A carbohydrate-based synthesis of the C13-C22 fragment of amphidinolide X

Article abstract of DOI:10.1002/ejoc.201101605

A facile carbohydrate-based route was developed for the synthesis of the tetrahydrofuran (C13-C22) fragment of amphidinolide X. Starting from L-sorbose, the key reactions followed include the stereoselective synthesis of a quaternary center at C1, Barton-

Full text of DOI:10.1002/ejoc.201101605

FULL PAPER
DOI: 10.1002/ejoc.201101605
A Carbohydrate-Based Synthesis of the C13–C22 Fragment of
Amphidinolide X
Mukund K. Gurjar,*[a][‡] Gorakh S. Yellol,[a] and Debendra K. Mohapatra*[a,b]
Keywords: Natural products / Cytotoxicity / Macrolides / Mitsunobu inversion / Wittig reactions
A facile carbohydrate-based route was developed for the
synthesis of the tetrahydrofuran (C13–C22) fragment of am-
phidinolide X. Starting from L-sorbose, the key reactions fol-
center at C1, Barton–McCombie deoxygenation at C2, Mitsu-
nobu inversion at C3, and chain elongation by a Wittig reac-
tion at C5.
lowed include the stereoselective synthesis of a quaternary
toxicity, scarcity, and unique structural features have
prompted many groups to view amphidinolide X as a syn-
thesis target.
Introduction
Amphidinolides are a unique class of biologically inter-
esting secondary metabolites isolated from marine dinoflag-
ellates of the genus Amphidinium sp.[1] To date, more than
30 amphidinolides have been isolated from this species
which are symbionts of the Okinawan marine acoel flat-
worms, Amphiscolops sp.[2] These macrolides have a variety
of backbone skeletons and different sizes of macrocyclic
lactone rings (12 to 29 membered) that are endowed with
exo-methylene groups, vicinal one-carbon branches, and
1,3-diene units. All of the amphidinolides exhibit potent
cytotoxic properties against various cancer cell lines and
thus have attracted great interest as challenging targets for
total synthesis and for further biological studies.[3]
Amphidinolide X (1), a 16-membered cytotoxic macrodi-
olide (Figure 1), was isolated by Kobayashi and co-workers
in 2003 from the laboratory-cultured dinoflagellates Amphi-
dinium sp.[4] The detailed structure of 1, including the dispo-
sition of the chiral centers, was elucidated on the basis of
1D and 2D spectroscopic data. Amphidinolide X is known
to possess good cytotoxicity against murine lymphoma
L1210 (IC50 = 0.6 μgmL–1) and human epidermoid carci-
noma KB cells (IC50 = 7.5 μgmL–1) in vitro. Structurally, it
has neither the characteristic exo-methylene group nor the
1,3-diene unit found in virtually all other members of this
series. Moreover, it is the only naturally occurring macrodi-
olide known to date that consists of a diacid and a diol unit
rather than of two hydroxy acid entities. Its promising
Figure 1. Amphidinolide X (1).
Fürstner et al. reported the first total synthesis of amphi-
dinolide X.[5] Here, the main tetrahydrofuran fragment was
constructed from a chiral allene by iron-catalyzed opening
of propargyl epoxide and further assembly by silver nitrate
catalyzed cyclization as a mixture of diastereomers in a ra-
tio of 8:1. The target molecule was achieved by assembling
the fragments by Suzuki cross-coupling and macrolactoniz-
ation by using Yamaguchi conditions. Dai et al. also
achieved the synthesis of the tetrahydrofuran fragment by
an acid-catalyzed 5-endo ring-opening cyclization of the ep-
oxide possessing a vinyl moiety and the total synthesis of
amphidinolide X by formation of the C12–C13 trisubsti-
tuted double bond by ring-closing metathesis.[6] In parallel
with our studies, Urpi and Vilarrasa reported the total syn-
thesis of amphidinolide X by a silicon-tethered metathesis
reaction.[7] It was envisaged that construction of the tetra-
hydrofuran fragment of 1 in a stereocontrolled manner re-
mains central to the total synthesis of amphidinolide X.
