Total synthesis of C19 lipid diols containing a 2,5-disubstituted-3-oxygenated tetrahydrofuran

Article abstract of DOI:10.1039/c0ob00754d

The total synthesis of the C₁₉ lipid diols 5 and 6, the enantiomers of the anthelmintic marine natural products 1 and 3, is described. Key steps in the divergent syntheses include a syn selective epoxidation of a homoallylic alcohol, a one-pot alkoxypalladation-carbonylation-lactonisation reaction sequence and a DMEAD promoted Mitsunobu inversion.

Full text of DOI:10.1039/c0ob00754d

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PAPER
Total synthesis of C19 lipid diols containing a 2,5-disubstituted-3-oxygenated
tetrahydrofuran†‡
Caroline L. Nesbitt and Christopher S. P. McErlean*
Received 21st September 2010, Accepted 17th December 2010
DOI: 10.1039/c0ob00754d
The total synthesis of the C19 lipid diols 5 and 6, the enantiomers of the anthelmintic marine natural
products 1 and 3, is described. Key steps in the divergent syntheses include a syn selective epoxidation
of a homoallylic alcohol, a one-pot alkoxypalladation-carbonylation-lactonisation reaction sequence
and a DMEAD promoted Mitsunobu inversion.
on the epoxide-opening reaction being under enzymatic control.12
The diastereomeric lipid diol 3 was isolated from N. anomala
Introduction
in 1998, and also displays anthelmintic activity.4 It is tempting
to hypothesize that this compound arises from either conserved
enzymatic action on the as yet unidentified anti, methylene skipped
cis, cis-bis-epoxide 4, or through a disfavoured (perhaps non-
enzymatic) exo epoxide-opening, ring-closing cascade on the
stereochemically defined bis-epoxide 2 (Scheme 1).5 In any event,
enzymatic involvement in the formation and/or ring-opening
of the bis-epoxide precursors means that natural access to the
tetrahydrofuran containing C19 lipid diols is restricted to one
enantiomeric series.
Compounds 1 and 3 provide conspicuous examples of the
2,5-disubstituted-3-oxygenated tetrahydrofuran unit present in
many marine natural products. We recently outlined a general
synthetic strategy capable of delivering any stereoisomer of this
important structural unit.13 We had initially planned to highlight
our approach by completing a total synthesis of 1 and 3. Upon
reflection, however, we revised our targets to the enantiomeric
compounds 5 and 6 (Fig.1). Our decision was based on the fact that
there is no shortage of compound 1. Not only have several total
syntheses of this molecule been reported,5,14–21 but the metabolite is
available in plentiful quantities from the natural source. Extraction
of 25 grams of N. anomala delivered more than half a gram of 1.10
The commonly occurring brown algae Notheia anomala is native
to Australian and New Zealand waters.1,2 This epiphytic species
has been the focus of research by Capon and co-workers to
uncover biologically active secondary metabolites and examine
their chemistry and biochemistry.3–10 The major metabolite from
this species, the C19 lipid (6S, 7S, 9R, 10R)-6,9-epoxynonadec-
18-ene-7,10-diol 1 (Scheme 1), was first isolated in 1980 and
displays potent in vitro anthelmintic activity.11 Capon and Barrow
hypothesized that this compound was biogenetically derived
from the co-isolate syn methylene skipped cis, cis-bis-epoxide
2 through an acid-catalysed endo ring-opening, ring-closing
cascade.5 Supporting this hypothesis, Faber and co-workers have
recently demonstrated that the stereochemical outcome of THF
formation from methylene skipped bis-epoxides is dependant only
School of Chemistry, The University of Sydney, NSW, 2006, Australia.
E-mail: christopher.mcerlean@sydney.edu.au; Fax: +61 2 9351 3329;
Tel: +61 2 9351 3970
† Electronic supplementary information (ESI) available: 1H NMR and
13C NMR spectra. CCDC reference number 794007. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c0ob00754d
‡ C. L. N. gratefully acknowledges receipt of an Australian Postgraduate
Award.
Scheme 1 Proposed biogenetic relationship between C19 lipid diols 1 and 3.
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Fig. 1 Target compounds 5 and 6.
In contrast, the isolation or synthesis of the antipodal compounds
5 and 6 has not been reported. We therefore embarked on a total
synthesis of 5 and 6, the realisation of which is reported below.
Our retrosynthetic analysis is depicted in Scheme 2. Disconnec-
tion of the C10–C11 bond revealed the aldehyde 7. We anticipated
that the nine carbon side-chain could be appended using an
organometallic reagent that, under appropriate conditions, would
facilitate the diastereoselective installation of the C10 stereocentre.
The aldehyde 7 was envisaged to arise from the bicyclic lactone
8, which could be accessed from the enediol 9 using a palladium
catalysed carbonylation reaction. The enediol 9 could be generated
using one of several methods from the homoallyllic alcohol 10.
The ultimate disconnection revealed benzyl glycidyl ether 11 as
the starting material for the sequence. As both isomers of this
epoxide are commercially available, the same synthetic sequence
could be employed to generate either enantiomeric series.
Scheme 3 Carbonate extension strategy. Reagents and conditions: (a)
H2C CHMgBr, CuCl, 0 ◦C, 94%; (b) n-BuLi, (Boc)2O, -78 ◦C, 74%;
(c) IBr, toluene, -78 ◦C, 25%.
syn-diastereocontrol can be moderate. Bartlett noted that simply
lowering the temperature of the reaction mixture may appear to be
a straightforward solution to this problem.22 Unfortunately, mild
iodinating or brominating reagents generally require temperatures
approaching ambient in order to participate in the reaction. We
thought that we may be able to circumvent this problem by
utilising a nucleophilic catalyst to generate a reactive halogenating
reagent in situ at temperatures favouring formation of the syn
diastereomer.
Ishihara’s seminal work on phosphine-based nucleophilic pro-
moters for the generation of asymmetric halonium species at
low temperature prompted us to investigate the use of nucle-
ophilic catalysts for the iodocyclisation reaction.24 When the Boc-
protected alcohol 12 was treated with N- bromosuccinimide and
triphenylphosphine in toluene at -78 ◦C, the desired cyclised
product was not observed and the starting material was recovered
intact. Switching to a more polar solvent (CH2Cl2) offered no
improvement. Employing N-iodosuccinimide under the same
reaction conditions and raising the reaction temperatures to
-40 ◦C were also ineffectual. We reasoned that the lack of reactivity
might reflect the low relative nucleophilicity of the phosphine,
but the reaction also failed when the highly nucleophilic catalyst,
tributylphosphine, was employed. To ensure that the Boc unit was
itself nucleophilic enough to react with the initially formed halo-
nium ion, compound 12 was treated with iodine monobromide in
◦
toluene at -78 C.23 The use of this powerful iodinating reagent
delivered the desired iodocarbonate 13 with good levels of syn-
diastereoselectivity, but in low yield. Competitive cyclisation of
the benzyl ether gave tetrahydrofurans 14 and 15 as the major
reaction products.25 This result demonstrated that the Boc unit
would participate in ring-forming reaction at low temperatures if
the alkene could be halogenated, but the competitive side-reactions
rendered this approach untenable. Given the previous success with
nucleophilic phosphine catalysts at low temperature to generate
highly active halonium species that engage in cyclisations,24 the
current failure may point to the required electronic characteristics
of the participating alkene.
Scheme 2 Retrosynthetic analysis of target compound 5.
The synthesis began by opening the (S)-configured epoxide 11
with vinylmagnesium bromide under copper catalysis (Scheme 3).
We anticipated that the stereochemically defined hydroxyl group
which would become C10 in the target molecule could be used
to direct the installation of the neighbouring stereocentre. To
that end, alcohol 10 was converted into the tert-butylcarbonate
12 with the expectation that this group would participate in
a Bartlett carbonate-extension reaction.22,23 It is known that
unsubstituted homoallylic alcohols (such as 12) are the least
satisfactory substrates for these cyclisations, and the level of
Rather than pursue alternative methods to effect the halo-
cyclisation, our attention turned to forming the epoxide 16 directly.
We had already reported that treatment of the alcohol 10 with
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Scheme 4 Synthesis of 5. Reagents and conditions: (a) VO(acac)2 (2 mol%), t-BuOOH, 81 ◦C, 63%, 16:17 2 : 1; (b) Me3SI, n-BuLi, 93%; (c) Pd(OAc)2
(10 mol%), NaOAc, CuCl2, HOAc, CO, 47% 8, 23% 19; (d) DiBAl-H, -78 ◦C; (e) (Ph)3PPrI, n-BuLi, 0 ◦C, 59% from 8; (f) TBSOTf, Et3N, 0 ◦C, 96% (g)
∑
H2, Pd/C, 97%; (h) DMSO, SO3 py, Et3N; (i) H2C CH(CH2)6CH2MgBr, DCE, 83 ◦C, 39% from 22; (j) TBAF, 95%.
m-CPBA gave a 1 : 1 mixture of diastereomeric epoxides 16 and
17 (Scheme 4).13 That result showed that hydrogen bonding
control was unlikely to be effective for selective generation of
the syn-epoxyalcohol 16. We therefore examined the vanadium-
catalysed syn-selective epoxidation.26 A systematic study of the
diastereoselective epoxidation of homoallylic alcohols has been
reported by Mihelich,27 revealing that the direction and magni-
tude of stereoselection can be predicted by comparing plausible
transition state models. That author noted that the observed
asymmetric induction was largely the result of minimisation of
steric interactions of the various substituents according to the
normal principles of conformational analysis. Since compound 10
lacked any vinylic or allylic substitution, we anticipated that the
levels of diastereoselection may be low.
As shown in Scheme 4, homoallylic alcohol 10 was subjected to
the action of tert-butylhydroperoxide in the presence of VO(acac)2.
