Synthesis of the 1,6,8-trioxadispiro[4.1.5.2]tetradec-11-ene ring system present in the spirolide family of shellfish toxins and its conversion into a 1,6,8-trioxadispiro[4.1.5.2]-tetradec-9-en-12-ol via base-induced rearrangement of an epoxide

Article abstract of DOI:10.1039/b412883d

The synthesis of the 1,6,8-trioxadispiro[4.1.5.2]tetradec-11-enes 12 present in the shellfish toxins spirolides B 1 and D 2, is reported. The two spirocentres were constructed via iterative radical oxidative cyclization of hydroxyalkyl dihydropyran 14 and

Full text of DOI:10.1039/b412883d

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A R T I C L E
Synthesis of the 1,6,8-trioxadispiro[4.1.5.2]tetradec-11-ene ring
system present in the spirolide family of shellfish toxins and its
conversion into a 1,6,8-trioxadispiro[4.1.5.2]-tetradec-9-en-12-ol via
base-induced rearrangement of an epoxide†
Margaret A. Brimble* and Daniel P. Furkert
Department of Chemistry, University of Auckland, 23 Symonds St., Auckland, New Zealand.
E-mail: m.brimble@auckland.ac.nz; Fax: +64 9 3737422
Received 20th August 2004, Accepted 28th September 2004
First published as an Advance Article on the web 4th November 2004
The synthesis of the 1,6,8-trioxadispiro[4.1.5.2]tetradec-11-enes 12 present in the shellfish toxins spirolides B 1 and D
2, is reported. The two spirocentres were constructed via iterative radical oxidative cyclization of hydroxyalkyl
dihydropyran 14 and hydroxyalkyl spiroacetal 13 using iodobenzene diacetate and iodine. This procedure initially
afforded a 1 : 1 : 1 : 1 mixture of bis-spiroacetals 12a : 12b : 12c : 12d, however subsequent acid catalysed equilibration
afforded a 3 : 1 : 0.9 thermodynamic mixture of 12a : 12b : 12c. The major bis-spiroacetal 12a underwent
stereoselective epoxidation using dimethyldioxirane to a-epoxide 33a. Subsequent base induced rearrangement of this
epoxide 33a using lithium diethylamide in pentane afforded allylic alcohol 34a, that was converted to the more
thermodynamically favoured homoallylic alcohol 11a upon treatment with lithium pyrrolidinylamide in
tetrahydrofuran. Homoallylic alcohol 11a possesses a hydroxyl group at C-12 as required for introduction of the
tertiary alcohol group present at this position in spirolides B 1 and D 2.
the spirolides. Therefore, herein we report the full details11 of this
synthetic work, addressing the stereochemical issues associated
with the assembly of bis-spiroacetals 12 and the base-induced
rearrangement of the derived epoxides.
Introduction
Spirolides B 1 and D 2 are toxic metabolites of the marine
dinoflagellate Alexandrium ostenfeldii that were isolated from
the digestive glands of mussels (Mytilus edulis) and scallops
(Placopecten magellanicus) during routine monitoring for diar-
rhetic shellfish toxins in Nova Scotia, Canada, in 1995.1,2 Further
investigations afforded spirolides A 3, C 4, 13-desmethyl-C 53
Results and discussion
and biologically inactive spirolides E 6 and F 7.4 Spirolides A–D
The key disconnection in our proposed retrosynthesis of
contain an unusual 5,5,6-bis-spiroacetal moiety, together with a
spirolides B 1 and D 2 (Scheme 1) involves Ni(II)/Cr(II)-
rare 6,7-spirocyclic imine. Spirolides E 6 and F 7 are keto amine
mediated Kishi–Nozaki coupling12 between an aldehyde and a
hydrolysis derivatives resulting from ring opening of the cyclic
vinyl iodide to form the C-9–C-10 bond of the macrocyclic ring
imine, suggesting that this functionality is the pharmacophore
responsible for toxicity. Although the absolute stereochemistry
of the spirolide family of toxins has not been established to
date, a computer-generated relative assignment of 13-desmethyl
in a similar fashion to that used by Kishi et al. in the synthesis
of pinnatoxin A 8. The substituted allyl group at C-22 can be
introduced via Lewis acid-mediated addition of an allyl stannane
to bis-spiroacetal 10 that possesses an acetate functionality at
spirolide C 5 showing the same relative stereochemistry as
the anomeric position. Precedent for this latter step has been
the related toxins pinnatoxin A 8 and D 95 in the region
demonstrated by this research group13 using a simpler 6,6-
of their common structure, was later reported.6 Preliminary
spiroacetal. Acetate 10 is available via hydration and acetylation
of alkene 11, that in turn can be synthesised from alkene 12
pharmacological research into the mode of action of the
spirolides suggested that they are antagonists of the muscarinic
by epoxidation followed by a base-induced rearrangement. The
acetylcholine receptor.7
C-19 tertiary alcohol group in spirolides B 1 and D 2 is then
A total synthesis of the spirolides has not been reported to
accessible by oxidation of the hydroxyl group introduced in the
rearrangement step, followed by addition of a methyl group.
Our earlier successful application of radical chemistry to
date, however, an elegant total synthesis of pinnatoxin A 8
has been reported by Kishi et al.8 Partial syntheses of the bis-
spiroacetal moiety of the pinnatoxins are also discussed in a
the synthesis of bis-spiroacetal ring systems suggested that an
recent review on the synthesis of bis-spiroacetal ring systems.9
iterative oxidative radical cyclization strategy might provide a
Our continued interest in the synthesis of natural products
valuable route to the key bis-spiroacetal intermediate 12. This
containing bis-spiroacetal ring systems led us to pursue the
synthetic approach forms the basis of the current study. Thus,
synthesis of the bis-spiroacetal ring system present in the
bis-spiroacetal 12 can be derived from spiroacetal alcohol 13
spirolides using a radical oxidative cyclization strategy that we
using a radical oxidative cyclization mediated by hypervalent
have previously applied to the synthesis of several polyether
iodine. The spirocentre in 13 can, in turn, be formed using a
similar cyclization of dihydropyran 14, that is available from
aldehyde 15, and the Grignard reagent, prepared from dihy-
dropyranyl bromide 16. The Brown and Bhat crotyl metallation
methodology can be used to prepare aldehyde 15 in a flexible
approach that also allows access to varying configurations at
the two stereogenic centres by the appropriate choice of (Z)- or
(E)-2-butene and (−)- or (+)-diisopinocampheylborane starting
materials.14
antibiotics.10 In the present case, it was envisaged that radical ox-
idative cyclizations would provide an ideal method to construct
the two five membered rings in the 5,5,6-bis-spiroacetal unit of
† Electronic supplementary information (ESI) available: General ex-
perimental details together with full experimental procedures, 1H
NMR, 13C NMR and mass spectral data for compounds 15–31. See
http://www.rsc.org/suppdata/ob/b4/b412883d/
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 7 3 – 3 5 8 3
3 5 7 3
©

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Scheme 1 Proposed retrosynthesis of spirolides B 1 and D 2.
Scheme 2 Reagents and conditions and yields: (i) tBuMe2SiCl, Et3N, CH2Cl2, room temp., 16 h, 76%; (ii) PCC, NaOAc, CH2Cl2, rt, 4 h, 78%; (iii) 18,
BuLi, THF, −78 ◦C, 25 min then 17, warm to room temp., 86%; (iv) MeOH, cat. K2CO3, 30 min, 97%; (v) Lindlar, H2, THF, 1.5 h, 96%; (vi) TsCl,
Et3N, CH2Cl2, rt, 16 h, 82%; (vii) NaH, THF, 0 ◦C then room temp., 16 h, 75%; (viii) Bu4NF, THF, rt, 4 h, 80%; (ix) TsCl, NEt3, DMAP, CH2Cl2,
room temp., 16 h, 89%; (x) LiBr, acetone, heat, 1.5 h, 91%.
The most practical preparative route to dihydropyran 16
(Scheme 2) involved addition of the lithium acetylide of 18 to
aldehyde 17 (available in two steps from propane-1,3-diol). The
trimethylsilyl ether in the resultant alcohol 19 was selectively
cleaved to alcohol 20 using K2CO3 (catalytic) in methanol,
followed by careful partial hydrogenation of the acetylene over a
Lindlar catalyst to give (Z)-alkene 21 in high yield. Conversion
of the primary alcohol 21 into the tosylate 22, followed by
treatment with sodium hydride (1.0 equiv.) in THF afforded
dihydropyran 23. After cleavage of the silyl ether, alcohol 24 was
converted to bromide 16 via displacement of the corresponding
tosylate 25.
(−)-b-methoxydiisopinocampheylborane to give (3R,4R)-27 in
82% yield and 90% ee.14,15 The (3R,4R) configuration was
selected by both analogy with pinnatoxin A 8 and the relative
stereochemistry of the spirolides proposed by Falk et al.6 The 1H
NMR spectrum of the known Mosher ester derivative prepared
by treatment of 27 with (R)-2-methoxy-2-trifluoromethyl-2-
phenylacetyl chloride, exhibited a methoxy group singlet at d
3.46 ppm and a methyl group doublet at d 0.98 ppm (J 6.9 Hz),
as reported previously. The 19F NMR spectrum of the Mosher
ester derivative contained two resonances for the trifluoromethyl
group at d −72.47 and −72.28 ppm, in the ratio of 19.2 : 1,
corresponding to an enantiomeric excess of 90%.
Aldehyde 15 was prepared via stereocontrolled crotyl met-
allation of aldehyde 26 (Scheme 3) using (Z)-2-butene and
The secondary hydroxyl group in alcohol 27 was subsequently
protected as a triethylsilyl ether 28. Subsequent hydroboration
3 5 7 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 7 3 – 3 5 8 3

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Scheme 3 Reagents and conditions and yields: (i) (Z)-CH3CH CHCH2(−)-B(iPc)2, BF3OEt2, THF, −78 ◦C, then NaOH, H2O2, heat, 1 h, 84%;
(ii) Et3SiCl, 2,6-lutidine, DMAP, CH2Cl2, room temp., 16 h, 95%; (iii) BH3·SMe2, THF, 0 ◦C, 30 min, then room temp., 2 h, then MeOH, NaOH,
H2O2, 82%; (iv) Dess–Martin periodinane, py, CH2Cl2, room temp., 0.5 h, 92%.
=
to alcohol 29 followed by Dess–Martin oxidation afforded
aldehyde 15, required for union with bromide 16.
14c, 14d (more polar fraction). The alcohols 14a, 14b and
14c, 14d were converted to the diols 30a, 30b and 30c, 30d
and then to the seven-membered acetonides 31a, 31b and 31c,
31d in order to establish the stereochemistry of these two
fractions. The strong NOE observed between H-3 and H-6 in
acetonides 31a, 31b (derived from less polar 14a, 14b) established
that acetonides 31a, 31b possessed the (3S)-configuration. The
absence of a similar correlation in acetonides 31c, 31d (derived
from more polar 14c, 14d) established that 31c, 31d had the (3R)-
configuration. Both 31a, 31b and 31c, 31d were 1 : 1 mixtures
as the stereogenic centre at C-2ꢀ was not controlled during
the synthesis. This position is transformed into a quaternary
spirocentre and its configuration was later determined by the
outcome of the oxidative radical cyclization step and the
thermodynamically controlled isomerisation of the 5,5,6-bis-
spiroacetal ring system (vide infra).
