Synthesis of the ABC tricyclic fragment of the pectenotoxins via stereocontrolled cyclization of a γ-hydroxyepoxide appended to the AB spiroacetal unit

Article abstract of DOI:10.1039/b600951d

The stereocontrolled synthesis of the C1-C16 ABC spiroacetal-containing tricyclic fragment of pectenotoxin-7 6 has been accomplished. The key AB spiroacetal aldehyde 9 was successfully synthesized via acid catalyzed cyclization of protected ketone precurs

Full text of DOI:10.1039/b600951d

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of the ABC tricyclic fragment of the pectenotoxins via
stereocontrolled cyclization of a c-hydroxyepoxide appended to the AB
spiroacetal unit†
Rosliana Halim, Margaret A. Brimble* and Jo¨rn Merten
Received 20th January 2006, Accepted 13th February 2006
First published as an Advance Article on the web 1st March 2006
DOI: 10.1039/b600951d
The stereocontrolled synthesis of the C1–C16 ABC spiroacetal-containing tricyclic fragment of
pectenotoxin-7 6 has been accomplished. The key AB spiroacetal aldehyde 9 was successfully
synthesized via acid catalyzed cyclization of protected ketone precursor 28 that was readily prepared
from aldehyde 12 and sulfone 13. The syn stereochemistry in aldehyde 12 was installed using an
asymmetric aldol reaction proceeding via a titanium enolate. The stereogenic centre in sulfone 13 was
derived from (R)-(+)-glycidol. The absolute stereochemistry of the final spiroacetal aldehyde 9 was
confirmed by NOE studies establishing the (S)-stereochemistry of the spiroacetal centre. Construction
of the tetrahydrofuran C ring system began with Wittig olefination of the AB spiroacetal aldehyde 9
with (carbethoxyethylidene)triphenylphosphorane 10 affording the desired (E)-olefin 32. Appendage of
a three carbon chain to the AB spiroacetal fragment was achieved via addition of acetylene 11 to the
unstable allylic iodide 39. Epoxidation of (E)-enyne 8 via in situ formation of L-fructose derived
dioxirane generated the desired syn-epoxide 36. Semi-hydrogenation of the resulting epoxide 36
followed by dihydroxylation of the alkene effected concomitant cyclization, thus completing the
synthesis of the ABC spiroacetal ring fragment 6.
Introduction
The pectenotoxins are a family of polyether lactones that were first
isolated in 1985 by Yasumoto et al.1 They were named after the
generic name of the scallop initially used for the toxin extraction,
Patinopecten yessoensis and were originally produced by toxic
dinoflagellate species of the genera Dinophysis (D. acuta and
D. fortii). The first pectenotoxins to be isolated were pectenotoxin-
1 (PTX1, 1), −2 (PTX2, 2), −3 (PTX3), −4 (PTX4 3) and −5
(PTX5) (Fig. 1). The absolute stereochemistry of PTX1 1 was
established by X-ray crystallography1 and the remaining structure
of the family was elucidated by comparison of NMR and mass
spectroscopic data. Since then, more pectenotoxins have been
isolated2,3,4,5,6 and characterised and the most recent compound
to be isolated from algae and mussels in Norway is PTX12.6
Fig. 1 Structure of PTXs and the key disconnections used for their
synthesis.
The pectenotoxins comprise a macrolide structure containing a
spiroacetal, three substituted tetrahydrofurans and 19 (or 20 in the
attention of several research groups9,10,11,12 however, only Evans
case of PTX11) stereocentres embedded within a 40-carbon chain
et al.13 have achieved the total synthesis of PTX4 2 and PTX8. In
light of this research group’s interest in the synthesis of spiroacetal-
containing natural products we herein report the full details14
(Fig. 1). PTX2 2 exhibited selective and potent cytotoxicity against
several cancer cell lines at the nanomolar level.7 PTX2 2 and PTX6
4 have also been shown to interact with the actin cytoskeleton at
of our synthetic work focused on the synthesis of the ABC
a unique site8 thus providing an important research tool for the
spiroacetal-containing tricyclic ring system.
study of basic cellular behaviour.
The architecturally complex structure of the pectenotoxins
together with their potent biological activity has attracted the
Results and discussion
Our retrosynthetic analysis of the key spiroacetal containing ABC
tricyclic fragment 6 is depicted in Scheme 1. The ABC fragment
6 is constructed via a 5-exo-tet cyclisation of epoxy-diol 7, in
which all the necessary stereogenic centres of the C ring are
already installed. Epoxy-diol 7 in turn is obtained from enyne
8 by asymmetric epoxidation followed by semi-hydrogenation and
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 12, 13 and 14–24. See DOI:
10.1039/b600951d
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effect and is in fact thermodynamically favoured stereochemistry
when the spiroacetal ring is not embedded in the macrocyclic
structure. It was therefore planned to obtain the natural (7R)-
isomer of PTX2 2 at a later stage in the synthesis after assembly of
macrolide ring based on the precedent reported by Sasaki and co-
workers4 for PTX4 3. Our initial attention was therefore directed
towards the synthesis of spiroacetal 9 with the (7S)-configuration
as present in PTX7 5.
The execution of our synthetic plan towards the synthesis of the
ABC tricyclic system of PTX7 5 commenced with the synthesis
of the C1-C11 AB spiroacetal fragment starting from aldehyde 12
and sulfone 13. The first issue to address was to install the syn
stereochemistry in the aldehyde fragment 12 using an asymmetric
aldol reaction (Scheme 2). Initial attempts to execute the aldol
reaction between aldehyde 1615 and propanoyloxazolidinone 1416
R
using commercial (Aldrichꢀ) dibutylboron triflate (Bu2BOTf) as
a 1 M solution in dichloromethane with diisopropylethylamine
as the base to form the Z-enolate of propanoyloxazolidinone 14
followed by condensation with aldehyde 16 at 0 ◦C gave the desired
syn-adduct 17 exclusively in only 43% yield. It was postulated
that the quality of the boron reagent was responsible for the low
yields observed in this reaction. Fuentes et al.17 reported non-
reproducible results in related aldol reactions using commercial
dibutylboron triflate18 as a solution in CH2Cl2 and diethyl ether.
In 1997, Crimmins and co-workers19 reported the formation of
titanium enolates of N-acyloxazolidinethiones rather than acylox-
azolidinones using TiCl4. The use of (−)-sparteine (2.5 equiv.) was
found to be the most effective base, giving high rate enhancement
and high selectivity for the Evans’ syn adducts using only 1
equiv. of aldehyde and 1 equiv. of TiCl4. Further investigation
showed that there was minimal asymmetric induction provided
by (−)-sparteine and the rate enhancement may be related to
bidentate coordination of (−)-sparteine to the metal centre. The
Evans syn adduct is the major product as coordination of the
diamine to the metal centre prevents coordination of the imide
or thioimide carbonyl group to the metal. Crimmins et al.20
later found that use of N-methyl-2-pyrrolidinone (NMP, 1 equiv.)
Scheme 1 Retrosynthetic analysis of ABC fragment 6.
asymmetric dihydroxylation. Enyne 8 is prepared from spiroacetal
aldehyde 9, stabilised ylide 10 and acetylene 11. Finally spiroacetal
9 is derived from the union of aldehyde 12 with sulfone 13.
The synthesis of PTX2 2 requires establishment of the (7R)
configuration of the spirocentre. However, the (7S)-configuration
as present in PTX4 3 and PTX7 5 is stabilized by the anomeric
Scheme 2 Reagents and conditions and yields: (i) 14, TiCl4 (1 M in CH2Cl2), (−)-sparteine, CH2Cl2, 0 ◦C then NMP, 16, CH2Cl2, −78 ◦C to 0 ◦C, 17,
90%; or 15, TiCl4 (1 M in CH2Cl2), (−)-sparteine, CH2Cl2, 0 ◦C then NMP, 16, CH2Cl2, −78 ◦C to 0 ◦C, 18 : 19 : 20 (4.6 : 2 : 1), 76%; (ii) LiBH4, THF,
0
◦C, 5 min, 87%; (iii) TBDPSCl, imidazole, CH2Cl2, 20 h, 77%; (iv) TBDMSOTf, 2,6-lutidine, DMAP, DMF, 20 h, 95%; (v) 10% Pd/C, MeOH, H2,
99%; (vi) PCC, K2CO3, CH2Cl2, 3 h, 99%.
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as a co-reagent proved to be compatible with the reaction and the
amount of (−)-sparteine could be reduced to 1.0 equiv.
It was next decided to use propanoyloxazolidinethione 1521
rather than propanoyloxazolidinone 14 and form the titanium
enolate in the presence of (−)-sparteine as the base. Attempts
to perform the aldol reaction following the Crimmins’ protocol
using neat TiCl4 and oxazolidinethione 15 were not successful.
Using a 1 M solution of TiCl4 in dichloromethane to form the
enolate improved the yield of the reaction (76% yield) however, the
diastereoselectivity observed was disappointing giving a 4.6 : 2 : 1
mixture of Evans syn isomer 18 : non-Evans syn isomer 19 : anti
isomer 20. The absolute stereochemistry of the Evans syn adduct
18 compared to the non-Evans syn adduct 19 was determined
by cleaving the chiral auxiliary with lithium borohydride and
comparing the optical rotation of the resulting diols with the diol
21 derived from syn-adduct 17 that was prepared using a boron
enolate as discussed above. The diol derived from compound 18
has the same optical rotation as the diol derived from compound
17 and was therefore assigned as the Evans syn adduct. On the
other hand, the diol derived from compound 19 had the opposite
optical rotation and was assigned as the non-Evans syn adduct.
The reasons for the low selectivity using the Crimmins’ pro-
cedure using propanoyloxazolidinethione 15 were not clear but
the different substituents on the oxazolidinethione employed may
play a role in the selectivity. In the Crimmins’ experiments, an
oxazolidinethione possessing a benzyl group at C4 was used19,20
while in our case oxazolidinethione 15 only contains a methyl
group at C4 and a phenyl group at C5.
The next attempt to generate the syn configuration involved the
use of oxazolidinone 14 that had been prepared earlier for the aldol
reactions using boron enolates. This study also probed whether
the nature of the substituents attached to the chiral auxiliary was
responsible for the low selectivity in the reaction of the titanium
enolate of oxazolidinethione 15 with aldehyde 16. Enolisation of 14
with 1.0 equiv. of 1 M TiCl4 in CH2Cl2 in the presence of 1.0 equiv.
of (−)-sparteine was carried out at 0 ◦C. The mixture was cooled
to −78 ◦C, NMP was then added followed by the addition of
1.1 equiv. of aldehyde 16. Pleasingly, this reaction afforded the
desired Evans syn adduct 17 in 90% yield with the anti isomer
only being observed in small quantities (<1% yield). This reaction
was reproducible giving consistent and satisfactory results and was
adopted as the method of choice for use in the subsequent steps
towards the ABC ring of PTX7 5.
Fig. 2 Chelation and non-chelation transition states.
protecting group at the resulting terminal hydroxyl group. The
chiral auxiliary in 17 was first removed using lithium borohydride
to give diol 21. The primary alcohol in diol 21 was then selectively
protected as a TBDPS ether 22 and the secondary alcohol was
also protected to give TBDMS ether 23 (Scheme 2). These steps
proceeded smoothly giving an overall yield of 64% over three steps
from the syn adduct 17. The benzyl group was next removed by
hydrogenolysis using palladium on carbon as catalyst to give a
quantitative yield of alcohol 24. Oxidation of 24 using pyridinium
chlorochromate in the presence of potassium carbonate afforded
the desired aldehyde 12 in 99% yield.
