, C8), 31.3 (CH2,
C3), 33.4 (CH2, C10), 38.0 (CH2, C4), 39.3 (CH2, C1ꢀ), 60.5 (CH2,
C2ꢀ), 66.9 (CH, C7), 73.4 (CH, C2), 105.9 (quat., C5), 127.5 (CH,
SitBuPh2, m), 129.5 (CH, SitBuPh2, p), 134.2 (quat., SitBuPh2),
134.1 (quat., SitBuPh2*), and 135.5 (CH, SitBuPh2, o); m/z (EI):
and H10ꢀꢀ), 1.76 (1 H, ddd, J 12.7, 10.4 and 6.7 Hz, H4ꢀꢀ ), 1.82–
a
2.00 (4 H, m, H4ꢀꢀ , H9ꢀꢀ and H2ꢀ), 2.15 (1 H, dddd, J 11.9, 8.8,
b
b
6.7 and 6.7 Hz, H3ꢀꢀ ), 3.35–3.50 (2 H, m, H1ꢀ), 3.95 (1 H, dddd,
b
J 11.4, 9.0, 3.6 and 2.3 Hz, H7ꢀꢀ), 4.18 (1 H, qd, J 6.7 and 6.7 Hz,
H2ꢀꢀ), 7.27 (1 H, td, J 7.7 and 1.0 Hz, H6), 7.39 (1 H, td, J 7.7 and
1.0 Hz, H5), 7.74 (1 H, d, J 7.7 Hz, H7) and 7.85 (1 H, d, J 7.7 Hz,
H4); dC (100 MHz, CDCl3): 20.2 (CH2, C9ꢀꢀ), 21.3 (CH3, Me), 30.1
(CH2, C1ꢀ), 30.8 (CH2, C8ꢀꢀ), 31.3 (CH2, C3ꢀꢀ), 33.3 (CH2, C10ꢀꢀ),
35.6 (CH2, C2ꢀ), 37.9 (CH2, C4ꢀꢀ), 68.4 (CH, C7ꢀꢀ), 73.9 (CH, C2ꢀꢀ),
106.1 (quat., C5ꢀꢀ), 120.8 (CH, C7), 121.4 (CH, C4), 124.0 (CH,
C6), 125.9 (CH, C5), 135.1 (quat., C7a), 153.4 (quat., C3a) and
167.5 (quat., C2); m/z (EI): 349 (M+, 19%), 334 (M−Me, 4), 182
(M−C7H5NS, 78), 167 (C7H5NS, 100), 125 (28), 111 (78), 98 (78),
83 (12), 55 (24), 43 (23), and 41 (26); HRMS (EI): Found M+,
349.11682. C18H23NO2S2 requires M, 349.11702.
t
381 (M− Bu, 54%), 303 (6), 295 (5), 281 (7), 199 (51), 165 (28),
111 (100), 98 (19), 83 (18) and 55 (18); HRMS (CI, NH3): Found
MH+, 439.26730. C27H39O3Si requires M, 439.26685.
(2R, 5R, 7S)-7-(2ꢀ-Hydroxyethyl)-2-methyl-1,
6-dioxaspiro[4.5]decane (28b)
To a stirred solution of silyl ether 27b (1.81 g, 4.11 mmol) in
tetrahydrofuran (15 cm3) was added tetrabutylammonium fluoride
(6.17 cm3, 6.17 mmol, 1 mol dm−3). After stirring for 2 h, brine
(5 cm3) was added and the mixture extracted with diethyl ether
(4 × 20 cm3). The combined extracts were dried over magnesium
sulfate, filtered, and the solvent removed under reduced pressure.
