Synthesis of an oxaspirolactone intermediate for the synthesis of spirolides

Article abstract of DOI:10.1071/CH00111

A new method has been established for the preparation of C2-oxidized 5,5-spiroacetals, which are key intermediates for the synthesis of the bis-spiroacetal moiety of the spirolides. A bridged orthoester was used as a masked carboxylic acid in the preparat

Full text of DOI:10.1071/CH00111

C S I R O P U B L I S H I N G
Australian Journal
of Chemistry
Volume 53, 2000
© CSIRO 2000
A journal for the publication of original research
in all branches of chemistry and chemical technology
w w w. p u b l i s h . c s i ro . a u / j o u rn a l s / a j c
All enquiries and manuscripts should be directed to
The Managing Editor
Australian Journal of Chemistry
CSIRO PUBLISHING
PO Box 1139 (150 Oxford St)
Collingwood
Vic. 3066
Australia
Telephone: 61 3 9662 7630
Facsimile: 61 3 9662 7611
Email: john.zdysiewicz@publish.csiro.au
Published by CSIRO PUBLISHING
for CSIRO and
the Australian Academy of Science

Aust. J. Chem., 2000, 53, 845–851
Synthesis of an Oxaspirolactone Intermediate for the Synthesis of
Spirolides
Margaret A. Brimble,A,D Fares A. FaresB and Peter TurnerC
A
Department of Chemistry, University of Auckland, Private Bag 92019, Auckland, New Zealand.
Department of Chemistry, American University of Beirut, P.O. Box 11-0236, Beirut, Lebanon.
School of Chemistry, University of Sydney, Camperdown, N.S.W. 2006, Australia.
Author to whom correspondence should be addressed (e-mail: m.brimble@auckland.ac.nz).
B
C
D
A new method has been established for the preparation of C 2-oxidized 5,5-spiroacetals, which are key
intermediates for the synthesis of the bis-spiroacetal moiety of the spirolides. A bridged orthoester was used as a
masked carboxylic acid in the preparation of these bicyclic oxaspirolactones. The synthesis of chiral lactone (12),
a building block for the synthesis of the spirolides, is also reported. The two chiral centres in lactone (12) were
assembled by addition of a chiral crotyl borane to an aldehyde. The structure of lactone (12) was determined by
single-crystal X-ray diffraction; orthorhombic space group P2 2 2 (No. 19), a 12.437(2), b 23.881(4), c 7.545(1)
1 1 1
3
Å, V 2240.9(5) Å , R(F) 0.0460, and R (F) 0.0458.
w
C
H0011
MSe
.
B
r
b
e
esandPeterTurne
r
Keywords: Spirolides, oxaspirolactones; spirolactones.
Introduction
Spirolides B (1a) and D (1b) were isolated in 1995 by Wright
1
et al. and were found to be structurally related to the
pinnatoxins (2a–d) in that they contain a 6,5,5-bis-spiroacetal
system, whereas the pinnatoxins contain a 6,5,6-spiroacetal
system. The spiro bicyclic imine is common to both the
spirolides and the pinnatoxins. To date no synthesis of the
spirolides has been reported and the stereochemistry of the
spirolides has yet to be determined. We herein report the
synthesis of oxaspirolactone (3), which is a key intermediate
forthesynthesisofthebis-spiroacetalmoietyofthespirolides.
The syntheses of 6,6-, 5,6- and 5,5-oxaspirolactones have
been reported by either a mercury(II) oxide promoted
photodemetallation, afforded an oxaspirolactone on acid
4
treatment. A common approach has also involved the
5
addition of organocerium reagents to succinic anhydride.
Furyl alcohols have also provided useful precursors to
6,7
α,β-unsaturated spirolactones.
We herein report a new method for the synthesis of
5,5-oxaspirolactones which makes use of
orthoester as a masked carboxylic acid.
a bridged
2
cyclization of a hydroxy alkynoic acid, or an analogous
3
palladium(II)-induced cyclization. DeShong generated a
Results and Discussion
manganese complex from tetrahydrofuran, which, after
regiospecific insertion of methyl acrylate and
Our retrosynthesis adopted for the bis-spiroacetal moiety of
the spirolides involved initial assembly of the C,D ring,
spirolactone (3), followed by attachment of the B ring. The
lactone functionality in oxaspirolactone (3) would be used to
append the B ring and the protected hydroxy group would
provide a handle for further elaboration of the left-hand side
of the molecule. The synthesis of bicyclic lactone (3)
requires flexibility in the introduction of the two substituents
on the D ring so that a number of stereoisomers can be
prepared for comparison with the natural product. For the
present study, we decided to introduce substituents on the D
ring which have the same stereochemistry as that found in
the pinnatoxins (2a–d).
Methodology wasinitially developed for thepreparation of
unsubstituted oxaspirolactone(4). Thissynthetic strategy was
then applied to the synthesis of the chiral oxaspirolactone (3).
Manuscript received 21 August 2000
© CSIRO 2000
10.1071/CH00111
0004-9425/00/100845

846
M. A. Brimble et al.
8
provide the corresponding alcohols. Lactones have not been
used as electrophiles and added to the acetylide generated
from orthoester (5).
With orthoester (5) in hand, the addition of the
corresponding acetylide to γ-butyrolactone could now be
investigated. Addition of γ-butyrolactone as a solution in
tetrahydrofuran to a solution of the lithium acetylide
generated from orthoester (5), by using n-butyllithium at
–10°C in tetrahydrofuran, afforded hydroxy ketone (8) in
71% yield (Scheme 2). The appearance of a strong
–
1
carbonyl group absorbance at 1686 cm and a strong
–
1
absorbance at 3445 cm due to an hydroxy group, in the
infrared spectrum, supported formation of this product. In
the 13C n.m.r. spectrum a quaternary carbon due to the
carbonyl group was observed at δ 186.3 and another
quaternary resonance at δ 82.7 was assigned to C 1′, the
orthoester carbon.
Hydrogenation of (8) over 10% Pd/C in ethyl acetate gave
the saturated keto alcohol (9), which was not isolated. The
carboxylic acid was then regenerated from the orthoester in
two steps. First, orthoester (9) was treated with a catalytic
quantity of pyridinium p-toluenesulfonate in MeOH-H2O
(4 : 1) to afford the intermediate diol ester (10). In situ
treatment of this latter ester (10) with an aqueous solution of
lithium hydroxide (LiOH) gave a carboxylate salt which was
then acidified to pH 3 with 2 M hydrochloric acid solution to
give keto acid (11).