Sulfone 13 was prepared starting from (R)-(+)-benzylglycidol
25 (Scheme 3). Treatment of methyl phenyl sulfone with BuLi
in a mixture of THF and hexamethylphosphoramide (HMPA)
followed by addition of glycidol 25 effected regioselective ring
opening of the epoxide. The resulting alkoxide was then trapped
directly with a premixed solution of tert-butyldimethylsilyl tri-
fluoromethanesulfonate and 2,6-lutidine in THF affording the
required sulfone 13 in 97% yield. It was also crucial to use two
molar equivalents of HMPA in this reaction in order to obtain a
high yield.23
With sulfone 13 efficiently in hand, the next step was to effect its
union with aldehyde 12. The union of aldehyde 12 with sulfone 13
in THF using BuLi as base proceeded smoothly giving a mixture
of the four diastereomeric alcohols 26 (Scheme 3). Oxidation of
the resulting alcohols 26 to the two diastereomeric ketones 27
was next effected using Dess–Martin reagent24 in dichloromethane
with pyridine as base proceeding in 82% yield over 2 steps. Excess
unreacted sulfone13 could be recovered from the coupling reaction
and reused in the synthesis. The mixture of sulfone diastereomers
27 was then exposed to sodium mercury amalgam in methanol to
give ketone 28 as a single isomer in 68% yield.
Selective deprotection of the TBDMS groups in the presence of
the benzyl and TBDPS groups was achieved by heating ketone 28
at reflux with p-toluenesulfonic acid in toluene for several hours.
This method resulted in clean cyclisation of the resulting diol to
give the 5,6-spiroacetal 29 as a single isomer in 84% yield. The
next step after formation of spiroacetal 29 required removal of
The fact that oxazolidinethione 15 was less selective for for-
mation of the expected Evans syn adduct 18 than the analogous
formation of Evans syn adduct 17 from oxazolidinone 14 might
be attributed to the known higher affinity of sulfur for titanium
than oxygen22 resulting in a competitive pathway proceeding via
a chelation transition state TS I rather than a non-chelation
transition state TS II (Fig. 2). In the case of oxazolidinone
14, where the oxygen of the oxazolidinone carbonyl group has
less affinity to bind to titanium, reaction proceeds via the non-
chelation transition state TS II affording the Evans syn adduct 17
especially in the presence of (−)-sparteine which coordinates to the
titanium and prevents further coordination of the oxazolidinone
carbonyl group.
Having finally fully ascertained the conditions required to
execute the aldol reaction with the desired syn stereochemistry,
the next step was to remove the chiral auxiliary and install a
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Scheme 3 Reagents and conditions and yields: (i) MeSO2Ph, BuLi, HMPA, 25, THF, then premixed solution of TBDMSOTf and 2,6-lutidine, THF,
97%; (ii) BuLi, THF, then 12, −78 ◦C, 88%; (iii) Dess–Martin periodinane, py, CH2Cl2, 93%; (iv) 10% Na/Hg, Na2HPO4, MeOH, 68%; (v) p-TsOH,
toluene, 80 ◦C, 4 h, 84%; (vi) Raney Ni, EtOH, 35 ◦C, 2 d, 30, 82%; or 10% Pd/C, EtOAc, 4.5 h, 30 : 31 (3 : 1), 100%; (vii) Dess–Martin periodinane, py,
CH2Cl2, 95%.
the terminal benzyl group to the primary alcohol 30. Initially, the
deprotection step was carried out using 10% palladium on carbon
under a hydrogen atmosphere in ethyl acetate. Unfortunately these
conditions also effected ring opening of the spiroacetal resulting
in formation of a 3 : 1 mixture of the desired 5,6-spiroacetal 30
and the more thermodynamically favoured 6,6-spiroacetal system
31. Changing the nature of the palladium catalyst to palladium
hydroxide also afforded substantial quantities of the undesired
6,6-spiroacetal 31 and use of lithium aluminium hydride afforded
a low yield of 5,6-spiroacetal 30 together with several other by-
products. Finally, use of Raney nickel in ethanol at 35 ◦C for 48 h
gave exclusively the desired 5,6-spiroacetal 30 in 82% yield and no
6,6-spiroacetal 31 was detected.
from the corresponding methine carbon in 5,6-spiroacetal systems
(cf. 78–85 ppm).25,26 Further support for structure 31 comes from
the coupling pattern observed for H-2ax (dd, Jgem 10.3, J2ax,3ax
10.3 Hz), consistent with the presence of an axial proton at C-
3 with the hydroxyl group at C-3 being assigned to an equatorial
position. The absolute configuration of the spiroacetal centre was
determined from NOE studies. As depicted in Fig. 3, the isomer
with the (6R)-configuration at the spirocentre shows a correlation
between H-2ax and the methyl group at C-1ꢀ. A similar NOE effect
was not expected in the spiroacetal with the (6S)-configuration.
An additional correlation was expected between H-2ax and H-
1
8ax. However, the resonance for H-8 in the H NMR spectrum
overlapped with other signals, namely H-3 and H-2ꢀB. However,
given the correlation observed between H-2 and the methyl group,
spiroacetal 31 was assigned the (6R)-configuration. The (6R)-
isomer was also expected to be the major product due to operation
of the anomeric effect. Similar observations were also reported for
PTX8 and PTX9 that also contain a 6,6-spiroacetal ring system.4
The structure of the 5,6-spiroacetal ring system in 30 was
established from the resonance assigned to the spirocarbon at dC
106.4 ppm in the 13C NMR spectrum similar to the spirocarbon
observed at dC 106.2 ppm in PTX7 5.4 The methine proton H-2 in
5,6-spiroacetal 30 was observed at dC 77.6 ppm. A summary of the
characteristic 13C NMR resonances is given in Table 1.
The formation of 6,6-spiroacetal 31 was confirmed by the 13C
NMR spectrum that exhibited a spiroacetal carbon at dC 94.6 ppm,
similar to the 6,6-spiroacetal carbon observed in the natural
products PTX8 or PTX94 (Fig. 3). The methine carbon assigned
to C-3 in 31 was observed at dC 69.6 ppm, considerably upfield
Once the debenzylation step had been successfully achieved,
oxidation of the alcohol to the corresponding aldehyde 9 was
required in preparation for the Wittig olefination step (see
retrosynthesis, Scheme 1). The oxidation step was effected us-
ing Dess–Martin reagent24 in pyridine affording aldehyde 9 in
Fig. 3 NOE correlations for spiroacetal 31.
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Table 1 Characteristic 13C NMR resonances for spiroacetals 31 and 30 compared to PTX9 and PTX7, respectively
31
PTX9 (R)-6,6-spiroacetal
30
PTX7 (R)-5,6-spiroacetal
spirocarbon centre (dC)
CHO of B ring (dC)
94.6 ppm
C3 = 69.6 ppm
96.6 ppm
C3 = 67.4 ppm
106.4 ppm
C2 = 77.6 ppm
106.2 ppm
C2 = 79.7 ppm
quantitative yield (Scheme 3). The aldehyde thus obtained was not
stable upon prolonged storage and was therefore freshly prepared
immediately before use in the subsequent step. NOE correlations
were observed for spiroacetal 9 (Fig. 4) between H-2 and H-7 and
also between H-2 and the methyl group, thus suggesting that O1
and O6 are axial to each other and that C4 adopts an equatorial
position on the A ring. These observations established the (5S)-
configuration of the 5,6-spiroacetal ring system as was expected
due to anomeric stabilization dominating the thermodynamically
controlled cyclization process. This conclusion was also consistent
with the NOE studies carried out for PTX7 5 that also contains
a 5,6-spiroacetal core system with the (S)-configuration at the
spirocentre.4 Furthermore these NOE studies also established
that no epimerisation had occurred during the debenzylation and
oxidation steps.
Assembly of the ABC tricyclic ring system began with Wittig
olefination of spiroacetal aldehyde 9 with ylide 10 (Scheme 4) af-
fording olefin 32 (E : Z = 100 : 1 by 1H NMR) in quantitative yield.
Reduction of ester 32 to alcohol 33 was then achieved in 91% yield
◦
using di-iso-butylaluminium hydride in CH2Cl2 at −78 C. With
our sights set on epoxydiol 7 as the immediate precursor to the
desired tricyclic fragment 6 (see retrosynthesis, Scheme 1) it was
decided to install the epoxide functionality at this stage by taking
advantage of the allylic alcohol which can be used to effect a
Sharpless asymmetric epoxidation. Treatment of allylic alcohol
33 with Ti(O-iPr)4, (+)-diethyl L-tartrate, tert-butylhydroperoxide
afforded epoxy alcohol 34 in 71% yield with the required (S,S)-
stereochemistry in accordance with the Sharpless mnemonic. The
1H NMR spectra established the diastereomeric ratio to be >100 :
1. Conversion of the primary alcohol 34 to an iodide 35 was
successfully carried out in 83% yield via formation of the mesylate.
Iodide 35 was isolated as a yellow oil and was able to be stored in
the freezer for a few days before subsequent use.
With iodide 35 in hand, the next step was to install the
remaining three carbons required for subsequent assembly of
the tetrahydrofuran ring. Attempts to displace iodide 35 with
the lithium acetylide generated from acetylene 1127 in THF only
afforded recovered starting material. Use of hexamethylphospho-
ramide (HMPA) as an additive to improve the reactivity of the
acetylide28 only led to the formation of allylic alcohol 37 (86%
yield) presumably resulting from lithium–halogen exchange of
Fig. 4 NOE correlations for spiroacetal 9.
Scheme 4 Reagents and conditions and yields: (i) CH2Cl2, 0 ◦C to 20 ◦C, 20 h, 99%; (ii) 1 M DIBAL-H, CH2Cl2, −78 ◦C, 91%; (iii) Ti(OiPr)4 (10 mol%),
L-(+)-DET (12 mol%), BuOOH, 4 A MS, CH2Cl2, 71%; (iv) MsCl, Et3N, DMAP, THF, 0 ◦C, 1 h, then NaI, NaHCO3, acetone, 50 ◦C, 24 h, 83%;
t
˚
(v) acetylene 11, BuLi, THF, −78 ◦C, then HMPA, 35, THF, −78 ◦C to 20 ◦C, 86%.
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the epoxy iodide 35 followed by rapid elimination of the b-epoxy
bond. None of the desired displacement product 36 was observed.
Formation of the acetylenic Grignard reagent of 11 followed by
reaction with iodide 35 in the presence of copper iodide (0.1 equiv.)
and HMPA in THF also only afforded allylic alcohol 37.
dioxirane (DMDO) hoping that the neighbouring C–O bond
on the adjacent chiral centre may influence the stereochemical
outcome of epoxidation. Epoxidation of (E)-enyne 8 using m-
CPBA in CH2Cl2 afforded a 1.2 : 1 mixture of the syn-epoxide
36 and anti-epoxide 42 in 76% yield. Epoxidation of (E)-enyne 8
using freshly prepared DMDO33,34,35 in acetone for 36 h afforded
a 1.8 : 1 mixture of the syn-epoxide 36 and anti-epoxide 42 in 78%
yield.
At the time this work was being carried out, Millar and
Underhill29 reported that the addition of 1-iodo-cis-2,3-epoxides
to alkynyl-lithium or alkynyl-Grignard reagents in THF–HMPA,
with or without CuI catalysis, afforded the allylic alcohol products
in preference to the displacement product. This study con-
firmed that reductive elimination as a result of metal halogen
exchange was a common issue faced when attempting to dis-
place halides in a halo epoxide, by an acetylide. An alternative
method involving addition of 1-halo or 1-tosyl-cis-2,3-epoxides to
divinylcuprates30,31 in either THF, ether, or a THF–ether mixture
with varying proportions of HMPA and/or triethyl phosphite,
also afforded the elimination product rather than the desired
displacement product. In order to overcome this problem, Millar
and Underhill used methodology initially reported by Nicolaou
et al.32 whereby inverse addition of a substituted vinylmagnesium
bromide to preformed solutions of 1-iodo-2,3-epoxides with a
catalytic amount of copper iodide in THF–HMPA afforded good
yields of the nucleophilic substitution products.29 In our case,
however, attempts to displace iodide 35 with either (E)- or (Z)-
vinylmagnesium bromide 38 were unsuccessful.
