One-pot stereoselective double intramolecular oxymercuration: Synthesis of four isomers of an unsymmetrical bis-tetrahydrofuran ring system

Article abstract of DOI:10.1002/ejoc.201000861

Stereoselective one-pot double intramolecular oxymercuration has been demonstrated to be the key reaction in the efficient preparation of the mono-hydroxylated bis-tetrahydrofuran ring system present in asimitrin and salzmanolin, two naturally occurring b

Full text of DOI:10.1002/ejoc.201000861

FULL PAPER
DOI: 10.1002/ejoc.201000861
One-Pot Stereoselective Double Intramolecular Oxymercuration: Synthesis of
Four Isomers of an Unsymmetrical Bis-Tetrahydrofuran Ring System
Debendra K. Mohapatra,*[a] P. Ramesh Naidu,[a] D. Srinivas Reddy,[a] Sabita Nayak,[a][‡] and
Seetaram Mohapatra[a][‡]
Keywords: Natural products / Stereoselectivity / Toxicity / Mercury / Oxygen heterocycles
Stereoselective one-pot double intramolecular oxymercur-
ation has been demonstrated to be the key reaction in the
efficient preparation of the mono-hydroxylated bis-tetra-
hydrofuran ring system present in asimitrin and salzmanolin,
two naturally occurring biologically active nonclassical ace-
togenins.
characterized by a long aliphatic chain bearing a terminal
methyl-substituted α,β-unsaturated γ-lactone ring (some-
times rearranged to a keto lactone) with one, two, or three
tetrahydrofuran (THF) rings located along the hydrocarbon
chain and a number of oxygenated moieties (OH, OAc,
ketones, epoxides) and/or double bonds being present. To a
lesser extent, tetrahydropyran (THP) ring compounds and
acyclic compounds are also found.
Introduction
In recent years, the Annonaceous acetogenins have been
the focus of extensive synthetic efforts as a result of their
remarkable range of biological activities such as antitumor,
antifeedant, immunosuppressive, pesticidal, anthelmintic,
and microbial activities. In particular, after the identifica-
tion of uvaricin[1] as an in vivo active antitumor agent there
has been significant interest in the isolation and biological
evaluation of acetogenins derived from the Annonaceous
family.[2] Annonaceous acetogenins are known to be highly
potent and selective antitumor agents. More interestingly,
some members of this family have been shown to possess
the ability to combat resistance in multi-drug-resistant can-
cerous cells.[3,4] The origin of the selective cytotoxicity of
acetogenins is believed to result from their complexation
with ubiquinone-linked NADH oxidase present in the
plasma membrane of tumor cells. Acetogenins also bind
NADH-ubiquinone oxidoreductase (Complex I), which is a
membrane protein present in the mitochondrial electron-
transport system.[5–9] Complex I has been implicated in sev-
eral diseases including idiopathic Parkinson’s disease, matu-
rity onset diabetes, stroke-like episodes, and Huntington’s
disease.[10] However, the precise mode of complexation of
acetogenins with target proteins has not been delineated.
Structurally, the Annonaceous acetogenins are a series of
C35/C37 natural products derived from C32/C34 fatty acids
that are combined with a 2-propanol unit. They are usually
Asimitrin (1),
a mono-hydroxylated unsymmetrical
bis-tetrahydrofuran acetogenin, was isolated from the seeds
of Asimina triloba in 2005.[11] Salzmanolin (2), another
mono-hydroxylated unsymmetrical bis-tetrahydrofuran
acetogenin, was isolated by Queiroz et al. in 2003[12]
and displayed significant activities towards a cancer cell
line when compared with normal cells (Vero,
ED50 Ͼ 1ϫ10–2 µgmL–1). These novel acetogenins were
found to be selectively cytotoxic against prostate (PC-3) and
colon adenocarcinoma (HT-29) with about 10000 and 100
times the potency of adriamycin, respectively. Because of
their diverse array of biological activities and by virtue of
their extremely limited availability in nature, these com-
pounds have attracted the attention of synthetic organic
chemists worldwide (Figure 1).
The stereocontrolled construction of the tetrahydrofuran
unit plays a pivotal role in the total synthesis of Annona-
ceous acetogenins. Among the more successful approaches
to bis-tetrahydrofuran ring formation are the cyclization of
hydroxy epoxides[13] and hydroxyalkenes,[14] and variations
of the Williamson ether synthesis.[15] Protocols based on
Sharpless epoxidation and dihydroxylation,[16] the addition
of chiral allenyltin reagents to aldehydes,[17] and the elabo-
ration of natural enantiopure materials[18] have been em-
ployed in the synthesis of the tetrahydrofuran precursors.