With the Barbier coupling products 14 in hand, attention
turned to formation of the bis-spiroacetal system via iterative
oxidative radical cyclization. Although the pairs of diastere-
omers 14a, 14b and 14c, 14d could be separated and cyclized
independently for spectroscopic purposes, the 1 : 1 mixture
resulting from the Barbier coupling was routinely used for the
preparation of bis-spiroacetals 12 (Scheme 5). Towards this end,
a 1 : 1 : 1 : 1 mixture of alcohols 14a, 14b, 14c, 14d was stirred
with iodobenzene diacetate (2.0 equiv.) and iodine (2.0 equiv.)
in cyclohexane with irradiation using a standard 40 W tungsten
filament desk lamp. The iodobenzene produced as a by-product
from this reaction was easily separated by flash chromatography
affording spiroacetals 32 as a 1 : 1 : 1 : 1 mixture of diasteromers
in 90% yield.
With both the required coupling partners in hand, addition of
aldehyde 15 to the Grignard reagent prepared from dihydropy-
ran bromide 16 was investigated. It was initially disappointing
to find that the use of standard Grignard conditions in either
diethyl ether or tetrahydrofuran at room temperature or reflux
afforded none of the desired product 14 (Scheme 4). Pre-
activation of the magnesium metal, the use of iodine, or pro-
longed dry stirring of the magnesium under an inert atmosphere,
only led to the formation of the undesired Wurtz coupling of
bromide 16.
The one-step Barbier reaction16, in which the halide and
aldehyde are introduced to the magnesium concomitantly, has
proven successful in cases where formation of the Grignard
reagent is troublesome or leads to high levels of dimerisation.17
Thus, a Barbier mixture of aldehyde 15 and an excess of bromide
16 w◦as slowly added to a slurry of magnesium powder in THF
at 0 C. Standard work-up and flash column chromatography
afforded alcohols 14 as a 1 : 1 : 1 : 1 mixture of diastereomers
in 64% yield. Prolonged vigorous dry stirring of the magnesium
powder under an inert atmosphere or a high vacuum in a pear-
shaped flask, addition of a crystal of iodine and entrainment with
1,2-dibromoethane were necessary to ensure consistent yields.
Use of the analogous dihydropyran iodide in the Barbier
reaction or the generation of an organolithium reagent via
lithium–iodide exchange18 using tert-butyllithium (2.0 equiv.)
did not improve the yield of 14.
The 1 : 1 : 1 : 1 mixture of Barbier coupled products 14
could be further separated by flash chromatography into two
fractions. The 13C NMR spectra of each of these fractions
established the presence of two diastereomers in each fraction
that were later assigned as 14a, 14b (less polar fraction) and
Selective deprotection of the triethylsilyl group in 32 using
HF·pyridine resulted in significant loss of the tert-butyldi-
phenylsilyl ether, possibly attributed to the steric influence of
Scheme 4 Reagents and conditions and yields: (i) Mg, Et2O, 0 ◦C, 64%; (ii) HF·py, THF, room temp., 3 h, 14a, 14b, 58% or 14c, 14d, 46%; (iii)
2,2-dimethoxypropane, toluene, room temp., 1 h, 31a, 31b, 84% or 31c, 31d, 80%.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 7 3 – 3 5 8 3
3 5 7 5

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Scheme 5 Reagents and conditions and yields: (i) Phl(OAc)2, I2, cyclohexane, 40 W tungsten hm, 90%; (ii) HCL·py, py, 48 h, 87%; (iii) Phl(OAc)2, I2,
cyclohexane, 40 W tungsten hm, 83%.
the C-4 methyl substituent hindering access to the secondary
triethylsilyl ether. Alcohols 13 were therefore best prepared by
deprotection of bis-silyl ethers 32 using hydrogen chloride in
pyridine19 for 48 h. (2R,3R)-5,5,6-Bis-spiroacetals 12 were then
successfully obtained as an equimolar mixture of four diastere-
omers in 83% yield upon further irradiation with iodobenzene
diacetate and iodine.
chemistry of bis-spiroacetals 12a, 12b, 12c was assigned using
extensive two-dimensional NMR studies in conjunction with
molecular modelling studies.
Close examination of NOESY correlations involving H-2,
H-4a, H-4b, H-12 and the methyl group provided the most
useful information about the relative disposition of the rings
of the bis-spiroacetal system (Fig. 1). The bis-spiroacetal ring
system in the less polar minor band was assigned as trans
syn 12b in the following manner. The trans stereochemistry
of the bis-spiroacetal rings was established from the NOE
correlation observed between H-14 and both H-2 and H-12.
Nicolaou et al.21 reported similar correlations as evidence for
the assignment of trans stereochemistry to the bis-spiroacetal
moiety of azaspiracid. The absence of a correlation between H-
4 and the methylene protons H-13 and H-14 indicated that this
diastereomer also possessed a syn relationship between the C-2
alkyl substituent and the central C-5–O-6 bond.
The possibility of a direct one-step formation of bis-
spiroacetals 12 from diols 30 was also investigated. Treatment
of diols 30 with iodobenzene diacetate and iodine afforded a
complex mixture in line with the findings of Suarez et al.20 who
were unable to effect the formation of a 6,6,5-spiroacetal system
in one-step from a diol precursor that contained the central ring.
The four diastereomers of the 5,5,6-bis-spiroacetal system
12a, 12b, 12c, 12d result from the stereogenic spiroacetal centres
at C-5 and C-7. These can be designated cis or trans based on the
disposition of oxygen atoms across the central tetrahydrofuran
ring. These two pairs of diastereomers can be further classified as
syn or anti, defined in this case by the relationship of the central
ring C-5–O-6 bond and the hydroxyalkyl substituent at C-2
(Scheme 6). Bis-spiroacetal systems exhibit a thermodynamic
preference for particular configurations at the spiroacetal centres
based on stereoelectronic, steric and hydrogen bonding effects.
It was therefore decided to equilibrate the 1 : 1 : 1 : 1 mixture
of bis-spiroacetals 12a, 12b, 12c, 12d obtained from the final
radical cyclization with the idea of obtaining a simpler mixture
of thermodynamically favoured diastereomers.
Accordingly, the equimolar mixture of bis-spiroacetals 12a,
12b, 12c, 12d was dissolved in dichloromethane and stirred
at room temperature for 24 h with a catalytic quantity of p-
toluenesulfonic acid. Analysis of the crude product mixture by
1H and 13C NMR spectroscopy indicated that only three of the
four possible diastereomers (Scheme 6) were now present, in
a ratio of 3 : 1 : 0.9. This equilibrium product distribution
proved largely independent of the choice of reaction solvent
or acid catalyst, although the use of trifluoroacetic acid or
camphorsulfonic acid resulted in substantial destruction of the
bis-spiroacetal ring system. The mixture was partially separable
by careful preparative layer chromatography on glass-backed
plates using hexane–diethyl ether (9 : 1) as eluant that also
contained ca. 0.1% triethylamine to prevent epimerisation. After
several consecutive elutions, a less polar minor band and a more
polar major band were isolated. The 1H and 13C NMR spectra
of the less polar minor band indicated that a single diastereomer
1
was present, while the H and 13C NMR spectra of the more
polar major band indicated that two further diastereomers were
present in a 3 : 0.9 ratio. Further separation of these latter two
diastereomers proved elusive.
In an effort to unambiguously assign the stereochemistry of
the individual bis-spiroacetals using X-ray crystallography, the
tert-butyldiphenylsilyl ethers 12 were deprotected with tetra-
butylammonium fluoride and converted to their bromobenzoate
esters. Disappointingly, none of the bromobenzoate derivatives
yielded crystals suitable for X-ray analysis and the stereo-
Fig. 1 Putative assignments for bis-spiroacetals 12a, 12b and 12c
showing selected NOEs.
The major component 12a, of the 3 : 0.9 mixture of
diastereomers present in the more polar major band, was
also assigned as syn due to the lack of an NOE correlation
between H-14 and H-4, whereas the stereochemistry of the minor
3 5 7 6
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 7 3 – 3 5 8 3

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Scheme 6 Reagents and conditions and yields: (i) p-TsOH, CH2Cl2, room temp., 24 h, 12b, 80%, 12a : 12c (3 : 1), 68%; (ii) dimethyldioxirane, acetone,
K2CO3, 0 ◦C, 16 h, 33a : 33c (3 : 1), 78%, 33b, 74%; (iii) LiEt2 (10 equiv.), pentane, −78 ◦C then room temp., 16 h, 34a : 34c (3 : 1), 74%; (iv) Ac2O,
py, DMAP, room temp., 1 h, 35a : 35c (3 : 1), 75%; (v) lithium pyrrolidinylamide, THF, −78 ◦C then room temp., 16 h, 11a : 11c (3 : 1), 50%; (vi)
Ac2O, py, DMAP, room temp., 1 h, 36a : 36c (3 : 1), 67%.
component 12c was established as having an anti relationship
between the C-2 alkyl substituent and the C-5–O-6 bond due
to the strong NOE correlation observed between H-4a and the
unresolved methylene protons H-13 and H-14. Assignment of
these latter two diasteromers as cis or trans was more difficult.
For the anti diastereomer 12c, NOEs were observed between
the vinylic proton H-12 and one of the geminal methylene
protons H-14a, as well as between the other geminal proton
H-14b and H-4, suggesting that H-12 and H-4 were on opposite
faces of the central five-membered ring, thus establishing the
stereochemistry of the terminal rings to be trans. The minor
component of the more polar band was therefore assigned as
trans anti 12c. The lack of similar NOEs being observed in the
case of the major component of the more polar major band
suggested assignment of this bis-spiroacetal diastereomer as cis
syn 12a.
of the four diastereomers 12a, 12b, 12c, 12d were examined using
computer-based molecular modelling (tert-butyldiphenylsilyl
ether replaced by trimethylsilyl ether for calculations). Relative
energies were calculated at the ab initio level (Hartree–Fock, 3–21
G* basis set), using semi-empirical optimized geometries (AM1)
for all molecular mechanics conformers (MMFF94) within 3
kcal−1 mol−1 of the global minimum. The calculated energies
followed the trend: cis syn 12a < trans syn 12b < trans anti 12c
ꢁ cis anti 12d (Fig. 1), thus further supporting the assignment of
the major component of the more polar band as cis syn 12a and
the minor component as trans anti 12c. The major isomer formed
in the present work is the most stable cis syn diastereomer 12a
and this isomer has the same configuration as the bis-spiroacetal
ring system present in spirolides B 1 and D 2.
With bis-spiroacetals 12a, 12b, 12c in hand, epoxidation of
the alkene and subsequent base-induced rearrangement of the
resultant epoxides 33 to allylic alcohols 34 and homoallylic alco-
hols 11 was next investigated (Scheme 6). The more polar major
In an effort to gain more information about the thermody-
namic preferences of the 5,5,6-bis-spiroacetal ring system, each
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 7 3 – 3 5 8 3
3 5 7 7

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band, containing alkenes 12a and 12c (3 : 1), was treated with
a solution of dimethyldioxirane in acetone22 to afford epoxides
33a and 33c (3 : 1) in 78% yield. H-12 of the predominant
component of the product mixture 33a resonated as a doublet at
d 3.02 ppm in the 1H NMR spectrum (CDCl3), while H-12 of the
remaining component 33c resonated as a doublet at d 2.87 ppm.