Disappointed by the lack of selectivity in the epoxidation of
(E)-enyne 8 using achiral epoxidation agents, it was decided to use
a chiral dioxirane generated in situ from potassium peroxomono-
R
sulfate (Oxoneꢀ) and a chiral fructose-derived ketone, a method
reported by Shi et al.36 to effect epoxidation of unfunctionalised
(E)-olefins in a highly enantioselective fashion. Based on the
predictive model, invoking the spiro transition state model36 it was
envisaged that use of ketone 41, derived from L-fructose, would
generate the desired syn-epoxide 36 whilst use of the enantiomeric
D-fructose derived ketone would result in predominant formation
of the undesired anti-epoxide 42.
The chiral ketone ent-41, derived from naturally occurring
D-fructose, was commercially available whereas the ketone 41,
derived from L-fructose, was not commercially available and was
prepared from L-sorbose.37 Reaction of (E)-enyne 8 with the more
readily available chiral dioxirane prepared in situ from D-fructose
R
der◦ived ketone ent-41 (3 equiv.) and oxoneꢀ (3 equiv.) at −10 to
In light of the fact that nucleophilic substitution of AB
spiroacetal epoxy iodide 35 by the derived-from acetylene 11 was
not successful, it was decided to pursue an alternative strategy
involving epoxidation at a later stage. It was postulated that the
remaining carbon chain of the C1–C16 fragment 8 could be
installed via nucleophilic substitution of allylic iodide 39 rather
than epoxy iodide 35 (Scheme 5).
20 C in acetonitrile and dimethoxymethane (DMM) (1 : 2 v/v)
for 2 h afforded an inseparable 1 : 8 mixture of the syn-epoxide
36 : anti-epoxide 42 in 52% yield (see Table in Scheme 5). In this
case the major epoxide formed had the opposite configuration to
the major epoxide formed using m-CBPA and DMDO.
Epoxidation of (E)-enyne 8 with the chiral dioxirane formed
from L-fructose derived ketone 41 was then attempted in an effort
to produce more of the desired syn-epoxide 36. Epoxidation of
AB spiroacetal-containing allylic alcohol 33 was converted to
the corresponding iodide 39 via the mesylate. Treatment of the
mesylate with sodium iodide at room temperature for 2 h afforded
iodide 39, which was used in the next step without any purification.
Addition of the iodide 39 in THF to the acetylide formed from
acetylene 11 with BuLi in THF at −78 ◦C followed by warming the
mixture to 0 ◦C afforded the (E)-enyne 8 in 56% yield together with
(Z)-enyne 40 in 18% yield. The formation of two diastereomers of
the coupled product was unexpected given that the starting allylic
alcohol used was a pure single isomer therefore only a single isomer
of the coupled product was expected. The NOESY spectra for the
major (E)-alkene 8 showed a correlation between H-1ꢀ and H-3ꢀ
and no correlation between H-3ꢀ and H-2 (Fig. 5). For the minor
alkene 40, an NOE correlation was observed between H-2 and H-
3ꢀ and no NOE correlation was observed between H-1ꢀ and H-3ꢀ,
thereby establishing the (Z)-stereochemistry of alkene 40.
Having finally fully assembled the C1–C16 carbon chain frag-
ment of PTX7 5, in the form of spiroacetal enyne 8, our attention
next focused on the conversion of the enyne unit to the required
epoxy diol fragment 7 which could be transformed into the target
ABC ring fragment 6 by acid catalysed cyclization (Scheme 5).
The syn-epoxide was envisaged to be formed via asymmetric
epoxidation and the diol by asymmetric dihydroxylation of the
olefin formed upon subsequent semi-hydrogenation of the triple
bond.
R
(E)-enyne 8 using chiral ketone 41 and oxoneꢀ was carried out
using the same conditions as those described above using D-
fructose derived ketone ent-41. However, in this case (see Table
in Scheme 5) conversion to the epoxide proceeded in a lower 37%
yield. Encouragingly the stereoselectivity observed was promising
with a 5.5 : 1 ratio of the desired syn-epoxide 36 to anti-epoxide
42 being observed.
Although the epoxides 36 and 42 obtained were in fact
an inseparable mixture of two isomers, the two isomers were
1
distinguishable by H NMR, with the epoxide resonance, H-1ꢀ,‡
providing a diagnostic tool. H-1ꢀ in syn-epoxide 36 resonated as a
doublet at dH 2.89 ppm with coupling constant, J 8.0 Hz whereas
H-1ꢀ in anti-epoxide 42 resonated as a doublet further downfield
at dH 2.92 ppm with J 7.6 Hz.
The 5.5 : 1 mixture of syn-epoxide 8 : anti-epoxide 41 was
subjected to semi-hydrogenation over Lindlar catalyst affording
a 5.5 : 1 mixture of (Z)-olefin 43: (Z)-olefin 44 in 88% yield
in preparation for the subsequent asymmetric dihydroxylation38
(AD) step. High enantioselectivity in the AD of (Z)-olefins is
usually observed when the size of the two olefinic substituents is
significantly different. In the case of (Z)-olefin 43, we hoped that
high enantioselectivity would be observed given that it contains
two sterically different substituents. High enantioselectivity in
The first attempts to effect epoxidation of alkene 8 were carried
out using achiral epoxidation reagents m-CPBA and dimethyl-
‡ The numbering system based on a 1,7-dioxaspiro[5.5]undecane ring
system is used rather than PTX numbering system.
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Scheme 5 Reagents and conditions and yields: (i) MsCl, Et3N, THF, 0 ◦C, 20 min, then NaI, THF, 20 ◦C, 2 h, filter; (ii) acetylene 11, BuLi, THF,
−78 ◦C, then iodide 39, THF, −78 ◦C to 0 ◦C, 20 h, 8: 56%, 40: 18%; (iii) see Table in Scheme; (iv) H2, Pd/CaCO3 (5% Pb), Et3N, hexane, 50 min, 43,
88%; (v) DHQ-IND, K3Fe(CN)6, MeSO2NH2, OsO4, tBuOH–H2O (1 : 1), 20 h, 6, 38%; or OsO4, acetone–H2O (5 : 1), 18 h, 6, 70%.
Fig. 5 NOE correlations for (E)-8 and (Z)-40.
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the AD of (Z)-olefins can be achieved by using an indoline
type of ligand (DHQ-IND or DHQD-IND)39 and application
of the mnemonic developed for predicting stereoselectivity in
AD reactions predicts that using DHQ-IND, the hydroxyl group
would be predominantly delivered to (Z)-olefin 43 from the a-
face affording diol 7 that would undergo cyclization to the desired
spiroacetal-containing tetrahydrofuran 6.
AD reaction of the 5.5 : 1 mixture of (Z)-olefins 43 : 44 using
DHQ-IND as the chiral ligand afforded the ABC ring fragment
6 in 38% yield together with a complex diastereomeric mixture of
diols (43% yield). The exact stereochemistry of the diol mixture
obtained was not established and the lack of diastereoselectivity
observed in this reaction was disappointing.
The low yield of the desired tricyclic fragment 6 obtained using
DHQ-IND as the chiral ligand prompted us to investigate the
use of OsO4 without the asymmetric catalyst to see whether the
neighbouring chiral centres in the olefin substrate might influence
the stereoselectivity in the dihydroxylation step. Somewhat sur-
prisingly treatment of the 5.5 : 1 mixture of (Z)-olefins 43 : 44
with OsO4 afforded the desired tricyclic fragment 6 as the major
product in 70% yield together with a mixture of diols (<10% yield).
Thus, the neighbouring chiral centres in this system clearly play
a role in the hydroxylation which may contribute to the lower
diastereoselectivity being observed in the above reaction using
DHQ-IND as the chiral ligand.
The NOESY spectrum for tricyclic fragment 6 showed a
clear correlation between C2ꢀꢀ-Me and H-5ꢀꢀ thus establishing
the desired syn relationship between these two groups on the
tetrahydrofuran C ring system. The 13C NMR data for the ABC
tricyclic fragment 6 was compared to the 13C NMR data reported
for the ABC fragment of PTX7 5 since both of these compounds
contain a spiroacetal ring system with the (S)-configuration at
the spiroacetal centre (cf. PTX2 2 has the (R)-configuration at
the spirocentre). The 13C NMR data obtained for both tricyclic
fragments were in fact similar rendering support for the successful
synthesis of the ABC tricyclic fragment 6 of PTX7 5 (Fig. 6).
Synthetic efforts towards the synthesis of the E and FG fragments
of the pectenotoxins are now underway in preparation for union
with the ABC fragment 6 reported herein.
was stirred for 2.5 h at −78 ◦C. The reaction was quenched with
saturated NH4Cl solution (1 mL), warmed to room temperature
and extracted with Et2O (3 × 5 mL). The combined organic phase
was washed with brine (2 × 3 mL) and dried over MgSO4. The
solvent was removed under reduced pressure to give the crude
mixture that was purified by flash chromatography using hexane–
ethyl acetate (9 : 1) as eluent to afford alcohols 26 as a mixture of
four diastereomers (0.185 g, 88%) as a pale yellow oil.
The mixture of alcohols 26 (0.176 g, 0.19 mmol), Dess–
Martin periodinane24 (0.15 g, 0.37 mmol) and pyridine (0.06 mL,
0.74 mmol) in dry CH2Cl2 (3 mL) was stirred at room temperature
for 5 h. Saturated NH4Cl solution (2 mL) was added and the
organic layer was separated. The aqueous layer was extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were washed
with brine (2 × 10 mL) and dried over MgSO4. The solvent was
removed under reduced pressure and the residue purified by flash
chromatography using hexane–ethyl acetate (95 : 5) as eluent to
afford sulfones 27 (0.163 g, 93%) as a mixture of diastereomers.
To a stirred solution of sulfones 27 (0.13 g, 0.14 mmol) and
anhydrous Na2HPO4 (0.078 g, 0.55 mmol) in MeOH (2 mL)
was added 10% Na/Hg amalgam (0.1 g) at room temperature.
The reaction mixture was vigorously stirred for 1 h then poured
into saturated NH4Cl solution (4 mL). Residual amalgam was
removed by decantation and the mixture extracted with Et2O (3 ×
10 mL). The combined organic layers were washed with brine
(2 × 15 mL) and dried over NaSO4. The solvent was removed
under reduced pressure. The crude mixture was purified by flash
chromatography using hexane–ethyl acetate (95 : 5) as eluent to
afford the title compound 28 (75 mg, 68%) as a pale yellow oil;
[a]D −2.5◦ (c = 1.4, CHCl3); found: MH+, 805.5079, C47H77O5Si3
−1
=
requires 805.5079; mmax (cm ) 1604s (C O), 1495s, 1460m, 1250w
t
(Si–O–C); dH (300 MHz, CDCl3) −0.001 (3H, s, Me2 BuSi), 0.02
t
t
(3H, s, Me2 BuSi), 0.05 (6H, s, Me2 BuSi), 0.83 (3H, d, J 7.5 Hz,
t
t
Me), 0.85 (9H, s, Me2 BuSi), 0.89 (9H, s, Me2 BuSi), 1.07 (9H, s,
tBuPh2Si), 1.20–1.98 (7H, m, H-3, H-7, H-8, H-10), 2.37 (2H, t,
J 7.0 Hz, H-6), 2.46 (2H, m, H-4), 3.34–3.41 (2H, m, H-1), 3.48
(1H, dd, J 6.6, 9.8 Hz, H-11A), 3.62 (1H, dd, J 6.6, 9.8 Hz, H-1B),
3.79–3.82 (2H, m, H-2 and H-9), 4.52 (2H, s, CH2Ph), 7.26–7.43
(11H, m, Ph), 7.64–7.70 (4H, m, Ph); dC (75 MHz, CDCl3) −4.8
t
t
t
(CH3, Me2 BuSi), −4.6 (CH3, Me2 BuSi), −4.4 (CH3, Me2 BuSi),
t
t
−4.2 (CH3, Me2 BuSi), 10.7 (CH3, Me), 18.0 (C, Me2 BuSi), 18.1
(C, Me2 BuSi), 19.2 (C, Ph2 BuSi), 20.1 (CH, C-7), 25.7 (CH3,
t
t
Experimental
t
t
t
Me2 BuSi), 25.8 (CH3, Me2 BuSi), 26.9 (CH3, Ph2 BuSi), 28.4 (CH2,
C-3), 34.1 (CH2, C-8), 38.1 (CH2, C-4), 39.9 (CH, C-10), 42.8 (CH2,
C-6), 66.1 (CH2, C-1), 70.4 (CH, C-2), 71.9 (CH, C-9), 73.3 (CH2,
CH2Ph), 74.4 (CH2, C-11), 127.55 (CH, Ph), 127.57 (CH, Ph),
127.6 (CH, Ph), 128.3 (CH, Ph), 128.47 (CH, Ph), 128.5 (CH, Ph),
133.9 (C, Ph), 134.0 (C, Ph), 135.6 (CH, Ph), 138.3 (C, Ph), 210.5
(C, C-5); m/z (FAB) 806 (MH+, 0.24%), 748 (M–tBu, 0.48%), 269
(5%), 135 (CH2CH2OBn, 34%), 91 (CH2Ph, 100%), 73 (76%).