We have recently shown that stereoselective intramole-
cular oxymercuration can be employed effectively with ex-
cellent selectivity in the synthesis of the bis-tetrahydrofuran
ring system present in nonclassical acetogenins.[19] As a fur-
View this journal online at
[a] Organic Chemistry Division-I, Indian Institute of Chemical
Technology (CSIR),
Hyderabad 500 007, India
Fax: +91-40-27160387
E-mail: mohapatra@iict.res.in
dkm_77@yahoo.com
[‡] Current address: Department of Developmental and Molecular
Biology, Albert Einstein College of Medicine, Bronx, NY10461,
USA
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000861.
wileyonlinelibrary.com
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D. K. Mohapatra et al.
FULL PAPER
olefin. Hydrogenation of the resulting double bond in the
presence of Raney Ni in ethanol at 40 psi gave the reduced
product, the spectral and analytical data of which were in
good agreement with reported values.[21] Selective deprotec-
tion of the 5,6-O-isopropylidene group and treatment of the
resulting diol with NaH and TsCl afforded the epoxide.
Copper-catalyzed epoxide ring-opening with allylmagne-
sium bromide in the presence of CuCN furnished the
alcohol 7 in 84% yield (Scheme 2).[22]
Figure 1. Structures of asimitrin and salzmanolin.
ther test of this protocol for the synthesis of the system
present in asimitrin, we reported the first stereoselective
synthesis of the C10–C34 fragment of asimitrin.[20] In both
these syntheses, the bis-tetrahydrofuran ring system was
prepared by stereocontrolled off-template construction of
the first tetrahydrofuran ring by utilizing an intramolecular
oxymercuration protocol followed by a second one at the
end. In this paper we report a one-pot double intramole-
cular oxymercuration protocol for the synthesis of the
mono-hydroxylated bis-tetrahydrofuran ring system present
in asimitrin and salzmanolin. Our retrosynthetic strategy is
depicted in Scheme 1. The one-pot stereoselective intramo-
lecular oxymercuration of 5 would lead to 3 and 4. Diol 5
would be furnished from 6 following the selective protection
of the allylic hydroxy group, one-carbon homologation, and
copper-catalyzed epoxide ring-opening as the key reactions.
Scheme 2. Reagents and conditions: (a) NaH, BnBr, THF, 0 °C to
r.t., 12 h, 91%; (b) 60% AcOH, H2SO4 (catalytic), 55 °C, 6 h, 90 %;
(c) PPh3MeBr, nBuLi, THF, –10 °C to r.t., 12 h, 87%; (d) 2,6-luti-
dine, TBSOTf, CH2Cl2, –78 °C, 2 h, 94%; (e) Na, naphthalene,
THF, –25 °C, 20 min, 89%; (f) Hg(OAc)2, CH2Cl2, room temp.,
2 h, 86%.
Treatment of compound 7 with BnBr in the presence of
NaH afforded the benzyl ether derivative 8 in 91% yield.
Compound 8 was treated with 60% acetic acid in the pres-
ence of a catalytic amount of sulfuric acid at 55 °C to afford
the hemiacetal, which, after purification by silica gel col-
umn chromatography, was subjected to one-carbon homol-
ogation[23] with Ph3P=CH2 to produce the olefin 9. The al-
lylic hydroxy group was selectively protected as its TBS
ether 10 in 94% yield. Deprotection of the benzyl group
with Na in the presence of naphthalene afforded the crucial
intermediate 5. Now the requisite structural skeleton was
set for stereoselective double intramolecular oxymercur-
ation. Diastereoselective intramolecular oxymercuration of
diol 5 with mercury(II) acetate in dichloromethane gave a
trans/cis mixture of tetrahydrofuran derivatives with 9:1
selectivity. The stereoisomers 3 and 4 were conveniently sep-
Scheme 1. Retrosynthetic analysis for mono-hydroxylated bis-tetra-
hydrofuran ring system.
Results and Discussion
The synthetic endeavor commenced starting from the arated by flash silica gel column chromatography and their
commercially available 1,2:5,6-di-O-isopropylidene-α--glu- purities and structures confirmed by 1H and 13C NMR and
cofuranose (6): The secondary hydroxy group was con- mass spectral analysis and the relative stereochemistries
verted into its tosylate derivative. Treatment with DBU re- were ascertained by NOESY experiments. As depicted in
sulted in the elimination of the tosylate group to afford the Figure 2, there are strong NOE interactions between H15
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Synthesis of an Unsymmetrical Bis-Tetrahydrofuran Ring System
and H16, and H23 and H24. No NOE interactions were
observed, however, between H16 and H17, H16 and H19,
and H20 and H23, which confirms the trans relationships.
Conclusions
Four isomers of the mono-hydroxylated bis-tetra-
hydrofuran ring system present in asimitrin and salzmano-
lin, two naturally occurring biologically active nonclassical
acetogenins, have been synthesized starting from the com-
mercially available 1,2:5,6-di-O-isopropylidene-α--gluco-
furanose by a one-pot stereoselective double intramolecular
oxymercuration reaction as the key step. The total synthesis
of asimitrin and its isomers is in progress, which will prove
the absolute stereochemistry, is underway and will be re-
ported in due course.