Cyclization to the spirolactone was then effected upon
treatment of a solution of keto acid (11) in ether with a
catalytic quantity of p-toluenesulfonic acid in the presence of
anhydrous magnesium sulfate. Spirolactone (4) was isolated
in 51% yield (over four steps) after 30 min at room
temperature. The relatively low yield was attributed to the
3
volatility and instability of the product. In the 13C n.m.r.
In our approach to oxaspirolactones, we focused on the
spectrum for (4) the resonance due to the spiro carbon
appeared at δ 116.2 and the quaternary resonance at δ 176.6
was assigned to the carbonyl carbon.
addition of an acetylide anion to butyrolactone, followed by
(after hydrogenation) an acid-catalysed cyclization of a
protected carboxylic acid. One requirement of this approach
is that the carboxylic acid must be protected before the
acetylide addition. The use of an orthoester (e.g. triethyl
orthopropiolate) as a protected carboxylic acid is hampered
The synthesis of spirolactone (4) was originally reported
3
by Kitching and coworkers by using a palladium(II)-induced
cyclization of hydroxyalkynoic acid. The alkynoic acid in
turn was prepared in four steps.
8
by the lability of these acyclic orthoesters. We therefore
Having successfully prepared the model spirolactone (4),
we next decided to prepare spirolactone (3) by using the
same strategy. Spirolactone (3) is a key building block for the
synthesis of the bis-spiroacetal moiety (the BCD ring
systems) of the spirolides (1a) and (1b).
decided to protect the carboxylic acid as a more stable
bridged orthoester.
Orthoester (5) (Scheme 1) has been used in the synthesis
9
of several natural products including retgeranic acid,
ginkolide and prostaglandins E1 and D2,
10
11,12
but its use in
In order to prepare spirolactone (3) enantioselectively, a
synthesis of lactone (12) was initially required. The route to
lactone (12) is summarized in Scheme 4, in which the key
step involves the addition of a chiral crotyl borane
the synthesis of spirolactones has not been reported. Bridged
orthoester (5) was prepared according to the procedure
8
described by Ducray et al., starting from 3-(hydroxy-
13
methyl)-3-methyloxetane and propiolic acid (Scheme 1),
affording 3-(hydroxymethyl)-3-methyloxetane ester (6) in
51% yield. Rearrangement to orthoester (5) then took place
upon exposure of (6) to a catalytic quantity of boron
trifluoride diethyl ether complex. Orthoester (5) was isolated
in 56% yield as a crystalline solid.
(α-B-methoxydiisocampheylborane) to an aldehyde.
14,15
The known aldehyde (13)
required for the synthesis
of lactone (12) was prepared in two steps from commercially
available propane-1,3-diol (Scheme 3). Thus propane-
1,3-diol was first monosilylated with sodium hydride and
t-butyldiphenylsilyl chloride in tetrahydrofuran in 67%
14
The acetylide generated from orthoester (5) was used in
reactions with electrophiles such as aldehydes and ketones to
yield, according to the method reported by McDougal et al.
Oxidation of the remaining hydroxy group afforded aldehyde

Synthesis of an Oxaspirolactone
847
This diastereomer was shown to exhibit an enantiomeric
excess of >97% by conversion to the corresponding
16
Mosher ester (18) by treatment with (R)-2-methoxy-2-
trifluoromethyl-2-phenylacetyl chloride (Scheme 5). The 1H
n.m.r. spectrum of the derived Mosher ester (18) displayed a
three-proton singlet at δ 3.46, assigned to the methoxy
group, and a doublet at δ 0.98 (J 6.9 Hz), assigned to the
methyl group.
Two new chiral carbon atoms are formed in this crotyl
metallation step; hence four isomeric alcohols could be
obtained. Under the reaction conditions adopted ((+)-α-
pinene as chiral auxiliary with
a (Z)-alkene) one
diastereomer (17) was formed. This approach is flexible in
that it provides access to all four possible stereoisomers of
(12) by selecting either the (Z)- or (E)-alkene for use with the
appropriate enantiomer of α-pinene.
Alcohol (17) was then protected as a triethylsilyl ether
(19) in 97% yield by using triethylsilyl trifluoro-
methanesulfonate and triethylamine in dichloromethane.
Hydroboration of alkene (19) with borane–dimethyl sulfide
complex in tetrahydrofuran, followed by alkaline peroxide
oxidation, afforded the primary alcohol (20) in 72% yield. A
protonated molecular ion at m/z 501.3211 in the high-
resolution mass spectrum supported the molecular formula
1
C29H48O3Si2. The absence of any vinylic protons in the H
n.m.r. spectrum and the appearance of a hydroxy group at
–
3613 and 3409 cm 1 in the infrared spectrum confirmed the
formation of alcohol (20).
Selective cleavage of the triethylsilyl protecting group by
camphorsulfonic acid (CSA) in methanol afforded diol (21)
in 88% yield. Conversion of diol (21) to lactone (12) was
then achieved by using tris(triphenylphosphine)ruthen-
ium(II) chlorideas catalyst and N-methylmorpholine-N-oxide
17,18
as oxidant in acetone
to give an intermediate lactol
which was further oxidized to lactone (12) in 72% yield.
Disappearance of the hydroxyl absorbance and appearance
–
of a lactone carbonyl absorbance at 1773 cm 1 in the infrared
spectrum was the preliminary evidence for formation of
lactone (12). This was confirmed by the 13C n.m.r. spectrum
which exhibited a characteristic resonance at δ 176.6,
assigned to the carbonyl carbon.
(13) in 80% yield by using pyridinium chlorochromate
(PCC) in dichloromethane.
The two substituents at C3 and C 4 were expected to be
syn to each other, on the basis of the relative stereochemistry
of the diol precursor (21). In the 1H n.m.r. spectrum of
lactone (12) the two geminal protons H2A and H2B resonated
at δ 2.71 and 2.18, respectively, with geminal coupling
constant J 16.9 Hz. H 4 appeared as a double triplet at δ 4.73
(J4,3 8.2 and J4,1′-CH2 5.6 Hz), while H 3 appeared as a
multiplet at δ 2.51−2.63. The methyl group resonated as a
doublet (J 6.9 Hz) at δ 0.99. The expected relative
stereochemistry of lactone (12) was confirmed with a single-
crystal X-ray diffraction analysis (Fig. 1).