Flash column chromatography using pentane–diethyl ether (9 : 1
to 6 : 4) as eluent gave the title compound 28b (0.68 g, 83%) as
a volatile yellow oil; [a]D +49.2 (c 2.32 in CHCl3); vmax(film)/cm−1
3435br (OH), 2941, 2872, 1456, 1440, 1386, 1364, 1220, 1164, 1065,
1031, 976, 944, 879 and 861; dH (300 MHz, CDCl3): 1.25 (3 H, d,
J 6.6 Hz, Me), 1.28–1.35 (1 H, m, H8a), 1.37–1.48 (1 H, m, H3a),
1.49–1.58 (1 H, m, H8b), 1.61–1.72 (5 H, m, H9a, H10 and H1ꢀ),
1.72–1.80 (1 H, m, H4a), 1.82–1.92 (2 H, m, H4b and H9b), 2.03
(1 H, dddd, J 12.1, 8.6, 6.6 and 6.6 Hz, H3b), 3.76 (2 H, m, H2ꢀ),
4.03 (1 H, dddd, J 12.3, 8.9, 2.8 and 2.8 Hz, H7) and 4.20 (1 H,
qd, J 6.6 and 6.6 Hz, H2); dC (75 MHz, CDCl3): 20.0 (CH2, C9),
21.2 (CH3, Me), 30.8 (CH2, C8), 31.1 (CH2, C3), 33.2 (CH2, C10),
37.6 (CH2, C1ꢀ), 38.0 (CH2, C4), 62.2 (CH2, C2ꢀ), 71.8 (CH, C7),
74.0 (CH, C2) and 106.2 (quat., C5); m/z (EI): 200 (M+, 2%), 185
(M−Me, 1), 155 (14), 126 (12), 111 (15), 101 (100), 98 (78), 83 (20),
55 (23), 43 (31) and 41 (28); HRMS (EI): Found M+, 200.14156.
C11H20O3 requires M, 200.14124.
(2ꢀꢀR,5ꢀꢀR,7ꢀꢀS)-2-[2ꢀ-(2ꢀꢀ-Methyl-1ꢀꢀ,6ꢀꢀ-dioxaspiro[4.5]dec-
7ꢀꢀ-yl)ethylsulfonyl]benzothiazole (4b)
To
a solution of thioether 29b (0.74 g, 2.12 mmol) in
dichloromethane (10 cm3) at 0 ◦C under an atmosphere of nitrogen
was added sodium bicarbonate (0.89 g, 10.59 mmol) and a
solution of m-chloroperoxybenzoic acid (0.91 g, 5.29 mmol) in
dichloromethane (10 cm3). After stirring the solution for 12 h,
saturated aqueous sodium bicarbonate (4 cm3) and saturated
aqueous sodium thiosulfate (4 cm3) were added. The aqueous
layer was extracted with dichloromethane (3 × 30 cm3), and the
combined extracts were dried over magnesium sulfate. Filtration
and removal of the solvent under reduced pressure provided an oil
that was purified by flash column chromatography using hexane–
diethyl ether (8 : 2 to 6 : 4) as eluent to afford the title compound
4b (13 g, 82%) as a yellow oil; [a]D +28.6 (c 1.07 in CHCl3);
v
max(film)/cm−1 2939, 2871, 1473, 1328s (SO), 1237, 1219, 1147s
(SO), 1084, 1062, 993, 980, 941, 853, 763 and 729; dH (300 MHz,
CDCl3): 1.12–1.25 (1 H, m, H8ꢀꢀ ), 1.21 (3 H, d, J 6.2 Hz, Me),
a
1.34–1.45 (1 H, m, H3ꢀꢀ ), 1.50–1.58 (1 H, m, H8ꢀꢀ ), 1.59–1.67 (3 H,
a
b
m, H9ꢀꢀ and H10ꢀꢀ), 1.69–1.76 (1 H, m, H4ꢀꢀ ), 1.76–1.87 (2 H, m,
a
a
H4ꢀꢀb and H9ꢀꢀ ), 1.87–2.03 (1 H, m, H2ꢀ), 2.03–2.14 (1 H, m, H3ꢀꢀ ),
b
b
3.49 (1 H, ddd, J 14.5, 10.8 and 5.2 Hz, H1ꢀa), 3.73 (1 H, ddd, J
14.5, 10.8 and 5.2 Hz, H1ꢀb), 3.89 (1 H, dddd, J 11.3, 8.7, 3.2 and
2.6 Hz, H7ꢀꢀ), 4.09 (1 H, qd, J 6.2 and 6.2 Hz, H2ꢀꢀꢀꢀ), 7.60 (1 H, td,
J 7.2 and 1.2 Hz, H6), 7.65 (1 H, td, J 7.2 and 1.2 Hz, H5), 8.02
(1 H, d, J 7.2 Hz, H7) and 8.24 (1 H, d, J 7.2 Hz, H4); dC (75 MHz,
CDCl3): 20.0 (CH2, C9ꢀꢀ), 21.1 (CH3, Me), 28.8 (CH2, C2ꢀ), 30.6
(CH2, C8ꢀꢀ), 31.2 (CH2, C3ꢀꢀ), 33.2 (CH2, C10ꢀꢀ), 37.7 (CH2, C4ꢀꢀ),
51.8 (CH2, C1ꢀ), 68.1 (CH, C7ꢀꢀ), 73.9 (CH, C2ꢀꢀ), 106.1 (quat., C5ꢀꢀ),
122.3 (CH, C7), 125.4 (CH, C4), 127.6 (CH, C5), 127.9 (CH, C6),
136.8 (quat., C7a), 152.7 (quat., C3a) and 165.6 (quat., C2); m/z
(EI): 381 (M+, 3%), 366 (M−Me, 3), 282 (15), 205 (18), 189 (33),
149 (26), 135 (39), 98 (100), 55 (32), 43 (27) and 41 (30); HRMS
(EI): Found M+, 381.10666. C18H23NO4S2 requires M, 381.10685.