The sluggish epoxidation proceeded only at◦elevated temperatures,
but we were pleased to observe that at 80 C, the epoxyalcohols
16 and 17 were produced in a 2 : 1 ratio favouring the syn
diastereomer. At this stage the two compounds were not easily
separable and so were carried forward as the mixture.
Reaction with dimethylsulfonium methylide delivered the one
carbon homologated allylic alcohols 9 and 18 in quantita-
tive yield. The mixture was then subjected to Semmelhack’s
alkoxypalladation-carbonylation-lactonisation reaction condi-
tions to give the bicyclic lactones 8 and 19 as a 2 : 1 mixture.28–30
The two lactones were easily separable by chromatography and the
major compound 8 formed crystals suitable for X-ray analysis.31
As shown in Fig. 2, this demonstrated that the major product
had an anti relationship between the C5 substituent on the
tetrahydrofuran ring and the substituents at the ring junction.
This requires the vanadium epoxidation reaction to have favoured
formation of the syn-epoxyalcohol 16 as expected.
The lactone 8 was reduced to the lactol 20 and subjected
to Wittig olefination to give 21 as an inconsequential mixture
of geometric isomers (Scheme 4). After the secondary alcohol
was protected as a tert-butyldimethylsilyl ether, hydrogenation of
the alkene was accompanied by removal of the benzyl ether to
give alcohol 22 in good yield. Following the protocol of Britton
and co-workers,18 alcohol 22 was oxidized under Parikh-Doering
conditions and the product aldehyde 7 was treated immediately
with 8-nonenylmagnesium bromide. This delivered the desired
alcohol 23 as the major product in a 4 : 1 mixture with the C10
epimer 24. This outcome is consistent with chelation-controlled
addition of the organometallic reagent, where the carbonyl oxygen
and ether-ring oxygen coordinate to magnesium and facilitate
addition to the Si face of the aldehyde.32,33 Treatment of 23 with
TBAF smoothly effected removal of the TBS group giving the
desired product 5. This synthetic sequence delivered compound
5, the enantiomer of natural product 1, in 11 steps from benzyl
glycidyl ether 11.
Our second target, compound 6, differed from compound 5
in configuration at the C9 and C10 stereocentres. As outlined in
Scheme 5, we hoped that the installation of the C10 stereocentre
Fig. 2 X-ray crystal structure of compound 8.
Scheme 5 Retrosynthetic analysis of target compound 6.
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Scheme 6 Synthesis of 6. Reagents and conditions: (a) p-nitrobenzoic acid, PPh3, DMEAD, 93%, 28:29 2 : 1; (b) MeOH, K2CO3, 89%; (c) Me3SI, n-BuLi,
96%; (d) Pd(OAc)2 (10 mol%), NaOAc, CuCl2, HOAc, CO, 44% 26, 26% 32; (e) DiBAl-H, -78 ◦C; (f) (Ph)3PPrI, n-BuLi, 0 ◦C, 82% from 26; (g) TBSOTf,
∑
Et3N, 0 ◦C, 99% (h) H2, Pd/C, 85%; (i) DMSO, SO3 py, Et3N; (j) H2C CH(CH2)6CH2MgBr, DCE, 83 ◦C,; (k) TBAF; Path A, 35, 74% from 34; Path
B: 6, 31% from 34, and 35 10% from 34.
could be accomplished under the same reaction conditions used
above, with the C9 stereocentre directing the addition. Generation
of the appropriate 2,5-disubstituted-3-oxygenated tetrahydrofu-
ran 25 could be accomplished from the bicyclic lactone 26.
The all-cis stereochemical arrangement of 26 required the anti
epoxyaldehyde 27. We anticipated that 27 could be generated via
Mitsunobu inversion of 16.34 This meant that both of the desired
targets 5 and 6 would ultimately be derived from the same starting
material 11.
Capon reported that the C10 epimers of the naturally occurring
lipid diols 1 and 3 were the most active compounds in an in vitro
anthelmintic assay,4 so efficient access to this compound may be
advantageous. We rationalize the stereochemical outcome on the
basis of a configurationally driven switch from chelation-control
to Felkin-Ahn addition of the organometallic reagent. The all-
cis stereochemical arrangement around the tetrahydrofuran and
the steric bulk of the silyl protecting group, precludes magnesium
chelation between the carbonyl and the ether oxygens. Supporting
this interpretation is the observation that generally poor levels of
stereoselection have been reported using other protecting groups
on the C7 hydroxyl group.16 In contrast, Britton and co-workers
reported DFT calculations on a related system that lacked a
protecting group on the C7 hydroxyl, and concluded that an
intricate network involving the C7 alkoxide, the ether oxygen and
the carbonyl unit, predisposed the molecule to undergo a chelation
controlled reaction on the desired Si face of the aldehyde.33
We anticipated that removal of the silyl protecting group from
compound 34 prior to addition of the organometallic reagent
would remove the large steric bulk and favour chelation controlled
addition. In the event, compound 34 was oxidized under Parikh-
Doering conditions, subjected to TBAF mediated desilylation and
then treated with 8-nonenylmagnesium bromide. As shown in
Scheme 6, this synthetic sequence delivered compound 6 as a 3 : 1
mixture with the C10 epimer. The synthesis of compound 6, the
enantiomer of natural product 3, was completed in 13 steps from
benzyl glycidyl ether 11
The synthetic sequence is depicted in Scheme 6. The inseparable
2 : 1 mixture of epoxyalcohols 16 and 17 which was produced
by the action of tert-butylhydroperoxide and VO(acac)2 (see
Scheme 4), was subjected to standard Mitsunobu conditions with
p-nitrobenzoic acid, triphenylphosphine and diisopropyl azodi-
carboxylate (DIAD) as the coupling reagent. Disappointingly,
the product esters 28 and 29 co-eluted with reaction byproducts.
Exhaustive chromatography was required to obtain the purified
esters, and consequently the yields were low. We therefore turned to
the dimethoxyethyl azodicarboxylate (DMEAD) coupling reagent
devised by Sugimura which gives water soluble byproducts, greatly
facilitating product isolation.35,36 Treatment of epoxyalcohols
16 and 17 with p-nitrobenzoic acid, triphenylphosphine and
DMEAD delivered the esters 28 and 29 as a 1 : 2 mixture in high
yield on a gram scale. Ester hydrolysis and epoxide opening with
dimethylsulfonium methylide gave the desired enediols 30 and 31.
As in the previous synthesis, the enediols underwent a smooth one-
pot alkoxypalladation-carbonylation-lactonisation sequence to
give the readily separable bicyclic lactones 26 and 32. Compound
26, containing the required stereochemical arrangement was
reduced to the lactol, which underwent Wittig olefination to
give 33. The secondary alcohol was protected as a silyl ether
and the compound was subjected to the action of hydrogen and
palladium-on-charcoal. The debenzylated, fully saturated product
34 was then oxidized under Parikh-Doering conditions and the
aldehyde treated with 8-nonenylmagnesium bromide followed by a
TBAF mediated deprotection. In contrast to the previous synthetic
synthesis, this series of reactions exclusively delivered compound
35, the C10 epimer of the desired compound.
Conclusions
We have synthesised the two C19 lipid diols 5 and 6, the enantiomers
of the marine natural products 1 and 3. The divergent syntheses
began from commercially available benzyl glycidyl ether 11, and
proceeded under substrate control thereafter. The key reaction
in both syntheses was the palladium-catalysed transformation of
linear enediols into the corresponding fused bicyclic lactones,
which engendered the stereochemical framework of the desired
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2,5-disubstituted-3-oxygenated tetrahydrofuran. Compounds 5
and 6 were generated in 11 and 13 steps, respectively.
the combined organic extracts were washed with brine (50 mL),
dried over Na2SO4 and the solvent was removed. Purification by
flash chromatography eluting with 1% ethyl acetate in hexanes
20
gave compound 12 as a colourless oil (2.97 g, 74%). [a]D + 4.0
Experimental
(c 1.0, CHCl3); nmax/cm-1 (CHCl3) 3031, 2980, 2865, 1736, 1250,
1093; dH (300 MHz; CDCl3) 7.37–7.27 (5 H, m), 5.77 (1 H, dddd,
J 17.1, 10.1, 7.1, 7.1), 5.15–5.05 (2 H, m), 4.93–4.85 (1 H, m),
4.58 (1 H, d, J 12.1), 4.52 (1 H, d, J 12.1), 3.56 (2 H, d, J 5.2),
2.47–2.36 (2 H, m), 1.48 (9 H, s); dC (75 MHz; CDCl3) 153.3 (C),
138.2 (C), 133.2 (CH), 128.5 (CH), 127.9 (CH), 127.7 (CH), 118.2
(CH2), 82.1 (C), 75.0 (CH), 73.3 (CH2), 70.8 (CH2), 35.7 (CH2),
27.9 (CH3).
All reactions were conducted under an inert atmosphere (nitrogen
or argon) in oven-dried glassware. Dichloromethane was freshly
distilled from CaH2 and tetrahydrofuran was freshly distilled
from sodium/benzophenone. All other solvents and reagents
were used as received from commercial sources. Melting points
were determined using a Stanford Research Systems Optimelt
automated melting point system and are uncorrected. Infrared
spectra were acquired on a Shimadzu FTIR-8400S or Bruker
Alpha-E ATR spectrometer as a solution between sodium chloride
plates, as a KBR disk or neat. Absorption maxima are expressed
Iodocarbonate (13)25,38,39
. A solution of the Boc-protected
alcohol◦12 (250 mg, 0.86 mmol) in toluene (6.5 mL) was cooled
to -78 C and iodine monobromide (1.0 M in dichloromethane;
3.85 mL, 3.85 mmol) was added. The reaction mixture was stirred
in the dark for 2 h then warmed to 0 ◦C, diluted with ether
and quenched by the addition of aqueous sodium thiosulfate
(2.0 M; 5 mL) and saturated aqueous sodium hydrogen carbonate
(2.5 mL). The layers were separated and the aqueous phase was
extracted with ether (2 ¥ 10 mL). The organic extracts were washed
with brine (2 ¥ 10 mL), dried over Na2SO4 and the solvent was
evaporated. Purification by flash chromatography eluting 4% ethyl
acetate in hexanes then 100% ether gave, in order of elution, the
undesired anti-iodocarbonate as a pale yellow oil (19.9 mg, 6.5%).