Both doublets exhibited coupling constants of 3.9 Hz. It was
interesting to note that when the NMR spectrum was recorded in
deuterated benzene, these two H-12 doublets resonated at d 3.10
and 2.69 ppm, respectively. Analogous treatment of the minor
band 12b with dimethyldioxirane afforded a single epoxide 33,
exhibiting a doublet assigned to H-12 with a coupling constant
of 3.9 Hz, at d 2.92 in CDCl3 or 3.12 ppm in C6D6 respectively.
Due to the fact that a single alkene gave rise to a single
epoxide, it appeared that the epoxidation with dimethyldioxirane
proceeded with high facial selectivity, as previously observed13
in related 1,7-dioxaspiro[5,5]undec-4-ene ring systems. This can
be rationalised by significant steric interactions involving the
bulky tert-butyldiphenylsilyl ether which disfavour the approach
of dimethyldioxirane from the b face. Dipole–dipole repulsions,
which would also disfavour b approach,23 reinforce the steric
influence upon facial selectivity for the syn configurations cis
syn 12a and trans syn 12b, due to the b disposition of the central
Fig. 2 Transition states required for base-induced rearrangement of
a-epoxide 33a. The b-epoxide does not react due to the lack of an axial
syn-hydrogen atom.
11c was investigated using tetrahydrofuran as solvent. Thus, a
3 : 1 mixture of allylic alcohols 34a, 34c was added to a solution
of lithium diethylamide (10 equiv.) in tetrahydrofuran at −78 ◦C
and the mixture was warmed slowly to room temperature.
After 16 hours, subsequent work-up and purification by flash
chromatography afforded recovered starting materials 34a, 34c,
together with the desired homoallylic alcohols 11a, 11c (3 : 1
mixture) in 35% yield.
In the course of their investigations into the rearrangement
of epoxides with lithium amide bases, Rickborn and Kissel24
found that the secondary amine used to generate the amide
base also influenced the relative amounts of allylic alcohols and
homoallylic alcohols formed in these reactions. In particular, the
lithium amide of pyrrolidine was found to be the most effective
base to maximise the formation of the homoallylic alcohols.
Accordingly, allylic alcohols 34a, 34c (3 : 1) were treated with the
lithium amide base derived from pyrrolidine and n-butyllithium
(10 equiv.) at −78 ◦C and the mixture was allowed to warm
slowly to room temperature over 16 hours. Subsequent work-up
and purification by flash chromatography afforded homoallylic
alcohols 11a, 11c (3 : 1) in an improved 50% yield.
=
ring oxygen with respect to the C-11 12 double bond. Epoxides
33a, 33b, 33c were therefore all assigned as a and this assignment
was later verified by the successful execution of the base-induced
rearrangement reaction. Due to the small amount of epoxide
33b available, the rearrangement studies were only carried out
on epoxides 33a and 33c derived from the more predominant 3
: 1 mixture of bis-spiroacetal alkenes 12a and 12c.
Exposure of the 3 : 1 mixture of epoxides 33a and 33c◦to
lithium diethylamide (10 equiv.) in tetrahydrofuran at −78 C
disappointingly did not effect the desired rearrangement and
returned only the unreacted starting material. The reaction also
failed to proceed either at room temperature or under reflux
for periods of up to 24 h. It was concluded that the Lewis
basicity of the tetrahydrofuran solvent disrupted the required
coordination of lithium diethylamide and the epoxide oxygen.
The 3 : 1 mixture of epoxides 33a and 33c was therefore treated
with lithium diethylamide (10 equiv.) in the non-coordinating
solvent pentane at −78 ◦C (Scheme 6). The reaction mixture was
then allowed to warm slowly to room temperature and stirred
for a further 16 h, to afford a 3 : 1 mixture of allylic alcohols 34a
and 34c in 74% yield.
The 1H NMR spectrum of the mixture of homoallylic alcohols
11a, 11c (3 : 1) showed significant differences in the resonances
due to the alkene protons, in comparison to the allylic alcohol
starting materials. In the mixture of allylic alcohols 34a, 34c,
H-10 and H-11 resonated as a single multiplet at d 5.8 ppm,
however the spectrum of homoallylic alcohols 11a, 11c exhibited
multiplets at d 4.64 and 6.17 ppm corresponding to H-10 and H-
9 respectively. This large difference in chemical shifts observed
for the vinylic protons reflects the fact that honoallylic alcohols
11a, 11c are in fact cyclic enol ethers. In the 13C NMR spectrum,
the resonance due to C-9 appeared significantly downfield at d
141.2 ppm.
Alcohols 11a, 11c were also converted to their acetate
derivatives 36a, 36c under standard conditions in order to aid
in the interpretation of the NMR spectra. Acetylation of the
secondary alcohol caused a large downfield shift in the resonance
of H-12, from d 3.8 ppm in homoallylic alcohols 11a, 11c, to d
4.9 ppm in homoallylic acetates 36a, 36c. More importantly,
separate resonances were now observed for C-10 and C-7,
at d 98.0 and 105.0 ppm respectively, which were previously
coincidental at d 98.7 ppm in the homoallylic alcohols 11a, 11c.
In summary, the first synthesis of the 5,5,6-bis-spiroacetal ring
system present in spirolides B 1 and D 2 has been achieved using
a novel iterative oxidative radical cyclization strategy. The mild
conditions used, and the high yields obtained for the cyclization
steps, suggest that this approach is a practical method for the
construction of this ring system. The stereogenic centres at C-2
and C-3 on the bis-spiroacetal ring were assembled using the
Brown and Bhat crotyl metallation methodology. Unsaturated
bis-spiroacetals 12a, 12c were successfully elaborated to ho-
moallylic alcohols 11a, 11c via epoxidation and base-induced
rearrangement, however the synthetic utility of this approach is
limited by the presence of inseparable diastereomers due to the
stereogenic spirocentres at C-5 and C-7.
The 1H NMR spectrum of the 3 : 1 mixture of alcohols 34a and
34c lacked the doublets at d 3.02 and 2.87 ppm corresponding
to H-12 of epoxides 33a and 33c, respectively. A new two proton
multiplet was observed at d 5.8 ppm indicating the presence
of a double bond. In the 13C NMR spectrum, the methine
resonances at d 51.3 and 53.6 ppm corresponding to the epoxide
carbons C-11 and C-10 were no longer present. Two new vinylic
carbons assigned to C-10 and C-11 were observed at d 126.0
and 128.0 ppm together with a methine resonance at d 67.5 ppm
assigned to C-12. The C-7 spiro carbon also shifted downfield
from d 103.4 ppm in the epoxide to d 107.2 ppm. Alcohols 34a,
34c were also converted to their acetate derivatives 35a, 35c
under standard conditions in order to aid the interpretation of
the NMR spectra.
The outcome of this base-induced rearrangement confirmed
that 33a and 33c were in fact a-epoxides, as only the a-
epoxides possess a pseudo-axial proton required for base-
induced rearrangement to proceed successfully (Fig. 2).
With allylic alcohols 34a, 34c in hand, attention focussed on
their rearrangement to homoallylic alcohols 11. Our earlier
studies on base-induced rearrangements of epoxides using
bicyclic spiroacetal systems established that better yields of the
homoallylic alcohols were obtained using tetrahydrofuran as
solvent rather than hexane or hexane–diethyl ether mixtures.
In the present work isomerisation of allylic alcohols 34a, 34c to
the more thermodynamically favoured homoallylic alcohols 11a,
3 5 7 8
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 7 3 – 3 5 8 3

View Article Online
25.3 (CH2, CH2CH=CH, C-5ꢀ*), 26.8 (CH3, SitBuPh2), 31.7
(CH2, CH2CH2O, C-7), 33.1 (CH2, CH2CHO, C-1), 33.2 (CH2,
CH2CHO, C-1*), 35.37 (CH, CHMe, C-5), 35.43 (CH, CHMe,
C-5*), 35.55 (CH2, CH2CHO, C-2), 35.64 (CH2, CH2CHO, C-
2*), 40.0 (CH2, CH2CHMe, C-4), 61.1 (CH2, CH2OSi, C-8), 63.6
(CH2, CH2O, C-6ꢀ), 70.0 (CH, CHOH, C-3), 70.1 (CH, CHOH,
C-3*), 72.65 (CH, CHOSi, C-6), 72.69 (CH, CHOSi, C-6*),
74.0 (CH, CHO, C-2ꢀ), 74.1 (CH, CHO, C-2ꢀ*), 124.8 (CH,
CH=CHCH2, C-4ꢀ), 127.6 (CH, ArH, m), 129.6 (CH, ArH, p),
130.29 (CH, CH=CHCH2, C-3ꢀ), 130.34 (CH, CH=CHCH2,
C-3ꢀ*), 133.9 (quat., ArSi), 135.6 (CH, ArH, o); m/z (CI, NH3):
611 (MH+, 13%), 479 (19), 461 (9), 455 (12), 401 (14), 283 (12),
216 (26), 205 (27), 199 (30), 196 (32), 132 (29), 120 (35), 91 (48),
83 (48), 78 (100).
Experimental
(2ꢀR,3S,5R,6R)- and (2ꢀS,3S,5R,6R)-8-(tert-Butyldiphenyl-
silyloxy)-1-(5,6-dihydro-2H-pyran-2-yl)-5-methyl-6-(triethyl-
silyloxy)octan-3-ol (14a,14b) (2ꢀR,3R,5R,6R)- and (2ꢀS,3S,5R,
6R)-8-(tert-butyldiphenylsilyloxy)-1-(5,6-dihydro-2H-pyran-2-
yl)-5-methyl-6-(triethylsilyloxy)octan-3-ol (14c,14d)
Flame-dried magnesium powder (150 mg, 6.3 mmol) was
vigorously stirred in a pear-shaped flask under a nitrogen
atmosphere for 4 h, after which time diethyl ether (1.0 mL),
a single crystal of iodine (5 mg) and 1,2-dibromoethane (50 lL,
0.2 mmol) were added. When decolourisation had occurred the
flask was cooled to 0 ◦C in an ice bath and a mixture of bromide
16 (0.69 g, 3.63 mmol), aldehyde 15 (1.45 g, 2.91 mmol) and
diethyl ether (2.0 g) was added slowly dropwise over 60 min via
syringe. After stirring for a further 60 min at room temperature,
saturated aqueous sodium bicarbonate (1.0 mL) was added and
the reaction mixture extracted with diethyl ether (60 mL). The
organic layer was washed with water (15 mL) and brine (15 mL)
and was dried over MgSO4. Removal of the solvent under a
reduced pressure, followed by flash column chromatography
using hexane–ethyl acetate (19 : 1–1 : 1) gave a 1 : 1 : 1 : 1
mixture of the title compounds 14a, 14b, 14c, 14d (1.12 g, 64%)
as a colourless oil. 14a, 14b and 14c, 14d were separable by
careful chromatography if desired, but the 1 : 1 : 1 : 1 mixture
was routinely used for the preparation of spiroacetals 32.
(2S,2ꢀR,3ꢀR,5R)- and (2S,2ꢀR,3ꢀR,5S)-2-[5ꢀ-(tert-Butyldiphenyl-
silyloxy)-2ꢀ-methyl-3ꢀ-(triethylsilyloxy)pentyl]-1,6-dioxaspiro
[4.5]dec-9-ene (32a,32b)
Iodine (60 mg, 0.24 mmol) and iodobenzene diacetate (70 mg,
0.22 mmol) were added to a 1 : 1 solution of alcohols 14a, 14b
(60 mg, 0.10 mmol) in cyclohexane (10 mL). After stirring for
1 h under 40 W irradiation at room temperature, the reaction
mixture was diluted with diethyl ether (50 mL) and shaken with
saturated aqueous sodium thiosulfate–sodium bicarbonate (1 :
1, 10 mL) until colourless. The organic layer was washed with
brine (10 mL) and dried over anhydrous potassium carbonate.