(2ꢀꢀR,5ꢀꢀR,7ꢀꢀS)-2-[2ꢀ-(2ꢀꢀ-Methyl-1ꢀꢀ,6ꢀꢀ-dioxaspiro[4.5]dec-
7ꢀꢀ-yl)ethylsulfanyl]benzothiazole (29b)
Triphenylphosphine (1.34 g, 5.12 mmol) and mercaptobenzoth-
iazole (1.14 g, 6.82 mmol) were dissolved in tetrahydrofuran
(25 cm3) and cooled to 0 ◦C under an atmosphere of nitrogen. To
this stirred solution was added alcohol 28b (0.68 g, 3.41 mmol)
in tetrahydrofuran (5 cm3). After stirring for 0.25 h, diethyl
azodicarboxylate (0.53 cm3, 3.21 mmol) was added dropwise via
syringe. The resultant bright yellow solution was allowed to stir at
0 ◦C for 2 h. The reaction was quenched by the addition of brine
(10 cm3) and the mixture extracted with diethyl ether (3 × 40 cm3).
The combined extracts were dried over magnesium sulfate, filtered
and the solvent removed under reduced pressure. Purification of
the resultant oil by flash column chromatography using hexane–
diethyl ether (98 : 2 to 7 : 3) as eluent gave the title compound
4b (0.74 g, 62%) as a yellow oil; [a]D +94.77 (c 0.88 in CHCl3);
(3ꢀE, 3R, 2ꢀꢀR, 5ꢀꢀR, 7ꢀꢀR)- and (3ꢀZ, 3R, 2ꢀꢀR, 5ꢀꢀR, 7ꢀꢀR)-5,7-
Dimethoxy-3-[5ꢀ-(2ꢀꢀ-methyl-1ꢀꢀ,6ꢀꢀ-dioxaspiro[4.5]dec-7ꢀꢀ-yl)pent-
3ꢀ-en-1ꢀ-yl]-3H-isobenzofuran-1-one (30b)
v
max(film)/cm−1 2939, 2870, 1459, 1427, 1309, 1237, 1218, 1162,
1113, 1077, 994, 882, 848, 754 and 726; dH (400 MHz, CDCl3):
Sulfone 4b (150 mg, 0.39 mmol) was dissolved in tetrahydrofuran
(7.5 cm3) and cooled to −78 ◦C under an atmosphere of
nitrogen. To this stirred solution was added dropwise lithium
1.19–1.29 (1 H, m, H8ꢀꢀ ), 1.22 (3 H, d, J 6.7 Hz, Me), 1.37–1.45
a
(1 H, m, H3ꢀꢀ ), 1.55–1.60 (1 H, m, H8ꢀꢀ ), 1.64–1.69 (3 H, m, H9ꢀꢀ
a
b
a
2580 | Org. Biomol. Chem., 2007, 5, 2572–2582
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
diisopropylamide(0.43cm3, 0.43 mmol, 1 mol dm−3). The resultant
deep yellow solution was stirred for 0.75 h before a solution of
aldehyde 3a (98 mg, 0.39 mmol) in tetrahydrofuran (2.5 cm3) was
added dropwise. After stirring at −78 ◦C for 4 h, the solution
was allowed to slowly warm to room temperature then stirred
for 0.75 h. The reaction was quenched by the addition of brine
(3 cm3) and the aqueous layer was extracted with ethyl acetate
(3 × 15 cm3). The combined extracts were dried over magnesium
sulfate, filtered, and the solvent removed in vacuo. The resultant