Figure 2. Selected NOE correlations of 3.
Next our task was to convert the mercury chloride group
into a hydroxy functionality. Demercuration of 3 was car-
Experimental Section
ried out under a stream of oxygen in the presence of sodium General: Air- and/or moisture-sensitive reactions were carried out
in anhydrous solvents under argon in oven- or flame-dried glass-
ware. All anhydrous solvents were distilled prior to use: THF and
diethyl ether from Na and benzophenone, CH2Cl2 from CaH2,
MeOH, EtOH from Mg cake. Commercial reagents were used with-
out purification. Column chromatography was carried out by using
silica gel (60–120 mesh). Specific optical rotations [α]D are given in
10–1 degcm2 g–1. Infrared spectra were recorded in CHCl3/neat (as
borohydride to afford the diol 3a in 81% yield (Scheme 3).
1
mentioned) and are reported in cm–1. H and 13C NMR chemical
shifts are reported in ppm downfield from tetramethylsilane (TMS)
and coupling constants (J) are reported in Hz.
Scheme 3. Reagents and conditions: (a) O2, NaBH4, DMF, r.t., 1 h,
81%.
(3R,5R,6R)-2,2-Dimethyl-5-[(R)-oxiran-2-yl]tetrahydrofuro[2,3-d]-
[1,3]dioxole: Diol 11 (3.0 g, 14.7 mmol) in THF (20 mL) was added
to a slurry of NaH (1.17 g, 29.4 mmol) in THF (30 mL) at 0 °C.
After 20 min, p-toluenesulfonyl chloride (2.8 g, 14.7 mmol) in THF
(20 mL) was added and the mixture was stirred at 0 °C. After com-
Similarly, compound 13 was prepared from known inter-
mediate 12 by a slight modification of a reported pro-
cedure[24] in which the Grignard reaction was carried out in
diethyl ether by reverse addition of the Grignard reagent at pletion (monitored by TLC), the reaction was quenched by the slow
addition of water. The organic layer was separated and the aqueous
layer extracted with ethyl acetate (3ϫ50 mL). The combined or-
ganic layers were dried with Na2SO4, concentrated, and purified
by silica gel column chromatography using ethyl acetate and hexane
(12%) to give epoxide 8 (2.46 g, 90%) as a colorless liquid.
0 °C to improve the diastereoselectivity (4:1) in favor of 13.
Compound 13 was separated conveniently by silica gel col-
umn chromatography from the crude reaction mixture.[19]
Following the same sequence of reactions as described in
Scheme 2, compounds 14 and 15 were synthesized in 89%
yield (Scheme 4).
(R)-1-[(3R,5R,6R)-2,2-Dimethyltetrahydrofuro[2,3-d]dioxol-5-yl]-
pent-4-en-1-ol (7): A solution of allyl bromide (1.4 mL,
16.12 mmol) was added dropwise to a suspension of magnesium
metal pieces (0.52 g, 21.52 mmol) in diethyl ether (15 mL) and the
mixture was stirred for 30 min at room temperature. CuCN (47 mg,
0.54 mmol) was added at once, which resulted in a color change to
dark brown. After cooling to –10 °C, the epoxide (2.0 g,
10.75 mmol) in diethyl ether (20 mL) was added dropwise. The re-
action mixture was stirred for 1 h at –10 °C, quenched by the slow
addition of a saturated NH4Cl solution, and the resulting suspen-
sion was stirred for another 30 min at room temperature. The or-
ganic layer was separated and the aqueous layer extracted with
ethyl acetate (3ϫ40 mL). The combined organic layers were dried
with Na2SO4, concentrated, and purified by silica gel column
chromatography using ethyl acetate and hexane (8 %) to afford
compound 7 (2.05 g, 84%) as a colorless liquid. [α]2D6 = –2.02 (c =
1.3, CH Cl ). IR (KBr): ν = 3488, 2986, 2940, 1640, 1598 cm–1. 1H
˜
2
2
NMR (CDCl3, 200 MHz): δ = 5.91–5.71 (m, 2 H), 5.04–4.87 (m, 2
H), 4.69 (ddd, J = 1.3, 4.0, 6.0 Hz, 1 H), 3.89 (dt, J = 3.0, 8.2 Hz,
1 H), 3.71 (dt, J = 4.0, 8.2 Hz, 1 H), 2.69 (br. s, 1 H), 2.30–1.60
(m, 6 H), 1.47 (s, 3 H), 1.24 (s, 3 H) ppm. 13C NMR (CDCl3,
50 MHz): δ = 138.2, 114.7, 112.3, 106.1, 84.6, 80.7, 71.9, 33.5, 32.4,
29.7, 26.8, 25.9 ppm. MS (ESI): m/z = 251 [M + Na]+. HRMS
(ESI): calcd. for C12H20O4Na [M + Na]+ 251.1259; found 251.1262.