[a]D20 + 2.9 (c 5.4, CHCl3); nmax/cm-1 (neat) 3022, 2927, 2857, 1746,
1454, 1250; dH (300 MHz; CDCl3) 7.40–7.30 (5 H, m), 4.73–4.64
(1 H, m), 4.62–4.58 (2 H, m), 3.70 (1 H, ddd, J 18.3, 10.5, 4.8),
3.48 (1 H, dd, J 14.1, 7.2), 3.41 (1 H, dd, J 10.5, 4.2), 3.25 (1 H,
dd, J 10.5, 8.1), 2.38 (1 H, dt, J 14.4, 4.5), 2.17 (1 H, ddd, J 14.1,
8.4, 5.7), 2.04 (1 H, s); dC (75 MHz; CDCl3) 148.2 (C), 137.3 (C),
128.8 (CH), 128.3 (CH), 127.9 (CH), 75.4 (CH), 75.1 (CH), 74.0
1
in wavenumbers (cm-1). H and 13C NMR spectra were recorded
on a Bruker AVANCE DPX300, or Bruker DPX400 spectrometer
(1H frequencies 300, 400 MHz; 13C frequencies 75 and 100 MHz
respectively). 1H chemical shifts are expressed as parts per million
(ppm) with residual chloroform (d 7.26) or tetramethylsilane as
reference and are reported as chemical shift (dH); relative integral;
multiplicity (s = singlet, br = broad, d = doublet, t = triplet,
dd = doublet of doublets, dt = doublet of triplets, q = quartet,
m = multiplet); and coupling constants (J) reported in Hz. 13C
NMR chemical shifts are expressed as parts per million (ppm)
with residual chloroform (d 77.2) as internal reference and are
reported as chemical shift (dC); multiplicity (assigned from DEPT
experiments). High resolution mass spectra were recorded on a
Bruker ApexII Fourier Transform Ion Cyclotron Resonance mass
spectrometer with a 7.0 T magnet, fitted with an off-axis Analytical
electrospray source.
(S)-1-(Benzyloxy)pent-4-en-2-ol (10)37. Vinylmagnesium bro-
mide (1.0 M in THF; 21.8 mL, 21.8 mmol) was added at 0 ◦C to
a suspension of copper (I) chloride (144 mg, 1.45 mmol) in THF
(60 mL). After stirring for 15 min, a solution of (S)-benzyl glycidyl
ether (2.39 g, 14.5 mmol) in THF (60 mL) was added and the
mixture was stirred for 40 min at room temperature. The reaction
was quenched by the addition of saturated aqueous ammonium
chloride (60 mL). The mixture was extracted with ethyl acetate (3 ¥
60 mL), dried over Na2SO4, and the solvent was evaporated. Flash
column chromatography eluting with 15% ethyl acetate in hexanes
(CH), 70.8 (CH), 28.5 (CH2), 4.9 (CH2); followed by the desired
20
syn-iodocarbonate 13 as a pale yellow oil (77.4 mg, 25%). [a]D
+
20
16.4 (c 0.85, CHCl3) (lit. [a]D + 10.9 (c 0.73, CHCl3)); nmax/cm-1
(neat) 3021, 2921, 2866, 1739, 1496, 1395, 1372; dH (300 MHz;
CDCl3) 7.39–7.29 (5 H, m), 4.65–4.55 (3 H, m), 4.46 (1 H, m), 3.68
(1 H, dd, J 10.5, 4.5), 3.64 (1 H, dd, J 10.5, 4.5), 3.41 (1 H, dd, J
10.5, 4.5), 3.26 (1 H, dd, J 10.5, 7.5), 2.45 (1 H, dt, J 14.4, 3.3),
1.91 (1 H, dt, 14.1, 11.7); dC (75 MHz; CDCl3) 148.1 (C), 137.5
(C), 128.7 (CH), 128.2 (CH), 128.0 (CH), 77.3 (CH), 77.2 (CH),
74.0 (CH2), 70.7 (CH2), 30.3 (CH2), 5.0 (CH2).
25
gave compound 10 (2.63 g, 94%) as a pale yellow oil. [a]D + 3.3
(c 1.0, CHCl3); nmax/cm-1 (CHCl3) 3580, 3063, 3001, 2908, 2862,
1643; dH (300 MHz; CDCl3) 7.39–7.28 (5 H, m), 5.90–5.76 (1 H,
m), 5.15–5.09 (2 H, m), 4.56 (2 H, s), 3.89 (1 H, ddd, J 13.5, 6.6,
3.3), 3.52 (1 H, ddd, J 9.6, 3.3), 3.38 (1 H, dd, J 9.6, 7.5), 2.39–2.35
(1 H, m), 2.27 (2 H, dd, J 6.9, 6.6); dC (75 MHz; CDCl3) 138.1
(CH), 134.4 (C), 128.6 (CH), 127.92 (CH), 127.87 (CH), 117.8
(CH2), 74.0 (CH2), 73.5 (CH2), 69.9 (CH), 38.0 (CH2).
20
Compound 14. (66.3 mg, 24%); [a]D - 5.2 (c 1.0, CHCl3) (lit.
[a]D - 5.2 (c 1.1, CHCl3)); nmax/cm-1 (neat) 2980, 2934, 2875,
20
1734, 1369, 1348, 1275; dH (300 MHz; CDCl3) 5.20–5.17 (1 H, m),
4.18 (1 H, dd, J 10.8, 4.5), 4.11 (1 H, 9.3, 5.7), 3.79 (1 H, d, J 10.5),
3.27 (2 H, d, J 5.4), 2.29 (1 H, d, J 14.1, 5.7), 1.86 (1 H, ddd, J
13.8, 9.6, 6.0), 1.47 (9 H, s); dC (75 MHz; CDCl3) 153.1 (C), 82.8
(C), 77.9 (CH2), 77.4 (CH2), 73.8 (CH), 39.2 (CH), 27.9 (CH3), 9.4
(CH2).
(S)-1-(Benzyloxy)-2-(tert-butylcarbonyloxy)pent-4-ene
(12).
A solution of the alcohol 10 (2.63 g, 13.7 mmol) in anhydrous
THF (50 mL) was treated with n-butyllithium (2.36 M in hexanes;
8.12 mL, 19.1 mmol) at -78 ◦C. The resulting solution was
transferred via cannula to a solution of di-tert-butyl dicarbonate
(4.61 g, 20.5 mmol) in anhydrous THF (50 mL). After stirring
for 12 h at room temperature the reaction mixture was diluted
with ether and washed with aqueous NaOH (2 M; 2 ¥ 70 mL).
The aqueous layer was extracted with ether (3 ¥ 50 mL) and
20
Compound 15. (20.6 mg, 7.3%) [a]D -27.5 (c 4.8, CHCl3);
n
max/cm-1 (neat) 2922, 2853, 1734, 1461, 1377, 1273; dH (300 MHz;
CDCl3) 5.16 (1 H, ddd, J 9.0, 4.5, 2.1), 4.22–4.13 (1 H, m), 4.10
(1 H, d, J 10.2), 3.93 (1 H, dd, J 10.8, 4.8), 3.33 (1 H, dd, J 9.9,
6.3), 3.27 (1 H, dd, J 9.9, 7.5), 2.45 (1 H, dt, J 14.4, 7.2), 1.99 (1
H, dddd, J 14.4, 5.4, 2.4, 0.9), 1.49 (9 H, s); dC (75 MHz; CDCl3)
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153.3 (C), 82.8 (C), 79.0 (CH2), 77.3 (CH2), 73.7 (CH), 37.9 (CH),
27.9 (CH3), 8.7 (CH2).
(304 mg, 1.37 mmol) was added as an acetic acid solution (5.0 mL),
and the mixture was stirred vigorously while purging with nitrogen,
followed by purging the reaction mixture with carbon monoxide.
Palladium (II) acetate (30.8 mg, 0.14 mmol) was added and stirring
was continued overnight. The solution was poured into water
(30 mL), and sodium hydrogen carbonate was added until the
solution was neutralised. The solution was extracted with ethyl
acetate (3 ¥ 50 mL), dried over Na2SO4, and the solvent was
evaporated. Purification by column chromatography, eluting with
40% ethyl acetate in hexanes gave compound 19 as a colourless oil
(2S,4R)-1-(Benzyloxy)-4,5-epoxy-2-hydroxy-1-pentane
(16).