With chiral lactone (12) in hand, efforts were then
directed towards its reaction with orthoester (5) in an
attempt to synthesize lactone (3). The optimum results were
obtained by treating orthoester (5) with n-butyllithium (1.2
equivalents) in tetrahydrofuran at –10°C to generate the
acetylide, followed by addition of lactone (12) (1.2
13
Aldehyde (13) then underwent Brown crotylmetallation
with crotyl borane (16). Thus, treatment of the (–)-β-meth-
oxydiisopinocampheylborane (15) (derived from (+)-α-
pinene) with the organometallic reagent generated by
treatment of cis-but-2-ene with n-butyllithium and
potassium t-butoxide gave (Z)-but-2-enyl diisopinocam-
pheylborane (16) (Scheme 4) which was reacted in situ with
15
aldehyde (13) to give the syn homoallylic alcohol (17) in
89% yield.
A protonated molecular ion at m/z 369.2250 in the high-
resolution mass spectrum for (17) supported the molecular
formula C23H30O2Si. The infrared spectrum exhibited a
–
1
hydroxyl absorbance at 3502 cm , while vinylic protons
were evident at δ 5.11 and 5.86 in the 1H n.m.r. spectrum.
1
Upon examination by H and 13C n.m.r. spectroscopy,
alcohol (17) appeared to be essentially a single diastereomer.

848
M. A. Brimble et al.
stereochemistry at these chiral centres. The stereochemistry
at the two contiguous chiral centres C 7 and C 8 was
assigned as syn by analogy with the simpler lactone (12).
The successful completion of the synthesis of
spirolactone (3) constitutes a synthesis of the CD rings of
spirolides. It now remains to append the B ring to the CD
fragment. One advantage of this strategy is that it allows the
synthesis of stereoisomers of spirolactone (3) by the
appropriate choice of chiral crotyl borane used. One
limitation to the synthesis of spirolactone (3) is the low yield
observed in the final deprotection-cyclization step.
Experimental
General Details
Melting points were determined on a Kofler hot-stage apparatus and are
uncorrected. Optical rotations were measured on a PolAAR 2001
polarimeter at room temperature in the indicated solvent. Infrared
spectra were recorded on a Perkin–Elmer 1600 Fourier-transform
infrared spectrophotometer as thin film between sodium chloride
1
13
plates. H and C n.m.r. spectra were obtained by using a Bruker AC
13
200 spectrometer. C n.m.r. spectra were interpreted with the aid of
DEPT 135 experiments. Low-resolution mass spectra were recorded on a
VG 70-SE, VG 70-250S, VG 70-SD or AEI MS902 double-focusing
magnetic-sector mass spectrometer operating with an ionization
potential of 70 eV. High-resolution mass spectra were recorded at a
nominal resolution of 5000 or 10 000 as appropriate. Major fragments
are given as percentages relative to the base peak and assigned where
possible. Ionization methods employed were (i) electron impact (EI),
(ii) chemical ionization with ammonia or methane as reagent gas (CI)
and (iii) electrospray chemical ionization (ESI). Flash chromatography
was performed by using Merck Kieselgel 60 or Riedel-de-Haen
Kieselgel S silica gel (both 230–400 mesh) with the indicated solvents.
Compounds were visualized under ultraviolet light or by staining with
iodine or vanillin in methanolic sulfuric acid.
equivalents) in tetrahydrofuran (Scheme 6). A mixture of
the desired coupled product (22) (64%) was obtained
together with unreacted lactone (12) (10%) and orthoester
(5) (8%).
Examination of the infrared spectrum of the coupled
–
1
product (22) showed a large absorbance at 3494 cm
assigned to a hydroxy group and a strong absorbance at 1745
–
1
cm due to the carbonyl group. This provided strong
evidence that the product is the open-chain keto acetylene
(22) and not the hemiacetal.
Hydrogenation of keto acetylene (22) over 10%
palladium on charcoal (Pd/C) in ethyl acetate gave the
desired saturated ketone (23), which was not isolated.
Release of the latent carboxylic acid was then achieved in
two steps in methodology analogous to that used for the
preparation of lactone (4) via diol ester (24). In situ
hydrolysis of diol ester (24) gave carboxylic acid (25),
which, upon treatment with a catalytic quantity of
p-toluenesulfonic acid in the presence of anhydrous
magnesium sulfate in diethyl ether, cyclized to give the
desired spirolactone (3), albeit in low yield (10% yield).
Propiolic Acid 3-Methyl-3-(hydroxymethyl)oxetane Ester (6)
To a mixture of 3-(hydroxymethyl)-3-methyloxetane (3.7 g, 36 mmol),
DCC (10 g, 50 mmol) and 4-dimethylaminopyridine (220 mg,
1.8 mmol) in dry dichloromethane (10 ml) at 0°C was added propiolic
acid (2.55 g, 36 mmol) over 2.5 h, and the mixture was stirred for
another 2 h. After filtration the mixture was washed with 1%
ammonium chloride solution (50 ml) and 5% sodium hydrogen
carbonate solution (50 ml), and dried (MgSO4), and the solvent was
removed under reduced pressure. The crude oil was distilled under
reduced pressure to give the title compound (6) (2.87g, 51%) as a
8
colourless oil, b.p. 56°C/0.4 mmHg (lit. b.p. 50°C/0.3 mmHg). The
spectroscopic data were in good agreement with those reported in the
8
+ t
literature.
An ion at m/z 381.1522 (M – Bu) in the high-resolution
mass spectrum for spirolactone (3) supported the molecular
1-Ethynyl-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (5)
–
1
formula C26H34O4Si. An infrared absorbance at 1772 cm
Ester (6) (2.00 g, 13 mmol) was dissolved in dichloromethane (5 ml)
and stirred with boron trifluoride–diethyl ether complex (30 µl) at room
temperature under argon for 24 h. After treatment with triethylamine
(0.5 ml) the mixture was diluted with diethyl ether and filtered through
Celite to remove the boron trifluoride–triethylamine complex, and the
solvent was removed under reduced pressure. The crude product was
purified by flash chromatography with dichloromethane (containing
1% triethylamine) as eluant to give the title compound (5) (1.17 g,
56%). The spectroscopic data were in good agreement with those
1
indicated successful formation of a lactone. The H n.m.r.
spectrum exhibited a doublet (J 6.8 Hz) at δ 0.95, assigned
to the methyl group, and two multiplets (integrating for a
total of 10 protons) in the aromatic region provided strong
evidence that the protecting group (TBDPS) was intact. The
13C n.m.r. spectrum exhibited a characteristic resonance at δ
115.1, assigned to the newly formed spiro centre, and a
quaternary carbon due to the lactone carbonyl was observed
at δ 176.1.