oil was purified by flash column chromatography using hexane–
ethyl acetate (9 : 1 to 1 : 1) as eluent to give the title compound
30b (65 mg, 40%) as a yellow oil; [a]D +58.6 (c 0.97 in CHCl3);
6.6, H4ꢀꢀ ), 1.80–1.89 (2 H, m, H4ꢀꢀb and H9ꢀꢀ ), 1.94–2.01 (1 H, m,
a
b
H1ꢀb), 2.12 (1 H, dddd, J 11.9, 8.8, 6.6 and 6.6 Hz, H3ꢀꢀ ), 3.66–3.72
b
(1 H, m, H7ꢀꢀ), 3.89 (3 H, s, OMe), 3.95 (3 H, s, OMe), 4.14 (1 H,
qd, J 6.6 and 6.6 Hz, H2ꢀꢀ), 5.30 (1 H, dd, J 7.8 and 3.8 Hz, H3),
6.40 (1 H, apparent s, H6) and 6.42 (1 H, d, J 1.7 Hz, H4); dC
(100 MHz, CDCl3): 20.4 (CH2, C9ꢀꢀ), 21.3 (CH3, Me), 24.5 (CH2,
C2ꢀ), 25.4 (CH2, C4ꢀ), 29.3 (CH2, C3ꢀ), 30.9 (CH2, C8ꢀꢀ), 31.3 (CH2,
C3ꢀꢀ), 33.5 (CH2, C10ꢀꢀ), 34.8 (CH2, C1ꢀ), 36.1 (CH2, C5ꢀ), 38.0
(CH2, C4ꢀꢀ), 55.9 (CH3, OMe), 56.0 (CH3, OMe), 69.9 (CH, C7ꢀꢀ),
73.9 (CH, C2ꢀꢀ), 79.9 (CH, C3), 97.3 (CH, C6), 98.6 (CH, C4),
106.0 (quat., C5ꢀꢀ), 107.0 (quat., C7a), 155.2 (quat., C3a), 159.6
(quat., C7), 166.6 (quat., C5) and 168.5 (quat., C1); m/z (EI): 418
(M+, 6%), 361 (28), 318 (41), 293 (22), 290 (15), 261 (18), 207 (46),
193 (66), 155 (44), 111 (29), 98 (100), 57 (45), 55 (41), 43 (34) and
41 (45); HRMS (EI): Found M+, 418.23585. C24H34O6 requires M,
418.23554. This data was in agreement with that reported in the
literature.6,29
v
max(film)/cm−1 2929, 1758s (CO), 1613s, 1462, 1338, 1218, 1159,
1056 and 980; dH (400 MHz, CDCl3)‡: 1.08–1.30 (2 H, m, H8ꢀꢀa and
H8ꢀꢀ *), 1.21 (3 H, d, J 6.3 Hz, Me), 1.22 (3 H, d, J 6.3 Hz, Me*),
a
1.34–1.42 (2 H, m, H3ꢀꢀ and H3ꢀꢀ *), 1.55–1.59 (2 H, m, H8ꢀꢀ and
a
a
b
H8ꢀꢀ *), 1.62–1.67 (6 H, m, H9ꢀꢀ , H9ꢀꢀ *, H10ꢀꢀ and H10ꢀꢀ*), 1.70–
1.79 (4 H, m, H4ꢀꢀ , H4ꢀꢀ *, H1ꢀaa and H1ꢀa*), 1.80–1.89 (4 H, m,
b
a
a
a
H4ꢀꢀ , H4ꢀꢀ *, H9ꢀꢀb and H9ꢀꢀ *), 1.96–2.03 (2 H, m, H1ꢀb and H1ꢀb*),
2.03–2.11 [3 H, m, (E)-H5ꢀba, H3ꢀꢀ and H3ꢀꢀ *], 2.12–2.17 [3 H, m,
b
b
Acknowledgements
b
b
(E)-H5ꢀb and (Z)-H5ꢀ], 2.18–2.25 [3 H, m, (E)-H2ꢀ and (Z)-H2ꢀa],
2.26–2.34 [1 H, m, (Z)-H2ꢀb], 3.71–3.80 (2 H, m, H7ꢀꢀ and H7ꢀꢀ*),
3.89 (3 H, s, OMe), 3.89 (3 H, s, OMe*), 3.95 (6 H, s, OMe and
OMe*), 4.13 (1 H, qd, J 6.3 and 6.3 Hz, H2ꢀꢀ), 4.15 (1 H, qd, J 6.3
and 6.3 Hz, H2ꢀꢀ*), 5.31 (1 H, dd, J 8.3 and 3.4 Hz, H3), 5.33 (1 H,
dd, J 8.3 and 3.4 Hz, H3*), 5.41–5.55 (4 H, m, H3ꢀ, H3ꢀ*, H4ꢀ and
H4ꢀ*), 6.40–6.41 (2 H, m, H6 and H6*) and 6.42 (2 H, s, H4 and