Synthetic studies toward the total synthesis of amphidinol-
ides C, E, and W were previously reported by our group
by using a carbohydrate-based approach.[8] As part of our
ongoing research directed towards the synthesis of highly
substituted tetrahydrofuran ring systems bearing natural
products from carbohydrates,[9] we report here the synthesis
of the tetrahydrofuran (C13–C22) fragment of amphidinol-
ide X starting from l-sorbose.
[a] CSIR-National Chemical Laboratory,
Pune 411008, India
[b] CSIR-Indian Institute of Chemical Technology,
Hyderabad 500607, India
E-mail: mohapatra@iict.res.in
[‡] Current address: Emcure Pharmaceuticals Ltd.,
Pune 411057, India
E-mail: mukund.gurjar@emcure.co.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101605.
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M. K. Gurjar, G. S. Yellol, D. K. Mohapatra
FULL PAPER
As amphidinolide X has two ester linkages along with MeOH at room temperature.[14,15] The resulting free hy-
two olefin functionalities forming the macrodiolide ring, droxy groups were protected as their benzyl ethers by treat-
the obvious sites of disconnection were at the C12–C13 and ment with sodium hydride followed by benzyl bromide in
C1–O bonds, resulting in two building blocks: main tetra- DMF at ambient temperature to furnish dibenzyl derivative
hydrofuran fragment 2 and left dicarbonyl entity fragment 8 in 96% yield.
3 (Figure 2). The critical carbon–carbon bond formation
between fragment 2 and 3 (C12–C13 bond) was planned to
proceed through a modified Julia olefination procedure.[10]
The final cyclization to form the C1–O ester bond could
be accomplished by using Yamaguchi lactonization.[11] To
construct the 16-membered multifunctionalized macro-
lactone as the first target towards the total synthesis of am-
phidinolide X, fragment 2 (Figure 2) was chosen to permit
the incorporation of the side chain at a later stage by using
Wittig olefination. Key intermediate 4 was planned from 5
by reduction, deoxygenation, and inversion of the hydroxy
center by using a Mitsunobu[12] inversion protocol, and 5
in turn by stereoselective installation of an allyl group by
simultaneous stereocontrolled removal of the 1,2-isoprop-
ylidine protection from the deoxygenated derivative of sorb-
ose diacetonide 6 (Figure 2).
Scheme 1. Synthesis of intermediate 8.
Compound 8 was treated with allyl trimethylsilane and
BF3·OEt2 in dichloromethane at –78 °C and allowed grad-
ually to reach room temperature to afford 5 with high stere-
oselectivity (Ն98%de, Scheme 2). The structure of 5 is sup-
ported by spectroscopic data.
Scheme 2. Stereoselective construction of the quaternary center.
The stereochemistry of the newly generated stereocenter
was confirmed by NOESY experiments. NOESY analysis
of 5 showed a strong NOE between C1-Me and C4-H as
well as between C1-Me and C3-H indicating their cis rela-
tionship, whereas C2-H showed an NOE with the C5
methylenic proton confirmed the cis relationship between
C2-H and the C5 methylenic protons. There was no NOE
between C1-Me and C2-H. All these observations con-
firmed the stereochemical assignment of 5 (Figure 3).
Figure 2. Retrosynthetic strategy for amphidinolide X.
Results and Discussion
The synthesis of the tetrahydrofuran fragment began
with the preparation of 2,3:4,6-di-O-isopropylidene-l-sorb-
ose (6) by employing a literature procedure[13] (Scheme 1).
Deoxygenation of 6 at C1 was carried out through a two-
step halogenation and dehalogenation protocol. Sorbose di-
acetonide 6 was subjected to iodine, a stoichiometric
amount of triphenylphosphane, and imidazole to afford the
iodide in 85% yield, which was subsequently heated at re-
flux with tributyltin hydride in the presence of a catalytic
Figure 3. Key nuclear Overhauser effects of 5.