8
reported in the literature.
6-Hydroxy-1-(4'-methyl-2',6',7'-trioxabicyclo[2.2.2]octyl)hex-1-yn-3-
one (8)
Unfortunately, the 1H n.m.r. spectrum did not provide any
stereochemical information, since both key protons (H 7 and
H 8) resonated as part of a multiplet. Hence the key coupling
constant J7,8 could not be used to assign the relative
To a solution of orthoester (5) (200 mg, 1.3 mmol) in dry
tetrahydrofuran (5 ml) cooled to –10°C under argon was added
n-butyllithium (1.12 ml of a 1.4 M solution in hexanes, 1.56 mmol)

Synthesis of an Oxaspirolactone
849
dropwise under argon. After stirring at –10°C for 1 h, a solution of
γ-butyrolactone (134 mg, 1.56 mmol) in dry tetrahydrofuran (4 ml) was
added in one portion and the mixture was stirred at –10°C for 1 h.
Saturated aqueous ammonium chloride solution (3 ml) was added and
the reaction mixture was extracted with ethyl acetate (3 × 10 ml),
washed with brine (7 ml) and dried over potassium carbonate. Removal
of solvent at reduced pressure gave a colourless oil which was purified
by flash chromatography with hexane/ethyl acetate (1 : 1) as eluant to
give the title compound (8) (221 mg, 71%) as a colourless solid, m.p.
(+)-(3R,4R)-6-(t-Butyldiphenylsilyloxy)-3-methylhex-1-en-4-ol (17)
To a stirred mixture of potassium t-butoxide (1.69 g, 15 mmol) and cis-
but-2-ene (2.8 ml, 30 mmol) in tetrahydrofuran (12 ml) at –78°C, was
added dropwise n-butyllithium (6 ml, 15 mmol, 2.5 M solution in
hexanes). The resulting mixture was stirred at –45°C for 10 min, then
the orange solution was recooled to –78°C and (–)-β-methoxy-
diisopinocampheylborane (5.1 g, 16 mmol) in tetrahydrofuran (18 ml)
was added dropwise. After the reaction mixture was stirred at –78°C for
30 min, boron trifluoride etherate (2.33 ml, 19.9 mmol) was added
dropwise, followed by a solution of the aldehyde (13) (6.54 g, 21 mmol)
in tetrahydrofuran (15 ml). The mixture was stirred for a further 3 h at
–78°C then treated with 3 N sodium hydroxide (8 ml) and 30% hydrogen
peroxide (3.5 ml) and heated under reflux for 1 h. The tetrahydrofuran
was partially evaporated and the residue extracted with diethyl ether
(3 × 40 ml). The combined organic layers were washed with water
(25 ml) and brine (25 ml) and then dried over MgSO4. Evaporation of
the solvent under reduced pressure afforded a yellow oil which was
purified by flash chromatography with hexane/ethyl acetate (4 : 1) as
eluant, to give the title compound (17) (3.26 g, 89%) as a colourless oil,
57–59°C (Found: MH+, 241.1072. C12H17O requires MH, 241.1076).
5
–1
υmax (CHCl3)/cm 3445 (OH), 2935, 2886m (CH), 1686s (C=O),
1
1467, 1395, 1304, 1044. H n.m.r. δH (200 MHz, CDCl3) 0.84, s, CH3;
1.70–1.95, 3H, m, CH2CH2C=O and OH; 2.71, t, J 7.1 Hz, CH2C=O;
13
3.62, t, J 6.2 Hz, CH2OH; 3.98, 6H, s, 3 × CH2O. C n.m.r. δC (50
MHz, CDCl3) 14.2, CH3, Me; 26.4, CH2, CH2CH2OH; 30.3, quat.,
CMe; 42.0, CH2, CH2C=O; 61.5, CH2, CH2OH; 73.1, CH2, 3 × CH2O;
78.2, quat., C≡C–CO3; 82.7, quat., C≡C–CO3; 101.9, quat., CO3;
186.3, quat., C=O. m/z (EI) 240 (M+, 5%), 181 (C9H9O4, 29), 142 (13),
113 (61), 89 (63), 70 (100).
15
[α] +17.0° (c, 1.23, acetone), lit. [α] +3.3° (c, 1.06, CHCl ). The
D
D
3
1,6-Dioxaspiro[4.4]nonan-2-one (4)
spectroscopic data were in good agreement with those reported in the
15
A solution of alkyne (8) (180 mg, 0.75 mmol) in ethyl acetate (25 ml)
was stirred with 10% Pd/C catalyst (10–15 mg) at room temperature
under a balloon of hydrogen for 1 h. Removal of the catalyst by
filtration through a short pad of Celite followed by removal of the
solvent at reduced pressure afforded a colourless oil which was
dissolved in methanol (4 ml) and H2O (1 ml). Pyridinium
p-toluenesulfonate (10 mg) was added and the mixture was stirred at
room temperature for 1 h. Lithium hydroxide (60 mg) in water (3 ml)
was then added, followed by water (4 ml) after 25 min, and the methanol
was removed under reduced pressure. The reaction mixture was
acidified with 2 M HCl, extracted with diethyl ether (3 × 10 ml) and
dried over MgSO4. Fresh MgSO4 was then added, followed by
p-toluenesulfonic acid (10 mg), and the mixture was stirred at room
temperature for 30 min. After filtration the solvent was evaporated at
0°C to give a pale yellow oil which was purified by flash
chromatography with pentane/diethyl ether (1 : 1) to give the unstable
and volatile title compound (4) as a colourless oil (55 mg, 51%). The
spectroscopic data were in good agreement with those reported in the
literature.
Mosher Ester (18)
(R)-2-Methoxy-2-trifluoromethyl-2-phenylacetyl chloride (32 µl,
0.17 mmol) was added to a solution of alcohol (17) (52 mg, 0.14 mmol)
in carbon tetrachloride/pyridine (1 ml of a 1 : 1 mixture). The mixture
was stirred at room temperature for 24 h and water (1 ml) was added.