To a solution of alkene 10 (2.50 g, 13.0 mmol) in toluene (60 mL)
was added VO(acac)2 (69 mg, 0.26 mmol) and the solution was
heated to 81 ◦C. Tert-butyl hydroperoxide (5.5 M in decane;
2.6 mL, 14.3 mmol) was added dropwise over 1 h, and the mixture
was stirred at 81 ◦C for 3 h. The reaction was quenched by
the addition of aqueous sodium thiosulfate (2 M; 50 mL). The
mixture was extracted with ethyl acetate (3 ¥ 50 mL), dried over
Na2SO4 and the solvent was evaporated. Flash chromatography
eluting with 10% ethyl acetate in hexanes followed by 20%
ethyl acetate in hexanes gave compound 16 (1.71 g, 63%) as a
(77 mg, 23%): [a]D - 53.8 (c 1.55, CHCl3); nmax/cm-1 (neat) 3040,
20
2993, 2616, 2862, 1782; dH (300 MHz; CDCl3) 7.36–7.27 (5 H, m),
5.03–4.99 (1 H, m), 4.60–4.56 (1 H, m), 4.52 (2 H, d, J 12.0), 4.27–
4.18 (1 H, m), 3.52–3.50 (2 H, m), 2.79–2.66 (2 H, m), 2.38 (1 H,
ddd, J 14.7, 7.5, 6.9), 2.03 (1 H, ddd, J 14.7, 7.2, 1.5); dC (75 MHz;
CDCl3) 175.4 (C), 137.9 (C), 128.5 (CH), 127.9 (CH), 127.8 (CH),
84.2 (CH), 79.3 (CH), 79.2 (CH), 73.5 (CH2), 72.3 (CH2), 36.6
(CH2), 35.2 (CH2); HRMS (ESI) for C14H16O4Na (MNa+) calcd
271.0941, found 271.0941; and compound 8 (160 mg, 47%) as a
20
colourless oil as a 2 : 1 mixture of diastereomers. [a]D - 9.8 (c
1.0, MeOH); nmax/cm-1 (CHCl3) 3580, 3063, 3032, 3016, 2916,
2862; dC (75 MHz; CDCl3) 7.45–7.28 (5 H, m), 4.57 (2 H, s),
4.09–4.01 (1 H, m), 3.53 (1 H, ddd, J 18.6, 9.3, 3.3), 3.46–3.36 (1
H, m), 3.15–3.07 (1 H, m), 2.79 (1 H, ddd, J 12.3, 7.8, 4.5), 2.53
(1 H, ddd, J 10.2, 4.8, 2.7), 1.89 (1 H, ddd, J 21.6, 12.9, 6.3), 1.51
(1 H, ddd, J 21.6, 10.5, 6.6); dC (75 MHz; CDCl3) major isomer
138.0 (C), 128.5, (CH), 127.9 (CH), 74.1 (CH), 73.59 (CH2),
73.56 (CH2), 68.78 (CH), 49.8 (CH), 46.8 (CH2), 36.1 (CH2);
minor isomer 138.0 (C), 128.5, (CH), 128.0 (CH), 74.4 (CH),
73.59 (CH2), 73.56 (CH2), 68.54(CH), 49.9 (CH), 47.2 (CH2), 36.3
(CH2); HRMS (ESI) for C12H16O3Na (MNa+) calcd 231.0992,
found 231.0991.
white solid; [a]D + 39.0 (c 1.0, CHCl3); nmax/cm-1 (neat) 3040,
20
3001, 2932, 2860, 1728 cm-1; dH (300 MHz; CDCl3) 7.37–7.27 (5
H, m), 5.11–5.08 (1 H, m), 4.83 (1 H, ddd, J 9.0, 5.4, 2.7), 4.57 (2
H, s), 4.40–4.32 (1 H, m), 3.62 (1 H, dd, J 10.5, 3.0), 3.48 (1 H, dd,
J 10.5, 4.8), 2.71 (2 H, d, J 4.8), 2.34 (1 H, dd, J 14.1, 6.0), 2.04
(1 H, ddd, J 14.1, 9.3, 5.1); dC (75 MHz; CDCl3) 175.8 (C), 138.0
(C), 128.6 (CH), 127.9 (CH), 127.8 (CH), 84.8 (CH), 78.6 (CH),
76.7 (CH), 73.6 (CH2), 71.7 (CH2), 36.8 (CH2), 35.0 (CH2); HRMS
(ESI) for C14H16O4Na (MNa+) calcd 271.0941, found 271.0941.
(2S,4R)-1-(Benzyloxy)-5-hexene-2,4-diol (9)40,41
. To a stirred
mixture of trimethylsulfonium iodide (4.22 g, 20.7 mmol) in
anhydrous THF (100 mL) at -10 ◦C was added n-butyllithium
(1.26 M in THF; 16.4 mL, 20.7 mmol). The solution was stirred for
30 min then a solution of epoxides 16 and 17 (1.08 g, 5.17 mmol)
in dry THF (20 mL) was added and the reaction mixture was
stirred for 2 h at room temperature. The reaction was quenched by
the addition of saturated aqueous ammonium chloride (60 mL),
the aqueous layer was extracted with ethyl acetate (3 ¥ 50 mL),
dried over Na2SO4, and the solvent was evaporated. Flash column
chromatography eluting with 40% ethyl acetate in hexanes gave
compound 9 (565 mg, 93%) as a pale yellow oil as a 2 : 1 mixture
(2R,3R,5S)-5-((Benzyloxy)methyl)-tetrahydro-2-(pent-2-enyl)-
furan-3-ol (21). To a solution of 8 (279 mg, 1.13 mmol) in THF
(14 mL) at -78 ◦C was added diisobutylaluminium hydride (1 M in
hexanes; 6.78 mL, 6.78 mmol). The mixture was stirred for 5 h and
◦
then quenched by the slow addition of methanol at -10 C until
no more gas was evolved. After warming to room temperature,
hydrochloric acid (2 M; 3.39 mL) was added and the mixture was
stirred for 30 min. The aqueous layer was extracted with ethyl
acetate (3 ¥ 30 mL) and the organic extracts were washed with
saturated aqueous sodium hydrogen carbonate (2 ¥ 30 mL), brine
(2 ¥ 30 mL), then dried over Na2SO4. The solvent was evaporated
to give the crude lactol as yellow oil which was used without further
purification. To a suspension of propyltriphenylphosphonium
iodide (1.48 g, 3.39 mmol) in THF (12 mL) at 0 ◦C was added
n-butyllithium (2.24 M in hexanes; 1.51 mL, 3.39 mmol). After
15 min, a solution of the lactol (283 mg, 1.13 mmol) in THF
(12 mL) was added and the mixture was stirred overnight. The
reaction was quenched by the addition of saturated aqueous
ammonium chloride (30 mL), the aqueous layer was extracted
with ethyl acetate (3 ¥ 30 mL), dried over Na2SO4, and the solvent
was evaporated. Flash column chromatography eluting with 25%
ethyl acetate in hexanes gave compound 21 (185 mg, 59%) as a
of diastereomers. [a]D + 3.2 (c 1.0, MeOH); nmax/cm-1 (neat)
20
3587, 3487, 3086, 3040, 3009, 2939, 2916, 2862; dH (300 MHz;
CDCl3) 7.38–7.26 (5 H, m), 5.96–5.81 (1 H, m), 5.27 (1 H, ddd,
J 17.1, 7.5, 1.2), 5.11 (1 H, dd, J 10.2, 9.0), 4.55 (2 H, s), 4.43–
4.35 (1 H, m), 4.18–4.03 (1 H, m), 3.38 (1 H, ddd, J 17.1, 9.6,
3.6), 3.40 (1 H, ddd, J 16.8, 9.6, 2.4), 3.17 (1 H, br), 2.87 (1
H, br), 1.76 (1 H, ddd, J 14.4, 9.0, 3.3), 1.67–1.55 (1 H, m); dC
(75 MHz; CDCl3) major isomer 140.7 (CH), 138.1 (C), 128.7 (CH),
128.1 (CH), 114.8 (CH2), 74.6 (CH2), 73.64 (CH2), 72.9 (CH), 70.9
(CH), 68.1 (CH), 39.8 (CH2); minor isomer 140.9 (CH), 138.1 (C),
128.7 (CH), 128.0 (CH), 114.6 (CH2), 74.6 (CH2), 73.64 (CH2),
73.59 (CH), 70.3 (CH), 68.1 (CH), 39.1 (CH2); HRMS (ESI) for
C13H18O3Na (MNa+) calcd 245.1154, found 245.1147.
20
colourless oil and an ca. 2 : 1 mixture of geometric isomers. [a]D
- 20.0 (c 0.54, CHCl3); nmax/cm-1 (CHCl3) 3625, 2931, 2854, 1080;
(3aR,5S,6aR)-5-(Benzyloxymethyl)tetrahydrofuro[3,2-b]furan-
2(5H)-one (8)42 and (3aS,5S,6aS)-5-(benzyloxymethyl)-tetra-
hydrofuro[3,2-b]furan-2(5H)-one (19)40. Sodium acetate (337 mg,
4.11 mmol) and copper (II) chloride (552 mg, 4.11 mmol) were
dissolved in glacial acetic acid (5.0 mL), and the solution was
stirred until the solid dissolved. The mixture of diols 9 and 18
dH (300 MHz; CDCl3) 7.36–7.28 (5 H, m), 5.61–5.36 (2 H, m), 4.60
(2 H, s), 4.49–4.41 (1 H, m), 4.28 (1 H, br), 3.88 (1 H, ddd, J 10.8,
8.7, 3.0), 3.56–3.51 (2 H, m), 2.55–2.34 (2 H, m), 2.17–1.93 (4 H,
m), 1.76 (1 H, br s), 0.99 (3 H, app t, J 7.5); dC (75 MHz; CDCl3)
major isomer 138.4 (C), 134.3 (CH), 128.4 (CH), 127.7 (CH), 127.6
(CH), 124.1 (CH), 82.3 (CH), 76.2 (CH), 73.4 (CH2), 72.9 (CH),
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72.6 (CH2), 37.7 (CH2), 27.2 (CH), 20.8 (CH2), 14.2 (CH3); minor
isomer 138.4 (C), 134.9 (CH), 128.4 (CH), 127.7 (CH), 127.6 (CH),
124.7 (CH), 82.3 (CH), 76.3 (CH), 73.4 (CH2), 73.0 (CH), 72.6
(CH2), 37.6 (CH2), 32.4 (CH2), 25.7 (CH2), 13.8 (CH3); HRMS
(ESI) for C17H24O3Na (MNa+) calcd 299.1618, found 299.1618.
dichloromethane (3 ¥ 10 mL), and dried over Na2SO4. The
solvent was evaporated to give the crude aldehyde, which was
used without further purification.