The pronounced selectivity of the allylation reaction can
amount of AIBN in toluene to furnish 1-deoxysorbose di- be explained on the basis of the plausible mechanism de-
acetonide 7 in 87% yield. Selective removal of the 4,6-iso- picted in Figure 4. The isopropylidine oxygen at C1 com-
propylidene protecting group, retaining the 2,3-isopropylid- plexes with the Lewis acid and cleavage of the C1–O bond
ene functionality was achieved by using 0.8% H2SO4 in is assisted by the ring oxygen. It is known[16] that for stereo-
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Carbohydrate-Based Synthesis of the C13–C22 Fragment of Amphidinolide X
selective C-glycosylation reactions of ribose derivatives, the col. For this purpose, the benzyl protecting group was re-
C3 alkoxy group exerts the largest influence on selectivity moved by using lithium metal in liquid ammonia to obtain
leading to the 1,3-cis product. With the C3 alkoxy group the diol, and selective protection of the primary hydroxy
having a strong tendency to be pseudoaxial and the C2 alk- group as its silyl ether then afforded 10. The requisite
oxy group having a strong tendency to be pseudoequatorial, stereochemistry at C3 was achieved by applying Mitsunobu
conformer A is strongly favored. The C4 alkyl group exerts inversion conditions. Thus, compound 10 was treated with
no discernible influence on the conformational preference. 4-nitrobenzoic acid in the presence of triphenylphosphane
Thus, the C1 methyl group and the C2 hydroxy group direct (TPP) and diethyl azodicarboxylate (DEAD) to afford the
a syn conformation leading to the desired stereochemistry benzoate ester. Hydrolysis of the benzoate ester was
at the C1 quaternary center.
achieved upon treatment with lithium hydroxide mono-
hydrate in aqueous methanol to yield alcohol 11 in 84%
yield over two steps.
The C3 hydroxy group was protected as its benzyl ether
by using sodium hydride and benzyl bromide in DMF at
0 °C followed by removal of the silyl protecting group of
the primary hydroxy with TBAF at 0 °C to afford alcohol
12 in 90% yield over two steps (Scheme 3). The terminal
double bond was reduced with Raney Ni to obtain alcohol
4 in 93% yield, which was oxidized by using Dess–Martin
periodinane.[18] Upon treatment with (acetylmethylene)tri-
phenylphosphorane, the resulting aldehyde afforded unsatu-
rated ketone 13 in 80% yield over two steps. Finally, hydro-
genation of 13 with Pd/C furnished ketone 2 at room tem-
perature in 92% yield. The structure of 2 was confirmed
1
by H NMR, 13C NMR, and IR spectroscopy and mass
spectrometry.
Figure 4. Plausible mechanism for establishment of the quaternary
center.
Conclusions
With the quaternary center installed in a highly stereose-
In summary, we have successfully accomplished the syn-
lective manner, we then proceeded to the construction of theses of the C13–C22 fragment with suitable protections
the tetrahydrofuran fragment. The free hydroxy at C2 of 5 for the projected total synthesis of amphidinolide X. Start-
was deoxygenated under Barton–McCombie conditions.[17] ing from l-sorbose, the tetrahydrofuran (C13–C22) frag-
Compound 5 was treated with NaH, carbon disulfide, and ment of amphidinolide X was synthesized in a highly
methyl iodide to obtain the xanthate derivative, which upon stereoselective manner in 17 steps in 14.5% overall yield.
heating at reflux with nBu3SnH and a catalytic amount of The allylation and simultaneous installation of the quater-
AIBN in toluene afforded deoxy derivative 9 in 81% yield nary center with correct stereochemistry of the tetra-
over two steps. The next critical transformation was the in- hydrofuran fragment was achieved with excellent dia-
version of the stereochemistry at C3 by a Mitsunobu proto- stereocontrol.
Scheme 3. Synthesis of the tetrahydrofuran fragment 2.
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M. K. Gurjar, G. S. Yellol, D. K. Mohapatra
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79.5, 82.1, 84.9, 110.8, 113.2, 127.3 (2 C), 127.5, 127.6, 127.7 (2 C),
128.2 (2 C), 128.3 (2 C), 137.7, 138.0 ppm. MS (ESI): m/z = 407
[M + Na]+. C23H28O5 (384.47): calcd. C 71.85, H 7.34; found C
71.57, H 7.39.