The mixture was diluted with diethyl ether (20 ml), washed with
aqueous hydrogen chloride (0.1 M, 5 ml), saturated aqueous sodium
hydrogen carbonate (5 ml), water (5 ml) and brine (5 ml), and dried
(MgSO ). After concentration of the organic extracts under reduced
4
pressure, chromatography of the residue with hexane/ethyl acetate (9 :
1) as eluant afforded ester (18) (57 mg, 69%) as a colourless oil. H
n.m.r. δH (200 MHz, CDCl3) 0.98, d, J 6.9 Hz, CH3; 1.07, s, (CH3)3;
1.72–1.94, m, CH2CH2OSi; 2.50–2.62, m, CHMe; 3.46, s, OCH ;
1
3
3.65–3.72, m, CH2OSi; 4.88–5.01, m, HC=CH2, 5.31–5.39, m,
CHOC=O; 5.65, ddd, J 6.8, 10.5, 17.0 Hz, CH=CH2; 7.32–7.55, 11H,
+
m, ArH; 7.63–7.68, 4H, m, ArH. m/z (ESI) 607 [(M+Na) , 100%], 1190
3
+
literature.
[(2M+Na) , 15].
3-(t-Butyldiphenylsilyloxy)propan-1-ol (14)
(+)-(3R,4R)-6-(t-Butyldiphenylsilyloxy)-4-(triethylsilyloxy)-3-
methylhex-1-ene (19)
Sodium hydride (60%, 1.0 g, 25 mmol) was washed with dry pentane
(3 × 6 ml) and suspended in dry tetrahydrofuran (45 ml) under argon. A
solution of propane-1,3-diol (1.9 g, 0.025 mol) in dry tetrahydrofuran
(5 ml) was then added dropwise at room temperature and the mixture
was stirred for 1 h, resulting in formation of a white precipitate.
t-Butyldiphenylsilyl chloride (6.78 g, 6.5 ml, 25 mmol) was then added
dropwise and the reaction was stirred vigorously for 18 h. The reaction
mixture was poured into diethyl ether (200 ml) then washed with 10%
aqueous K2CO3 (50 ml) and brine (50 ml). After drying over Na2SO4,
concentration under reduced pressure afforded an oil which was
purified by flash chromatography with hexane/ethyl acetate (3 : 1) as
eluant, to afford the title compound (14) (5.23 g, 67%) as a colourless
oil. The spectroscopic data were in good agreement with those reported
To a solution of alcohol (17) (988 mg, 2.7 mmol) in tetrahydrofuran (35
ml) at room temperature was added dry triethylamine (542 mg, 747 µl,
5.4 mmol) followed by chlorotriethylsilane (485 mg, 540 µl, 3.2 mmol).
The reaction mixture was stirred at room temperature for 24 h,
whereupon a white precipitate formed. Water (7 ml) was added and the
reaction mixture was extracted with diethyl ether (3 × 40 ml). The
organic extract was washed with water (30 ml) and brine (30 ml) and
dried over magnesium sulfate. Removal of the solvent under reduced
pressure gave a pale yellow liquid which was purified by flash
chromatography with hexane/ethyl acetate (95 : 5) as eluant to give the
title compound (19) (1.25 g, 97%) as a colourless oil. [α] +19.1° (c,
D
2.1, acetone). (Found: MH+, 483.3115. C29H47O Si requires MH,
2
2
19
–1
in the literature.
483.3114). υmax (CHCl3)/cm 2958s, 2876m, 1589w, 1472w, 1427w,
1
1240w, 1110s, 1007m, 940w, 823m. H n.m.r. δH (200 MHz, CDCl3)
3-(t-Butyldiphenylsilyloxy)propanal (13)
0.59, q, J 8.0 Hz, 3 × CH2Si; 0.90–0.98, m, 3 × CH3CH2Si and CH3;
1.07, br s, (CH3) ; 1.52–1.79, m, CH2CH2OSi; 2.21–2.39, m,
Activated powdered molecular sieves (4 Å, 420 mg) and sodium acetate
(21 mg, 0.26 mmol) were added to a solution of the alcohol (14) (200
mg, 0.6 mmol) in dry dichloromethane (10 ml) at room temperature
under argon. To the suspension was added pyridinium chlorochromate
(276 mg, 1.28 mmol), and the dark mixture was stirred for 2 h then
filtered through silica gel. The filtrate was concentrated under reduced
pressure and purified by flash chromatography with hexane/diethyl
ether (9 : 1) as eluant to afford the title compound (13) (159 mg, 80%)
as a colourless oil. The spectroscopic data were good in agreement with
3
CHCH=CH2; 3.74, t, J 6.3 Hz, CH2OSi; 3.81–3.89, m, CHOSi; 4.96–
5.04, m, HC=CH2; 5.80–5.97, m, CH=CH2; 7.38–7.45, 6H, m, ArH;
13
7.65–7.72, 4H, m, ArH. C n.m.r. δC (50 MHz, CDCl3) 5.2, CH2, 3 ×
CH2Si; 7.0, CH3, 3 × CH3CH2Si; 14.7, CH3, Me; 19.2, quat., C(CH ) ;
3
3
26.8, CH3, C(CH ) ; 36.6, CH2, C 5; 43.2, CH, CHCH ; 60.9, CH2,
3 3
3
CH2OSi; 72.8; CH, CHOSi; 114.1, CH2, CH=CH2; 127.6, 129.5, 135.6,
3 × CH, ArC; 134.0; quat., ArC; 141.1, CH, CH=CH2. m/z (CI, CH4)
483 (MH+, 100%), 453 (M–C H , 60), 405 (M–C H , 32), 351 (M–
2
5
6 6
15,20
OSiEt , 29).
those reported in the literature.