(2S, 9S, 10S)-(−)-1-Benzyloxy-2,9-bis-(tert-
butyldimethylsilyloxy)-11-(tert-butyldiphenylsilyloxy)-10-
methylundecane-5-one (28)
To a solution of sulfone 13 (0.1 g, 0.23 mmol) in dry THF (1 mL)
at −78 ◦C was added a solution of BuLi (0.15 mL, 1.6 M solution
in hexane, 0.24 mmol). After 30 min, a solution of aldehyde 12
(0.11 g, 0.21 mmol) in dry THF 1.5 mL) was added and the mixture
Fig. 6 Comparison of 13C NMR data for 6 and the ABC fragment of PTX7 5.
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(2S, 5S, 7S, 1ꢀꢀS)-(+)-2-(1ꢀ-Benzyloxymethyl)-7-{2ꢀꢀ-(tert-butyl-
diphenylsilyloxy)-1ꢀꢀ-methylethyl}-1,6-dioxaspiro[4.5]decane (29)
filtration the solvent was evaporated and the residue purified
by flash chromatography using ethyl acetate–hexane (4 : 1) as
eluent to afford 5,6-spiroacetal 30 (80 mg, 75%) for which the
spectroscopic data was in agreement with that reported above and
6,6-spiroacetal 31 (26 mg, 25%) as a colourless oil; [a]D +25.5◦
(c = 0.59, CHCl3); found: MH+, 469.2778, C28H42O4Si requires
469.2774; mmax (cm−1) 3413br (OH), 1427m, 1216s (Si–O–C); dH
(300 MHz, CDCl3) 0.99 (3H, d, J 6.8 Hz, 1ꢀ-Me), 1.04 (9H, s,
tBuPh2Si), 1.15–1.82 (12H, m, H-4, H-5, H-9, H-10, H-11, H-
1ꢀ, OH), 3.35 (1H, dd, J 10.3, 10.3 Hz, H-2A), 3.50–3.58 (2H,
m, H-2B and H-2ꢀA), 3.64–3.72 (3H, m, H-3, H-8, H-2ꢀB), 7.24–
7.42 (6H, m, Ph), 7.62–7.68 (4H, m, Ph); dC (75 MHz, CDCl3)
12.5 (CH3, Me), 19.1 (CH2, C-10), 19.3 (C, tBuPh2Si), 26.9 (CH3,
tBuPh2Si), 28.1 (CH2, C-9), 28.4 (CH2, C-4), 34.3 (CH2, C-5 or C-
11), 35.0 (CH2, C-11 or C-5), 40.9 (CH, C-1ꢀ), 64.7 (CH2, C-2), 65.9
(CH2, C-2ꢀ), 66.5 (CH, C-8), 69.6 (CH, C-3), 94.6 (C, C-6), 127.58
(CH, Ph), 127.60 (CH, Ph), 129.5 (CH, Ph), 133.9 (C, Ph), 135.6
(CH, Ph); m/z (CI) 486 (MH+ + NH3, 8%), 469 (MH+, 100%),
411 (M–tBu, 33%), 391 (M–Ph, 56%), 313 (51%), 195 (64%),
127 (57%).
A mixture of ketone 28 (0.91 g, 1.13 mmol) and p-toluenesulfonic
acid monohydrate (0.43 g, 2.26 mmol) in toluene (10 mL) was
heated under reflux for 4 h. The brown solution was cooled to room
temperature, diluted with Et2O (20 mL) and washed with brine
(3 × 20 mL). The organic phase was dried over MgSO4 and the
solvent was evaporated under reduced pressure. The crude mixture
was purified by flash chromatography using hexane–ethyl acetate
(95 : 5) as eluent to afford◦the title compound 29 (0.53 g, 84%) as a
pale yellow oil; [a]D +21.5 (c = 0.9, CHCl3) [lit.10 [a]D +13.9◦ (c =
•
0.9, CHCl3)]; found: M+ , 558.3160; C35H46O4Si requires 558.3165;
mmax (cm−1) 1427w, 1265s (Si–O–C); dH (300 MHz, CDCl3) 0.94
(3H, d, J 6.8 Hz, Me), 1.04 (9H, s, tBuPh2Si), 1.28 (1H, m, H-8A),
1.45–1.69 (7H, m, H-3A, H-4A, H-8B, H-9A, H-10, H-1ꢀꢀ), 1.82
(2H, m, H-4B and H-9B), 2.04 (1H, m, H-3A), 3.48 (3H, m, H-1ꢀ
and H-2ꢀꢀA), 3.66 (1H, dd, J 5.5, 9.9 Hz, H-2ꢀꢀB), 3.76 (1H, m,
H-7), 4.18 (1H, m, H-2), 4.56 (2H, s, CH2Ph), 7.25–7.43 (11H, m,
Ph), 7.64–7.68 (4H, m, Ph); dC (75 MHz, CDCl3) 12.6 (CH3, Me),
t
19.3 (C, BuPh2Si), 20.5 (CH2, C-9), 26.4 (CH2, C-3), 26.9 (CH3,
tBuPh2Si), 28.1 (CH2, C-8), 32.9 (CH2, C-10), 37.3 (CH2, C-4),
40.8 (CH, C-1ꢀꢀ), 66.1 (CH2, C-2ꢀꢀ), 71.1 (CH, C-7), 72.6 (CH2,
C-1ꢀ), 73.2 (CH2, CH2Ph), 106.3 (C, C-5), 127.4 (CH, Ph), 127.5
(CH, Ph), 127.6 (CH, Ph), 128.3 (CH, Ph), 129.5 (CH, Ph), 134.1
(C, Ph), 135.6 (CH, Ph), 138.6 (C, Ph); m/z 558 (M+, 0.1%), 501
(M–tBu, 501), 437 (M–OBn, 9%), 91 (CH2Ph, 100%).
(2S, 5S, 7S, 1ꢀꢀS)-(+)-7-{2ꢀꢀ-(tert-Butyldiphenylsilyloxy)-1ꢀꢀ-
methylethyl}-2-formyl-1,6-dioxaspiro[4.5]decane (9)
A mixture of alcohol 30 (68 mg, 0.14 mmol), dry pyridine (0.18 mL,
2.18 mmol) and Dess–Martin periodinane24 (120 mg, 0.29 mmol)
was stirred in dry CH2Cl2 (4 mL) at room temperature for 3 h.
Saturated NH4Cl solution (2 mL) was added and the mixture
was extracted with Et2O (3 × 10 mL). The organic layer was
washed with brine (3 × 10 mL) and dried over MgSO4. The
solvent was evaporated under reduced pressure and the crude
mixture was purified by flash chromatography using ethyl acetate–
hexane (4 : 1) as eluent to afford t◦he title compound 9 (64 mg,
95%) as a pale yellow oil; [a]D +8.8 (c = 0.66, CHCl3) [lit.10 [a]D
(2S, 5S, 7S, 1ꢀꢀS)-(+)-7-{2ꢀꢀ-(tert-Butyldiphenylsilyloxy)-1ꢀꢀ-
methylethyl}-2-hydroxymethyl-1,6-dioxaspiro[4.5]decane (30)
To a slurry of Raney nickel (washed twice with absolute EtOH)
in absolute EtOH (2 mL) was added a solution of benzyl ether 29
(130 mg, 0.23 mmol) in absolute EtOH (2 mL) and the mixture
was stirred vigorously at 35 ◦C for 2 d. The mixture was then
filtered under nitrogen and the solvent evaporated under reduced
pressure. The residue was purified by flash chromatography using
ethyl acetate–hexane (4 : 1) as eluent to afford the title compound
30 (89 mg, 82%) as a colourless oil; [a]D +31.0◦ (c = 0.75, CHCl3);
found: MH+, 469.2768, C28H41O4Si requires 469.2774; mmax (cm−1)
3434br (OH), 1463m, 1428m,1215s (Si–O–C); dH (300 MHz,
+10.0◦ (c = 0.16, CHCl3)]; found: MH+, 467.2618, C28H39O4Si
−1
=
requires 467.2618; mmax (cm ) 1735s (C O), 1463m,1255s (Si–
O–C); dH (300 MHz, CDCl3) 0.91 (3H, d, J 6.8 Hz, 1ꢀꢀ-Me),
1.05 (9H, s, BuPh2Si), 1.28 (1H, m, H-8A), 1.45–1.79 (6H, m,
t
H-4A, H-8B, H-9A, H-10, H-1ꢀꢀ), 1.80–1.98 (3H, m, H-3A, H-
4B, H-9B), 2.25 (1H, m, H-3B), 3.50 (1H, dd, J 6.1, 9.9 Hz,
H-2ꢀꢀA), 3.63 (1H, dd, J 6.1, 9.9 Hz, H-2ꢀꢀB), 3.87 (1H, m, H-
7), 4.29 (1H, m, H-2), 7.39 (6H, m, Ph), 7.65 (4H, m, Ph), 9.67
(1H, d, J 1.2 Hz, H-1ꢀ); dC (75 MHz, CDCl3) 12.1 (CH3, Me),
t
CDCl3) 0.93 (3H, d, J 6.8 Hz, 1ꢀꢀ-Me), 1.05 (9H, s, BuPh2Si),
1.26 (1H, m, H-8A), 1.53–2.10 (10H, m, H-3, H-4, H-8B, H-9, H-
10, H-1ꢀꢀ), 3.50 (2H, m, H-1ꢀA and H-2ꢀꢀA), 3.65 (2H, m, H-1ꢀB and
H-2ꢀꢀB), 3.79 (1H, m, H-7), 4.09 (1H, m, H-2), 7.39 (6H, m, Ph),
7.65 (4H, m, Ph); dC (75 MHz, CDCl3) 12.4 (CH3, Me), 19.3 (C,
tBuPh2Si), 20.6 (CH2, C-9), 25.3 (CH2, C-3), 26.9 (CH3, tBuPh2Si),
28.0 (CH2, C-8), 32.8 (CH2, C-10), 37.9 (CH2, C-4), 40.7 (CH, C-
1ꢀꢀ), 65.0 (CH2, C-1ꢀ), 66.0 (CH2, C-2ꢀꢀ), 70.9 (CH, C-7), 77.6 (CH,
C-2), 106.4 (C, C-5), 127.5 (CH, Ph), 129.5 (CH, Ph), 134.1 (C,
Ph), 135.59 (CH, Ph), 135.6 (CH, Ph); m/z (CI) 486 (MH + NH3,
12%), 469 (MH+, 100%), 391 (M–Ph, 53%), 313 (54%), 195 (44%),
127 (41%).
t
19.2 (C, BuPh2Si), 20.4 (CH2, C-9), 25.8 (CH2, C-3), 26.8 (CH3,
tBuPh2Si), 27.8 (CH2, C-8), 32.4 (CH2, C-10), 37.0 (CH2, C-4),
40.5 (CH, C-1ꢀꢀ), 65.8 (CH2, C-2ꢀꢀ), 71.1 (CH, C-7), 81.6 (CH, C-
2), 107.4 (C, C-5), 127.5 (CH, Ph), 129.5 (CH, Ph), 133.9 (C, Ph),
135.52 (CH, Ph), 135.53 (CH, Ph), 202.5 (CH, C-1ꢀ); m/z 437 (M–
CHO, 13%), 409 (M–CHO–CO, 46%), 253 (41%), 199 (100%),
125 (65%).