Scheme 4. Reagents and conditions: (a) NaIO4, SiO2, CH2Cl2, r.t.,
30 min, 97%; (b) homoallylmagnesium bromide, CuCN, 0 °C, 1 h,
95% (13/7 = 4:1).
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D. K. Mohapatra et al.
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(3R,5R,6R)-5-[(R)-1-(Benzyloxy)pent-4-enyl]-2,2-dimethyltetra-
hydrofuro[2,3-d][1,3]dioxole (8): Compound 7 (1.63 g, 7.188 mmol)
in THF (10 mL) was added slowly to a suspension of NaH (0.34 g,
8.62 mmol) in dry THF (15 mL) at 0 °C. After 20 min, benzyl bro-
mide (0.94 mL, 7.9 mmol) was added at 0 °C. The reaction mixture
was stirred for 12 h at room temperature. After completion (moni-
tored by TLC), the reaction mixture was quenched with ice-cooled
water and extracted with ethyl acetate (3ϫ25 mL). The combined
organic layers were dried with Na2SO4, concentrated under reduced
pressure, and purified by silica gel column chromatography using
ethyl acetate and hexane (4%) to afford compound 8 (2.08 g, 91%)
tracted with CH2Cl2 (2ϫ 30 mL). The combined organic layers
were dried with Na2SO4, concentrated, and purification of the
crude product by silica gel column chromatography using ethyl
acetate and hexane (5%) afforded the TBS ether 10 (1.59 g, 94%)
as a colorless liquid. [α]2D8 = +5.3 (c = 1.0, CHCl ). IR (CHCl ): ν
˜
3
3
= 3483, 3074, 2950, 1641, 1461, 1074 cm–1
.
1H NMR (CDCl3,
300 MHz): δ = 7.35–7.22 (m, 5 H, Ph), 5.87–5.7 (m, 2 H, 2
CH2=CH), 5.25–4.9 (m,4 H, 2 CH=CH2), 4.55 (ABq, J = 13.6,
24.9 Hz, 2 H, OCH2Ph), 4.45 (m, 1 H, CH2CHOSi), 3.87 (m, 1 H,
CHOCHOHCH2), 3.30–3.23 (dt, J = 4.5, 6.8 Hz, 1 H, CH2CHO-
CHOH), 2.63 (br. s, 1 H, CHOH), 2.19–2.08 (m, 2 H,
=CHCH2 CH2 ), 1.80–1.50 (m, 4 H, CHOHCH2 CHOSi,
CH2CH2CHO), 0.91 (s, 9 H, 3 CH3), 0.09 (s, 3 H, SiCH3), 0.05 (s,
as a colorless liquid. [α]2D6 = –5.4 (c = 1.0, CHCl ). IR (KBr): ν =
˜
3
3031, 2985, 1640, 1377, 1067 cm–1. 1H NMR (CDCl3, 300 MHz):
δ = 7.37–7.16 (m, 5 H, Ph), 5.83–5.62 (m, 2 H, CH=CH2, CHO- 3 H, SiCH3) ppm. 13C NMR (CDCl3, 75 MHz): δ = 140.9, 138.5,
CHOO), 5.01–4.89 (m, 3 H, CH=CH2, CH2CHOCHOO), 4.71–
4.54 (m, 2 H, OCH2Ph), 4.07 (m, 1 H, CHOCHOCH2), 3.67–3.57 28.0, 25.8, 18.1, –4.5, –5.1 ppm. MS (ESI): m/z = 413 [M + Na]+.
(dt, J = 3.2, 8.7 Hz, 1 H, CH2CHOCHO), 2.30–1.87 (m, 4 H,
HRMS (ESI): calcd. for C23H38O3NaSi [M + Na]+ 413.2487; found
128.3, 127.9, 127.7, 114.7, 114.1, 81.7, 72.4, 71.5, 68.6, 39.9, 29.7,
=CHCH2CH2, CHOCH2CHO), 1.53 (s, 3 H, CH3), 1.5–1.36 (m, 2 413.2502.
H, CH2CH2CHO), 1.31 (s, 3 H, CH3) ppm. 13C NMR (CDCl3,
(3R,5R,6R)-3-(tert-Butyldimethylsilyloxy)deca-1,9-diene-5,6-diol
75 MHz): δ = 139.1, 138.4, 128.2, 128.0, 127.3, 114.9, 112.4, 106.2,
84.2, 80.5, 80.1, 77.0, 73.6, 34.1, 31.0, 29.5, 27.2, 26.2 ppm. MS
(ESI): m/z = 341 [M + Na]+. HRMS (ESI): calcd. for C19H26O4Na
[M + Na]+ 341.1728; found 341.1727.