3

850
M. A. Brimble et al.
(+)-(3R,4R)-6-(t-Butyldiphenylsilyloxy)-4-(triethylsilyloxy)-3-
CHCH3; 2.71, dd, J
16.9, J
7.8 Hz, H 2; 3.82–3.88, m,
2B,2A
2B,3 B
methylhexan-1-ol (20)
CH OSi; 4.73, dt, J 8.2, J
7.65–7.72, 4H, m, ArH. C n.m.r. δC (50 MHz, CDCl3) 14.0, CH3, Me;
19.0, quat., C(CH3)3; 26.8, CH3, C(CH3)3; 32.8, CH2, CH CH2OS;
5.6 Hz, H 4; 7.34–7.46, 6H, m, ArH;
2
4,3
4,1'
13
To a solution of (19) (299 mg, 0.62 mmol) in dry tetrahydrofuran (8 ml)
at 0°C and under argon was added dropwise a solution of borane–
dimethylsulfide complex (2.0 M in tetrahydrofuran, 0.93 ml, 1.86
mmol), and the mixture was stirred at room temperature until all the
alkene had been consumed (t.l.c.). The mixture was cooled to 0°C and
treated with aqueous sodium hydroxide (3 M, 10 ml). Oxidation was
then carried out by slow dropwise addition of hydrogen peroxide (35%,
5 ml), the temperature being maintained below 40°C. After stirring for
1 h, the solvent was evaporated and the residue extracted with diethyl
ether (3 × 30 ml). The combined extracts were washed with brine (20
ml), dried over sodium sulfate and concentrated under reduced pressure
to give a colourless oil which was purified by flash chromatography
with hexane/ethyl acetate (9 : 1) as eluant to afford the title compound
(20) (224 mg, 73%) as a colourless oil. [α] + 21.4° (c, 0.45, CH Cl )
2
32.8, CH, C 3; 37.4, CH , C 2; 60.3, CH2, CH2OSi; 80.1, CH, C 4;
2
127.6, 129.6, 135.4, 3 × CH, ArC; 133.3 and 133.5, quat., ArC; 176.6,
t
quat., C=O. m/z (CI, CH4) 383 (MH+, 3%), 325 (M– Bu, 10), 305 (MH–
C H , 100).
6
6
(5R,6R)-8-(t-Butyldiphenylsilyloxy)-6-hydroxy-5-methyl-1-(4'-methyl-
2',6',7'-trioxabicyclo[2.2.2]octyl)hex-1-yn-3-one (22)
To a solution of orthoester (5) (77 mg, 0.5 mmol) in dry tetrahydrofuran
(6 ml) cooled to –10°C under argon was added n-butyllithium (0.4 ml
of a 1.5 M solution in hexanes, 0.6 mmol) dropwise under argon. After
stirring at –10°C for 1 h, a solution of lactone (12) (246 mg, 0.64 mmol)
in dry tetrahydrofuran (5 ml) was added in one portion. The mixture
was stirred at –10°C for 3 h and then saturated aqueous ammonium
chloride solution (3 ml) was added. The reaction mixture was extracted
with ethyl acetate (3 × 20 ml), washed with brine (15 ml) and dried over
magnesium sulfate. Removal of solvent at reduced pressure gave a
colourless oil which was purified by flash chromatography with
hexane/ethyl acetate (7 : 3) as eluant to give (22) (172 mg, 64%) as a
D
2
2
(Found: MH+, 501.3211. C29H49O Si requires MH, 501.3220). υmax
3
2
–1
(CHCl3)/cm 3613, 3406 (OH), 3072w, 2957s, 2933s, 2876s, 1589w,
1
1472m, 1427m, 1390m, 1111s, 1081s, 1006m, 940w, 822m. H n.m.r.
δ
H (200 MHz, CDCl3) 0.63, q, J 7.9 Hz, 3 × CH2Si; 0.90, d, J 6.8 Hz,
CH3; 0.97, t, J 7.9 Hz, 3 × CH3CH2Si; 1.10, br s, (CH3) ; 1.63–1.84, m,
3
2-CH2 and 5-CH2; 2.20–2.38, m, CHCH3; 3.07, br s, OH; 3.57–3.69,
m, CH2OH; 3.76, t, J 6.3 Hz, CH2OSi; 3.89–3.97, m, CHOSi; 7.34–
colourless oil (Found: MH+, 537.2668. C31H41O Si requires MH,
6
–1
13
537.2672). υmax (CHCl3)/cm 3494w, 3069w, 2961s, 2884s, 1745m,
7.45, 6H, m, ArH; 7.67–7.74, 4H, m, ArH. C n.m.r. δC (50 MHz,
1
1471m, 1428m, 1191m, 1111s, 900s, 822m. H n.m.r. δH (200 MHz,
CDCl3) 4.9, CH2, 3 × CH2Si; 6.8, CH3, 3 × CH3CH2Si; 17.2, CH3, Me;
19.1, quat., C(CH ) ; 26.8, CH3, C(CH ) ; 34.8 and 35.3, 2 × CH2, C 5
CDCl3) 0.75, s, CH CO ; 0.96, d, J 6.8 Hz, CH3; 1.07, s, (CH3) ; 1.38–
3
3
3
3 3
3 3
1.97, m, CH CH OSi; 3.73–4.01, m, 3 × CH O, CH OSi and CHO;
and C 2; 37.8, CH, CHCH3; 60.8, CH2, CH2OSi; 62.1, CH2, CH2OH;
2
2
2
2
2.43–2.53, m, CH CO; 7.33–7.40, 6H, m, ArH; 7.62–7.75; 4H, m,
72.8, CH, CHOSi; 127.5, 129.5, 135.5, 3 × CH, ArC; 133.8, 133.9,
2
+
+
quat., ArC. m/z (CI, CH4) 501 (MH+, 53%), 483 (M–H O, 8), 387 (M–
ArH. m/z (ESI) 559 [(M + Na) , 39%], 1095 [(2M + Na) , 100].
2
t
t
SiEt , 89), 291 (M–2 × C H – Bu, 100), 175 (M–SiPh Bu–Me, 74).
3
6
5
2
(7S,8S)-7-[(2'-t-Butyldiphenylsilyloxy)ethyl]-8-methyl-1,6-
dioxaspiro[4.4]nonan-2-one (3)
(+)-(3R,4R)-6-(t-Butyldiphenylsilyloxy)-3-methylhexan-1,4-diol (21)
A solution of alkyne (22) (167 mg, 0.31 mmol) in ethyl acetate (10 ml)
was stirred with 10% Pd/C (15 mg) at room temperature under a
balloon of hydrogen for 18 h. The progress of the reaction was
A solution of alcohol (20) (195 mg, 0.39 mmol) in methanol (25 ml) was
cooled to 0°C and treated with solid camphorsulfonic acid (21 mg) in
one portion. The reaction mixture was stirred for 10 min then quenched
with solid NaHCO3 (30 mg) and concentrated under reduced pressure.