To a stirred solution of 8-nonenylmagnesium bromide (0.4 M
solution in diethyl ether; 6.0 mL, 2.4 mmol) in 1,2-dichloroethane
(2 mL) at 83 ◦C was added a solution of aldehyde (0.24 mmol)
in 1,2-dichloroethane (2.5 mL) and the resulting mixture was
stirred at this temperature for 1 h. The reaction mixture was
then treated with H2O (13 mL), and extracted with ether (3 ¥
13 mL). The combined organic layers were washed with brine
(15 mL), dried over Na2SO4 and the solvent evaporated to give
the crude alcohol and the C10 epimer (dr = 4 : 1). Purification
of the crude product by flash chromatography in hexanes (4%
ethyl acetate in hexanes) gave (6R,7R,9S,10R)-6,9-epoxy-7-((tert-
butyldimethylsilyl)oxy)-nonadec-18-ol as a colourless oil (39.8 mg,
(2R,3R,5S)-3-(tert-Butyl)dimethylsilyloxy-5-(benzyloxy-met-
hyl)tetrahydro-2-(pentyl)furan20. To a solution of 21 (133 mg,
0.48 mmol) in dichloromethane (10 mL) at 0 ◦C was added
triethylamine (268 mL, 1.92 mmol). After stirring for 5 min, tert-
butyldimethylsilyl trifluoromethanesulfonate (338 mL, 1.44 mmol)
was added and the mixture was stirred for 30 min. The reaction
was quenched by the addition of saturated aqueous ammonium
chloride (15 mL), the aqueous layer was extracted with ether (3 ¥
10 mL), dried over Na2SO4, and the solvent was evaporated. Flash
column chromatography eluting with 5% ethyl acetate in hexanes
gave silylated alkene (180 mg, 96%) as a pale yellow oil and an ca.
39%). [a]D - 29.2 (c 1.0, CHCl3); nmax/cm-1 (neat) 3464, 3452,
20
3077, 2926, 2855, 1733, 1641, 1463, 1361; dH (300 MHz; CDCl3)
5.81 (1 H, dddd, J 17.1, 10.2, 6.9, 6.6), 4.99 (1 H, dd, J 17.4, 1.8),
4.92 (1 H, dd, J 10.2, 1.5), 4.23 (1 H, br), 4.01 (1 H, ddd, J 9.0, 6.3,
6.3), 3.73 (1 H, ddd, J 9.6, 6.6, 6.6), 3.39–3.35 (1 H, m), 2.26 (1 H,
d, J 4.5), 2.07–2.00 (2 H, m), 1.88–1.80 (2 H, m), 1.56–1.26 (23 H,
m), 0.99–0.87 (9 H, m), 0.07 (6 H, d, J 4.2); dC (75 MHz; CDCl3)
139.4 (CH), 114.3 (CH2), 83.5 (CH2), 80.4 (CH), 74.4 (CH), 73.8
(CH), 38.6 (CH), 33.9 (CH2), 33.8 (CH2), 32.3 (CH2), 29.8 (CH2),
29.6 (CH2), 29.5 (CH2), 29.2 (CH2), 29.1 (CH2), 26.2 (CH2), 25.9
(CH2), 25.8 (CH2), 22.8 (CH3), 18.2 (C), 14.2 (CH3), -4.3 (CH3),
-4.9 (CH3); HRMS (ESI) for C25H51O3Si (MH+) calcd 427.3608,
found 427.3588.
20
2 : 1 mixture of geometric isomers. [a]D - 25.7 (c 0.92, CHCl3);
n
max/cm-1 (CHCl3) 2954, 2931, 1458, 1064; dH (300 MHz; CDCl3)
7.35–7.28 (5 H, m), 5.61–5.36 (2 H, m), 4.59 (2 H, s), 4.44–4.35 (1
H, m), 4.29–4.27 (1 H, m), 3.85 (1 H, td, J 6.9, 3.3), 3.56–3.52 (2 H,
m), 2.49–2.25 (2 H, m), 2.12–1.85 (4 H, m), 0.98 (3 H, app t, J 7.5),
0.91 (9 H, s), 0.06 (6 H, s); dC (75 MHz; CDCl3) major isomer 138.5
(C), 133.6 (CH), 128.4 (CH), 127.7 (CH), 127.6 (CH), 125.2 (CH),
83.4 (CH), 76.3 (CH), 73.4 (CH2), 73.0 (CH), 72.9 (CH2), 38.4
(CH2), 29.7 (CH2), 25.8 (CH3), 20.8 (CH2), 18.1 (C), 14.2 (CH3),
-4.9 (CH3), -4.4 (CH3); minor isomer 138.5 (C), 134.1 (CH), 128.4
(CH), 127.7 (CH), 127.6 (CH), 125.6 (CH), 83.6 (CH), 76.3 (CH),
73.4 (CH2), 73.0 (CH), 72.9 (CH2), 38.4 (CH2), 32.7 (CH2), 25.8
(CH3), 27.5 (CH2), 18.1 (C), 13.8 (CH3), -4.9 (CH3), -4.4 (CH3);
HRMS (ESI) for C23H38O3SiNa (MNa+) calcd 413.2482, found
413.2480.
The second fraction gave (6R,7R,9S,10S)-6,9-epoxy-7-((tert-
butyldimethylsilyl)oxy)-nonadec-18-ol as a colourless oil (17.6 mg,
17%). [a]D - 20.0 (c 0.5, CHCl3); nmax/cm-1 (neat) 3470, 3464,
20
2927, 2856, 1737, 1641, 1463, 1362; dH (300 MHz; CDCl3) 5.86–
5.76 (1 H, m), 4.99 (1 H, dd, J 17.2, 0.8), 4.93 (1 H, dd, J 10.4,
0.8), 4.25 (1 H, br s), 4.13 (1 H, ddd, J 9.2, 5.6, 3.2), 3.83–3.86
(1 H, m), 3.80 (1 H, dt, J 6.8, 3.2), 2.10–2.04 (2 H, m), 2.00 (2
H, dd, J 18.4, 5.6), 1.70 (1 H, dd, J 12.4, 5.6), 1.56–1.24 (23 H,
m), 0.99–0.87 (9 H, m), 0.08 (3 H, s), 0.07 (3 H, s); dC (75 MHz;
CDCl3) 139.4 (CH), 114.3 (CH2), 84.3 (CH2), 80.3 (CH), 73.6
(CH), 72.0 (CH), 34.7 (CH2), 33.9 (CH2), 32.5 (CH2), 32.3 (CH2),
29.83 (CH2), 29.75 (CH2), 29.5 (CH2), 29.2 (CH2), 29.1 (CH2), 26.2
(CH2), 26.1 (CH2), 25.9 (CH2), 22.8 (CH3), 18.2 (C), 14.2 (CH3),
-4.3 (CH3), -4.9 (CH3); HRMS (ESI) for C25H50O3SiNa (MNa+)
calcd 449.3421, found 449.3428.
(2R,3R,5S)-3-(tert-Butyl)dimethylsilyloxy-5-(hydroxymethyl)-
tetrahydro-2-(pentyl)furan (22). To a solution of the silylated
alkene (99 mg, 0.25 mmol) in ethyl acetate (15 mL) was added
palladium-on-charcoal (10% w/w; 71 mg) and the mixture was
stirred overnight under a balloon of hydrogen. After filtration
through a plug of celite the solvent was evaporated. Flash column
chromatography eluting with 20% ethyl acetate in hexanes gave
20
compound 22 (74 mg, 97%) as a colourless oil. [a]D - 11.0 (c
0.39, CHCl3); nmax/cm-1 (CHCl3) 3043, 2956, 1517, 1251, 1047; dH
(400 MHz; CDCl3) 4.33–4.21 (2 H, m), 3.79 (1 H, ddd, J 6.4, 6.4,
2.8), 3.74–3.70 (1 H, m), 3.50–3.45 (1 H, m) 1.93–1.82 (2 H, m),
1.63–1.55 (3 H, m), 1.32–1.30 (6 H, m), 0.91–0.89 (12 H, m), 0.08
(3 H, s), 0.07 (3 H, s); dC (100 MHz; CDCl3) 84.1 (CH), 77.6 (CH),
73.8 (CH), 65.2 (CH2), 37.7 (CH2), 32.5 (CH2), 29.9 (CH2), 26.4
(CH2), 26.1 (CH3), 23.0 (CH2), 18.4 (C), 14.4 (CH3), -4.1 (CH3),
-4.7 (CH3); HRMS for C16H34O3NaSi (MNa+) calcd 325.2169,
found 325.2169.
(6R,7R,9S,10R)-6,9-Epoxynonadec-18-en-7,10-diol
(5).