(3S, 6R, 8S, 1ꢀS)-(+)-8-{(2ꢀ-tert-Butyldiphenylsilyloxy)-1ꢀ-
methylethyl}-3-hydroxy-1,7-dioxaspiro[5.5]undecane (31)
(1ꢀE, 2S, 5R, 7S, 1ꢀꢀS)-(+)-7ꢀ-{2ꢀꢀ-(tert-Butyldiphenylsilyloxy)-1ꢀꢀ-
methylethyl}-2-(2ꢀ-ethoxycarbonyl-2ꢀ-methyl-1ꢀ-propenyl)-1,6-
dioxaspiro[4.5]decane (32)
A solution of benzyl ether 29 (130 mg, 0.23 mmol) in ethyl acetate
was stirred with 10% palladium on charcoal (10 mg) under a
balloon of hydrogen for 4.5 h. After removal of the catalyst by
To a solution of aldehyde 9 (115 mg, 0.25 mmol) in dry CH2Cl2
(3 mL) at 0 ◦C was added ylide 10 (270 mg, 0.74 mmol).
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(2S, 5S, 7S, 1ꢀS, 2ꢀS, 1ꢀꢀS)-(+)-7-{2ꢀꢀ-(tert-Butyldiphenylsilyloxy)-
1ꢀꢀ-methylethyl}-2-(1ꢀ,2ꢀ-epoxy-3ꢀ-hydroxy-2ꢀ-methylprop-1ꢀ-yl)-
1,6-dioxaspiro[4.5]decane (34)
The yellow solution was stirred at room temperature overnight.
Et2O (10 mL) was added and the solution was washed with brine
(2 × 7 mL) and dried over MgSO4. The solvent was evaporated
under reduced pressure and the crude mixture was purified by
flash chromatography using ethyl acetate–hexane (1 : 9) as eluent
to afford the title compound 32 (130 mg, 99%) as a pale yellow
oil; [a]D +13.7◦ (c = 1.22, CHCl3) [lit.10 [a]D +11.9◦ (c = 0.16,
˚
To a suspension of activated 4 A molecular sieves (ca. 50 mg) in
dry CH2Cl2 (0.5 mL) at −20 ◦C was added (+)-diethyl L-tartrate
(0.8 lL, 4.7 lmol) followed by titanium(IV) tetraisopropoxide
(1 lL, 3.9 lmol). After 5 min, anhydrous tert-butylhydroperoxide
(16 lL, 0.08 mmol) was added dropwise maintaining the tem-
perature of the mixture at −20 ◦C. The resulting complex was
stirred at −20 ◦C for 30 min then a solution of allylic alcohol 33
(20 mg, 0.04 mmol) in dry CH2Cl2 (0.5 mL) was slowly adde◦d. The
•
CHCl3)]; found: M+ , 550.3117, C33H46O5Si requires 550.3115; mmax
−1
=
(cm ) 1713s (C O), 1428m, 1247s (Si–O–C), 1111s; dH (300 MHz,
CDCl3) 0.98 (3H, d, J 6.8 Hz, 1ꢀꢀ-Me), 1.04 (9H, s, BuPh2Si),
t
1.29 (4H, m, OCH2CH3 and H-8A), 1.40–1.95 (12H, m, H-3A,
H-4, H-8B, H-9, H-10, H-1ꢀꢀ, 2ꢀ-Me), 2.24 (1H, m, H-3B), 3.52
(1H, dd, J 6.5, 9.9 Hz, H-2ꢀꢀA), 3.67 (1H, dd, J 5.3, 9.9 Hz,
H-2ꢀꢀB), 3.76 (1H, ddd, J 1.7, 5.1, 11.5 Hz, H-7), 4.18 (2H, q,
J 7.1 Hz, OCH2CH3), 4.72 (1H, q, J 7.6 Hz, H-2), 6.74 (1H,
dq, J 1.4, 7.6 Hz, H-1ꢀ), 7.37 (6H, m, Ph), 7.65 (4H, m, Ph);
dC (75 MHz, CDCl3) 12.5 (CH3, 1ꢀꢀ-Me), 12.9 (CH3, OCH2CH3),
14.3 (CH3, 2ꢀ-Me), 19.3 (C, tBuPh2Si), 20.5 (CH2, C-9), 26.9 (CH3,
tBuPh2Si), 28.0 (CH2, C-8), 30.4 (CH2, C-3), 33.0 (CH2, C-10),
37.9 (CH2, C-4), 40.8 (CH, C-1ꢀꢀ), 60.6 (CH2, OCH2CH3), 66.2
(CH2, C-2ꢀꢀ), 71.4 (CH, C-7), 73.8 (CH, C-2), 106.5 (C, C-5), 127.6
(CH, Ph), 128.7 (C, C-2ꢀ), 129.5 (CH, Ph), 134.1 (C, Ph), 135.58
(CH, Ph), 135.60 (CH, Ph), 141.9 (CH, C-1ꢀ), 167.9 (C, C-3ꢀ);
◦
mixture was stirred for 4 h at −20 C then warmed to 0 C for
5 min. Water (ca. 0.2 mL) was added and the mixture was stirred
at room temperature for 30 min. 30% NaOH saturated with NaCl
(ca. 1 mL) was added and the mixture was vigorously stirred for
15 min to hydrolyze the tartrate. The mixture was extracted with
CH2Cl2 (3 × 10 mL) and the combined organic extracts were
dried over MgSO4. The solvent was evaporated under reduced
pressure and the excess peroxide removed azeotropically with
toluene. The crude mixture was purified by flash chromatography
using hexane–ethyl acetate (3 : 1) as eluent to give the title
compound 34 (15 mg, 71%) as a pale yellow oil; [a]D +16.5◦ (c =
0.98, CHCl3) [lit. [a]D +13.2◦ (c = 0.42, CHCl3)]; found: MH+,
525.3050, C31H45O5Si requires 525.3036; mmax (cm−1) 3436br (OH),
1427m, 1112s (Si–O–C); dH (300 MHz, CDCl3) 0.97 (3H, d, J
6.8 Hz, 1ꢀꢀ-Me), 1.04 (9H, s, tBuPh2Si), 1.25 (1H, m, H-8A), 1.29
(3H, s, 2ꢀ-Me), 1.48–1.95 (9H, m, H-3A, H-4, H-8B, H-9, H-10,
H-1ꢀꢀ), 2.24 (1H, m, H-3B), 2.98 (1H, d, J 8.0, H-1ꢀ), 3.53 (1H,
dd, J 6.1, 9.9 Hz, H-2ꢀꢀA), 3.62 (2H, m, H-3ꢀA and H-2ꢀꢀB), 3.67
(2H, m, H-3ꢀB and H-7), 3.82 (1H, m, H-2), 7.39 (6H, m, Ph),
7.64 (4H, m, Ph); dC (75 MHz, CDCl3) 12.9 (CH3, 1ꢀꢀ-Me), 14.3
•
m/z 550 (M+ , 100%), 493 (M–tBu, 34%), 415 (14%), 277 (46%),
199 (100%).
(1ꢀE, 2S, 5R, 7S, 1ꢀꢀS)-(+)-7ꢀ-{2ꢀꢀ-(tert-Butyldiphenylsilyloxy)-1ꢀꢀ-
methylethyl}-2-(3ꢀ-hydroxy-1ꢀ-propenyl)-1,6-dioxaspiro[4.5]decane
(33)
To a solution of ester 32 (120 mg, 0.22 mmol) in dry CH2Cl2
(3 mL) at −78 ◦C was added a solution of di-iso-butylaluminium
hydride (0.36 mL, 20% solution in toluene, 0.44 mmol) and the
resulting solution was stirred at −78 ◦C for 45 min. An aqueous
solution of potassium sodium tartrate tetrahydrate (2 mL) was
added and the mixture was warmed to room temperature and
stirred until both phases became clear. The aqueous phase was
extracted with Et2O (3 × 10 mL) and the combined organic
extracts were dried over MgSO4. Removal of the solvent under
reduced pressure followed by flash chromatography using ethyl
acetate–hexane (4 : 1) as eluent afforded the title compound 33
(100 mg, 91%) as a colourless oil;[a]D +29.1 (c = 0.95, CHCl3) [lit.10
t
(CH3, 2ꢀ-Me), 19.3 (C, BuPh2Si), 20.5 (CH2, C-9), 26.9 (CH3,
tBuPh2Si), 28.1 (CH2, C-8), 28.2 (CH2, C-3), 32.8 (CH2, C-10),
37.3 (CH2, C-4), 40.8 (CH, C-1ꢀꢀ), 61.2 (CH, C-1ꢀ), 61.4 (C, C-2ꢀ),
65.2 (CH2, C-3ꢀ), 66.1 (CH2, C-2ꢀꢀ), 71.6 (CH, C-7), 75.0 (CH,
C-2), 106.5 (C, C-5), 127.6 (CH, Ph), 129.5 (CH, Ph), 134.0 (C,
Ph), 135.6 (C, Ph); m/z (CI) 525 (MH+, 4%), 507 (M–OH, 32%),
467 (M–tBu, 100%).
(2S, 5S, 7S, 1ꢀS, 2ꢀS, 1ꢀꢀS)-(+)-7-{2ꢀꢀ-(tert-
•
[a]D +9.0◦ (c = 0.19, CHCl3)]; found: M+ , 508.3003, C31H44O4Si
Butyldiphenylsilyloxy)-1ꢀꢀ-methylethyl}-2-(1ꢀ,2ꢀ-epoxy-3ꢀ-iodo-2ꢀ-
methylprop-1ꢀ-yl)-1,6-dioxaspiro[4.5]decane (35)
requires 508.3009; mmax (cm−1) 3411br (OH), 1427m, 1221m (Si–
O–C), 1112s; dH (300 MHz, CDCl3) 1.01 (3H, d, J 6.8 Hz, 1ꢀꢀ-Me),
t
1.05 (9H, s, BuPh2Si), 1.26 (1H, m, H-8A), 1.50–1.95 (12H, m,
To a solution of alcohol 34 (10 mg, 0.02 mmol) in dry THF
(1 mL) at 0 ◦C was added dry triethylamine (3 lL, 0.02 mmol)
followed by methanesulfonyl chloride (2 lL, 0.02 mmol). After
1 h, the mixture was filtered, NaI (4 mg, 0.03 mmol) and NaHCO3
(6 mg, 0.08 mmol) were added to the filtrate. The resulting yellow
mixture was heated under reflux for 24 h. The mixture was filtered
to remove the precipitate and the filtrate was concentrated under
reduced pressure. The residue was dissolved in Et2O (10 mL),
washed with saturated Na2S2O3 (5 mL) and dried over MgSO4. The
solvent was evaporated under reduced pressure. The crude mixture
was purified by flash chromatography using hexane–ethyl acetate
(9 : 1) as eluent to give the title compound 35 (10 mg, 83%) as a
yellow oil; [a]D +21.3◦ (c = 1.1, CHCl3); found: MH+, 635.2052,
C31H44IO4Si requires 635.2054; mmax (cm−1) 1427m, 1387m, 1265s
H-3A, H-4, H-8B, H-9, H-10, H-1ꢀꢀ, 2ꢀ-Me), 2.10 (1H, m, H-3B),
3.56 (1H, dd, J 6.6, 9.9 Hz, H-2ꢀꢀA), 3.67 (1H, dd, J 5.0, 9.9 Hz,
H-2ꢀꢀB), 3.76 (1H, ddd, J 1.7, 5.1, 11.5 Hz, H-7), 3.99 (2H, s, H-3ꢀ),
4.69 (1H, q, J 7.6 Hz, H-2), 5.49 (1H, dq, J 1.4, 7.6 Hz, H-1ꢀ),
7.37 (6H, m, Ph), 7.66 (4H, m, Ph); dC (75 MHz, CDCl3) 12.8
t
(CH3, 1ꢀꢀ-Me), 14.0 (CH3, 2ꢀ-Me), 19.3 (C, BuPh2Si), 20.5 (CH2,
C-9), 26.9 (CH3, tBuPh2Si), 28.1 (CH2, C-8), 30.7 (CH2, C-3), 33.1
(CH2, C-10), 38.1 (CH2, C-4), 40.8 (CH, C-1ꢀꢀ), 66.3 (CH2, C-2ꢀꢀ),
68.0 (CH2, C-3ꢀ), 71.5 (CH, C-7), 73.4 (CH, C-2), 106.0 (C, C-5),
126.0 (CH, C-1ꢀ), 127.5 (CH, Ph), 129.4 (CH, Ph), 134.0 (C, Ph),
•
135.56 (CH, Ph), 135.58 (CH, Ph), 138.1 (C, C-2ꢀ); m/z 508 (M+ ,
0.8%), 451 (M–tBu, 14%), 433 (M–tBu–H2O, 12%), 309 (22%),
199 (100%).