Purification by flash chromatography with hexane/ethyl acetate (1 : 1)
as eluant afforded the title compound (21) (133 mg, 88%) as a colourless
oil, [α] +10.3° (c, 1.63, acetone) (Found: MH+, 387.2358. C23H35O Si
1
monitored by H n.m.r. spectroscopy. Removal of the catalyst by
filtration through a short pad of Celite, followed by removal of the
solvent at reduced pressure, afforded a colourless oil which was
dissolved in methanol (8 ml) and water (1 ml). Pyridinium p-
toluenesulfonate (10 mg) was added and the mixture was stirred at
room temperature for 1 h. Lithium hydroxide (60 mg) in water (3 ml)
was then added. After stirring for 30 min, water (4 ml) was added and
the methanol was removed under reduced pressure. The aqueous
solution was acidified with 2 M hydrochloric acid, extracted with diethyl
ether (3 × 20 ml) and dried over MgSO4. After filtration, fresh MgSO4
was added, followed by p-toluenesulfonic acid (10 mg), and the mixture
was stirred at room temperature for 30 min. The MgSO4 was removed
by filtration and the solvent evaporated to give a yellow oil which was
purified by flash chromatography with hexane/ethyl acetate (4 : 1
containing 1% triethylamine) to give the title compound (3) as a
D
3
–1
requires MH, 387.2355). υmax (CHCl3)/cm 3687w, 3608w, 3501
(OH), 3072w, 2959s, 2931s, 2859m, 2364w, 1605w, 1472m, 1427m,
1
1390w, 1111s, 1077s, 822m. H n.m.r. δH (200 MHz, CDCl3) 0.94, d, J
6.7 Hz, CH3; 1.07, br s, (CH3) ; 1.44–1.59, m, 2-CH2; 1.67–1.92, m,
3
H 3 and 5-CH2; 3.25, br s, OH; 3.61–3.95, m, CH2OSi, CH2OH and
13
CHOSi; 7.36–7.46, 6H, m, ArH; 7.65–7.74; 4H, m, ArH. C n.m.r. δC
(50 MHz, CDCl3) 14.9, CH3, Me; 18.9, quat., C(CH3) ; 26.7, CH3,
3
C(CH3)3; 34.4 and 35.9, 2 × CH2, C 5 and C 2; 36.3, CH, CHCH ; 60.7,
3
CH2, CH2OSi; 64.0, CH2, CH2OH; 75.0, CH, CHOH; 127.7, 129.8,
135.5, 3 × CH, ArC; 132.8, 132.9, quat., ArC. m/z (CI, CH4) 387 (MH+,
t
55%), 329 (M– Bu, 15), 309 (MH–C H , 15), 291 (M–C H –H O),
6
6
6
6
2
t
+
t
colourless oil (13 mg, 10%) (Found: M – Bu, 381.1522. C22H25O4Si
231 (MH–2 × C H , 82) and 175 (M–2 × C H – Bu, 82).
6
6
6 6
t
–1
requires M– Bu, 381.1661. υmax (CHCl3)/cm 2958w, 2930s, 2857s,
1
(+)-(3S,4S)-4-[(2'-t-Butyldiphenylsilyloxy)ethyl]-3-methyl-γ-
butyrolactone (12)
1772s, 1463m, 1428s, 1209m, 1111s, 900w, 822. H n.m.r. δH (200
MHz,; CDCl3) 0.95, d, J 6.8 Hz, CH3; 1.05, s, (CH3) ; 1.7–2.83, m, 4 ×
3
CH and CHCH3; 3.72–3.82, m, CH OSi; 4.31–4.34, m, CHO; 7.35–
2
2
To a stirred suspension of the diol (21) (131 mg, 0.34 mmol) and
molecular sieves (4 Å, 300 mg) in dry acetone (10 ml) were added N-
13
7.41, 6H, m, ArH; 7.65–7.71, 4H, m, ArH. C n.m.r. δC (50 MHz,
CDCl3) 14.2, CH3, Me; 18.1, quat., C(CH3) ; 26.6, CH3, C(CH3) ;
3
3
methylmorpholine
N-oxide (118
mg,
1.0
mmol)
and
29.2, CH, CHCH ; 32.9, 33.4, 34.1, 3 × CH , C 4, C 6 and
3
2
tris(triphenylphosphine)ruthenium(II) chloride (12 mg). The gold
suspension was stirred under argon for 18 h then filtered through Celite.
The filtrate was concentrated under reduced pressure and purified by
flash chromatography with hexane/ethyl acetate (9 : 1) as eluant to
afford the title compound (12) (95 mg, 72%) as a colourless solid (from
CH CH2OSi; 41.5, CH , CH C=O; 61.0, CH2, CH2OSi; 79.6, CH,
2
2
2
CHO; 115.1, quat., C 5; 127.6, 129.5, 135.5, 3 × CH, ArC; 133.8, quat.,
+
ArC; 176.1, quat., C=O. m/z (ESI) 461 [(M + Na) , 100%], 898 [(2M +
+
Na) , 92].
hexane, m.p. 93–94°C). [α] +49.6° (c, 0.24, acetone) (Found: MH+,
D
Crystal Structure Determination for Lactone (12)
–1
383.2018. C23H31O Si requires MH, 383.2042). υmax (CHCl3)/cm
3051w, 2961, 2931m, 2858w, 1773s (C=O, lactone), 1472w, 1427m,
1210w, 1169m, 1112s, 1090m, 935w and 823w. H n.m.r. δH (200
MHz, CDCl3) 0.99, d, J 6.9 Hz, CH3; 1.08, s, (CH3) ; 1.78–1.88, m,
3
A colourless prismatic crystal was attached to a thin glass fibre and
mounted on a Rigaku AFC7R diffractometer employing graphite
monochromatized Cu Kα radiation generated from a rotating anode.
Cell constants were obtained from a least squares refinement against 25
1
3
CH CH2OSi; 2.18, dd, J
16.9, J
3.9 Hz, H 2; 2.51–2.63, m,
2
2A,2B
2A,3 A

Synthesis of an Oxaspirolactone
851
6
7
reflections located between 66.00 and 78.80° 2θ. Data were collected at
294.2 K with ω – 2θ scans to 135.46° 2θ. The intensities of three
standard reflections measured every 150 reflections did not change
significantly during the data collection. An empirical absorption
correction based on azimuthal scans of three reflections was applied
and the data were also corrected for Lorentz and polarization effects.