(5): Small pieces of sodium metal (0.12 g, 5.34 mmol) were added
to a stirred solution of naphthalene (0.91 g, 7.12 mmol) in THF
(20 mL) at room temperature and the reaction was stirred until the
sodium metal had completely dissolved. The resulting dark green
solution of sodium naphthalinide was cooled to –25 °C and TBS
ether 10 (1.39 g, 3.56 mmol) was added dropwise in dry THF
(10 mL). The resulting reaction mixture was stirred at –25 °C for
20 min. After completion (monitored by TLC), the reaction was
quenched with a saturated NH4Cl solution. The organic layer was
separated and the aqueous layer was extracted with ethyl acetate
(3ϫ40 mL). The combined organic layers were washed with brine,
dried with Na2SO4, concentrated, and purification of the crude
product by silica gel column chromatography using ethyl acetate
and hexane (8%) afforded compound 5 (0.95 g, 89%) as a colorless
(3R,5R,6R)-6-(Benzyloxy)deca-1,9-diene-3,5-diol (9): A 60% acetic
acid solution (10 mL) and catalytic conc. H2SO4 were added to
benzylated compound 8 (1.77 g, 5.56 mmol) and the mixture was
stirred at 55 °C. After 6 h, the reaction mixture was diluted with
ethyl acetate and neutralized with a saturated NaHCO3 solution.
The organic layer was separated and the aqueous layer washed with
ethyl acetate (4ϫ30 mL). The combined organic layers were dried
with Na2SO4, concentrated, and purified by silica gel column
chromatography using ethyl acetate and hexane (18%) to afford the
lactol (1.3 g, 90%) as a white solid.
liquid. [α]2D8 = –3.3 (c = 1.0, CHCl ). IR (CHCl ): ν = 3410, 3079,
˜
3
3
2929, 1641, 1064 cm–1. 1H NMR (CDCl3, 200 MHz): δ = 5.98–5.70
(m, 2 H, 2 CH2=CH), 5.35–4.92 (m, 4 H, 2 CH=CH2), 4.61–4.48
(m, 1 H, CH2CHOSi), 3.81–3.70 (m, 1 H, CHOHCHOHCH2),
3.68–3.62 (m, 1 H, CH2CHOHCHOH), 3.35 (br. s, 1 H, CHOH),
2.43 (br. s, 1 H, CHOH), 2.30–2.05 (m, 2 H, =CHCH2CH2), 1.97–
1.78 (m, 1 H, CHOHCH2CHOSi), 1.67–1.48 (m, 3 H, CHOHCH2-
CHOSi, CH2CH2CHOH), 0.93 (s, 9 H, 3 CH3), 0.12 (s, 3 H,
SiCH3), 0.09 (s, 3 H, SiCH3) ppm. 13C NMR (CDCl3, 50 MHz): δ
= 139.9, 138.4, 114.8, 96.1, 74.0, 72.3, 70.9, 39.7, 32.7, 29.9, 25.8,
18.1, –4.6, –5.2 ppm. MS (ESI): m/z = 323 [M + Na]+. HRMS
(ESI): calcd. for C16H32O3Na Si [M + Na]+ 323.2018; found
323.2019.
nBuLi (4.0 mL, 10.0 mmol) was added dropwise to a stirred solu-
tion of methyltriphenylphosphonium bromide (5.35 g, 15.0 mmol)
in THF (40 mL) at –10 °C. After stirring the reaction for 1 h, the
hemiacetal (1.39 g, 5.0 mmol) was added in THF (10 mL) to the
reaction mixture –10 °C. Stirring was continued for 12 h at room
temperature. The reaction was quenched with a saturated NH4Cl
solution. The organic layer was separated and the aqueous layer
extracted with ethyl acetate (2ϫ 40 mL). The combined organic
layers were dried with Na2SO4, concentrated, and the crude puri-
fied by silica gel column chromatography using ethyl acetate and
hexane (10%) to obtain compound 9 (1.2 g, 87%) as a viscous li-
quid. [α]2D7 = –17.2 (c = 1.0, CHCl ). IR (KBr): ν = 3421, 3081,
˜
3
2936, 1644, 1452, 1078 cm–1. 1H NMR (CDCl3, 300 MHz): δ =
7.36–7.26 (m, 5 H, Ph), 5.93–5.7 (m, 2 H, CHOHCH=CH2,
CH2=CHCH2), 5.31–4.93 (m, 4 H, 2 CH=CH2), 4.56 (ABq, J =
11.33, 33.9 Hz, 1 H, OCH2Ph), 4.40 (m, 1 H, CH2CHOHCH=),
3.88 (m, 1 H, CHOCHOHCH2), 3.35–3.39 (q, J = 6.04 Hz, 1 H,
CH2CHOCHOH), 2.6 (br. s, 1 H, CHOH), 2.19–2.10 (m, 2 H,
=CHCH2 CH2 ), 1.79–1.54 (m, 4 H, CHOHCH2 CHOH,
CH2CH2CHO) ppm. 13C NMR (CDCl3, 75 MHz): δ = 140.6,
138.2, 128.4, 127.8, 114.9, 114.2, 81.7, 72.5, 70.0, 69.7, 38.8, 29.3,
29.2 ppm. MS (ESI): m/z = 299 [M + Na]+. HRMS (ESI): calcd.