1396 | Org. Biomol. Chem., 2006, 4, 1387–1399
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(Si–O–C); dH (300 MHz, CDCl3) 0.96 (3H, d, J 6.8 Hz, 1ꢀꢀ-Me),
0.20 mmol) followed by methanesulfonyl chloride (0.015 mL,
0.19 mmol). After stirring for 20 min at 0 ◦C, the mixture
was filtered and washed with dry THF. To the filtrate was
added sodium iodide (31 mg, 0.21 mmol) and the yellow
mixture was stirred at room temperature for 2 h. The mixture
was then filtered to remove the precipitate and the solvent
was removed under reduced pressure. The resulting unstable
iodide 39 (110 mg) was used directly without further
purification.
t
1.04 (9H, s, BuPh2Si), 1.25 (1H, m, H-8A), 1.42 (3H, s, 2ꢀ-Me),
1.48–1.95 (9H, m, H-3A, H-4, H-8B, H-9, H-10, H-1ꢀꢀ), 2.24 (1H,
m, H-3B), 2.88 (1H, d, J 7.8, H-1ꢀ), 3.14 (1H, d, J 10.1 Hz, H-3ꢀA),
3.28 (1H, d, J 10.1 Hz, H-3ꢀB), 3.51 (1H, dd, J 6.1, 9.9 Hz, H-
2ꢀꢀA), 3.61 (1H, dd, J 5.1, 9.9 Hz, H-2ꢀꢀB), 3.65–3.77 (2H, m, H-2
and H-7), 7.34–7.44 (6H, m, Ph), 7.64 (4H, m, Ph); dC (100 MHz,
CDCl3) 12.8 (CH3, 1ꢀꢀ-Me), 14.1 (CH2, C-3ꢀ), 16.6 (CH3, 2ꢀ-Me),
t
t
19.3 (C, BuPh2Si), 20.5 (CH2, C-9), 26.9 (CH3, BuPh2Si), 28.0
(CH2, C-8), 28.04 (CH2, C-3), 32.9 (CH2, C-10), 37.3 (CH2, C-4),
40.7 (CH, C-1ꢀꢀ), 60.2 (C, C-2ꢀ), 66.0 (CH2, C-2ꢀꢀ), 67.9 (CH, C-
1ꢀ), 71.6 (CH, C-7), 75.7 (CH, C-2), 106.6 (C, C-5), 127.6 (CH,
Ph), 129.5 (CH, Ph), 133.9 (C, Ph), 135.6 (CH, Ph); m/z (CI)
635 (MH+, 17%), 577 (M–tBu, 11%), 437 (100%), 379 (67%),
199 (96%), 181 (68%).
To a solution of acetylene 1127 (57 mg, 0.39 mmol) in dry
THF (1.5 mL) at −78 ◦C was added BuLi (0.27 mL, 1.6 M
solution in hexane, 0.43 mmol). After 45 min, iodide 39 (110 mg)
in dry THF (2 mL) was added. The mixture was stirred at −78 ◦C
for 1 h then transferred to an ice-bath and stirred overnight.
Saturated NH4Cl (1 mL) was added and the mixture extracted
with Et2O (3 × 5 mL). The combined organic phase was washed
with brine (3 × 5 mL) and dried over MgSO4. The solvent was
evaporated at reduced pressure and the mixture was purified by
flash chromatography using hexane–ethyl acetate (95 : 5) as eluent
to give (E)-enyne 8 (68 mg, 56%) and (Z)-enyne 40 (22 mg,
18%) both as colourless oils; 8: [a]D +12.8◦ (c = 1.38, CHCl3);
(2S, 5S, 7S, 1ꢀR, 1ꢀꢀS)-(+)-7-{2ꢀꢀ-(tert-Butyldiphenylsilyloxy)-
1ꢀꢀ-methylethyl}-2-(1ꢀ-hydroxy-2ꢀ-methyl-2ꢀ-propen-1ꢀ-yl)-1,6-
dioxaspiro[4.5]decane (37)
To a solution of acetylene 1127 (17 mg, 0.12 mmol) in dry THF
(1.5 mL) at −78 ◦C was added BuLi (0.07 mL, 1.6 M solution
in hexane, 0.11 mmol). After 45 min, hexamethylphosphoramide
(0.02 mL, 0.11 mmol) was added followed by a solution of iodide
35 (15 mg, 0.02 mmol) in dry THF (1 mL). The mixture was stirred
at −78 ◦C for 15 min and then at room temperature overnight.
Saturated NH4Cl solution (1 mL) was added and the mixture was
extracted with Et2O (3 × 5 mL). The combined organic phase
was washed with brine (2 × 5 mL) and dried over MgSO4. The
solvent was evaporated under reduced pressure and the crude
mixture was purified by flash chromatography using hexane–ethyl
acetate (9 : 1) as eluent to give the title compound 37 (8.7 mg,
86%) as a pale yellow oil; [a]D +34.4◦ (c = 0.8, CHCl3); found:
MH+, 509.3093, C31H45O4Si requires 509.3087; mmax (cm−1) 3468br
(OH), 1428s, 1224m; dH (400 MHz, CDCl3) 0.94 (3H, d, J 6.8 Hz,
•
found: M+ , 636.3627, C41H52O4Si requires 636.3635; mmax (cm−1)
1455m, 1427s; dH (300 MHz, CDCl3) 1.02 (3H, d, J 6.9 Hz, 1ꢀꢀ-
Me), 1.04 (9H, s, tBuPh2Si), 1.21 (1H, m, H-8A), 1.50–1.91 (12H,
m, H-3A, H-4, H-8B, H-9, H-10, 2ꢀ-Me, H-1ꢀꢀ), 2.11 (1H, m, H-
3B), 2.96 (2H, s, H-3ꢀ), 3.54 (1H, dd, J 6.5, 9.9 Hz, H-2ꢀꢀA), 3.67
(1H, dd, J 4.8, 9.9 Hz, H-2ꢀꢀB), 3.78 (1H, ddd, J 1.7, 5.1, 11.5 Hz,
H-7), 4.19 (2H, t, J 1.9 Hz, H-6ꢀ), 4.60 (2H, s, CH2Ph), 4.67
(1H, q, J 7.6 Hz, H-2), 5.52 (1H, dq, J 1.1, 7.6 Hz, H-1ꢀ), 7.24–
7.43 (11H, m, Ph), 7.65 (4H, m, Ph); dC (75 MHz, CDCl3) 12.9
t
(CH3, 1ꢀꢀ-Me), 16.6 (CH3, 2ꢀ-Me), 19.3 (C, BuPh2Si), 20.5 (CH2,
t
C-9), 26.8 (CH3, BuPh2Si), 28.0 (CH2, C-8), 28.9 (CH2, C-3ꢀ),
30.7 (CH2, C-3), 33.1 (CH2, C-10), 38.1 (CH2, C-4), 40.8 (CH,
C-1ꢀꢀ), 57.7 (CH2, C-6ꢀ), 66.2 (CH2, C-2ꢀꢀ), 71.3 (CH2, CH2Ph),
71.5 (CH, C-7), 73.6 (CH, C-2), 78.3 (C, C-4ꢀ), 83.9 (C, C-5ꢀ)
106.0 (C, C-5), 127.1 (CH, C-1ꢀ), 127.5 (CH, Ph), 127.8 (CH,
Ph), 128.1 (CH, Ph), 128.4 (CH, Ph), 129.5 (CH, Ph), 133.7 (C,
Ph), 134.0 (C, Ph), 135.56 (CH, Ph), 135.58 (CH, Ph), 137.6
t
1ꢀꢀ-Me), 1.05 (9H, s, BuPh2Si), 1.25 (1H, m, H-8A), 1.48–1.87
(13H, m, H-3, H-4, H-8B, H-9, H-10, H-1ꢀꢀ, 2ꢀ-Me), 2.17 (1H,
br, OH), 3.51 (1H, dd, J 6.1, 9.9 Hz, H-2ꢀꢀA), 3.67 (1H, dd, J
5.1, 9.9 Hz, H-2ꢀꢀB), 3.82 (1H, ddd, J 1.9, 5.6, 11.6 Hz, H-7),
4.16 (1H, m, H-2), 4.25 (1H, br, H-1ꢀ), 4.89 (1H, d, J 1.3 Hz, H-
3ꢀA), 5.08 (1H, br, H-3ꢀB), 7.34–7.44 (6H, m, Ph), 7.64 (4H, m,
Ph); dC (100 MHz, CDCl3) 12.3 (CH3, 1ꢀꢀ-Me), 19.3 (C, tBuPh2Si),
19.7 (CH3, 2ꢀ-Me), 20.5 (CH2, C-9), 22.5 (CH2, C-3), 26.9 (CH3,
tBuPh2Si), 28.0 (CH2, C-8), 32.9 (CH2, C-10), 38.0 (CH2, C-4),
40.7 (CH, C-1ꢀꢀ), 66.0 (CH2, C-2ꢀꢀ), 70.9 (CH, C-7), 74.5 (CH, C-
1ꢀ), 78.7 (CH, C-2), 106.5 (C, C-5), 111.0 (CH2, C-3ꢀ), 127.6 (CH,
Ph), 129.5 (CH, Ph), 133.9 (C, Ph), 135.6 (CH, Ph), 143.3 (C, C-2ꢀ);
•
(C, C-2ꢀ); m/z 636 (M+ , 0.4%), 579 (M–tBu, 8%), 199 (68%),
91 (CH2Ph, 100%).
•
40: [a]D +47.8◦ (c = 0.97, CHCl3); found: M+ , 636.3636,
C41H52O4Si requires 636.3635; mmax (cm−1) 1428m, 1220m; dH
(300 MHz, CDCl3) 1.01 (3H, d, J 6.8 Hz, 1ꢀꢀ-Me), 1.05 (9H, s,
tBuPh2Si), 1.26 (1H, m, H-8A), 1.45–1.92 (12H, m, H-3A, H-4,
H-8B, H-9, H-10, 2ꢀ-Me, H-1ꢀꢀ), 2.13 (1H, m, H-3B), 2.88 (1H, m,
H-3ꢀA), 3.10 (1H, m, H-3ꢀB), 3.53 (1H, dd, J 6.5, 9.9 Hz, H-2ꢀꢀA),
3.64–3.77 (2H, m, H-7 and H-2ꢀꢀB), 4.14 (2H, t, J 2.0 Hz, H-6ꢀ),
4.57 (2H, s, CH2Ph), 4.63 (1H, m, H-2), 5.31 (1H, d, J 8.4 Hz, H-
1ꢀ), 7.24–7.41 (11H, m, Ph), 7.66 (4H, m, Ph); dC (75 MHz, CDCl3)
13.0 (CH3, 1ꢀꢀ-Me), 19.3 (C, tBuPh2Si), 20.5 (CH2, C-9), 22.0 (CH2,
C-3ꢀ), 26.9 (CH3, tBuPh2Si), 28.0 (CH2, C-8), 28.9 (CH2, C-3ꢀ), 30.9
(CH2, C-3), 33.2 (CH2, C-10), 38.1 (CH2, C-4), 40.8 (CH, C-1ꢀꢀ),
57.7 (CH2, C-6ꢀ), 66.1 (CH2, C-2ꢀꢀ), 71.3 (CH2, CH2Ph), 71.7 (CH,
C-7), 73.5 (CH, C-2), 76.3 (C, C-4ꢀ), 84.3 (C, C-5ꢀ), 106.0 (C, C-5),
127.2 (CH, C-1ꢀ), 127.5 (CH, Ph), 127.7 (CH, Ph), 127.9 (CH,
Ph), 128.0 (CH, Ph), 128.37 (CH, Ph), 128.43 (CH, Ph), 129.5
(CH, Ph), 134.0 (C, Ph), 134.03 (C, Ph), 135.6 (CH, Ph), 137.6
•
m/z 508 (M+ , 0.05%), 451 (M–tBu, 40%), 437 (M–tBu–CH2, 31%),
199 (100%).