Removal of the solvent under a reduced pressure, followed by
flash column chromatography using hexane–diethyl ether (9 :
1) as eluant afforded a 1 : 1 mixture of the title compounds
32a, 32b (54 mg, 90%) as a colourless oil [Found (CI, NH3):
MH+, 609.3791. C36H57O4Si2 requires Mr, 609.3795]; mmax/cm−1
(CDCl3): 3053, 2986, 2959, 2876, 2305, 1422, 1265, 1111, 1079,
1018, 895, 736; dH (300 MHz, CDCl3): 0.57 (6H, q, J 8.0,
SiCH2CH3), 0.82–0.91 (12H, m, Me and SiCH2CH3), 1.05
(9H, s, SitBuPh2), 1.48–2.29 (11H, m, H-1ꢀ, H-2ꢀ, H-3, H-
4, H-4ꢀ and H-8), 3.64–3.77 (3H, m, H-5ꢀ and H-7ax), 3.80–
3.84 (1H, m, CHOSi, H-3ꢀ), 3.92–4.01 (1H, m, CHaxHeqO,
Alcohols 14a, 14b [Found (CI, NH3): MH+, 611.3960;
C36H59O4Si2 requires Mr, 611.3952]; mmax/cm−1 (CDCl3): 3400,
3053, 2958, 2932, 2305, 1461, 1427, 1265, 1111, 1082, 895, 738,
705; dH (300 MHz, CDCl3): 0.59 (6H, q, J 8.2, SiCH2CH3),
0.84 (3H, d, JMe,5 7.0, Me), 0.93 (9H, t, J 8.2, SiCH2CH3), 1.05
(9H, s, SitBuPh2), 1.43–1.70 (8H, m, H-1, H-2, H-4 and H-7),
1.79–1.97 (2H, H-5 and H-5ꢀa), 2.19–2.32 (1H, m, CH=CHCH2,
H-5ꢀb), 3.54–3.73 (4H, m, H-3, H-6ꢀax and H-8), 3.84–3.91 (1H,
m, CHOSi, H-6), 3.93–4.03 (1H, m, CHaxHeqO, H-6ꢀeq), 4.05–
4.14 (1H, m, CHO, H-2ꢀ), 5.57–5.66 (1H, m, CH=CHCH2,
H-3ꢀ), 5.79–5.87 (1H, m, CH=CHCH2, H-4ꢀ), 7.33–7.45 (6H,
m, ArH, m and p), 7.60–7.69 (4H, m, ArH, o); dC (75 MHz,
CDCl3): 5.8 (SiCH2CH3), 6.6 (SiCH2CH3), 15.8 (CH3, Me), 15.9
(CH3, Me*), 19.0 (quat., SitBuPh2), 25.18 (CH2, CH2CH=CH,
C-5ꢀ), 25.21 (CH2, CH2CH=CH, C-5ꢀ*), 26.8 (CH3, SitBuPh2),
31.7 (CH2, CH2CH2O, C-7), 31.8 (CH2, CH2CH2O, C-7*), 34.2
(CH2, CH2CHO, C-1), 34.3 (CH2, CH2CHO, C-1*), 34.5 (CH2,
CH2CHO, C-2), 34.6 (CH2, CH2CHO, C-2*), 36.6 (CH, CHMe,
C-5), 40.9 (CH2, CH2CHMe, C-4), 41.0 (CH2, CH2CHMe, C-
4*), 63.6 (CH2, CH2O, C-6ꢀ), 63.7 (CH2, CH2O, C-6ꢀ*), 63.9
(CH2, CH2OSi, C-8), 64.0 (CH2, CH2OSi, C-8*), 70.2 (CH,
CHOH, C-3), 70.5 (CH, CHOH, C-3*), 74.1 (CH, CHO, C-
2ꢀ), 74.2 (CH, CHO, C-2ꢀ*), 75.1 (CH, CHOSi, C-6), 75.2 (CH,
CHOSi, C-6*), 124.8 (CH, CH=CHCH2, C-4ꢀ), 127.7 (CH,
ArH, m), 129.8 (CH, ArH, p), 130.2 (CH, CH=CHCH2, C-
3ꢀ), 133.0 (quat., ArSi), 135.6 (CH, ArH, o); m/z (CI, NH3): 611
(MH+, 4%), 501 (3), 485 (5), 479 (4), 455 (10), 291 (22), 216 (24),
199 (20), 196 (32), 132 (27), 120 (34), 78 (100).
ꢀ
ꢀ
H-7eq), 4.17–4.26 (1H, m, CHO, H-2), 5.60 (1H, br d, J10 ,9
11.3, CH=CHCH2, H-10), 5.93–6.02 (1H, m, CH=CHCH2,
H-9), 7.36–7.44 (6H, m, ArH, m and p), 7.64–7.70 (4H,
m, ArH, o); dC (100 MHz, CDCl3): 5.2 (CH3, SiCH2CH3),
7.0 (CH3, SiCH2CH3), 14.1 (CH3, Me), 14.5 (CH3, Me*),
19.2 (quat., SitBuPh2), 24.54 (CH2, CH2CH=CH, C-8), 24.59
(CH2, CH2CH=CH, C-8*), 26.8 (CH3, SitBuPh2), 31.1 (CH2,
CH2CH2O, C-4ꢀ), 31.4 (CH2, CH2CH2O, C-4ꢀ*), 35.4 (CH,
CHMe, C-2ꢀ), 36.2 (CH2, CH2CHO, C-3), 36.7 (CH2, CH2CHO,
C-3*), 37.3 (CH2, CH2CHO, C-4), 38.4 (CH2, CH2CHO, C-4*),
41.6(CH2, CH2CHMe, C-1ꢀ), 58.5(CH2, CH2O, C-7), 59.1 (CH2,
CH2O, C-7*), 61.2 (CH2, CH2OSi, C-5ꢀ), 72.9 (CH, CHOSi, C-
3ꢀ), 73.3 (CH, CHOSi, C-3ꢀ*), 76.4 (CH, CHO, C-2), 78.8 (CH,
CHO, C-2*), 102.2 (quat., C-5), 102.5 (quat., C-5*), 127.6 (CH,
ArH, m), 128.9 (CH, CH=CHCH2, C-9), 129.5 (CH, ArH, p),
130.2 (CH, CH=CHCH2, C-10), 134.0 (quat., ArSi), 135.6 (CH,
ArH, o); m/z (CI, NH3): 609 (MH+, 11%), 593 (6), 579 (11), 551
(6), 477 (54), 455 (23), 397 (12), 283 (16), 221 (20), 216 (25), 199
(26), 196 (28), 139 (35), 78 (100).
Alcohols 14c, 14d as a colourless oil [Found (CI, NH3):
MH+, 611.3944. C36H59O4Si2 requires Mr, 611.3952]; mmax/cm−1
(CDCl3): 3400, 3053, 2958, 2932, 2305, 1461, 1427, 1265, 1111,
1082, 895, 738, 705; dH (400 MHz, CDCl3): 0.57 (6H, q, J
8.2, SiCH2CH3), 0.84–0.93 (12H, m, SiCH2CH3 and Me), 1.05
(9H, s, SitBuPh2), 1.43–1.70 (8H, m, H-1, H-2, H-4 and H-7),
1.81 (1H, m, H-5), 1.88 (0.5H, br s, CH=CHCHaHb H-5ꢀa),
1.92 (0.5H, br s, CH=CHCHaHb H-5ꢀa*), 2.22–2.34 (1H, m,
CH=CHCH2, H-5ꢀb), 2.85 (0.5H, br s, OH), 3.05 (0.5H, br s,
OH*), 3.62–3.73 (4H, m, H-3, H-6ꢀax and H-8), 3.84–3.89 (1H,
m, CHOSi, H-6), 3.95–4.01 (1H, m, H-6ꢀeq), 4.12 (1H, br s,
(2R,2ꢀR,3ꢀR,5R)- and (2R,2ꢀR,3ꢀR,5S)-2-[5ꢀ-(tert-Butyldiphenyl-
silyloxy)-2ꢀ-methyl-3ꢀ-(triethylsilyloxy)pentyl]-1,6-dioxaspiro
[4.5]dec-9-ene (32c,32d)
Iodine (60 mg, 0.24 mmol) and iodobenzene diacetate (69 mg,
0.22 mmol) were added to a 1 : 1 solution of alcohols 14c, 14d
(60 mg, 0.10 mmol) in cyclohexane (10 mL). After stirring for
1 h under 40 W irradiation at rt, the reaction mixture was diluted
with diethyl ether (50 mL) and shaken with saturated aqueous
sodium thiosulfate–sodium bicarbonate (3 : 1, 10 mL) until
colourless. The organic layer was washed with brine (10 mL)
and dried over anhydrous potassium carbonate. Removal of
the solvent under a reduced pressure, followed by flash column
CHO, H-2ꢀ), 5.61 (1H, br d, J3 ,4 10.0, CH=CHCH2, H-3ꢀ),
5.78–5.85 (1H, m, CH=CHCH2, H-4ꢀ), 7.34–7.44 (6H, m, ArH,
m and p), 7.61–7.69 (4H, m, ArH, o); dC (100 MHz, CDCl3):
5.1 (SiCH2CH3), 6.9 (SiCH2CH3), 16.5 (CH3, Me), 16.6 (CH3,
Me*), 19.1 (quat., SitBuPh2), 25.2 (CH2, CH2CH=CH, C-5ꢀ),
ꢀ
ꢀ
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 7 3 – 3 5 8 3
3 5 7 9

View Article Online
chromatography using hexane–diethyl ether (9 : 1) as eluant
afforded a 1 : 1 mixture of the title compounds 32c, 32d (54 mg,
90%) as a colourless oil [Found (CI, NH3): MH+, 609.3791;
C36H57O4Si2 requires Mr, 609.3795]; mmax/cm−1 (CDCl3): 3053,
2986, 2959, 2876, 2305, 1422, 1265, 1111, 1079, 1018, 895,
736; dH (300 MHz, CDCl3): 0.55 (6H, q, J 8.0, SiCH2CH3),
0.84–0.93 (12H, m, Me and SiCH2CH3), 1.04 (9H, s, SitBuPh2),
1.40–2.30 (11H, m, H-1ꢀ, H-2ꢀ, H-3, H-4, H-4ꢀ and H-8), 3.68–
3.76 (3H, m, H-7ax and H-5ꢀ), 3.78–3.83 (1H, m, CHOSi, H-3ꢀ),
3.93–4.02 (1H, m, CHaxHeqO, H-7eq), 4.12–4.20 (1H, m, CHO,
H-2), 5.61 (1H, br d, J10 ,9 11.2, CH=CHCH2, H-10), 5.95–
6.01 (1H, m, CH=CHCH2, H-9), 7.36–7.44 (6H, m, ArH, m
and p), 7.64–7.70 (4H, m, ArH, o); dC (100 MHz, CDCl3): 5.2
(CH3, SiCH2CH3), 7.0 (CH3, SiCH2CH3), 15.0 (CH3, Me), 15.3
(CH3, Me*), 19.2 (quat., SitBuPh2), 24.5 (CH2, CH2CH=CH,
C-8), 24.6 (CH2, CH2CH=CH, C-8*), 26.9 (CH3, SitBuPh2),
30.4 (CH2, CH2CH2O, C-4ꢀ), 30.9 (CH2, CH2CH2O, C-4ꢀ*), 35.8
(CH2, CH2CHO, C-3), 36.0 (CH2, CH2CHO, C-3*), 36.49 (CH,
CHMe, C-2ꢀ), 36.52 (CH, CHMe, C-2ꢀ*), 37.2 (CH2, CH2CHO,
C-4), 37.4 (CH2, CH2CHO, C-4*), 38.4 (CH2, CH2CHO, C-
1ꢀ), 40.3 (CH2, CH2CHO, C-1ꢀ*), 58.5 (CH2, CH2O, C-7), 59.2
(CH2, CH2O, C-7*), 61.17 (CH2, CH2OSi, C-5ꢀ), 61.21 (CH2,
CH2OSi, C-5ꢀ*), 72.7 (CH, CHOSi, C-3ꢀ), 72.8 (CH, CHOSi,
C-3ꢀ*), 77.5 (CH, CHO, C-2), 80.2 (CH, CHO, C-2*), 102.3
(quat., C-5), 127.6 (CH, ArH, m), 128.2 (CH, CH=CHCH2, C-
9), 128.8 (CH, CH=CHCH2, C-9*), 129.0 (CH, CH=CHCH2,
C-10), 129.2 (CH, CH=CHCH2, C-10*), 129.5 (CH, ArH, p),
133.98 (quat., ArSi), 134.04 (quat., ArSi*), 135.6 (CH, ArH, o);
m/z (CI, NH3): 609 (MH+, 11%), 593 (6), 579 (11), 551 (6), 477
(54), 455 (23), 397 (12), 283 (16), 221 (20), 216 (25), 199 (26),
196 (28), 139 (35), 78 (100).