for C17H24O3Na [M + Na]+ 299.1623; found 299.1638.
[(2R,2ЈR,4R,5R,5ЈR)-5,5Ј-Bis(chloromercuriomethyl)octahydro-2,2Ј-
bifuran-4-yloxy](tert-butyl)dimethylsilane (3) and [(2R,2ЈR,4R,
5R,5ЈS)-5,5Ј-Bis(chloromercuriomethyl)octahydro-2,2Ј-bifuran-4-
yloxy](tert-butyl)dimethylsilane (4): Hg(OAc)2 (1.98 g, 7.2 mmol)
was added to a stirred solution of compound 5 (0.9 g, 3.0 mmol)
in CH2Cl2 (30 mL) at room temperature and the mixture was
stirred for 1 h. After completion (monitored by TLC), the reaction
was quenched with brine and stirred for 30 min. The reaction mix-
ture was extracted with CH2Cl2 (2ϫ25 mL), dried with Na2SO4,
concentrated, and purification of the crude by silica gel column
chromatography using ethyl acetate and hexane (15%) furnished
second eluted trans isomer 3 (1.78 g) and first eluted cis isomer 4
(199 mg) as white solids in a 9:1 ratio. Upper spot (cis): [α]3D2 = –5.6
(3R,5R,6R)-6-(Benzyloxy)-3-(tert-butyldimethylsilyloxy)deca-1,9-
dien-5-ol (10): 2,6-Lutidine (0.6 mL, 5.21 mmol) and TBDMSOTf
(1.0 mL, 4.34 mmol) were added to a solution of compound 9
(1.2 g, 4.34 mmol) in CH2Cl2 (25 mL) at –78 °C. The reaction was
stirred at 0 °C for 2 h. After completion (monitored by TLC), the
reaction was quenched with a saturated NaHCO3 solution and ex-
(c = 1.0, CHCl ). IR (CHCl ): ν = 2935, 1079 cm–1 1H NMR
.
˜
3
3
(CDCl3, 200 MHz): δ = 4.43–4.24 (m, 3 H, CHOCHO, CHOSi),
4.02–3.80 (m, 2 H, HgCH2CHO, HgCH2CHOSi), 2.49–2.12 (m, 4
H, 2 ClHgCH2), 2.09–1.80 (m, 6 H, 3 CH2 in THF rings), 0.94 (s,
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Synthesis of an Unsymmetrical Bis-Tetrahydrofuran Ring System
9 H, 3 CH3), 0.12 (s, 6 H, 2 CH3) ppm. 13C NMR (CDCl3,
200 MHz): δ = 96.2, 81.1, 81.0, 80.1, 78.4, 73.5, 39.2, 39.0, 35.3,
30.3, 28.1, 26.3, 18.5, –4.0, –4.4 ppm. MS (ESI): m/z = 795 [M +
2 H, CH=CH2), 4.69 (m, 1 H, CH2CHOCHOO), 3.95–3.88 (dt, J
= 3.0, 8.3 Hz, 1 H, CH2CHOCHOH), 3.76–3.68 (dt, J = 3.8,
8.3 Hz, 1 H, CHOCHOHCH2), 2.31–1.91 (m, 4 H, CHCH2CH2,
Na]+. HRMS (ESI): calcd. for C16H30O3NaSiCl2Hg2 [M + Na]+ CHOCH2CHO), 1.58–1.38 (m, 8 H, 2 CH3, CH2CH2CHOH) ppm.
795.0651; found 795.0620. Lower spot (trans): [α]3D2 = –10.6 (c =
1.0, CHCl3). 1H NMR (CDCl3, 200 MHz): δ = 4.51–3.94 (m, 5 H,
4 CHO, CHOSi), 2.39–2.15 (m, 6 H, 2 ClHgCH2, 1 CH2 of THF
rings), 1.88–1.72 (m, 2 H, 1 CH2 of THF rings), 1.70–1.48 (m, 2
H, 1 CH2 of THF rings), 0.96 (s, 9 H, 3 CH3), 0.15 (s, 6 H, 2
CH3) ppm. 13C NMR (CDCl3, 50 MHz): δ = 96.2, 80.7, 80.2, 78.5,
73.7, 38.6, 38.2, 36.5, 30.2, 29.4, 28.4, 26.3, 18.5, –4.3 ppm. MS
(ESI): m/z = 795 [M + Na]+. HRMS (ESI): calcd. for C16H30O3Na-
SiCl2Hg2 [M + Na]+ 795.0651; found 795.0678.