Experimental Section
General Remarks: Solvents were distilled following standard pro-
cedures before use. TLC was performed on precoated silica gel alu-
minum plates 60 F254. IR spectra were recorded with an FTIR
spectrometer. 1H and 13C NMR spectra were recorded with a
200 MHz spectrometer with TMS as an internal standard. Mass
spectra were obtained with a TSQ 70 mass spectrometer. Optical
rotations were determined with a JASCO 370 digital polarimeter
with a sodium light source. Elemental analyses were carried out
with a CHNS-O analyzer.
(2R,3S,4S,5S)-2-Allyl-4-(benzyloxy)-5-(benzyloxymethyl)-2-methyl-
tetrahydrofuran-3-ol (5): A solution of 8 (5.0 g, 13.0 mmol) and all-
yltrimethylsilane (12.4 mL, 78 mmol) in CH2Cl2 (40 mL) was co-
oled to –78 °C. Freshly distilled BF3·OEt2 (2.5 mL, 20 mmol) was
added dropwise, and the solution was allowed to attain ambient
temperature. After completion of the reaction (monitored by TLC),
the mixture was quenched with saturated NaHCO3 solution
(25 mL). The organic layer was separated, and the aqueous layer
was extracted with CH2Cl2 (2ϫ50 mL). The combined organic
layer was dried (Na2SO4) and concentrated. The crude residue was
purified by silica gel column chromatography (ethyl acetate/light
petroleum ether (2:9) to afford 5 (4.17 g, 86%) as a colorless liquid.
[α]2D5 = –4.5 (c = 1.0, CHCl3). 1H NMR (200 MHz, CDCl3): δ =
1.18 (s, 3 H), 1.70 (br. s, 1 H), 2.38 (d, J = 7.3 Hz, 2 H), 3.57 (dd,
J = 6.5, 10.1 Hz, 1 H), 3.71 (dd, J = 4.7, 10.1 Hz, 1 H), 4.05 (d, J
= 4.4 Hz, 1 H), 4.06 (s, 1 H), 4.31–4.34 (m, 1 H), 4.58 (ABq, J =
12.3, 17.2 Hz, 2 H), 4.61 (ABq, J = 11.7, 15.9 Hz, 2 H), 5.02–5.10
(m, 2 H), 5.73–5.94 (m, 1 H), 7.30–7.32 (m, 10 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 19.9, 44.8, 69.5, 72.4, 73.3, 75.9, 79.4, 82.4,
85.3, 118.0, 127.4 (2 C), 127.5, 127.6, 127.7 (2 C), 128.2 (2 C), 128.4
(2 C), 134.2, 138.0, 138.2 ppm. MS (ESI): m/z = 391 [M + Na]+.
C23H28O4 (368.47): calcd. C 74.97, H 7.66; found C 74.56, H 8.26.
1-Deoxy-2,3:4,6-di-O-isopropylidene-L-sorbofuranose (7): 2,3:4,6-
Di-O-isopropylidene-l-sorbofura-nose (6; 20.0 g, 0.077 mol), tri-
phenylphosphane (40.3 g, 153.8 mmol), I2 (39.0 g, 0.154 mol), and
imidazole (15.7 g, 0.231 mol) in toluene (300 mL) were heated at
reflux for 2 h. Toluene was removed, and the residue was parti-
tioned between water (100 mL) and ethyl acetate (150 mL). The
organic layer was separated, and the aqueous layer was extracted
with ethyl acetate (3ϫ100 mL). The combined organic phase was
washed with aqueous NaHCO3 (2ϫ150 mL), aqueous Na2S2O3
(2ϫ150 mL), and brine (200 mL), dried with Na2SO4, and concen-
trated. The residue was purified by silica gel column chromatog-
raphy (ethyl acetate/light petroleum ether, 1:3) to afford the iodide
(24.0 g, 85%) as
a light yellow syrup. This iodide (24.0 g,
0.065 mol) was dissolved in toluene (200 mL), and the solution was
degassed with argon. AIBN (100 mg) and tri-n-butyltin hydride
(26.0 mL, 0.098 mol) were added successively to the reaction mix-
ture. The contents were heated under reflux for 10 h and concen-
trated. The residue was purified by silica gel column chromatog-
raphy (ethyl acetate/light petroleum ether, 1:9) to afford 7 (13.7 g,
87%) as a colorless liquid. [α]2D5 = –15.1 (c = 1.25, CHCl3). 1H
NMR (200 MHz, CDCl3): δ = 1.36 (s, 3 H), 1.39 (s, 3 H), 1.44 (s,
3 H), 1.48 (s, 3 H), 1.72 (s, 3 H), 4.05 (m, 3 H), 4.22 (s, 1 H), 4.28
(m, 1 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 18.5, 24.5, 26.2,
27.1, 28.9, 60.2, 71.9, 73.6, 87.2, 97.2, 110.8, 113.5 ppm. MS (ESI):
m/z = 267 [M + Na]+. C12H20O5 (244.29): calcd. C 59.00, H 8.25;
found C 58.79, H 8.67.