(CH2, CH2CHMe, C-1ꢀ*), 58.8 (CH2, CH2O, C-7), 59.2 (CH2,
CH2O, C-7*), 63.3 (CH2, CH2OSi, C-5ꢀ), 73.6 (CH, CHOH,
C-3ꢀ), 74.2 (CH, CHOH, C-3ꢀ*), 76.9 (CH, CHO, C-2), 79.1
(CH, CHO, C-2*), 102.6 (quat., C-5), 127.7 (CH, ArH, m),
128.8 (CH, CH=CHCH2, C-9), 128.9 (CH, CH=CHCH2, C-
10), 129.7 (CH, ArH, p), 133.4 (quat., ArSi), 135.6 (CH, ArH,
o); m/z (CI, NH3): 495 (MH+, 2%), 479 (14), 477 (MH+ − H2O,
28), 274 (35), 216 (41), 199 (24), 196 (72), 98 (44), 94 (38), 78
(100).
Alcohols 13c, 13d [Found (CI, NH3): MH+, 495.2903;
C30H43O4Si requires Mr, 495.2931]; mmax/cm−1 (CDCl3): 3460,
2958, 2930, 2857, 1471, 1462, 1427, 1213, 1111, 1078, 1027,
ꢀ
ꢀ
ꢀ
997, 702; dH (400 MHz, CDCl3): 0.94 (1.5H, d, JMe,2 6.7, Me),
0.95 (1.5H, d, JMe,2 6.7, Me*), 1.04 (9H, s, SitBuPh2), 1.48–2.30
ꢀ
(10.5H, m, H-1ꢀ, H-2ꢀ, H-3, H-4, H-4ꢀ and H-8), 2.40 (0.5H, dd,
J1 ,2 = J1 ,2 7.4, CHaHbCHO, H-1ꢀb*), 3.41 (0.5H, d, JOH,3 2.1,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
OH), 3.43 (0.5H, d, JOH,3 2.1, OH*), 3.74 (1H, ddd, J7ax,7eq
=
J7ax,8ax 10.3 and J7ax,8eq 5.7, CHaxHeqO, H-7ax), 3.80–3.98 (4H, m,
H-3ꢀ, H-5ꢀ and H-7eq), 4.24–4.30 (1H, m, CHO, H-2), 5.57–5.63
(1H, m, CH=CHCH2, H-10), 5.95–6.02 (1H, m, CH=CHCH2,
H-9), 7.36–7.43 (6H, m, SiArH, m and p), 7.66–7.69 (4H, m,
SiArH, o); dC (100 MHz, CDCl3): 13.9 (CH3, Me), 14.2 (CH3,
Me*), 19.1 (quat., SitBuPh2), 24.4 (CH2, CH2CH=CH, C-8),
24.5 (CH2, CH2CH=CH, C-8*), 26.8 (CH3, SitBuPh2), 30.6
(CH2, CH2CHO, C-4ꢀ), 31.1 (CH2, CH2CHOSi, C-4ꢀ*), 35.5
(CH2, CH2CH2, C-4), 35.9 (CH2, CH2CH2, C-4*), 36.1 (CH,
CHMe, C-2ꢀ), 36.3 (CH, CHMe, C-2ꢀ*), 37.3 (CH2, CH2CH2,
C-3), 38.4 (CH2, CH2CH2, C-3*), 38.9 (CH2, CH2CHO, C-1ꢀ),
41.8 (CH2, CH2CHO, C-1ꢀ*), 58.7 (CH2, CH2O, C-7), 59.3 (CH2,
CH2O, C-7*), 63.5 (CH2, CH2OSi, C-5ꢀ), 63.6 (CH2, CH2OSi,
C-5ꢀ*), 73.8 (CH, CHOH, C-3ꢀ), 74.0 (CH, CHOH, C-3ꢀ*), 76.4
(CH, CHO, C-2), 79.7 (CH, CHO, C-2*), 102.5 (quat., C-5),
127.7 (CH, ArH, m), 128.4 (CH, CH=CHCH2, C-9), 128.7 (CH,
CH=CHCH2, C-9*), 128.9 (CH, CH=CHCH2, C-10), 129.0
(CH, CH=CHCH2, C-10*), 129.7 (CH, ArH, p), 133.2 (quat.,
ArSi), 133.3 (quat., ArSi*), 135.6 (CH, ArH, o); m/z (CI, NH3):
495 (MH+, 1%), 477 (2), 447 (1), 399 (1), 274 (2), 216 (4), 199
(5), 139 (2), 102 (100), 86 (47).
(2S,2ꢀR,3ꢀR,5R)- and (2S,2ꢀR,3ꢀR,5S)-2-[5ꢀ-(tert-Butyldiphenyl-
silyloxy)-3ꢀ-hydroxy-2ꢀ-methylpentyl]-1,6-dioxaspiro[4.5]dec-9-
ene (13a,13b) (2R,2ꢀR,3ꢀR,5R)- and (2R,2ꢀR,3ꢀR,5S)-2-[5ꢀ-(tert-
butyldiphenylsilyloxy)-3ꢀ-hydroxy-2ꢀ-methylpentyl]-1,6-dioxa-
spiro[4.5]dec-9-ene (13c,13d)
A solution of pyridinium hydrochloride was prepared by bub-
bling freshly prepared hydrogen chloride gas through pyridine
(100 mL) with the formation of a crystalline precipitate.
Further pyridine was added portionwise until the precipitate
just redissolved. An equimolar mixture of bis-silyl ethers 13a,
13b, 13c, 13d (150 mg, 0.25 mmol) was dissolved in an aliquot
of this HCl–pyridine solution (5.0 mL) and stirred for 48 h at
50 ◦C. Saturated aqueous sodium bicarbonate (1.0 mL) was then
added and the reaction mixture extracted with ethyl acetate (2 ×
15 mL). The organic extracts were washed with brine (5 mL) and
dried over magnesium sulfate. Removal of the solvent under a
reduced pressure afforded an oil which was purified by flash
column chromatography using hexane–diethyl ether (9 : 1–0 : 1)
as eluant to afford a 1 : 1 : 1 : 1 mixture of the title compounds
13a, 13b, 13c, 13d (105 mg, 87%) as a colourless oil.
(2R,3R,5S,7R)-, (2R,3R,5R,7S)-, (2R,3R,5S,7S)- and
(2R,3R,5R,7R)-2-[2ꢀ-(tert-Butyldiphenylsilyloxy)ethyl]-3-
methyl-1,6,8-trioxadispiro[4.1.5.2]tetradec-11-ene
(12a,12b,12c,12d)
Iodine (230 mg, 0.91 mmol) and iodobenzene diacetate (280 mg,
0.87 mmol) were added to a 1 : 1 : 1 : 1 mixture of spiroacetal
alcohols 13a, 13b, 13c, 13d (205 mg, 0.41 mmol) in cyclohexane
(10 mL). After stirring for 1 h under 40 W irradiation at room
temperature, the reaction mixture was diluted with diethyl ether
(50 mL) and shaken with saturated aqueous sodium thiosulfate–
sodium bicarbonate (3 : 1, 10 mL) until colourless. The organic
layer was washed with brine (10 mL) and dried over anhydrous
potassium carbonate. Removal of the solvent under a reduced
pressure, followed by flash column chromatography using
hexane–diethyl ether (9 : 1) as eluant afforded a 1 : 1 : 1 : 1 mixture
of four diastereomers 12a, 12b, 12c, 12d (165 mg, 83%) as a
colourless oil [Found (CI, NH3): MH+, 493.2782. C30H41O4Si
requires Mr, 493.2774]; mmax/cm−1 (CDCl3): 2958, 2931, 2877,
2857, 1472, 1462, 1427, 1111, 1078, 994, 975, 702; dH (400 MHz,
CDCl3): 0.85–0.91 (3H, m, Me), 1.60–2.61 (11H, m, H-1ꢀ, H-3,
H-4, H-10, H-13 and H-14), 3.58–4.29 (5H, m, H-2, H-2ꢀ and
H-9), 5.53–5.66 (1H, m, CH=CHCH2, H-12), 5.85–5.99 (1H,
m, CH=CHCH2, H-11), 7.33–7.44 (6H, m, SiArH, m and p),
7.62–7.70 (4H, m, SiArH, o); dC (100 MHz, CDCl3): 14.1 (CH3,
Me), 14.3 (CH3, Me*), 14.5 (CH3, Me**), 14.6 (CH3, Me***),
19.17 (quat., SitBuPh2), 19.22 (quat., SitBuPh2*), 24.3 (CH2,
CH2CH=CH, C-10), 24.4 (CH2, CH2CH=CH, C-10*), 24.5
(CH2, CH2CH=CH, C-10**), 26.9 (CH3, SitBuPh2), 33.3 (CH2,
CH2CH2O, C-1ꢀ), 33.49 (CH2, CH2CH2O, C-1ꢀ*), 33.56 (CH2,
CH2CH2O, C-1ꢀ**), 33.64 (CH2, CH2CH2O, C-1ꢀ***), 34.5 (CH,
Alcohols 13a, 13b [Found (CI, NH3): MH+, 495.2910;
C30H43O4Si requires Mr, 495.2931]; mmax/cm−1 (CDCl3): 3460,
2958, 2930, 2857, 1471, 1462, 1427, 1213, 1111, 1078, 1027,
ꢀ
997, 702; dH (400 MHz, CDCl3): 0.92 (1.5H, d, JMe,2 6.8, Me),
0.94 (1.5H, d, JMe,2 6.8, Me*), 1.05 (9H, s, SitBuPh2), 1.40–
ꢀ
2.08 (10H, m, H-1ꢀa, H-2ꢀ, H-3, H-4, H-4ꢀ and H-8), 2.12–
228 (1H, m, CHaHbCHO, H-1ꢀb), 3.12 (0.5H, br s, OH), 3.17
(0.5H, br s, OH*), 3.73 (1H, m, CHaxHeqO, H-7ax), 3.80–3.96
(4H, m, H-3ꢀ, H-5ꢀ and H-7eq), 4.19–4.28 (1H, m, CHO, H-
2), 5.57–5.63 (1H, m, CH=CHCH2, H-10), 5.95–6.01 (1H, m,
CH=CHCH2, H-9), 7.37–7.44 (6H, m, SiArH, m and p), 7.65–