13C NMR (CDCl3, 75 MHz): δ = 138.3, 114.9, 112.6, 106.0, 84.0,
80.8, 71.4, 32.4, 31.4, 29.8, 27.3, 26.3 ppm.
(3R,5R,6R)-5-[(S)-1-(Benzyloxy)pent-4-enyl]-2,2-dimethyltetra-
hydrofuro[2,3-d][1,3]dioxole: [α]2D9 = +9.3 (c = 1.0, CHCl3). 1H
NMR (CDCl3, 300 MHz): δ = 7.31–7.20 (m, 5 H, Ph), 5.81 (m, 1
H, CH=CH2), 5.7 (d, J = 3.8 Hz, 1 H, OCHO), 5.04–4.9 (m, 2 H,
CH=CH2), 4.68 (m, 1 H, CH2CHOCHOO), 4.55 (ABq, J = 11.3,
12.8 Hz, 2 H, OCH2Ph), 4.0–3.93 (dt, J = 3.8, 8.3 Hz, 1 H,
CH2CHOCHO), 3.70 (m, 1 H, CHOCHOCH2), 2.29–2.03 (m, 4 H,
= C H C H 2 C H 2 , C H O C H 2 C H O ) , 1 . 8 5 – 1 . 6 2 ( m , 2 H ,
CH2CH2CHO), 1.46 (s, 3 H, CH3), 1.28 (s, 3 H, CH3) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 138.7, 138.4, 128.3, 127.8, 127.5,
114.5, 112.1, 106.3, 81.8, 80.6, 79.1, 72.4, 33.4, 30.4, 28.6, 27.0,
26.0 ppm.
(3R,5R,6S)-6-(Benzyloxy)deca-1,9-diene-3,5-diol: [α]3D0 = –9.1 (c =
1.5, CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 7.33–7.23 (m, 5 H,
Ph), 5.89 (m, 1 H, CHOHCH=CH2), 5.75 (m, 1 H, CH2=CHCH2),
5.30–4.92 (m, 4 H, 2 CH=CH2), 4.57 (ABq, J = 11.7, 24.4 Hz, 1
H, OCH2Ph), 4.42 (m, 1 H, CH2CHOHCH=), 4.09–4.05 (dt, J =
2.9, 10.7 Hz, 1 H, CHOCHOHCH2), 3.39–3.35 (dt, J = 3.9, 8.8 Hz,
1 H, CH2CHOCHOH), 2.31–2.02 (m, 2 H, =CHCH2CH2), 1.76–
[(2R,2ЈR,4R,5S,5ЈR)-4-(tert-Butyldimethylsilyloxy)octahydro-2,2Ј-bi-
furan-5,5Ј-diyl]dimethanol (3a): O2 was bubbled through a long sy-
ringe needle into a stirred solution bis-mercurated compound 3
(0.2 g, 0.26 mmol) in dry DMF (5 mL) for 10 min. In an another
flask, a suspension of NaBH4 (0.03 g, 0.78 mmol) in DMF (2 mL)
was prepared and O2 was passed through it for 20 min. The former
reaction mixture was added dropwise to the latter through a can-
nula over 10 min. The reaction mixture was diluted with ethyl acet-
ate, filtered, and concentrated. DMF was removed under reduced
pressure and the resulting crude brown oily material was purified
by silica gel column chromatography using ethyl acetate and hexane
(85%) to afford diol 3a (0.069 g, 81%) as a colorless liquid. [α]3D0
=
1
–8.5 (c = 1.0, CHCl ). IR (CHCl ): ν = 3403, 2958, 1074 cm–1. H 1.66 (m, 2 H, CHOHCH2 C HO H) , 1 . 5 6– 1. 48 (m, 2 H,
˜
3
3
NMR (CDCl3, 300 MHz): δ = 4.60 (br. s, 1 H, CH2OH), 4.46 (br. CH2CH2CHO) ppm. 13C NMR (CDCl3, 75 MHz): δ = 140.7,
s, 1 H,CH2OH), 4.35–3.99 (m, 5 H, 4 CHO, CHOSi), 3.97–3.81 138.2, 128.3, 127.7, 127.6, 114.8, 114.2, 81.4, 71.9, 69.9, 68.8, 37.6,
(m, 2 H, CH2OH), 3.78–3.68 (dd, J = 2.8, 11.7 Hz, 1 H, CH2OH), 29.6, 28.0 ppm.