H4*); dC (100 MHz, CDCl3)‡: 20.3 (CH2, C9ꢀꢀ), 20.3 (CH2, C9ꢀꢀ*),
21.1 (CH3, Me), 21.2 (CH3, Me*), 22.8 [CH2, (Z)-C2ꢀ], 27.8 [CH2,
(E)-C2ꢀ], 30.4 (CH2, C8ꢀꢀ), 31.3 (CH2, C3ꢀꢀ), 33.4 (CH2, C10ꢀꢀ), 33.5
(CH2, C10ꢀꢀ*), 34.0 [CH2, (Z)-C5ꢀ], 34.8 (CH2, C1ꢀ), 34.8 (CH2,
C1ꢀ*), 38.0 (CH2, C4ꢀꢀ), 38.0 (CH2, C4ꢀꢀ*), 39.5 [CH2, (E)-C5ꢀ],
55.9 (CH3, OMe), 56.0 (CH3, OMe), 69.9 (CH, C7ꢀꢀ), 73.6 (CH,
C2ꢀꢀ), 73.7 (CH, C2ꢀꢀ*), 79.0 (CH, C3), 79.2 (CH, C3*), 97.3 (CH,
C6), 98.7 (CH, C4), 106.1 (quat., C5ꢀꢀ), 106.8 (quat., C7a), 106.9
(quat., C7a*), 127.9 (CH, C3ꢀ), 128.8 (CH, C3ꢀ*), 129.0 (CH, C4ꢀ),
129.9 (CH, C4ꢀ*), 155.1 (quat., C3a), 155.2 (quat., C3a*), 159.6
(quat., C7), 166.7 (quat., C5) and 168.5 (quat., C1); m/z (EI): 416
(M+, 3%), 398 (11), 316 (7), 262 (14), 207 (42), 193 (50), 155 (100),
137 (39), 111 (47), 98 (25), 95 (26), 55 (38) and 41 (36); HRMS
(EI): Found M+, 416.21999. C24H32O6 requires M, 416.21989.
Auckland Uniservices Ltd. is thanked for the award of a postgrad-
uate scholarship to JER.
References
1 J. Mackay, A. Jemal, N. C. Lee and D. M. Parkin, The Cancer Atlas,
American Cancer Society, New York, 2nd edn, 2006.
2 B. J. Marshall and J. R. Warren, Lancet, 1984, 323, 1311.
3 C. Montecucco and M. D. Bernard, Microbes Infect., 2003, 5, 715.
4 C. Stoicov, R. Saffari, X. Cai, C. Hasyagar and J. Houghton, Gene,
2004, 341, 1.
5 J. H. Walsh and W. L. Peterson, N. Engl. J. Med., 1995, 333, 984; B.
Rathbone, Scrip Magazine, 1993, 25.
6 A. Arnone, G. Assante, G. Nasini and O. Vajna de Pava, Phytochem-
istry, 1990, 29, 613; M. A. Gaudliana, L. H. Huang, T. Kaneko, P. C.
Watts, PCT Int. Appl., 1996, W0 9605204; CAN 125:58200.
7 G. Deffieu, R. Baute, M.-A. Baute and A. Neven, C. R. Seances Acad.
Sci., Ser. D, 1979, 288, 647.
8 K. A. Dekker, T. Inagake, T. D. Gootz, K. Kaneda, E. Nomura, T.
Sakakibara, S. Sakemi, Y. Sugie, Y. Yamauchi, N. Yoshikawa and N. J.
Kojima, J. Antibiot., 1997, 50, 833.
9 M. J. Blaser, Clin. Infect. Dis., 1992, 15, 386.
10 S. Penco, C. Pisano and G. Giannini, WO Pat. 01/68070.
11 For a preliminary communication of this work see:J. E. Robinson and
M. A. Brimble, Chem. Commun., 2005, 1560.
12 A. Bava, M. Clericuszio, G. Giannini, L. Malpezzi, S. V. Meille and G.
Nasini, Eur. J. Org. Chem., 2005, 11, 2292.
13 R. Nannei, S. Dallavalle, L. Merlini, A. Bava and G. Nasini, J. Org.
Chem., 2006, 71, 6277.