(1ꢀE, 2S, 5R, 7S, 1ꢀꢀS)-(+)-2-(6ꢀ-Benzyloxy-2ꢀ-methyl-1ꢀ-hexen-4ꢀ-
yn-1ꢀ-yl)-7-{2ꢀꢀ-(tert-butyldiphenylsilyloxy)-1ꢀꢀ-methylethyl}-1,6-
dioxaspiro[4.5]decane 8 and (1ꢀZ, 2S, 5R, 7S, 1ꢀꢀS)-(+)-2-(6ꢀ-
benzyloxy-2ꢀ-methyl-1ꢀ-hexen-4ꢀ-yn-1ꢀ-yl)-7-{2ꢀꢀ-(tert-
butyldiphenylsilyloxy)-1ꢀꢀ-methylethyl}-1,6-dioxaspiro[4.5]decane
(40)
•
To a solution of alcohol 33 (96 mg, 0.19 mmol) in dry THF
(C, C-2ꢀ); m/z 636 (M+ , 0.6%), 579 (M–tBu, 4%), 199 (64%), 91
(2 mL) at 0 ◦C was added dry triethylamine (0.028 mL,
(CH2Ph, 100%).
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(2S, 5S, 7S, 1ꢀS, 2ꢀS, 1ꢀꢀS)-2-(6ꢀ-Benzyloxy-1ꢀ,2ꢀ-epoxy-2ꢀ-
methylhex-4ꢀ-yn-1ꢀ-yl)-7-{2ꢀꢀ-(tert-butyldiphenylsilyloxy)-1ꢀꢀ-
methylethyl}-1,6-dioxaspiro[4.5]decane (syn-epoxide 36) and (2S,
5S, 7S, 1ꢀR, 2ꢀR, 1ꢀꢀS)-2-(6ꢀ-benzyloxy-1ꢀ-epoxy-2ꢀ-methylhex-4ꢀ-
yn-1ꢀyl)-7-{2ꢀꢀ-(tert-butyldiphenylsilyloxy)-1ꢀꢀ-
methylethyl}-1,6-dioxaspiro[4.5]decane (anti-
(4ꢀZ, 2S, 5S, 7S, 1ꢀS, 2ꢀS, 1ꢀꢀS)-2-(6ꢀ-Benzyloxy-1ꢀ,2ꢀ-epoxy-2ꢀ-
methylhex-4ꢀ-en-1ꢀ-yl)-7-{2ꢀꢀ-(tert-butyldiphenylsilyloxy)-1ꢀꢀ-
methylethyl}-1,6-dioxaspiro[4.5]decane (syn-epoxide 43) and (4ꢀZ,
2S, 5S, 7S, 1ꢀR, 2ꢀR, 1ꢀꢀS)-2-(6ꢀ-benzyloxy-1ꢀ,2ꢀ-epoxy-2ꢀ-
methylhex-4ꢀ-en-1ꢀ-yl)-7-{2ꢀꢀ-(tert-butyldiphenylsilyloxy)-1ꢀꢀ-
methylethyl}-1,6-dioxaspiro[4.5]decane (anti-epoxide 44)
epoxide 42)
A mixture of epoxides 36 and 42 (14 mg, 0.04 mmol, syn-
epoxide 36 : anti-epoxide 42 = 5.5 : 1), Lindlar catalyst (1–2 mg)
and triethylamine (0.1 mL) in hexane (1.5 mL) was stirred
under an atmosphere of hydrogen (balloon pressure) for 50 min.
(E)-Enyne 8 (0.02 mmol) was dissolved in a mixture of CH3CN–
DMM (0.3 mL, 1 : 2 v/v). A solution of buffer [0.05 M of
Na2B4O7·10H2O in 4 × 10−4 M of Na2(EDTA)] (0.2 mL) was
added followed by tetrabutylammonium sulfate (0.02 mmol) and
ketone 41 or ent-41 (0.06 mmol). After cooling to −10 ◦C, a
solution of oxone (0.1 mmol) in 4 × 10−4 M Na2(EDTA) (0.3 mL)
and a solution of K2CO3 (0.3 mmol) in water (0.3 mL) were added
dropwise simultaneously over 40 min. After the last addition, the
mixture was stirred for 1 h. Water was added and the mixture was
extracted with diethyl ether (3 × 3 mL). The combined organic
extracts were washed with brine (3 × 1 mL) and dried over
MgSO4. The solvent was evaporated and the mixture was purified
by flash chromatography using hexane–ethyl acetate (9 : 1) as
eluent.
1
The progress of the reaction was monitored by H NMR. The
R
mixture was filtered through a pad of Celiteꢀ and the solvent
was evaporated under reduced pressure. The crude mixture was
purified by flash chromatography using hexane–ethyl acetate (9 :
1) as eluent to give the title compounds (12 mg, 91%) as an
inseparable 5.5 : 1 mixture of syn-epoxide 43 : anti-epoxide 44;
found: MH+, 655.3821, C41H55O5Si requires 655.3819; mmax (cm−1)
1458m, 1265s (Si–O–C); dH (300 MHz, CDCl3)¶ 0.94 (1.07H, d, J
6.7 Hz, 1ꢀꢀ-Me*), 0.96 (1.93H, d, J 6.7 Hz, 1ꢀꢀ-Me), 1.03 (5.79H, s,
t
tBuPh2Si), 1.04 (3.21H, s, BuPh2Si*), 1.18–1.27 (4H, m, H-8A,
2ꢀ-Me), 1.45–1.93 (9H, m, H-3A, H-4, H-8B, H-9, H-10, H-1ꢀꢀ),
2.04–2.42 (3H, m, H-3B and H-3ꢀ), 2.69 (0.64H, d, J 8.0 Hz, H-1ꢀ),
2.74 (0.36H, d, J 7.7 Hz, H-1ꢀ*), 3.45–3.82 (4H, m, H-2, H-7, H-2ꢀꢀ),
4.06 (2H, m, H-6ꢀ), 4.51 (2H, s, CH2Ph), 5.53–5.67 (1H, m, H-5ꢀ),
5.71–5.82 (1H, m, H-4ꢀ), 7.26–7.42 (11H, m, Ph), 7.65 (4H, m,
Ph); dC (75 MHz, CDCl3) 12.7 (CH3, 1ꢀꢀ-Me), 12.9 (CH3, 1ꢀꢀ-Me*),
Using ketone ent-41 derived from D-fructose afforded a
1 : 8 mixture of syn-epoxide 36 : anti-epoxide 42 in 52%
yield.
Using ketone 41 derived from L-fructose afforded a 5.5 :
1
mixture of syn-epoxide 36
:
anti-epoxide 42 in 37%
t
yield.
17.0 (CH3, 2ꢀ-Me), 17.5 (CH3, 2ꢀ-Me*), 19.3 (C, BuPh2Si), 20.3
•
syn-Epoxide 36 and anti-epoxide 42, colourless oil; found: M+ ,
652.3589, C41H52O5Si requires 652.3584; mmax (cm−1) 1428m, 1265m
(Si–O–C); dH (300 MHz, CDCl3)§ 0.94 (1.35H, d, J 6.7 Hz, 1ꢀꢀ-
Me*), 0.96 (1.65H, d, J 6.7 Hz, 1ꢀꢀ-Me), 1.036 (4.95H, s, tBuPh2Si),
(CH2, C-9), 20.4 (CH2, C-9*), 26.85 (CH3, tBuPh2Si), 26.87 (CH3,
tBuPh2Si*), 26.9 (CH2, C-3), 27.9 (CH2, C-3*), 28.08 (CH2, C-8),
28.10 (CH2, C-8*), 32.9 (CH2, C-10), 36.1 (CH2, C-3ꢀ), 36.6 (CH2,
C-3ꢀ*), 37.3 (CH2, C-4), 37.5 (CH2, C-4*), 40.7 (CH, C-1ꢀꢀ), 59.2
(C, C-2ꢀ), 60.9 (C, C-2ꢀ*), 63.9 (CH, C-1ꢀ), 64.5 (CH, C-1ꢀ*), 65.7
(CH2, C-6ꢀ), 66.03 (CH2, C-2ꢀꢀ), 66.09 (CH2, C-2ꢀꢀ*), 71.49 (CH,
C-7), 71.53 (CH, C-7*), 72.2 (CH2, CH2Ph), 72.3 (CH2, CH2Ph*),
75.3 (CH, C-2), 76.8 (CH, C-2*), 106.4 (C, C-5), 106.7 (C, C-5*),
127.49 (CH, Ph), 127.54 (CH, Ph), 127.55 (CH, Ph), 127.6 (CH,
C-4ꢀ), 127.6 (CH, C-4ꢀ*), 127.80 (CH, Ph), 128.4 (CH, Ph), 129.0
(CH, C-5ꢀ), 129.2 (CH, C-5ꢀ*), 129.3 (CH, Ph), 129.4 (CH, Ph),
129.5 (CH, Ph), 133.9 (C, Ph), 133.96 (C, Ph), 134.1 (C, Ph), 135.6
(CH, Ph), 138.16 (C, Ph), 138.24 (C, Ph); m/z (FAB) 655 (MH+,
3%), 437 (16%), 199 (25%), 91 (CH2Ph, 82%).