7.69 (4H, m, SiArH, o); dC (100 MHz, CDCl3): 14.2 (CH3,
Me), 19.1 (quat., SitBuPh2), 24.4 (CH2, CH2CH=CH, C-8), 24.5
(CH2, CH2CH=CH, C-8*), 26.8 (CH3, SitBuPh2), 31.3 (CH2,
CH2CHO, C-4ꢀ), 31.4 (CH2, CH2CHOSi, C-4ꢀ*), 35.7 (CH2,
CH2CH2, C-4), 36.6 (CH, CHMe, C-2ꢀ), 37.3 (CH2, CH2CH2, C-
3), 38.4 (CH2, CH2CH2, C-3*), 39.5 (CH2, CH2CH2, C-1ꢀ), 41.9
3 5 8 0
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 7 3 – 3 5 8 3

View Article Online
CHMe, C-3), 34.6 (CH, CHMe, C-3*), 35.3 (CH, CHMe, C-
3**), 35.7 (CH2, CH2CHO, C-13 or C-14), 36.2 (CH2, CH2CHO,
C-13* or C-14*), 36.4 (CH2, CH2CHO, C-13** or C-14**), 36.6
(CH2, CH2CHO, C-13*** or C-14***), 37.0 (CH2, CH2CHO, C-
14 or C-13), 37.2 (CH2, CH2CHO, C-14* or C-13*), 37.4 (CH2,
CH2CHO, C-14** or C-13**), 37.5 (CH2, CH2CHO, C-14*** or
C-13***), 44.97 (CH2, CH2CHO, C-4), 45.01 (CH2, CH2CHO, C-
4*), 45.2 (CH2, CH2CHO, C-4**), 45.9 (CH2, CH2CHO, C-4***),
59.20 (CH2, CH2O, C-9), 59.26 (CH2, CH2O, C-9*), 59.31 (CH2,
CH2O, C-9**), 59.3 (CH2, CH2O, C-9***), 61.5 (CH2, CH2O, C-
2ꢀ), 61.6 (CH2, CH2O, C-2ꢀ*), 61.69 (CH2, CH2O, C-2ꢀ**), 61.71
(CH2, CH2O, C-2ꢀ***), 78.0 (CH, CHO, C-2), 78.8 (CH, CHO,
C-2*), 79.3 (CH, CHO, C-2**), 102.6 (quat., C-7), 102.9 (quat.,
C-7*), 114.3 (quat, C-5), 114.8 (quat, C-5*), 115.3 (quat, C-5**),
127.6 (CH, ArH, m), 127.8 (CH, CH=CHCH2, C-11), 128.2
(CH, CH=CHCH2, C-11*), 128.4 (CH, CH=CHCH2, C-11**),
128.98 (CH, CH=CHCH2, C-11***), 129.03 (CH, CH=CHCH2,
C-12), 129.4 (CH, CH=CHCH2, C-12*), 129.5 (CH, ArH, p),
129.8 (CH, CH=CHCH2, C-12**), 130.1 (CH, CH=CHCH2, C-
12***), 133.9 (quat., ArSi), 134.1 (quat., ArSi*), 135.6 (CH, ArH,
o); m/z (EI): 492 (M+, 1%), 474 (M+ − H2O, 83), 447 (1), 435
2877, 2857, 1472, 1462, 1427, 1111, 1078, 994, 975, 702; dH
ꢀ
(400 MHz, CDCl3): 0.87 (0.75H, d, JMe,3 6.8, Me*), 0.89 (2.25H,
d, JMe,3 6.8, Me), 1.04 (9H, s, SitBuPh2), 1.54–1.73 (3H, m, H-1ꢀ
ꢀ
and H-4a), 1.82–2.31 (7H, m, H-4b, H-10, H-13 and H-14), 2.38–
2.52 (1H, m, CHMe, H-3), 3.7 (3H, m, H-2ꢀ and H-9eq), 3.87–
3.98 (1H, m, CHaxHeqOSi, H-9ax), 4.19–4.28 (1H, m, CHO, H-2),
5.57 (0.25H, br d, J12,11 10, CH=CHCH2, H-12*), 5.64 (0.75H,
br d, J12,1110, CH=CHCH2, H-12), 5.96 (1H, m, CH=CHCH2,
H-11), 7.34–7.42 (6H, m, SiArH, m and p), 7.65–7.71 (4H,
m, SiArH, o); dC (100 MHz, CDCl3): 14.5 (CH3, Me), 14.6
(CH3, Me*), 19.2 (quat., SitBuPh2), 24.3 (CH2, CH2CH=CH,
C-10*), 24.4 (CH2, CH2CH=CH, C-10), 26.9 (CH3, SitBuPh2),
33.56 (CH2, CH2CH2O, C-1ꢀ), 35.4 (CH, CHMe, C-3), 35.6
(CH, CHMe, C-3*), 35.7 (CH2, CH2CH2, C-13 or C-14), 36.2
(CH2, CH2CH2, C-13* or C-14*), 37.0 (CH2, CH2CH2, C-14
or C-13), 37.4 (CH2, CH2CH2, C-14* or C-13*), 45.2 (CH2,
CH2CHMe, C-4), 45.9 (CH2, CH2CHMe, C-4*), 59.27 (CH2,
CH2O, C-9), 61.71 (CH2, CH2OSi, C-2ꢀ), 78.0 (CH, CHO, C-2),
79.3 (CH, CHO, C-2*), 102.6 (quat., C-7), 114.3 (quat., C-5),
127.6 (CH, ArH, m), 128.2 (CH, CH=CHCH2, C-11), 128.4
(CH, CH=CHCH2, C-11*), 129.5 (CH, ArH, p), 129.0 (CH,
CH=CHCH2, C-12*), 129.8 (CH, CH=CHCH2, C-12), 134.1
(quat., ArSi), 135.6 (CH, ArH, o); m/z (EI): 492 (M+, 1%), 474
t
(M+ − Bu, 55), 417 (13), 337 (6), 219 (14), 199 (69), 136 (56),
109 (100).
t
(M+ − H2O, 83), 447 (1), 435 (M+ − Bu, 55), 417 (13), 337 (6),
219 (14), 199 (69), 136 (56), 109 (100).
(2R,3R,5S,7R)-, (2R,3R,5S,7S)- and (2R,3R,5R,7R)-2-[2ꢀ-(tert-
Butyldiphenylsilyloxy)ethyl]-3-methyl-1,6,8-trioxadispiro
[4.1.5.2]tetradec-11-ene 12a,12b,12c
(2R,3R,5S,7R,11S,12S)- and (2R,3R,5R,7R,11R,12R)-2-[2ꢀ-
(tert-Butyldiphenylsilyloxy)ethyl]-3-methyl-1,6,8-trioxa-
dispiro[4.1.5.2]-11,12-epoxy-tetradecanes (33a,33c)
A 1 : 1 : 1 : 1 mixture of the four diastereomers 12a, 12b, 12c, 12d
(165 mg, 0.33 mmol) was dissolved in dichloromethane (10 mL)
and stirred with p-toluenesulfonic acid (5 mg, 0.03 mmol) at
room temperature. After 24 h, triethylamine (50 lL) was added
and the solution filtered through a plug of silica. Removal of the
solvent under a reduced pressure afforded a colourless oil which
was purified by preparative layer chromatography (8 sweeps,
hexane–diethyl ether (9 : 1) containing 0.1% triethylamine) to
give band A containing the less polar trans syn bis-spiroacetal
12b (30 mg, 18%) and band BC containing an inseparable 3 : 1
mixture of the more polar bis-spiroacetals cis syn 12a and trans
anti 12c (113 mg, 68%).
Dimethyldioxirane (2.0 mL of a ca. 0.1 M solution in acetone,
0.2 mmol) was added dropwise to a stirred solution of the
major bis-spiroacetal band BC containing a 3 : 1 mixture of
cis syn 12a and trans anti 12c (50 mg, 0.10 mmol), potassium
˚
carbonate (20 mg, 0.14 mmol) and activated 4 A molecular
sieves in acetone (2.0 mL) at 0 ◦C. After stirring for 16 h at room
temperature, further dimethyl dioxirane (1.0 mL, 0.1 mmol) was
added and stirring continued for 8 h. The reaction mixture was
then filtered and the solvents removed under a reduced pressure
to afford a pale yellow oil which was purified by flash column
chromatography using hexane–diethyl ether (9 : 1–1 : 1) as eluant
to afford the title compounds 33a, 33c (40 mg, 3 : 1, 78%)
as a colourless clear oil [Found (CI, NH3): MH+, 509.2718;
C30H41O5Si requires Mr, 507.2723]; mmax/cm−1 (CDCl3): 2955,
2929, 2856, 1471, 1427, 1359, 1272, 1111, 1083, 999, 885, 840,
822, 739, 702, 614; dH (400 MHz, CDCl3): 0.90 (0.75H, d, J
6.9, Me*), 0.91 (2.25H, d, J 6.9, Me), 1.05 (9H, s, SitBuPh2),
1.58–1.72 (3H, m, H-1ꢀ and H-4a), 1.79–2.36 (7H, m, H-4b,
H-10, H-13 and H-14), 2.40–2.50 (1H, m, CHMe, H-3), 2.87
(0.25H, d, J12,11 3.9, CHOCHCH2, H-12*), 3.02 (0.75H, d,
J12,11 3.9, CHOCHCH2, H-12*), 3.35 (0.75H, dd, J11,12 = J11,10a
3.9, CHOCHCH2, H-11), 3.39 (0.25H, dd, J11,12 = J11,10a 3.9,
CHOCHCH2, H-11*), 3.42–3.48 (1H, m, CHaxHeqO, H-9eq),
3.70–3.82 (3H, m, H-2ꢀ and H-9ax), 4.25–4.32 (1H, m, CHO,
H-2), 7.34–7.43 (6H, m, SiArH, m and p), 7.67–7.70 (4H, m,
SiArH, o); dC (100 MHz, CDCl3): 14.6 (CH3, Me), 19.2 (quat,.