(2R,4S,5S)-2-Allyl-4-(benzyloxy)-5-(benzyloxymethyl)-2-methyl-
tetrahydrofuran (9): To a solution of 5 (5.0 g, 13.5 mmol) in dry
THF (50 mL) at 0 °C was added NaH (60% w/w dispersion in min-
eral oil, 0.8 g, 20.4 mmol) followed by carbon disulfide (1.6 mL,
20.4 mmol). After 20 min, methyl iodide (1.3 mL, 20.4 mmol) was
added at the same temperature. After completion of the reaction
(monitored by TLC), the reaction mixture was quenched with water
(30 mL). The reaction mixture was extracted with ethyl acetate
(3 ϫ 50 mL). The combined organic extracts were washed with
water (100 mL), dried (Na2SO4), and concentrated under reduced
pressure. The crude xanthate derivative (5.2 g, 11.4 mmol) was dis-
solved in toluene (60 mL), and the solution was degassed with ar-
gon. AIBN (50 mg) and tri-n-butyltin hydride (4.6 mL, 17.1 mmol)
were added to the reaction mixture. The reaction mixture was
heated under reflux for 10 h and concentrated. The residue was
purified by silica gel column chromatography (ethyl acetate/light
petroleum ether, 1:9) to afford 9 (3.45 g, 81%) as a colorless liquid.
[α]2D5 = +41.9 (c = 1.20, CHCl3). 1H NMR (200 MHz, CDCl3): δ =
1.21 (s, 3 H), 1.75 (dd, J = 5.8, 13.2 Hz, 1 H), 2.11 (dd, J = 2.2,
13.2 Hz, 1 H), 2.40 (d, J = 6.6, Hz, 2 H), 3.66 (dd, J = 5.1, 9.5 Hz,
1 H), 3.78 (dd, J = 5.1, 9.5 Hz, 1 H), 4.11–4.21 (m, 2 H), 4.35–4.64
(m, 4 H), 5.00–5.08 (m, 2 H), 5.78–5.87 (m, 1 H), 7.27–7.32 (m, 10
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 26.5, 41.3, 46.6, 69.1,
70.8, 73.1, 79.7, 79.9, 81.8, 117.2, 127.0 (2 C), 127.2 (2 C), 127.5 (2
C), 128.0 (2 C), 128.1 (2 C), 134.9, 138.1, 138.2 ppm. MS (ESI):
m/z = 375 [M + Na]+. C23H28O3 (352.47): calcd. C 78.38, H 8.01;
found C 78.58, H 8.49.