14 P. K. Jadhav, K. S. Bhat, P. T. Perumal and H. C. Brown, J. Org. Chem.,
1986, 51, 432.
(3R, 2ꢀꢀR, 5ꢀꢀR, 7ꢀꢀR)-5,7-Dimethoxy-3-[5ꢀ-(2ꢀꢀ-methyl-1ꢀꢀ,6ꢀꢀ-
dioxaspiro[4.5]dec-7ꢀꢀ-yl)pent-1ꢀ-yl]-3H-isobenzofuran-1-
one (2b) (spirolaxine methyl ether)
15 D. R. Gauthier and E. M. Carreira, Angew. Chem., Int. Ed. Engl., 1996,
35, 2363.
16 M. R. Paleo, C. Lamas, L. Castedo and D. Dom´ınguez, J. Org. Chem.,
1992, 57, 2029.
Alkene 30b (10 mg, 0.02 mmol) was dissolved in tetrahydrofuran
(10 cm3) and hydrogenated using a hydrogen-filled double balloon
in the presence of platinum(IV) oxide (1 mg) for 6 h. The catalyst
17 A. S. Cotterill, M. Gill, A. Gimenez and N. M. Milanovic, J. Chem.
Soc., Perkin Trans. 1, 1994, 3269.
R
was removed by filtration through a pad of Celiteꢀ and the solvent
removed under reduced pressure. Purification of the resultant oil
by flash column chromatography using pentane–diethyl ether (4 :
6 to 2 : 8) as eluent gave the title compound 2b (10 mg, 99%) as a
yellow oil; [a]D +63.7 (c 0.85 in CHCl3); vmax(film)/cm−1 2933, 2860,
1756s (CO), 1605s, 1494, 1459, 1432, 1336, 1218, 1158, 1052, 1029
and 980; dH (400 MHz, CDCl3): 1.14 (1 H, dddd, J 13.0, 13.0, 13.0
18 T. Shibata, K. Iiono and Y. Sugimura, Heterocycles, 1986, 24,
1331.
19 J. A. Frick, J. B. Klassen, A. Bathe, J. M. Abramson and H. Rapoport,
Synthesis, 1992, 7, 621.
20 Y. Mori and M. Suzuki, Tetrahedron Lett., 1989, 38, 4383.
21 B. Achmatowicz, M. M. Kabat and J. Krajewski, Tetrahedron, 1992,
48, 10201.
22 B. H. Lipshutz, R. Crow, S. H. Dimock, E. L. Ellsworth, R. A. Smith
and J. R. Behling, J. Am. Chem. Soc., 1990, 112, 4063.
23 B. H. Lipshutz and T. R. Elworthy, J. Org. Chem., 1990, 55,
1695.
and 3.8 Hz, H8ꢀꢀ ), 1.23 (3 H, d, J 6.6 Hz, Me), 1.25–1.48 (9 H, m,
a
H2ꢀ, H3ꢀ, H4ꢀ, H5ꢀ and H3ꢀꢀ ), 1.51–1.56 (1 H, m, H8ꢀꢀ ), 1.59–1.72
a
b
(4 H, m, H1ꢀa, H9ꢀꢀ and H10ꢀꢀ), 1.74 (1 H, ddd, J 12.7, 10.4 and
a
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 2572–2582 | 2581
©

View Article Online
24 H. C. Brown, U. S. Racherla and S. M. Singh, Tetrahedron Lett., 1984,
25, 2411.
28 For reviews on the anomeric effect see: P. Deslongchamps, Stereoelec-
tronic Effects in Organic Chemistry, Pergamon Press, New York, 1983;
A. J. Kirby, The Anomeric Effect and Related Stereoelectronic Effects
at Oxygen, Springer-Verlag, New York, 1983.
25 M. Yamaguchi, K. Shibato, S. Fujiwara and I. Hirao, Synthesis, 1986,
421.
26 P. E. van Rijn, S. Mommers, R. G. Visser, H. D. Verkruijsse and L.
Brandsma, Synthesis, 1981, 459.
27 E. M. Carreira and J. Du Bois, J. Am. Chem. Soc., 1994, 116, 10825.
29 T. Adachi, I. Takagi, K. Kondo, A. Kawashima, A. Kobayashi, I.
Taneoka, S. Morimoto, B. M. He and Z. Chen, PCT Int. Appl., 1996,
WO 9610020; CAN 125:86482.
2582 | Org. Biomol. Chem., 2007, 5, 2572–2582
This journal is
The Royal Society of Chemistry 2007
©