tBuPh2), 22.7 (CH2, CH2CH2O, C-10*), 23.1 (CH2, CH2CH2O,
trans syn Bis-spiroacetal 12b (minor band A), colourless oil
[Found (CI, NH3): MH+, 493.2782; C30H41O4Si requires Mr,
493.2774]; [a]D20 = +10.0 10−1 deg cm2 g−1 (c = 1.8, CDCl3);
mmax/cm−1 (CDCl3): 2958, 2931, 2877, 2857, 1472, 1462, 1427,
1111, 1078, 994, 975, 702; dH (400 MHz, CDCl3): 1.01 (3H, d,
JMe,3 6.8, Me), 1.04 (9H, s, SitBuPh2), 1.67–1.75 (1H, m, H-1ꢀa),
ꢀ
1.82–2.06 (6H, m, H-1ꢀb, H-4a, H-10a, H-13a, H-14), 2.13–2.26
(4H, m, H-3, H-4b, H-10b and H-13b), 3.74 (1H, dddd, Jgem
11.2, J9eq,10ax 5.6 and J9eq,10eq = J9eq,11 1.2, CHeqHaxO, H-9eq), 3.77–
3.82 (2H, m, CH2OSi, H-2ꢀ), 3.91 (1H, ddd, Jgem = J9ax,10ax 11.2
and J9ax,10eq 3.8, CHeqHaxO, H-9ax), 4.09 (1H, m, CHO, H-2),
5.57 (1H, ddd, J12,11 10.0, J12,10a 2.6 and J12,10b 1.4, CH=CHCH2,
H-12), 5.89 (1H, dddd, J11,12 10.0, J11,10a 5.4, J11,10b 2.2 and J11,9a
1.2, CH=CHCH2, H-11), 7.36–7.42 (6H, m, SiArH, m and p),
7.65–7.70 (4H, m, SiArH, o); dC (100 MHz, CDCl3): 14.3 (CH3,
Me), 19.2 (quat., SitBuPh2), 24.4 (CH2, CH2CH=CH, C-10),
26.9 (CH3, SitBuPh2), 33.7 (CH2, CH2CH2O, C-1ꢀ), 35.3 (CH,
CHMe, C-3), 36.5 (CH2, CH2CH2, C-13 or C-14), 36.6 (CH2,
CH2CH2, C-14 or C-13), 45.0 (CH2, CH2CHO, C-4), 59.4 (CH2,
CH2O, C-9), 61.5 (CH2, CH2OSi, C-2ꢀ), 78.8 (CH, CHO, C-
2), 102.9 (quat., C-7), 114.8 (quat., C-5), 127.6 (CH, ArH, m),
127.8 (CH, CH=CHCH2, C-11), 129.5 (CH, ArH, p), 130.1
(CH, CH=CHCH2, C-12), 134.1 (quat., ArSi), 135.6 (CH, ArH,
o); m/z (EI): 492 (M+, 1%), 474 (M+ − H2O, 83), 447 (1), 435
t
C-10), 26.9 (CH3, BuPh2), 33.4 (CH2, CH2CH2O, C-1ꢀ), 34.5
(CH, CHMe, C-3), 34.6 (CH2, CH2CHO, C-13 or C-14), 34.9
(CH2, CH2CHO, C-14 or C-13), 35.4 (CH2, CH2CHO, C-14* or
C-13*), 44.4 (CH2, CH2CHMe, C-4), 51.3 (CH, CHOCHCH2,
C-11), 53.4 (CH, CHOCHCH2, C-12), 56.7 (CH2, CH2O, C-9),
61.5 (CH2, CH2OSi, C-2ꢀ), 77.9 (CH, CHO, C-2), 78.1 (CH,
CHO, C-2*), 103.4 (quat., C-7), 115.4 (quat., C-5), 127.6 (CH,
ArH, m), 129.5 (CH, ArH, p), 134.0 (quat., ArSi), 135.6 (CH,
ArH, o); m/z (EI): 508 (M+, 1%), 490 (M+-H2O, 10), 451 (21),
433 (10), 325 (32), 199 (100), 149 (63), 91 (65), 57 (78), 42 (67),
41 (68); m/z (CI, NH3): 509 (MH+, 41%), 491 (MH+ − H2O,
35), 475 (27), 325 (30), 216 (42), 199 (79), 109 (46), 91 (52), 78
(100), 75 (51).
t
(M+ − Bu, 55), 417 (13), 337 (6), 219 (14), 199 (69), 136 (56),
109 (100).
cis syn Bis-spiroacetal 12a and trans anti bis-spiroacetal 12c
(major band BC), colourless oil [Found (CI, NH3): MH+,
493.2782. C30H41O4Si requires Mr, 493.2774]; [a]2D0 = +17.2 10−1
deg cm2 g−1 (c = 1.8, CDCl3); mmax/cm−1 (CDCl3): 2958, 2931,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 7 3 – 3 5 8 3
3 5 8 1

View Article Online
(2R,3R,5S,7S,11R,12R)-2-[2ꢀ-(tert-Butyldiphenylsilyloxy)
ethyl]-3-methyl-1,6,8-trioxadispiro[4.1.5.2]-11,12-epoxy-tetra-
decane (33b)
CH2CHO, C-2), 79.3 (CH, CH2CHO, C-2*), 107.2 (quat., C-
7), 107.6 (quat., C-7*), 115.2 (quat., C-5), 115.5 (quat., C-5*),
125.0 (CH, CH=CHCH2, C-10*), 126.0 (CH, CH=CHCH2, C-
10), 127.6 (CH, ArH, m), 128.0 (CH, CH=CHCH2, C-11), 129.5
(CH, ArH, p), 129.8 (CH, CH=CHCH2, C-11*), 133.8 (quat.,
ArSi), 134.0 (quat., ArSi*), 135.6 (CH, ArH, o); m/z (CI, NH3):
509 (MH+, 11%), 491 (MH+ − H2O, 100), 216 (47), 199 (55),
196 (40), 78 (48).
Using a similar procedure to that described for 33a, 33c
above, band A containing trans syn bis-spiroacetal 12b (18 mg,
0.037 mmol) was reacted with dimethyldioxirane (2.0 mL,
0.2 mmol) to give the title compound 33b (14 mg, 74%) as a
colourless oil [Found (CI, NH3): MH+, 509.2718; C30H41O5Si
requires Mr, 507.2723]; mmax/cm−1 (CDCl3): 2955, 2929, 2856,
1471, 1427, 1359, 1272, 1111, 1083, 999, 885, 840, 822, 739, 702,
(2R,3R,5S,7R,12S)- and (2R,3R,5R,7R,12R)-12-Acetoxy-2-[2ꢀ-
(tert-butyldiphenylsilyloxy)ethyl]-3-methyl-1,6,8-trioxadispiro
[4.1.5.2]tetradec-10-ene (35a,35c)
ꢀ
614; dH (400 MHz, CDCl3): 0.96 (3H, d, JMe,3 7.0, CH3, Me),
1.05 (9H, s, SitBuPh2), 1.65–2.32 (11H, m, H-1ꢀ, H-3, H-4, H-10,
H-13 and H-14), 2.92 (1H, d, J12,11 3.9, CHOCHCH2, H-12),
3.31 (1H, dd, J11,12 = J11,10a 3.9, CHOCHCH2, H-11), 3.42–3.50
(1H, m, CHaxHeqO, H-9eq), 3.70–3.86 (3H, m, H-2ꢀ and H-9ax),
4.11–4.19 (1H, m, CHO, H-2), 7.34–7.43 (6H, m, SiArH, m
and p), 7.67–7.70 (4H, m, SiArH, o); dC (100 MHz, CDCl3):
A mixture of allylic alcohols 34a, 34c (3 : 1, 14 mg, 0.029 mmol),
pyridine (1.5 mL), acetic anhydride (0.25 mL, 2.6 mmol) and
a catalytic quantity of DMAP was stirred at room temperature
for 60 min. Saturated aqueous sodium bicarbonate (1.0 mL) was
added and the reaction mixture extracted with dichloromethane
(2 × 10 mL). The organic layer was washed with brine, dried
over a mixture of potassium carbonate and magnesium sulfate
and eluted through a short column of silica. Removal of the
solvent under a reduced pressure afforded a 3 : 1 mixture of
the title compounds 35a, 35c (11 mg, 75%) as a pale yellow oil
[Found (CI, NH3): MH+, 551.2825; C32H43O6Si requires Mr,
551.2830]; mmax/cm−1(neat): 3584, 2966, 2928, 2863, 1737, 1642,
1598, 1428, 1369, 1260, 1110, 1093, 1020, 799; dH (400 MHz,
CDCl3): 0.90 (2.25H, d, J 6.9, Me), 0.97 (0.75H, d, J 6.9, Me*),
1.04 (9H, s, SitBuPh2), 1.58–1.75 (3H, m, H-1ꢀ and H-4a), 1.81–
2.42 (9H, m, H-3, H-4b, H-13, H-14 and OAc), [2.07 (2.25H, s,
OAc) and 2.09 (0.75H, s, OAc*)],‡ 3.72–3.82 (2H, m, CH2OSi,
H-2ꢀ), 4.05–4.37 (3H, m, H-2 and H-9), 4.90 (0.25H, dd, J12,11 4.9
and J12,10 1.9, CHOAc, H-12*), 4.90 (0.75H, dd, J12,11 5.0 and
J12,10 1.8, CHOAc, H-12), 5.80–6.05 (2H, m, CH=CH, H-10
and H-11), 7.35–7.43 (6H, m, SiArH, m and p), 7.63–7.69 (4H,
m, SiArH, o); dC (100 MHz, CDCl3): 14.2 (CH3, Me*), 14.6
(CH3, Me), 19.2 (quat., SitBuPh2), 21.0 (CH3, OAc), 21.1 (CH3,
OAc*), 26.9 (CH3, SitBuPh2), 33.4 (CH2, CH2CH2O, C-1ꢀ), 34.3
(CH2, CH2CH2, C-13 or C-14), 34.4 (CH, CHMe, C-3), 34.5
(CH2, CH2CH2, C-14* or C-13*), 34.7 (CH2, CH2CH2, C-14 or
C-13), 44.4 (CH2, CH2CHMe, C-4), 46.1 (CH2, CH2CHMe, C-
4*), 61.2 (CH2, CH2O, C-9), 61.4 (CH2, CH2O, C-9*), 62.6 (CH2,
CH2OSi, C-2ꢀ), 67.9 (CH, CHOAc, C-12*), 69.0 (CH, CHOAc,
C-12), 77.2 (CH, CH2CHO, C-2), 78.0 (CH, CH2CHO, C-2*),
104.7 (quat., C-7), 115.5 (quat., C-5), 120.9 (CH, CH=CHCH2,
C-10*), 121.5 (CH, CH=CHCH2, C-10), 127.6 (CH, ArH, m),
129.5 (CH, ArH, p), 131.2 (CH, CH=CHCH2, C-11), 132.1
(CH, CH=CHCH2, C-11*), 133.9 (quat., ArSi), 135.6 (CH,
ArH, o), 170.1 (quat., OAc); m/z (CI, NH3): 568 (M+ + NH3,
18%), 551 (MH+, 100), 553, (MH+ − H2O, 34), 475 (28), 381
(52), 274 (38), 263 (35), 216 (44), 196 (78), 94 (63), 78 (71).
t
14.3 (CH3, Me), 19.2 (quat,. BuPh2), 23.1 (CH2, CH2CH2O,
t
C-10), 26.9 (CH3, BuPh2), 33.8 (CH2, CH2CH2O, C-1ꢀ), 34.5
(CH, CHMe, C-3), 35.3 (CH2, CH2CHO, C-13 or C-14), 35.4
(CH2, CH2CHO, C-14 or C-13), 44.2 (CH2, CH2CHMe, C-4),
51.3 (CH, CHOCHCH2, C-11), 53.5 (CH, CHOCHCH2, C-12),
56.7 (CH2, CH2O, C-9), 61.5 (CH2, CH2OSi, C-2ꢀ), 79.2 (CH,
CHO, C-2), 103.4 (quat., C-7), 115.4 (quat., C-5), 127.6 (CH,
ArH, m), 129.5 (CH, ArH, p), 133.9 (quat., ArSi), 135.6 (CH,
ArH, o); m/z (EI): 508 (M+, 1%), 490 (M+-H2O, 10), 451 (21),
433 (10), 325 (32), 199 (100), 149 (63), 91 (65), 57 (78), 42 (67),
41 (68); m/z (CI, NH3): 509 (MH+, 41%), 491 (MH+ − H2O,
35), 475 (27), 325 (30), 216 (42), 199 (79), 109 (46), 91 (52), 78
(100), 75 (51).