1-Deoxy-4-benzyloxy-5-(benzyloxymethyl)-2,3-O-isopropylidene-L-
sorbofuranose (8): A solution of compound 7 (15.0 g, 61.4 mmol)
and 0.8% aqueous H2SO4 (1 mL) in MeOH (150 mL) was stirred
at room temperature for 6 h. The reaction mixture was neutralized
with aqueous NaHCO3 (100 mL), and methanol was removed un-
der reduced pressure. The aqueous layer was extracted with ethyl
acetate (3ϫ150 mL). The combined organic layer was dried with
Na2SO4 and concentrated. The crude product was purified by silica
gel column chromatography (ethyl acetate/light petroleum ether,
1:1) to obtain the diol compound (11.3 g, 90%) as a colorless li-
quid. To a solution of the diol (10.0 g, 0.049 mol) in DMF
(100 mL) was added NaH (60 % w/w dispersion in paraffin oil,
4.9 g, 0.123 mol) portionwise over a period of 30 min at 0 °C. BnBr
(14.5 mL, 0.123 mol) was then introduced into the reaction mixture
dropwise. After stirring for 4 h, the reaction mixture was quenched
with ice-cold water (110 mL) and extracted with diethyl ether
(3ϫ150 mL). The combined organic layers were washed with water
(150 mL), brine (150 mL), dried (Na2SO4), and concentrated. The
crude residue was purified by silica gel column chromatography
(ethyl acetate/light petroleum ether, 1:9) to afford 8 (17.93 g, 96%)
as a colorless liquid. [α]2D5 = +41.1 (c = 1.10, CHCl3). 1H NMR
(200 MHz, CDCl3): δ = 1.34 (s, 3 H), 1.47 (s, 3 H), 1.65 (s, 3 H),
3.74 (dd, J = 3.7, 6.5 Hz, 2 H), 3.95 (d, J = 3.0 Hz, 1 H), 4.30 (s,
1 H), 4.42 (dd, J = 3.0, 6.2 Hz, 1 H), 4.50 (ABq, J = 2.4, 12.3 Hz,
2 H), 4.64 (ABq, J = 10.1, 12.0 Hz, 2 H), 7.28–7.33 (m, 10 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 24.7, 26.3, 27.2, 67.5, 71.8, 73.4,
(2S,3S,5R)-5-Allyl-2-[(tert-butyldimethylsilyloxy)methyl]-5-methyl-
tetrahydrofuran-3-ol (10): A solution of 9 (4.5 g, 12.8 mmol) in an-
hydrous THF (20 mL) was added to a solution of lithium (0.76 g,
128.0 mmol) in liquid NH3 (50 mL) maintained at –78 °C. The re-
action mixture was stirred for 1 h and quenched with solid NH4Cl.
The excess ammonia gas was allowed to evaporate, and then the
resulting residue was taken up in ethyl acetate (75 mL), washed
with water (2ϫ50 mL) and brine (50 mL), dried (Na2SO4), and
concentrated. The residue was purified by silica gel column
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Carbohydrate-Based Synthesis of the C13–C22 Fragment of Amphidinolide X
chromatography (ethyl acetate/light petroleum ether, 4:1) to obtain
the diol (1.8 g, 81%), which was used for the next step without
further purification. TBDMSCl (1.7 g, 11.5 mmol) was added to a
solution of the diol (1.8 g, 10.5 mmol) and triethylamine (2.2 mL,
15.7 mmol) in CH2Cl2 (30 mL) at 0 °C and stirred for 1 h. After
completion of the reaction (monitored by TLC), the reaction mix-
ture was quenched with saturated aqueous NaHCO3 (15 mL) and
extracted with CH2Cl2 (3ϫ25 mL). The combined organic layer
was washed with brine (50 mL), dried (Na2SO4), and concentrated
under reduced pressure. The crude residue was purified by silica gel
column chromatography (ethyl acetate/light petroleum ether, 1:4) to
afford 10 (2.8 g, 92%) as colorless liquid. [α]2D5 = +17.1 (c = 1.10,
purified by silica gel column chromatography (ethyl acetate/light
petroleum ether, 1:3) to afford 4 (0.84 g, 93%) as a colorless liquid.
1
[α]2D5 = –34.4 (c = 0.95, CHCl3). H NMR (200 MHz, CDCl3): δ =
0.92 (t, J = 7.3 Hz, 3 H), 1.29–1.37 (m, 2 H) 1.33 (s, 3 H), 1.46–
1.52 (m, 2 H), 1.85 (dd, J = 3.8, 13.2 Hz, 1 H), 1.95 (dd, J = 7.3,
13.2 Hz, 1 H), 2.30 (s, 1 H), 3.55 (dd, J = 4.5, 11.5 Hz, 1 H), 3.71
(dd, J = 3.3, 11.5 Hz, 1 H), 3.98–4.02 (m, 1 H), 4.04–4.07 (m, 1
H), 4.48 (ABq, J = 11.5, 17.4 Hz, 2 H), 7.32–7.34 (m, 5 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 14.5, 17.8, 25.6, 42.8, 44.7, 63.1,
71.5, 80.6, 83.1, 83.6, 126.7, 127.3 (2 C), 128.2 (2 C), 138.1 ppm.