To stirred solution of (6R,7R,9S,10R)-6,9-epoxy-7-((tert-
a
butyldimethylsilyl)oxy)-nonadec-18-ol (22 mg, 0.05 mmol) in
THF (10 mL) was added tetrabutylammonium fluoride (1 M
in THF; 68 mL, 0.07 mmol). After stirring for 24 h at room
temperature, water (10 mL) was added. The aqueous layer was
extracted with ethyl acetate (3 ¥ 15 mL), and the organic extracts
washed with brine (2 ¥ 10 mL), dried over Na2SO4, and the
solvent was evaporated. Flash column chromatography eluting
with 30% ethyl acetate in hexanes gave compound 5 (15.5 mg,
(6R,7R,9S,10R)-6,9-Epoxy-7-((tert-butyldimethylsilyl)oxy)-
nonadec-18-ol and (6R,7R,9S,10S)-6,9-epoxy-7-((tert-butyl-
dimethylsilyl)oxy)nonadec-18-ol. To
a solution of alcohol
22 (74 mg, 0.24 mmol) in dimethylsulfoxide (1.1 mL) was
successively added triethylamine (526 mL, 2.4 mmol) and SO3-
pyridine complex (195 mg, 1.22 mmol) and the resulting solution
was stirred at room temperature for 45 min. The reaction was
quenched by the addition of sodium hydrogen sulfate (10%
aqueous solution; 7 mL). The aqueous layer was extracted with
20
95%) as a white solid. [a]D - 17.6 (c 1.0, CHCl3); nmax/cm-1
(neat) 3442, 2920, 2847, 1642, 1464, 1324, 1089; dH (300 MHz;
CDCl3) 5.81 (1 H, dddd, J 17.4, 10.2, 6.6, 6.6), 4.98 (1 H, dd, J
17.4, 1.8), 4.93 (1 H, d, J 10.2), 4.24 (1 H, br s), 4.02 (1 H, dt,
J 8.7, 6.6), 3.75 (1 H, ddd, J 6.9, 6.9, 2.7), 3.41–3.35 (1 H, m),
2204 | Org. Biomol. Chem., 2011, 9, 2198–2208
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2.34 (1 H, br s), 2.01 (3 H, dd, J 12.9, 6.6), 1.87 (1 H, ddd, J
13.5, 9.0, 4.5), 1.64–1.47 (1 H, m), 1.43–1.25 (20 H, m), 0.89 (3 H,
app t, J 6.0); dC (75 MHz; CDCl3) 139.4, 114.3, 82.7, 80.4, 74.3,
73.7, 38.1, 34.0, 33.4, 32.2, 29.8, 29.6, 29.3, 29.1, 29.0, 26.2, 25.8,
22.8, 14.2; HRMS (ESI) for C19H36O3Na (MNa+) calcd 335.2557,
found 335.2558.
2.59 mmol) in dry THF (8 mL) was added and the reaction mixture
was stirred for 2 h at room temperature. The reaction was quenched
by the addition of saturated aqueous ammonium chloride (30 mL),
the aqueous layer was extracted with ethyl acetate (3 ¥ 25 mL),
dried over Na2SO4, and the solvent was evaporated. Flash column
chromatography eluting with 40% ethyl acetate in hexanes gave
compounds 30 and 31 (556 mg, 96%) as a pale yellow oil as a
(2R,4R)-1-(Benzyloxy)-4,5-epoxy-2-(4-nitrobenzyloxy)-1-pen-
tane 28 and (2R,4S)-1-(benzyloxy)-4,5-epoxy-2-(4-nitrobenzy-
loxy)-1-pentane (29). To a solution of the alcohols 16 and 17
(1.0 g, 4.8 mmol), p-nitrobenzoic acid (1.12 g, 6.72 mmol) and
triphenylphosphine (1.76 g, 6.72 mmol) in toluene (25 mL), was
added a solution of DMEAD (1.57 g, 6.72 mmol) in toluene
(10 mL) dropwise at room temperature. After 2 h, the mixture was
washed with H2O (40 mL). The aqueous phase was re-extracted
with toluene (2 ¥ 20 mL), and the combined organic extracts
washed with water (10 mL), brine (20 mL), dried over Na2SO4
and the solvent was evaporated. Flash chromatography eluting
with 20% ethyl acetate in hexanes gave compound 29 as a pale
20
ca. 2 : 1 mixture of diastereomers. [a]D + 3.2 (c 1.0, MeOH);
n
max/cm-1 (neat) 3370, 3088, 3030, 2940, 2913, 2862, 1645, 1469,
1072; dH (300 MHz; CDCl3) 7.38–7.26 (5 H, m), 5.96–5.81 (1 H,
m), 5.27 (1 H, ddd, J 17.1, 7.5, 1.2), 5.11 (1 H, dd, J 10.2, 9.0),
4.55 (2 H, s), 4.43–4.35 (1 H, m), 4.18–4.03 (1 H, m), 4.38 (1 H,
ddd, J 17.1, 9.6, 3.6), 3.40 (1 H, ddd, J 16.8, 9.6, 2.4), 3.17 (1 H,
br), 2.87 (1 H, br), 1.76 (1 H, ddd, J 14.4, 9.0, 3.3), 1.67–1.55 (1
H, m); dC (75 MHz; CDCl3) major isomer 140.9 (CH), 138.1 (C),
128.7 (CH), 128.0 (CH), 114.6 (CH2), 74.6 (CH2), 73.64 (CH2),
73.59 (CH), 70.3 (CH), 68.1 (CH), 39.1 (CH2); minor isomer 140.7
(CH), 138.1 (C), 128.7 (CH), 128.1 (CH), 114.8 (CH2), 74.6 (CH2),
73.64 (CH2), 72.9 (CH), 70.9 (CH), 68.1 (CH), 39.8 (CH2); HRMS
(ESI) for C13H18O3Na (MNa+) calcd 245.1154, found 245.1148.
yellow oil (1.60 g, 93%). [a]D + 7.7 (c 1.0, CHCl3); nmax/cm-1
20
(neat) 3425, 3055, 2997, 2924, 2866, 1728, 1608, 1542, 1350, 1288;
dH (300 MHz; CDCl3) 8.29 (2 H, d, J 8.7), 8.21 (2 H, dd, J 2.4,
9.0), 7.32–7.27 (5 H, m), 5.55–5.48 (1 H, m), 4.61 (1 H, dd, J 12.0,
1.2), 4.54 (1 H, d, J 12.0), 3.82–3.69 (2 H, m), 3.08–3.00 (1 H, m),
2.78–2.74 (1 H, m), 2.51 (1 H, m), 2.22–2.09 (1 H, m), 1.94–1.84
(1 H, m); dC (75 MHz; CDCl3) major isomer 164.4 (C), 150.8 (C),
137.9 (C), 135.8 (C), 131.0 (CH), 130.9 (CH), 128.6 (CH), 127.8
(CH), 123.7 (CH), 73.4 (CH2), 72.7 (CH), 70.8 (CH2), 49.1 (CH),
46.4 (CH2), 34.4 (CH2); minor isomer 164.3 (C), 150.8 (C), 137.9
(C), 135.7 (C), 131.0 (CH), 130.9 (CH), 128.6 (CH), 128.0 (CH),
123.7 (CH), 73.4 (CH2), 72.5 (CH), 70.9 (CH2), 49.0 (CH), 47.0
(CH2), 34.6 (CH2); HRMS (APCI) for C19H19NO6Na (MNa+);
calcd 380.1110, found 380.1105.
(3aR,5R,6aR)-5-(Benzyloxymethyl)tetrahydrofuro[3,2-b]furan-
2(5H)-one
(26)
and
(3aS,5R,6aS)-5-(benzyloxymethyl)-
tetrahydrofuro[3,2-b]furan-2(5H)-one (32). Sodium acetate
(295 mg, 3.60 mmol) and copper (II) chloride (484 mg,
3.60 mmol) were dissolved in glacial acetic acid (4.5 mL), and the
solution was stirred until the solid dissolved. The diol 3 (267 mg,
1.20 mmol) was added as an acetic acid solution (4.5 mL), and
the solution was stirred vigorously while purging with nitrogen,
followed by purging the reaction mixture with carbon monoxide
gas. Palladium (II) acetate (26.9 mg, 0.12 mmol) was added and
stirring was continued overnight under these conditions. The
solution was poured into water (30 mL), and sodium hydrogen
carbonate was added until the solution was neutralized. The
solution was extracted with ethyl acetate (3 ¥ 50 mL), dried over
Na2SO4, and the solvent was evaporated. Purification by column
chromatography, eluting with 40% ethyl acetate in hexanes gave
(2R,4R)- 1-(Benzyloxy)-4,5-epoxy-2-hydroxy-1-pentane and
(2R,4S)-1-(benzyloxy)-4,5-epoxy-2-hydroxy-1-pentane.
A mix-
ture of the benzoate esters 28 and 29 (1.40 g, 3.92 mmol) and
K2CO3 (135 mg, 0.98 mmol) in MeOH (15 mL) was stirred at
room temperature for 4 h. The solvent was evaporated and the
crude material was purified by flash chromatography (25% ethyl
acetate in hexanes) to give the title compounds as a colourless oil
20
compound 32 as a white solid (77 mg, 26%): [a]D - 42.4 (c 1.0,
CHCl3); nmax/cm-1 (neat) 3040, 3001, 2932, 2860, 1728 cm-1; dH
(300 MHz; CDCl3) 7.35–7.27 (5 H, m), 5.10 (1 H, dd, J 4.5, 4.8),
4.83 (1 H, ddd, J 6.6, 4.5, 2.4), 4.57 (2 H, s), 4.40–4.32 (1 H,
m), 3.62 (1 H, dd, J 10.5, 3.3), 3.48 (1 H, dd, J 10.5, 4.8), 2.71
(2 H, d, J 4.5), 2.34 (1 H, dd, J 14.1, 6.0), 2.05 (1 H, ddd, J
14.1, 11.8, 5.1); dC (75 MHz; CDCl3) 175.8 (C), 138.0 (C), 128.6
(CH), 127.9 (CH), 127.8 (CH), 84.9 (CH), 78.6 (CH), 78.0 (CH),
73.7 (CH2), 71.7 (CH2), 36.8 (CH2), 35.0 (CH2); HRMS (ESI)
for C14H16O4Na (MNa+) calcd 271.0941, found 271.0942; and
(728 mg, 89%); [a]D + 6.4 (c 1.0, CHCl3); nmax/cm-1 (neat) 3454,
20
3006, 2862, 1453, 1090; dH (300 MHz; CDCl3) 7.39–7.28 (5 H, m),
4.57 (2 H, s), 4.11–4.04 (1 H, m), 3.54 (1 H, ddd, J 9.6, 9.6, 3.6),
3.43 (1 H, ddd, J 23.1, 9.6, 7.2), 3.15–3.07 (1 H, m), 2.79 (1 H,
ddd, J 12.3, 4.5, 4.5), 2.53 (1 H, ddd, J 10.2, 5.1, 2.7), 1.86 (1 H,
dddd, J 14.4, 12.9, 8.7, 4.2), 1.71–1.61 (1 H, m), 1.51 (1 H, ddd, J
14.4, 7.2, 4.5); dC (75 MHz; CDCl3) major isomer 138.0 (C), 128.5,
(CH), 128.0 (CH), 74.4 (CH), 73.59 (CH2), 73.56 (CH2), 68.54
(CH), 49.9 (CH), 47.2 (CH2), 36.3 (CH2); minor isomer 138.0 (C),
128.5, (CH), 127.9 (CH), 74.1 (CH), 73.59 (CH2), 73.56 (CH2),
68.78 (CH), 49.8 (CH), 46.8 (CH2), 36.1 (CH2); HRMS (ESI) for
C12H16O3Na (MNa+) calcd 230.0992, found 231.0993.