(2R,3R,5S,7R,12S)- and (2R,3R,5R,7R,12R)-2-[2ꢀ-(tert-Butyl-
diphenylsilyloxy)ethyl]-3-methyl-1,6,8-trioxadispiro[4.1.5.2]
tetradec-10-en-12-ol (34a,34c)
n-Butyllithium (0.36 mL of a 1.6 M solution in hexanes,
0.58 mmol) was added dropwise to a solution of freshly distilled
diethylamine (60 lL, 0.58 mmol) in pentane (3.0 mL) at
−40 ◦C. The resultant slurry was stirred for 25 min then cooled
to −78 ◦C and a solution of bis-spiroacetal epoxides cis syn
33a and trans anti 33c (38 mg, 3 : 1, 0.075 mmol) in pentane
(1.5 mL) was added via syringe. After 25 min the reaction was
allowed to warm to room temperature and stirred for a further
2 h. Saturated aqueous sodium bicarbonate (1.0 mL) was added
after 2 h and the reaction mixture extracted with diethyl ether
(2 × 5 mL). The organic layer was washed with water (3 mL),
brine (3 mL) and dried over potassium carbonate. Removal of
the solvent under a reduced pressure gave an orange oil which
was purified by flash column chromatography using hexane–
diethyl ether (4 : 1–1 : 1) as eluant to afford the title compounds
34a, 34c (28 mg, 74%) as a colourless oil [Found (CI, NH3):
MH+, 509.2747; C30H41O5Si requires Mr, 509.2723]; mmax/cm−1
(CDCl3): 3435, 2961, 2931, 2857, 1468, 1462, 1260, 1111, 1088,
988, 742, 703; dH (400 MHz, CDCl3): 0.88 (2.25H, d, J 6.9, Me),
0.98 (0.75H, d, J 6.9, Me*), 1.04 (9H, s, SitBuPh2), 1.59–1.75
(3H, m, H-1ꢀ and H-4a), 1.88–2.45 (6H, m, H-3, H-4b, H-13 and
H-14), 3.71–3.87 (3H, m, H-2ꢀ and H-12), 4.09–4.11 (0.25H,
m, CHaHbO, H-9a*), 4.12–4.16 (0.75H, m, CHaHbO, H-9a),
4.20–4.27 (1H, m, CHO, H-2), 4.28–4.31 (0.75H, m, CHaHbO,
H-9b), 4.32–4.35 (0.25H, m, CHaHbO, H-9b*), 5.76–5.99 (2H,
m, CH=CH, H-10 and H-11), 7.35–7.43 (6H, m, SiArH, m and
p), 7.63–7.69 (4H, m, SiArH, o); dC (100 MHz, CDCl3): 14.3
(CH3, Me*), 14.6 (CH3, Me), 19.2 (quat., SitBuPh2), 26.9 (CH3,
SitBuPh2), 31.4 (CH2, CH2CH2O, C-1ꢀ), 33.3 (CH2, CH2CH2,
C-13 or C-14), 34.5 (CH, CHMe, C-3), 34.9 (CH2, CH2CH2, C-
14 or C-13), 35.2 (CH, CHMe, C-3*), 35.4 (CH2, CH2CH2,
C-14* or C-13*), 43.7 (CH2, CH2CHMe, C-4*), 44.0 (CH2,
CH2CHMe, C-4), 61.4 (CH2, CH2O, C-9), 61.7 (CH2, CH2O,
C-9*), 62.5 (CH2, CH2OSi, C-2ꢀ), 62.8 (CH2, CH2OSi, C-2ꢀ),
67.5 (CH, CHOH, C-12), 67.6 (CH, CHOH, C-12*), 77.8 (CH,
(2R,3R,5S,7R,12S)- and (2R,3R,5R,7R,12R)-2-[2ꢀ-(tert-
Butyldiphenylsilyloxy)ethyl]-3-methyl-1,6,8-trioxadispiro
[4.1.5.2]tetradec-9-en-12-ol (11a,11c)
n-Butyllithium (0.120 mL of a 1.6 M solution in hexanes,
0.19 mmol) was added dropwise to a stirred solution of freshly
distilled pyrrolidine (20 lL, 0.19 mmol) in THF (1.0 mL)
at −40 ◦C. The resultant slurry was stirred for 25 min then
cooled to −78 ◦C before a solution of allylic alcohols 34a,
34c (18 mg, 3 : 1, 0.035 mmol) in THF (1.0 mL) was added
via syringe. After 30 min the reaction was allowed to warm
slowly to room temperature and stirred for a further 16 h.
Saturated aqueous sodium bicarbonate (2 mL) was added and
the reaction mixture extracted with diethyl ether (2 × 5 mL). The
organic layer was washed with water (2 mL), brine (2 mL) and
dried over potassium carbonate. Removal of the solvent under
‡ These two acetate methyl group resonances were contained within the
multiplet at d 1.81–2.42 ppm.
3 5 8 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 7 3 – 3 5 8 3

View Article Online
a reduced pressure, followed by flash column chromatography
using hexane–diethyl ether (9 : 1) as eluant afforded a 3 :
1 mixture of the title compounds 11a, 11c (9 mg, 50%) as a
colourless oil [Found (EI): MH+, 508.2633; C30H40O5Si requires
Mr, 509.2645]; mmax/cm−1(CDCl3): 3435, 2956, 2927, 2853, 1650,
1428, 1260, 1111, 1085, 1025, 742, 702; dH (400 MHz, CDCl3):
0.87 (0.75H, d, J 6.9, Me*), 0.89 (2.25H, d, J 6.9, Me), 1.04
(9H, s, SitBuPh2), 1.73–2.52 (11H, m, H-1ꢀ, H-3, H-4, H-11, H-
13, H-14), 2.86 (1H, br s, OH), 3.74–3.82 (3H, m, H-2ꢀ and H-12),
4.12–4.17 (0.25H, m, CHO, H-2*), 4.26–4.34 (0.75H, m, CHO,
H-2), 4.64 (1H, m, OCH=CH, H-10), 6.17 (1H, m, OCH=CH,
H-9), 7.36–7.42 (6H, m, SiArH, m and p), 7.64–7.69 (4H, m,
SiArH, o); dC (100 MHz, CDCl3): 14.5 (CH3, Me), 19.2 (quat.,
SitBuPh2), 26.9 (CH3, SitBuPh2), 27.2 (CH2, CH=CHCH2, C-
11), 29.2 (CH2, CH2CH2, C-13), 33.2 (CH2, CH2CH2O, C-1ꢀ),
34.7 (CH, CHMe, C-3), 34.9 (CH2, CH2CH2, C-14), 43.5 (CH2,
CH2CHMe, C-4), 61.2 (CH2, CH2OSi, C-2ꢀ), 67.2 (CH, CHOH,
C-12), 77.2 (CH, CH2CHO, C-2), 78.2 (CH, CH2CHO, C-2*),
98.7 (quat., C-7 and CH, OCH=CH, C-10), 115.2 (quat., C-5),
127.6 (CH, ArH, m), 129.5 (CH, ArH, p), 133.9 (quat., ArSi),
135.6 (CH, ArH, o), 141.2 (CH, OCH=CH, C-9); m/z (EI): 508
(MH+, 1%), 490 (M+ − H2O, 1), 451 (52), 433 (27), 235 (42), 199
(100), 183 (25), 135 (38), 85 (33).
(M++ NH3, 4%), 551 (MH+, 83), 493 (15), 381 (44), 274 (44),
263 (35), 216 (37), 196 (84), 94 (100), 78 (89).
Acknowledgements
The authors thank the University of Auckland and the Royal
Society of New Zealand Marsden Fund for financial support of
this work.
References
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(2R,3R,5S,7R,12S)- and (2R,3R,5R,7R,12R)-12-Acetoxy-2-[2ꢀ-
(tert-Butyldiphenylsilyloxy)ethyl]-3-methyl-1,6,8-trioxadispiro
[4.1.5.2]tetradec-9-ene (36a,36c)
Using a similar procedure to that described for 35a, 35c, a 3 :
1 mixture of homoallylic alcohols 11a, 11c (4.0 mg, 7.9 lmol)
was reacted with pyridine (1.0 mL), acetic anhydride (0.1 mL,
1.0 mmol) and a catalytic quantity of DMAP. The resultant pale
yellow semi-solid was purified by flash column chromatography
in a Pasteur pipette using hexane–diethyl ether (4 : 1) as eluant
to afford a 3 : 1 mixture of the title compounds 36a, 36c (2.9 mg,
67%) as a colourless oil [Found (CI, NH3): MH+, 551.2825;
C32H43O6Si requires Mr, 551.2830]; mmax/cm−1(neat): 3585, 2955,
2929, 2870, 1737, 1658, 1511, 1455, 1265, 1240, 1110, 1018,
737; 702; dH (400 MHz, CDCl3): 0.87 (3H, br d, J 6.9, Me),
1.04 (9H, s, SitBuPh2), 1.59–1.74 (3H, m, H-1ꢀ and H-4a), 1.88–
2.02 (2H, m, H-13a and H-14a), 2.03 (2.25H, s, OAc), 2.04
(0.75H, s, OAc*), 2.06–2.41 (5H, m, H-3, H-4b, H-11a, H-13b
and H-14b) 2.43–2.47 (1.5H, m, CH=CHCH2, H-11), 2.49–2.54
ꢀ
ꢀ
(0.5H, m, CH=CHCH2, H-11*), 3.75 (2H, t, J2 ,1 6.7, CH2O,
H-2ꢀ), 4.04–4.12 (0.25H, m, CHO, H-2*), 4.14–4.22 (0.75H, m,
CHO, H-2), 4.63–4.72 (1H, m, OCH=CH, H-10), 4.98–5.03
(1H, m, CHOAc, H-12), 6.17–6.24 (1H, m, OCH=CH, H-9),
7.33–7.42 (6H, m, SiArH, m and p), 7.63–7.69 (4H, m, SiArH,
o); dC (100 MHz, CDCl3): 14.6 (CH3, Me), 19.2 (quat., SitBuPh2),
21.2 (CH3, OAc), 24.3 (CH2, CH=CHCH2, C-11), 26.9 (CH3,
SitBuPh2), 33.2 (CH2, CH2CH2, C-13), 33.5 (CH2, CH2CH2O, C-
1ꢀ), 33.8 (CH2, CH2CH2O, C-1ꢀ*), 34.3 (CH, CHMe, C-3), 34.6
(CH2, CH2CH2, C-14), 44.4 (CH2, CH2CHMe, C-4), 61.4 (CH2,
CH2OSi, C-2ꢀ), 69.2 (CH, CHOAc, C-12), 78.0 (CH, CH2CHO,
C-2), 79.6 (CH, CH2CHO, C-2*), 98.0 (CH, OCH=CH, C-10),
105.0 (quat., C-7), 115.4 (quat., C-5), 127.6 (CH, ArH, m), 129.5
(CH, ArH, p), 133.9 (quat., ArSi), 135.6 (CH, ArH, o), 140.9
(CH, OCH=CH, C-9), 170.2 (quat., OAc); m/z (CI, NH3): 568
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O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 7 3 – 3 5 8 3
3 5 8 3