MS (ESI): m/z = 287 [M + Na]+. C16H24O3 (264.36): calcd. C 72.69,
H 9.15; found C 71.98, H 9.21.
1
CHCl3). H NMR (200 MHz, CDCl3): δ = 0.10 (2s, 6 H), 0.91 (s,
4-[(2S,3R,5R)-3-(Benzyloxy)-5-methyl-5-propyltetrahydrofuran-2-
yl]butan-2-one (2): To a stirred solution of 4 (1.0 g, 3.8 mmol) in
anhydrous CH2Cl2 (20 mL) was added Dess–Martin periodinane
(3.2 g, 7.6 mmol), and the mixture was stirred for 2 h. After com-
pletion of the reaction (monitored by TLC), the reaction mixture
was quenched with water (20 mL), and the organic layer was sepa-
rated. The aqueous layer was extracted with CH2Cl2 (3ϫ25 mL).
The combined organic layer was dried with Na2SO4 and concen-
trated under reduced pressure at room temperature to obtain the
aldehyde (0.89 g, 90%). A mixture of the aldehyde (0.89 g,
3.4 mmol) and (acetylmethylene)triphenylphosphorane (2.2 g,
6.8 mmol) was heated at reflux in benzene for 2 h. The solvent was
evaporated to leave a residue, which was purified by silica gel col-
umn chromatography (ethyl acetate/light petroleum ether, 1:9) to
afford 13 (0.91 g, 89%) as a colorless liquid. To a solution of 13
(0.91 g, 3.16 mmol) in MeOH (5 mL) was added 10% Pd/C
(10 mg), and the mixture was stirred under a H2 atmosphere at
room temperature for 30 min. The reaction mixture was filtered
through a pad of Celite and concentrated under reduced pressure.
The crude product was purified by silica gel column chromatog-
raphy (ethyl acetate/light petroleum ether, 1:9) to give 2 (0.85 g,
92%) as a colorless liquid. [α]2D5 = –42.9 (c = 0.80, CHCl3). IR
9 H), 0.92 (s, 1 H), 1.18 (s, 3 H), 1.93–2.05 (m, 2 H), 2.41 (d, J =
7.3 Hz, 2 H), 3.40 (d, J = 5.6 Hz, 1 H), 3.92–3.95 (m, 2 H), 4.48–
4.58 (m, 1 H), 5.06–5.12 (m, 2 H), 5.73–5.94 (m, 1 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = –5.5 (2 C), 18.3, 25.9 (3 C), 27.2,
44.2, 47.0, 64.6, 75.0, 82.5, 83.5, 117.8, 134.5 ppm. MS (ESI): m/z
= 309 [M + Na]+. C15H30O3Si (286.49): calcd. C 62.89, H 10.55;
found C 62.19, H 11.34.
(2S,3R,5R)-5-Allyl-2-[(tert-butyldimethylsilyloxy)methyl]-5-methyl-
tetrahydrofuran-3-ol (11): To a solution of 10 (2.0 g, 7.0 mmol),
TPP (3.7 g, 14.0 mmol), and p-nitrobenzoic acid (2.4 g, 14.0 mmol)
in THF (23 mL) at 0 °C was added DEAD (2.5 mL, 17.5 mmol)
dropwise. Stirring was continued at 0 °C for 1 h and then at room
temperature for the next 6 h. The solvent was removed under re-
duced pressure, and the crude residue was purified by silica gel
column chromatography (ethyl acetate/light petroleum ether, 1:9)
to afford the ester (2.7 g, 88%). To a solution of the ester (2.7 g,
6.2 mmol) in moist methanol (27 mL) was added LiOH·H2O
(945 mg, 24.8 mmol), and the reaction mixture was stirred at room
temperature for 0.5 h and concentrated. The residue was purified
by silica gel column chromatography (ethyl acetate/light petroleum
ether, 1:5) to furnish 11 (1.70 g, 95%) as a colorless liquid. [α]2D5
=
1
–6.5 (c = 1.35, CHCl3). H NMR (200 MHz, CDCl3): δ = 0.08 (2
s, 6 H), 0.90 (s, 9 H), 1.34 (s, 3 H), 1.65 (s, 1 H), 1.72 (dd, J = 6.3,
12.9 Hz, 1 H), 2.14–2.25 (m, 3 H), 3.58 (dd, J = 2.7, 8.7 Hz, 1 H),
3.77–3.89 (m, 2 H), 4.21–4.31 (m, 1 H), 5.02–5.10 (m, 2 H), 5.70–
5.91 (m, 1 H) ppm. 13C NMR (50 MHz, CDCl3): δ = –5.4 (2 C),
18.0, 25.9 (3 C), 27.2, 44.3, 47.0, 64.6, 74.9, 82.4, 83.7, 117.7,
134.5 ppm. MS (ESI): m/z = 309 [M + Na]+. C15H30O3Si (286.49):
calcd. C 62.89, H 10.55; found C 62.82, H 11.18.