20
compound 26 (131 mg, 44%) as a colourless oil; [a]D + 58.0 (c
1.0, CHCl3); nmax/cm-1 (neat) 3533, 2925, 2866, 1772, 1451, 1355,
1067; dH (300 MHz; CDCl3) 7.35–7.28 (5 H, m), 5.02 (1 H, ddd,
J 6.3, 4.2, 1.8), 4.61 (1 H, ddd, J 6.3, 4.2, 1.8), 4.59 (1 H, d, J
12.0), 4.53 (1 H, d, J 12.3), 4.28–4.20 (1 H, m), 3.52–3.50 (2 H,
m), 2.81–2.67 (2 H, m), 2.40 (1 H, ddd, J 14.4, 7.8, 6.9), 2.04 (1 H,
ddd, J 14.7, 6.9, 1.5); dC (75 MHz; CDCl3) 175.4 (C), 137.9 (C),
128.5 (CH), 128.0 (CH), 127.9 (CH), 84.2 (CH), 79.4 (CH), 79.2
(CH), 73.6 (CH2), 72.4 (CH2), 36.7 (CH2), 35.3 (CH2); HRMS
(ESI) for C14H16O4Na (MNa+); calcd 271.0941, found 271.0942.
(2R,4R)-1-(Benzyloxy)-5-hexene-2,4-diol (30) and (2R,4S)-1-
(benzyloxy)-5-hexene-2,4-diol (31). To a stirred mixture of
trimethylsulfonium iodide (2.11 g, 10.4 mmol) in anhydrous THF
(40 mL) was added n-butyllithium (2.07 M in THF; 5.0 mL,
◦
10.4 mmol) at -10 C under an argon atmosphere. The solution
(2R,3R,4R)-5-((Benzyloxy)methyl)-tetrahydro-2-(pent-2-enyl)-
furan-3-ol (33). To a solution of 26 (84.2 mg, 0.34 mmol) in
was stirred for 30 min then a solution of the epoxides (540 mg,
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THF (4 mL) was added diisobutylaluminium hydride (1 M in
dichloromethane: 2.03 mL, 2.03 mmol). The mixture was stirred
for 5◦h and then quenched by the slow addition of methanol at
- 10 C until no more gas was evolved. After warming to room
temperature, hydrochloric acid (2 M; 1.02 mL, 2.04 mmol) was
added and the mixture was stirred for 30 min. The aqueous layer
was extracted with ethyl acetate (3 ¥ 10 mL) and the organic
extracts were washed with saturated aqueous sodium hydrogen
carbonate (2 ¥ 10 mL), brine (2 ¥ 10 mL), then dried over
Na2SO4 and the solvent was evaporated to give the crude 5-
((benzyloxy)methyl)-hexahydrofuro[3,2-b]furan-2-ol as a yellow
oil. To a suspension of propyltriphenyl-phosphonium iodide
(445 mg, 1.02 mmol) in THF (4.5 mL) at 0 ◦C was added n-
butyllithium (1.94 M in hexanes; 526 mL, 1.02 mmol). After
15 min, a solution of 5-((benzyloxy)methyl)-hexahydrofuro[3,2-
b]furan-2-ol (85.1 mg, 0.34 mmol) was added and the mixture was
stirred overnight. The reaction was quenched by the addition of
saturated aqueous ammonium chloride (10 mL), the organic layer
was extracted with ethyl acetate (3 ¥ 10 mL), dried over Na2SO4,
and the solvent was evaporated. Flash chromatography eluting
with 20% ethyl acetate in hexanes gave compound 33 (76.6 mg,
82%) as a yellow oil and an ca. 2 : 1 mixture of geometric isomers.
14.3 (CH3), -4.3 (CH3), -5.0 (CH3); minor isomer 138.6 (C), 134.2
(CH), 128.4 (CH), 127.9 (CH), 127.6 (CH), 125.8 (CH), 84.1 (CH),
76.6 (CH), 73.8 (CH2), 73.5 (CH2), 72.6 (CH2), 38.7 (CH2), 32.9
(CH2), 27.8 (CH2), 25.8 (CH3), 20.9 (CH2), 18.2 (C), 13.9 (CH3),
-4.3 (CH3), -5.0 (CH3); HRMS (ESI) for C23H38O3SiNa (MNa+)
calcd 413.2482, found 413.2484.
(2R,3R,5R)-3-(tert-Butyl)dimethylsilyloxy-5-(hydroxymethyl)-
tetrahydro-2-(pentyl)furan (34). To a solution of 3-(tert-butyl)-
dimethylsilyloxy-5-((benzyloxy)-methyl)-tetrahydro-2-(pent-2-
enyl)furans (186 mg, 0.48 mmol) in ethyl acetate (27.5 mL) was
added palladium-on-charcoal (10% w/w; 133 mg) and the mixture
was stirred overnight under a balloon of hydrogen. After filtration
through a plug of celite the solvent was evaporated. Flash column
chromatography eluting with 20% ethyl acetate in hexanes gave
20
compound 34 (123 mg, 85%) as a colourless oil. [a]D - 35.6 (c
1.0, CHCl3); nmax/cm-1 (neat) 3443, 2953, 2929, 2857, 1463, 1362,
1252; dH (300 MHz; CDCl3) 4.17–4.11 (2 H, m), 3.73 (1 H, ddd,
J 11.4, 5.1, 2.7), 3.63 (1 H, ddd, J 8.7, 7.2, 3.0), 3.54 (1 H, ddd,
J 10.2, 5.4, 4.5), 2.53 (1 H, dd, J 5.4, 5.4), 2.24 (1 H, ddd, J 13.8,
9.6, 5.4), 1.80 (1 H, dd, J 13.5, 4.2), 1.71–1.49 (2 H, m), 1.42–1.25
(6 H, m), 0.90–0.87 (12 H, m), 0.08 (3 H, s), 0.07 (3 H, s); dC
(75 MHz; CDCl3) 84.2 (CH), 77.8 (CH), 73.0 (CH), 65.1 (CH2),
37.6 (CH2), 32.2 (CH2), 29.4 (CH2), 26.3 (CH2), 25.9 (CH3), 22.8
(CH2), 18.2 (C), 14.2 (CH3), -4.1 (CH3), -4.7 (CH3); HRMS (ESI)
for C16H34O3NaSi (MNa+) calcd 325.2169, found 325.2172.
[a]D + 17.1 (c 1.0, CHCl3); nmax/cm-1 (neat) 3429, 3029, 2961,
20
2931, 2871, 1737, 1496; dH (300 MHz; CDCl3) 7.37–7.24 (5 H, m),
5.68–5.34 (2 H, m), 4.58 (2 H, s), 4.48–4.39 (1 H, m), 4.27 (1 H, br
s), 3.87 (1 H, ddd, J 8.1, 6.6, 3.0), 3.55–3.45 (2 H, m), 2.53–2.22
(2 H, m), 2.19–1.91 (4 H, m) 1.70 (1 H, br s), 0.97 (3 H, app t,
J 7.5); dC (75 MHz; CDCl3) major isomer 138.5 (C), 134.3 (CH),
128.5 (CH), 127.8 (CH), 127.7 (CH), 124.2 (CH), 82.4 (CH), 76.3
(CH), 73.4 (CH2), 73.0 (CH), 72.7 (CH2), 37.8 (CH2), 27.3 (CH2),
20.9 (CH2), 14.3 (CH3); minor isomer 138.5 (C), 135.1 (CH), 128.5
(CH), 127.8 (CH), 127.7 (CH), 124.8 (CH), 82.4 (CH), 76.3 (CH),
73.4 (CH2), 73.0 (CH), 72.7 (CH2), 37.7 (CH2), 32.6 (CH2), 25.8
(CH2), 13.9 (CH3); HRMS (ESI) for C17H24O3Na (MNa+) calcd
299.1618, found 299.1620
(6R,7R,9R,10S)-6,9-Epoxy-7-(tert-butyldimethylsilyloxy)-non-
adec-18-ol. To a solution of alcohol 34 (73 mg, 0.24 mmol)
in dimethylsulfoxide (1.2 mL) was added triethylamine (400 mL,
2.8 mmol) and SO3-pyridine complex (235 mg, 1.45 mmol) and the
mixture was stirred at room temperature for 45 min. The reaction
was quenched by the addition of sodium hydrogen sulfate (10%
aqueous solution; 7 mL). The aqueous layer was extracted with
dichloromethane (3 ¥ 15 mL), and dried over Na2SO4. The solvent
was evaporated to give the crude aldehyde which was used without
further purification. To a stirred solution of 8-nonenylmagnesium
bromide (0.4 M solution in diethyl ether; 6.3 mL, 2.4 mmol) in 1,2-
dichloroethane (2.2 mL) at 83 ◦C was added a solution of aldehyde
(0.24 mmol) in 1,2-dichloroethane (2.65 mL) and the mixture was
stirred at this temperature for 1 h. The reaction mixture was then
treated with H2O (13 mL), and extracted with ether (3 ¥ 13 mL).
The combined organic layers were washed with brine (15 mL),
dried over Na2SO4 and the solvent evaporated to give the crude
product. Flash chromatography eluting with 4% ethyl acetate in
hexanes gave the title compound as a colourless oil (76 mg, 75%).