t
1.043 (4.05H, s, BuPh2Si*), 1.20 (1H, m, H-8A), 1.35 (1.65H, s,
2ꢀ-Me), 1.37 (1.35H, s, 2ꢀ-Me*), 1.59–1.90 (9H, m, H-3A, H-4,
H-8B, H-9, H-10, H-1ꢀꢀ), 2.18 (1H, m, H-3B), 2.59 (2H, m, H-
3ꢀ), 2.89 (0.55H, d, J 8.0 Hz, H-1ꢀ), 2.92 (0.45H, d, J 7.7 Hz,
H-1ꢀ*), 3.48 (1H, m, H-2ꢀꢀA), 3.58–3.84 (3H, m, H-2, H-7, H-
2ꢀꢀB), 4.17 (2H, m, H-6ꢀ), 4.58 (1.1H, s, CH2Ph), 4.59 (0.9H, s,
CH2Ph*), 7.26–7.42 (11H, m, Ph), 7.65 (4H, m, Ph); dC (75 MHz,
CDCl3) 12.6 (CH3, 1ꢀꢀ-Me), 12.9 (CH3, 1ꢀꢀ-Me*), 16.9 (CH3, 2ꢀ-Me),
t
17.3 (CH3, 2ꢀ-Me), 19.3 (C, BuPh2Si), 20.36 (CH2, C-9), 20.42
(CH2, C-9*), 26.85 (CH3, tBuPh2Si), 26.87 (CH3, tBuPh2Si*), 27.0
(CH2, C-3), 27.9 (CH2, C-3*), 28.05 (CH2, C-8), 28.09 (CH2, C-
8*), 28.6 (CH2, C-3ꢀ), 29.1 (CH2, C-3ꢀ*), 32.8 (CH2, C-10), 32.9
(CH2, C-10*), 37.3 (CH2, C-4), 37.5 (CH2, C-4*), 40.7 (CH, C-
1ꢀꢀ), 57.6 (CH2, C-6ꢀ), 58.1 (C, C-2ꢀ), 59.5 (C, C-2ꢀ*), 63.8 (CH,
C-1ꢀ), 64.6 (CH, C-1ꢀ*), 66.03 (CH2, C-2ꢀꢀ), 66.07 (CH2, C-2ꢀꢀ*),
71.36 (CH2, CH2Ph), 71.44 (CH2, CH2Ph*), 71.6 (CH, C-7),
75.2 (CH, C-2), 76.7 (CH, C-2*), 78.4 (C, C-4ꢀ), 78.5 (C, C-4ꢀ*),
81.8 (C, C-5ꢀ), 81.9 (C, C-5ꢀ*), 106.5 (C, C-5), 106.8 (C, C-5*),
127.5 (CH, Ph), 127.6 (CH, Ph), 127.80 (CH, Ph), 127.84 (CH,
Ph), 128.0 (CH, Ph), 128.1 (CH, Ph), 128.4 (CH, Ph), 128.42
(CH, Ph), 129.4 (CH, Ph), 129.5 (CH, Ph), 133.9 (C, Ph), 133.95
(C, Ph), 134.0 (C, Ph), 134.1 (C, Ph), 135.6 (CH, Ph), 137.5
(2S, 5S, 7S, 1ꢀS, 2ꢀꢀR, 4ꢀꢀS, 5ꢀꢀR, 1ꢀꢀꢀꢀS)-(+)-2-[5ꢀꢀ-
Benzyloxymethyl-4ꢀꢀ-hydroxy-2ꢀꢀ-methyltetrahydrofur-2ꢀꢀ-yl)-
hydroxymethyl]-7-{2ꢀꢀꢀꢀ-(tert-butyldiphenylsilyloxy)-1ꢀꢀꢀꢀ-
methylethyl}-1,6-dioxaspiro[4.5]decane (6)
To a 5.5 : 1 mixture of syn-epoxide 43 : anti-epoxide 44 (10 mg,
15.2 lmol) in acetone–H2O (0.5 mL, 5 : 1 v/v) at room temperature
t
was added OsO4 (50 lL, 2.5wt% in BuOH). The mixture was
left at room temperature for 18 h. Saturated Na2S2O3 solution
(0.5 mL) was added and the mixture stirred vigorously for 45 min
at room temperature. The mixture was extracted with CH2Cl2
(5 × 1 mL) and dried over MgSO4. The solvent was evaporated
under reduced pressure and the crude mixture was purified by flash
chromatography using hexane–ethyl acetate (7 : 3) as eluent to give
•
(C, Ph); m/z 652 (M+ , 0.2%), 595 (M–tBu, 5%), 379 (20%),
199 (81%), 181 (57%), 135 (41%), 91 (CH2Ph, 100%).
§ Resonances assigned with the anti-epoxide 42 are designated with an
¶ Resonances assigned with the anti-epoxide 44 are designated with an
asterisk *.
asterisk *.
1398 | Org. Biomol. Chem., 2006, 4, 1387–1399
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ABC spiroacetal 6 (5.8 mg, 70%) as a colourless oil; [a]D +23.5◦
9 S. Amano, K. Fujiwara and A. Murai, SYNLETT, 1997, 1300; D.
Awakura, K. Fujiwara and A. Murai, SYNLETT, 2000, 1733; K.
Fujiwara, M. Kobayashi, F. Yamamoto, A. Fuyuki, K. Yu-ichi, M.
Kawamura, A. Mariko, Awakura, A. Daisuke, O. Seiji, A. Murai, H.
Kawai and T. Suzuki, Tetrahedron Lett., 2005, 46, 5067.
10 L. A. Paquette, X. Peng and D. Bondar, Org. Lett., 2002, 4, 937; X.
Peng, D. Bondar and L. A. Paquette, Tetrahedron, 2004, 60, 9589; D.
Bondar, J. Liu, T. Mueller and L. A. Paquette, Org. Lett., 2005, 7, 1813.
11 G. C. Micalizio and W. R. Roush, Org. Lett., 2001, 3, 1949.
12 P. M. Pihko and J. E. Aho, Org. Lett., 2004, 6, 3849.
13 D. A. Evans, H. A. Rajapakse and D. Stenkamp, Angew. Chem., Int.
Ed., 2002, 41, 4569; D. A. Evans, H. A. Rajapakse, A. Chiu and D.
Stenkamp, Angew. Chem., Int. Ed. Engl., 2002, 41, 4573.
14 For preliminary communication of this work see: R. Halim, M. A.
Brimble and J. Merten, Org. Lett., 2005, 7, 2659.
•
(c = 0.13, CHCl3); found: M+ , 688.3792, C41H56O7Si requires
688.3795; mmax (cm−1) 3444 br (OH), 1427m, 1362s, 1262s; dH
(300 MHz, CDCl3) 0.99 (3H, d, J 6.7 Hz, 1ꢀꢀꢀꢀ-Me), 1.05 (9H, s,
tBuPh2Si), 1.25 (1H, m, H-8A), 1.42 (3H, s, 2ꢀꢀ-Me), 1.44–2.21
(11H, m, H-3, H-4, H-8B, H-9, H-10, H-3ꢀꢀA, H-1ꢀꢀꢀꢀ), 2.41 (1H,
dd, J 7.6, 13.3 Hz, H-3ꢀꢀB), 3.45 (1H, d, J 7.6 Hz, H-1ꢀ), 3.48–
3.65 (5H, m, H1ꢀꢀꢀ, H-7, H-2ꢀꢀꢀꢀ), 3.80 (1H, q, J 7.0 Hz, H-2), 3.97
(1H, q, J 3.7 Hz, H-5ꢀꢀ), 4.32 (1H, m, H-4ꢀ), 4.56 (2H, AB, JAB
12.3 Hz, CH2Ph), 7.27–7.42 (11H, m, Ph), 7.64–7.67 (4H, m, Ph);
dC (75 MHz, CDCl3) 12.9 (CH3, 1ꢀꢀꢀꢀ-Me), 19.4 (C, tBuPh2Si), 20.6
(CH2, C-9), 25.6 (CH3, 2ꢀꢀ-Me), 26.9 (CH3, tBuPh2Si), 27.3 (CH2,
C-3), 28.1 (CH2, C-8), 33.2 (CH2, C-10), 37.1 (CH2, C-4), 40.2
(CH2, C-3ꢀꢀ), 40.8 (CH, C-1ꢀꢀꢀꢀ), 66.2 (CH2, C-1ꢀꢀꢀ), 69.7 (CH2, C-
2ꢀꢀꢀꢀ), 71.7 (CH, C-7), 73.4 (CH2, CH2Ph), 74.1 (CH, C-4ꢀꢀ), 77.4
(CH, C-2), 78.1 (CH, C-1ꢀ), 83.2 (CH, C-5ꢀꢀ), 86.5 (C, C-2ꢀꢀ), 106.2
(C, C-5), 127.6 (CH, Ph), 127.8 (CH, Ph), 127.82 (CH, Ph), 128.5
(CH, Ph), 129.5 (CH, Ph), 134.1 (C, Ph), 135.6 (CH, Ph), 137.6
15 L. Borjesson, I. Csoregh and C. J. Welch, J. Org. Chem., 1995, 60, 2989.
16 D. A. Evans, J. Bartroli and T. L. Shih, J. Am. Chem. Soc., 1981, 103,
2127.
17 L. M. Fuentes, I. Shinkai and T. N. Salzmann, J. Am. Chem. Soc., 1986,
108, 4675.
18 T. Inoue and T. Mukaiyama, Bull. Chem. Soc. Jpn., 1980, 53, 174.
19 M. T. Crimmins, B. W. King and E. A. Tabet, J. Am. Chem. Soc., 1997,
119, 7883.
•
(C, Ph); m/z 688 (M+ , 0.2%), 631 (9%), 221 (52%), 199 (49%), 91
20 M. T. Crimmins, B. W. King, E. A. Tabet and K. Chaudhary, J. Org.
Chem., 2001, 66, 894.
(CH2Ph, 100%).
21 Y. Nagao, T. Kumagi, S. Yamada and E. Fujita, J. Chem. Soc., Perkin
Trans. 1, 1985, 2361.
22 G. W. A. Fowles, D. A. Rice and J. D. Wilkins, J. Chem. Soc. A, 1971,
Acknowledgements
1920.
23 D. Craig and A. M. Smith, Tetrahedron Lett., 1990, 31, 2631.
24 D. B. Dess and J. C. Martin, J. C., J. Org. Chem., 1983, 48, 4155.
25 D. Uemura, K. Takahashi, T. Yamamoto, C. Katayama, J. Tanaka, Y.
Okumura and Y. Hirata, J. Am. Chem. Soc., 1985, 107, 4796.
26 G. R. Pettit, Y. Ichihara, G. Wurzel, M. D. Williams, J. M. Schmidt and
J. Chapuis, J. Chem. Soc., Chem. Commun., 1995, 383.
27 R. E. Sammelson, R. B. Miller and M. J. Kurth, J. Org. Chem., 2000,
65, 2225.
28 R. Matsumura, T. Suzuki, K. Sato, T. Inotsume, H. Hagiwara, T. Hoshi,
V. P. Kamat and M. Ando, Tetrahedron Lett., 2000, 41, 7697.
29 J. G. Millar and E. W. Underhill, J. Org. Chem., 1986, 51, 4726.
30 A. Alexakis, G. Cahiez and J. F. Normant, Synthesis, 1979, 826.
31 M. Gardette, A. Alexakis and J. F. Normant, J. Chem. Ecol., 1983, 9,
225.
The Royal Society of New Zealand is thanked for the award of a
James Cook Research to MAB.
References
1 T. Yasumoto, M. Murata, Y. Oshima, G. K. Sano and J. Matsumoto,
Tetrahedron, 1985, 41, 1019.
2 M. Murata, M. Sano, T. Iwashita, H. Naoki and T. Yasumoto, Agric.
Biol. Chem., 1986, 50, 2693.
3 T. Yasumoto, M. Murata and J.-S. Lee, in Bioactive Molecules:
Mycotoxins and Phycotoxins ‘88, vol. 10, ed. S. Natori, K. Hashimoto
and Y. Ueno, Elsevier, New York, 1989 p. 375.
4 K. Sasaki, J. L. C. Wright and T. Yasumoto, J. Org. Chem., 1998, 63,
2475.
32 K. C. Nicolau, M. E. Duggan and T. Ladduwahetty, Tetrahedron Lett.,
1984, 25, 2069.
5 T. Suzuki, V. Beuzenberg, L. Mackenzie and M. A. Quilliam, J. Chro-
matogr., A, 2003, 992, 141.
33 W. Adam, Y.-Y. Chan, D. Cremer, J. Gauss, D. Scheutzow and M.
Schindler, J. Org. Chem., 1987, 52, 2800.
34 R. W. Murray and R. J. Jeyaraman, J. Org. Chem., 1985, 50, 2847.
35 R. W. Murray and M. Singh, Org. Synth., 1997, 74, 91.
36 Z.-X. Wang, T. Tu, M. Frohn, J.-R. Zhang and Y. Shi, J. Am. Chem.
Soc., 1997, 119, 11224.
6 C. O. Miles, A. L. Wilkins, I. A. Samdal, M. Sandvik, D. Petersen, M. A.
Quilliam, L. J. Naustvoll, T. Rundberget, T. Torgersen, P. Hovgaard,
D. J. Jensen and J. M. Cooney, Chem. Res. Toxicol., 2004, 17, 1423.
7 J. H. Jung, C. J. Sim and C.-O. Lee, J. Nat. Prod., 1995, 58, 1722.
8 I. Spector, F. Braet, N. R. Shochet and M. R. Bubb, Microsc. Res.
Tech., 1999, 47, 18; F. Leira, A. G. Cabado, M. R. Vieytes, Y. Roman,
A. Alfonso, L. M. Botana, T. Yasumoto, C. Malaguti and G. P. Rossini,
Biochem. Pharmacol., 2002, 63, 1979.
37 C. C. Chen and R. L. Whistler, Carbohydr. Res., 1988, 175, 265.
38 H. C. Kolb, P. G. Andersson and K. B. Sharpless, J. Am. Chem. Soc.,
1994, 116, 1278.
39 L. Wang and K. B. Sharpless, J. Am. Chem. Soc., 1992, 114, 7568.
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