(CHCl ): ν = 2983, 1741, 1373, 1242, 1047 cm–1. 1H NMR
˜
3
(200 MHz, CDCl3): δ = 0.91 (t, J = 7.0 Hz, 3 H), 1.25–1.36 (m, 2
H), 1.28 (s, 3 H), 1.40–1.49 (m, 2 H), 1.64–1.82 (m, 2 H), 1.87–2.02
(m, 2 H), 2.12 (s, 3 H), 2.52 (dd, J = 6.2, 17.8 Hz, 1 H), 2.53 (d, J
= 6.2 Hz, 1 H), 3.66–3.79 (m, 1 H), 3.90 (dt, J = 4.6, 8.5 Hz, 1 H),
4.50 (ABq, J = 11.8, 17.2 Hz, 2 H), 7.29–7.32 (m, 5 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 14.6, 17.8, 26.3, 28.4, 29.9, 40.1, 42.4,
45.2, 71.6, 81.4, 82.9, 84.0, 127.6 (3 C), 128.4 (2 C), 138.2,
208.7 ppm. MS (ESI): m/z = 304 [M + Na]+. C19H28O3 (304.43):
calcd. C 74.96, H 9.27; found C 75.23, H 8.87.
[(2S,3R,5R)-3-(Benzyloxy)-5-methyl-5-propyltetrahydrofuran-2-yl]-
methanol (4): To an ice-cooled solution of 11 (1.4 g, 4.9 mmol) in
anhydrous DMF (12 mL) was added NaH (60% w/w dispersion in
mineral oil, 295 mg, 7.4 mmol) portionwise. Stirring was continued
at the same temperature for 1 h. To the above stirred reaction mix-
ture was added BnBr (0.7 mL, 5.9 mmol) dropwise at 0 °C. The
reaction mixture was stirred at the same temperature for an ad-
ditional 3 h. The reaction mixture was quenched by the addition
of ice, diluted with water (25 mL), and extracted with ethyl acetate
(3ϫ40 mL). The combined organic layer was washed with brine
(75 mL), dried (Na2SO4), and concentrated to afford the benzyl-
protected compound. This benzyl derivative (1.8 g, 4.8 mmol) was
taken up in THF (15 mL) and treated with TBAF (1 m in THF,
7.2 mL, 7.2 mmol). The reaction mixture was stirred for 3 h at 0 °C
and then concentrated. The residue was purified by silica gel col-
umn chromatography (ethyl acetate/light petroleum ether, 1:3) to
afford alcohol 12 (1.14 g, 90% over two steps). To a suspension of
catalytic Raney nickel in EtOH (10 mL) was added a solution of
12 (0.9 g, 3.4 mmol) in EtOH (10 mL), and the mixture was stirred
for 1 h under a hydrogen atmosphere. The reaction mixture was
filtered through a plug of Celite and concentrated. The residue was
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H NMR and 13C NMR spectra of all synthe-
sized compounds and the NOESY spectrum of compound 5.
Acknowledgments
G. S. Y. thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi for a research fellowship. D. K. M. thanks the
Directors of the CSIR-Indian Institute of Chemical Technology
and CSIR-National Chemical Laboratory for providing necessary
facilities for our research activities.
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Received: November 4, 2011
Published Online: February 6, 2012
1758
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1753–1758