(2R,3R,5R)-3-(tert-Butyl)dimethylsilyloxy-5-((benzyloxy)-met-
hyl)-tetrahydro-2-(pent-2-enyl)furan. To a solution of 33 (158 mg,
0.57 mmol) in dichloromethane (11.5 mL) at 0 ◦C was added
triethylamine (319 mL, 2.29 mmol). After stirring for 5 min, tert-
butyldimethylsilyl trifluoromethanesulfonate (403 mL, 1.72 mmol)
was added and the mixture was stirred for 30 min. The reaction
was quenched by the addition of saturated aqueous ammonium
chloride (15 mL), the aqueous layer was extracted with ether (3 ¥
10 mL), dried over Na2SO4, and the solvent was evaporated. Flash
column chromatography eluting with 5% ethyl acetate in hexanes
gave the title compound (221 mg, 99%) as pale yellow oil and an
20
[a]D - 18.0 (c 1.0, CHCl3) nmax/cm-1 (neat) 3511, 3077, 2927,
20
ca. 2 : 1 mixture of geometric isomers. [a]D - 15.6 (c 1.0, CHCl3);
2856, 1731, 1641, 1463, 1439, 1289, 1052; dH (300 MHz; CDCl3)
5.80 (1 H, dddd, J 17.1, 10.2, 6.6, 6.6), 4.98 (1 H, dd, J 17.1,
1.8), 4.94–4.90 (1 H, m), 4.18–4.15 (1 H, m), 3.94 (1 H, ddd, J
8.7, 4.8, 2.4), 3.84–3.80 (1 H, m), 3.55 (1 H, ddd, J 7.2, 6.0, 3.3),
2.80–2.64 (1 H, m), 2.10–1.99 (2 H, m), 1.89 (2 H, ddd, J 13.5,
5.1, 1.2), 1.64–1.25 (23 H, m), 0.98–0.87 (9 H, m), 0.09 (3 H, s),
0.07 (3 H, s); dC (75 MHz; CDCl3) 139.4 (CH), 114.2 (CH2), 83.5
(CH2), 80.7 (CH), 72.8 (CH), 71.7 (CH), 34.6 (CH), 33.9 (CH2),
33.8 (CH2), 32.3 (CH2), 29.8 (CH2), 29.5 (CH2), 29.2 (CH2), 29.1
(CH2), 26.3 (CH2), 26.0 (CH2), 22.8 (CH3), 18.3 (C), 14.2 (CH3),
-4.4 (CH3), -4.9 (CH3); HRMS (ESI) for C25H50O3NaSi (MNa+)
calcd 427.3602, found 427.3611.
n
max/cm-1 (neat) 2956, 2929, 2856, 1462, 1362, 1253; dH (300 MHz;
CDCl3) 7.34–7.28 (5 H, m), 5.58–5.29 (2 H, m), 4.61 (1 H, d, J
12.0), 4.54 (1 H, d, J 12.0), 4.24–4.22 (1 H, m), 4.13 (1 H, m),
3.70–3.65 (1 H, m), 3.63 (1 H, dd, J 9.6, 6.6), 3.48 (1 H, ddd, J
9.6, 5.4, 2.1), 2.50–2.41 (1 H, m) 2.33 (1 H, app t, J 6.6), 2.26 (1 H,
app t, J 6.3), 2.19 (1 H, ddd, J 11.7, 5.4, 3.3), 2.11–1.99 (2 H, m),
1.72 (1 H, ddd, J 13.2, 5.1, 2.4), 1.72–1.66 (1 H, m), 0.97 (3 H, app
t, J 7.5), 0.88 (9 H, s), 0.06 (6 H, s); dC (75 MHz; CDCl3) major
isomer 138.6 (C), 133.5 (CH), 128.4 (CH), 127.9 (CH), 127.6 (CH),
125.4 (CH), 83.9 (CH), 76.6 (CH), 73.8 (CH2), 73.5 (CH2), 72.6
(CH2), 38.7 (CH2), 27.8 (CH2), 25.9 (CH3), 20.9 (CH2), 18.2 (C),
2206 | Org. Biomol. Chem., 2011, 9, 2198–2208
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©

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(6R,7R,9R,10S)-6,9-Epoxynonadec-18-en-7,10-diol (35). To a
stirred solution of alcohol (42 mg, 0.10 mmol) in THF (20 mL)
was added tetrabutylammonium fluoride (1 M in THF; 129 mL,
0.13 mmol). After stirring for 24 h at room temperature water
(20 mL) was added. The aqueous layer was extracted with ethyl
acetate (3 ¥ 30 mL) and the organic extracts washed with brine
(2 ¥ 20 mL), dried over Na2SO4, and the solvent was evaporated.
Flash column chromatography eluting with 30% ethyl acetate in
2557. The 10S diastereomer 35 was also obtained as a white solid
(2.4 mg, 10%).
Notes and references
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hexanes gave compound 35 (30.5 mg, 99%) as a white solid. [a]D
- 22.8 (c 1.00, CHCl3); nmax/cm-1 (MeOH) 3332, 3056, 2943, 2831,
1650, 1447, 1276, 1024; dH (300 MHz; CDCl3) 5.80 (1 H, dddd,
J 16.8, 10.2, 6.6, 6.6), 4.99 (1 H, dd, J 17.4, 1.8), 4.93 (1 H, d, J
11.1), 4.02–3.97 (2 H, m), 3.83–3.81 (1 H, m), 3.59 (1 H, ddd, J 6.9,
6.9, 2.4), 3.26 (1 H, br s), 2.49 (1 H, br s), 2.18 (1 H, ddd, J 14.1,
9.9, 5.4), 2.03 (2 H, dd, J 13.5, 6.6), 1.92 (1 H, dd, J 14.1, 3.3),
1.69–1.62 (1 H, m), 1.36–1.25 (19 H, m), 0.89 (3 H, app t, J 6.5); dC
(75 MHz; CDCl3) 139.3 (CH), 114.3 (CH2), 84.0 (CH), 80.1 (CH),
72.2 (CH), 71.4 (CH), 34.5 (CH2), 33.9 (CH2), 33.5 (CH2), 32.2
(CH2), 29.6 (CH2), 29.5 (CH2), 29.2 (CH2), 29.02 (CH2), 28.97
(CH2), 26.2 (CH2), 26.0 (CH2), 22.8 (CH2), 14.2 (CH3); HRMS
(ESI) for C19H36O3Na (MNa+) calcd 335.2557, found 335. 2557.
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(6R,7R,9R,10R)-6,9-Epoxynonadec-18-en-7,10-diol (6). To a
solution of alcohol 34 (22.4 mg, 0.07 mmol) in dimethylsulfoxide
(460 mL) was successively added triethylamine (124 mL, 0.88 mmol)
and SO3-pyridine complex (72.1 mg, 0.44 mmol) and the resulting
solution was stirred at room temperature for 45 min. The reaction
was quenched by the addition of sodium hydrogen sulfate (10%
aqueous solution; 3 mL). The aqueous layer was extracted with
dichloromethane (3 ¥ 5 mL) and dried over Na2SO4. The solvent
was evaporated to give the crude aldehyde which was used without
further purification. To a stirred solution of the aldehyde (22.2 mg,
0.07 mmol) in THF (15 mL) was added tetrabutylammonium
fluoride (1 M in THF; 96 mL, 0.10 mmol). After stirring for 30 min
at room temperature water (5 mL) was added. The aqueous layer
was extracted with ethyl acetate (3 ¥ 5 mL) and the organic extracts
washed with brine (5 mL), dried over Na2SO4, and the solvent was
evaporated. Crude aldehyde (13.8 mg, 0.07 mmol) was dissolved
in 1,2-dichloroethane (800 mL) and added to a stirred solution
of 8-nonenylmagnesium bromide (0.4 M solution in diethyl ether;
1.9 mL, 0.74 mmol) in 1,2-dichloroethane (700 mL) at 83 ◦C. The
resulting mixture was stirred at that temperature for 1 h. The
reaction mixture was then treated with H2O (5 mL), and extracted
with ether (3 ¥ 5 mL). The combined organic layers were washed
with brine (5 mL), dried over Na2SO4 and the solvent evaporated
to give the crude product and its C10 epimer (dr = 3 : 1). Flash
chromatography, eluting with 20% ethyl acetate in hexanes, gave
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20
compound 6 as a white solid (7.2 mg, 31%). [a]D -23.1 (c 0.4,
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CHCl3); nmax/cm-1 (MeOH) 3346, 3079, 2925, 2855, 1729, 1640,
1465, 1283, 1128; dH (400 MHz; CDCl3) 5.81 (1 H, ddd, J 16.8,
10.2, 6.9, 6.9), 4.99 (1 H, d, J 17.4), 4.93 (1 H, d, J 10.2), 4.05
(1 H, m), 3.95 (1 H, d, J 9.3), 3.63 (1 H, ddd, J 6.9, 6.6, 2.7),
3.48 (1 H, m), 2.38 (2 H, ddd, J 14.1, 9.9, 5.4), 2.26 (2 H, dd, J
14.1, 7.5), 1.84 (1 H, dd, J 13.8, 3.3), 1.67–1.26 (21 H, m), 0.89
(3 H, m); dC (100 MHz; CDCl3) 139.4 (CH), 114.3 (CH2), 84.5
(CH), 79.2 (CH), 74.1 (CH), 71.7 (CH), 38.9 (CH2), 34.6 (CH2),
33.9 (CH2), 32.2 (CH2), 29.62 (CH2), 29.55 (CH2), 29.2 (CH2), 29.0
(CH2), 28.9 (CH2), 26.2 (CH2), 26.1 (CH2), 22.8 (CH2), 14.2 (CH3);
HRMS (ESI) for C19H36O3Na (MNa+) calcd 335.2557, found 335.
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