O’Shea, M. G., Ph.D. Dissertation, University of Queensland,
1990.
Fukuda, H., Takeda, M., Sato, Y., and Mitsunobu, O., Synthesis,
1979, 368.
Ducray, P., Lamotte, H., and Rousseau, B., Synthesis, 1997, 404.
Corey, E. J., Desai, M. C., and Engler, T. A., J. Am. Chem. Soc.,
1985, 107, 4339.
Corey, E. J., Kang, M.-C., Desai, M. C., Ghosh, A. K., and Houpis,
I. N., J. Am. Chem. Soc., 1988, 110, 649.
Corey, E. J., Niimura, K., Konishi, Y., Hashimoto, S., and Hamada,
Y., Tetrahedron Lett., 1986, 27, 2199.
Corey, E. J., and Shimoji, K., J. Am. Chem. Soc., 1983, 105, 1662.
Brown, H. C., and Bhat, K. S., J. Am. Chem. Soc., 1986, 108, 293.
McDougal, P. G., Rico, J. G., Oh, Y.-I., and Condon, B. D., J. Org.
Chem., 1986, 51, 3388.
Boeckman, R. K. Jr, Charette, A. B., Asberom, T., and Johnston, B.
H., J. Am. Chem. Soc., 1991, 113, 5337.
Dale, J. A., and Mosher, H. S., J. Am. Chem. Soc., 1973, 95, 512;
Sullivan, G. R., Dale, J. A., and Mosher, H. S., J. Org. Chem., 1973,
38, 2143.
Kocienski, P. J., Brown, R. C. D., Pommier, A., Proctor, M., and
Schmidt, B., J. Chem. Soc., Perkin Trans. 1, 1988, 9.
Brimble, M. A., Aust. J. Chem., 1990, 43, 1035.
Harnden, M. R., and Jarvest, R. L., J. Chem. Soc., Perkin Trans. 1,
1989, 2207.
Smith III, A. B., Lin, Q, Nakayama, K., Boldi, A. M., Brook, C. S.,
McBriar, M. D., Moser, W. H., Sobukawa, M., and Zhuang L.,
Tetrahedron Lett., 1997, 38, 8675; Boeckman, R. K. Jr., Charette,
A. B., Asberom, T., and Johnston, B. H., J. Am. Chem. Soc., 1987,
109, 7553.
teXsan: Crystal Structure Analysis Package, Molecular Structure
Corporation The Woodlands, Texas, U.S.A, 1985 and 1992.
SIR92: Altomare, A., Cascarano, M., Giacovazzo, C., and
Guagliardi, A., J. Appl. Crystallogr., 1993, 26, 343.
DIRDIF94: Beurskens, P. T., Admiral, G., Beurskens, G., Bosman, W.
P., de Gelder, R., Israel, R. and Smiths, J. M. M., (1994). The DIRDIF-
94 program system, Technical Report of the Crystallography
Laboratory, University of Nijmegen, The Netherlands.
Flack, H. D., Acta Crystallogr., Sect. A, 1983, 39, 876;
Bernardinelli, G., and Flack, H. D., Acta Crystallogr., Sect. A,
1985, 41, 500.
8
9
21
Processing and calculations were undertaken with teXsan. The
10
11
structure was solved in the space group P2 2 2 (No. 19) by direct
1
1 1
22
methods with SIR92 , and extended with difference maps generated by
23
DIRDIF.
In general the non-hydrogen atoms were modelled with
anisotropic displacement parameters, and the hydrogen atoms were
included in the model at calculated positions with group thermal
parameters. The C(2) and C(23) atoms are both disordered about two
sites, with occupancies of 0.6 for C(2A) and C(23A) and 0.4 for C(2B)
and C(23B). The partially occupied sites were modelled with isotropic
12
13
14
24
15
16
displacement parameters. The Flack parameter refined to 0.12(4). An
ORTEP25
projection of the molecule with 20% displacement ellipsoids is
provided in Fig. 1.
Crystallographic data. Formula
C
H
O Si,
M
382.57,
23 30
3
orthorhombic, space group P2 2 2 (No. 19), a 12.437(2), b 23.881(4),
1
1 1
3
–3
17
c 7.545(1) Å, V 2240.9(5) Å , D 1.134 g cm , Z 4, crystal size 0.40
c
by 0.21 by 0.15 mm, colourless, habit prism, λ(Cu Kα) 1.5418 Å,
–1
18
19
µ(Cu Kα) 1.067 mm , T(psi scans)
0.850, 0.970, 2θ
obs
min,max
max
135.46, hkl range 0 14, 0 28, 0 8, N 2310, N 1688 (I > 3.00σ(I)),
*
N
242, residuals R(F) 0.0460, R (F) 0.0458, GoF(all) 2.880,
var
w
-
–3
20
∆ρ
–0.19, 0.23 e Å
.
min,max
*
2
2 1/2
R = Σ||F | – |F ||/Σ|F |; R = (Σw(F – F ) /Σ(wF ) )
o
c
o
w
o
c
c
2
w = 1/σ (F )
o
Crystallographic details for (12) have been deposited and copies are
available from the Australian Journal of Chemistry, P.O. Box 1139,
Collingwood, Vic. 3066, until 31 December 2005.
21
22
23
References
1
Hu, T., Curtis, J. M., Oshima, Y., Quillam, M. A., Walter, J. A.,
Watson-Wright, W., and Wright, J. L. C., J. Chem. Soc., Chem.
Commun., 1995, 2159.
Yamamoto, M., Yoshitake, M., and Yamada, K., J. Chem. Soc.,
2
24
25
Chem. Commun., 1983, 991.
Tu, Y. Q., Byriel, K. A., Kennard, C. H. L., and Kitching, W., J.
3
Chem. Soc., Perkin Trans. 1, 1995, 1309.
DeShong, P., and Rybczynski, P. J., J. Org. Chem., 1991, 56, 3207.
Mudryk, B., Shook, C. A., and Cohen, T., J. Am. Chem. Soc., 1990,
Johnson, C. K., ORTEPII. Report ORNL-5138. Oak Ridge National
Laboratory, Oak Ridge, Tennessee (1976); Hall, S. R., du Boulay,
D. J., and Olthof-Hazekamp, R. (1999) (Eds) XTAL3.6 System.
University of Western Australia.
4
5
112, 6389.
http://www.publish.csiro.au/journals/ajc