3.56–3.47 (dd, J = 5.3, 11.9 Hz, 1 H, CH2OH), 2.45–2.27 (m, 4 H,
(3R,5R,6S)-6-(Benzyloxy)-3-(tert-butyldimethylsilyloxy)deca-1,9-
2 CH2 of THF rings), 2.07–1.97 (m, 2 H, CH2 of THF rings), 1.25
(s, 9 H, 3 CH3), 0.07 (s, 6 H, 2 CH3) ppm. 13C NMR (CDCl3,
75 MHz): δ = 81.5, 81.1, 80.4, 80.0, 79.8, 64.3, 62.6, 38.4, 37.6,
33.8, 24.6, 19.0, –5.1, –5.3 ppm. MS (ESI): m/z = 355 [M + Na]+.
HRMS (ESI): calcd. for C16H32O5Na Si [M + Na]+ 355.2354;
found 355.2378.
dien-5-ol: [α]2D8 = –7.5 (c = 1.8, CHCl3). 1H NMR (CDCl3,
300 MHz): δ = 7.34–7.22 (m, 5 H, Ph), 5.89–5.69 (m, 2 H, 2
CH2=CH), 5.26–4.89 (m, 4 H, 2 CH=CH2), 4.57 (ABq, J = 11.3,
20.4 Hz, 2 H, OCH2Ph), 4.47 (m, 1 H, CH2CHOSi), 4.01–3.94 (dt,
J = 2.3, 8.3 Hz, 1 H, CHOCHOHCH2), 3.38–3.31 (dt, J = 3.8,
8.3 Hz, 1 H, CH2CHOCHOH), 2.76 (br. s, 1 H, CHOH), 2.27–2.01
(m, 2 H, =CHCH2CH2), 1.75–1.44 (m, 4 H, CHOHCH2CHOSi,
CH2CH2CHO), 0.92 (s, 9 H, 3 CH3), 0.09 (s, 3 H, SiCH3), 0.05 (s,
3 H, SiCH3) ppm. 13C NMR (CDCl3, 75 MHz): δ = 140.5, 138.6,
138.5, 128.3, 127.8, 127.5, 114.6, 114.2, 81.6, 72.2, 71.8, 69.2, 38.8,
29.6, 28.9, 25.8, 18.1, –4.5, –5.1 ppm.
(S)-1-[(3R,5R,6R)-2,2-Dimethyltetrahydrofuro[2,3-d]dioxol-5-yl]-
pent-4-en-1-ol (13): Silica-supported NaIO4 (19.6 g) was added to
a stirred solution of diol 11 (2.0 g, 9.8 mmol) in CH2Cl2 (70 mL)
and the mixture was stirred vigorously for 30 min at room tempera-
ture. After completion (monitored by TLC), the reaction mixture
was filtered off and the solvent was evaporated under reduced pres-
sure. The crude aldehyde (1.64 g, 97%) obtained was used for the
Grignard reaction without further purification.
(3R,5R,6R)-3-(tert-Butyldimethylsilyloxy)deca-1,9-dien-5,6-diol:
[α]2D6 = –3.0 (c = 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz): δ =
5.92–5.73 (m, 2 H, 2 CH2=CH), 5.30–4.92 (m, 4 H, 2 CH=CH2),
4.56 (m, 1 H, CH2CHOSi), 3.83–3.54 (m, 2 H, CHOHCHOHCH2,
CH2CHOHCHOH), 2.34–2.03 (m, 2 H, =CHCH2CH2), 1.86–1.37
(m, 4 H, CHOHCH2CHOSi, CH2CH2CHOH), 0.92 (s, 9 H, 3
CH3), 0.11 (s, 3 H, SiCH3), 0.07 (s, 3 H, SiCH3) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 139.5, 138.3, 114.8, 114.7, 73.5, 72.4, 71.3,
36.1, 31.0, 30.1, 25.7, 18.0, –4.7, –5.3 ppm.
A solution of homoallyl bromide (1.45 mL, 14.25 mmol) was added
dropwise to a suspension of Mg metal pieces (0.68 g, 28.5 mmol)
in anhydrous diethyl ether (25 mL) and the mixture was stirred for
30 min at room temperature. CuCN (42 mg, 0.475 mmol) was
added at once, which resulted in an immediate color change to
dark brown. After cooling to –20 °C, the crude aldehyde (1.63 g,
9.5 mmol) in diethyl ether (15 mL) was added dropwise. The reac-
tion mixture was stirred for 30 min at –20 °C and quenched by the
slow addition of a saturated NH4Cl solution. The resulting suspen-
sion was stirred for another 30 min. The organic layer was sepa-
rated and the aqueous layer extracted with ethyl acetate (3ϫ 40
mL). The combined organic layers were dried with Na2SO4, con-
centrated, and purified by silica gel column chromatography using
ethyl acetate and hexane (8%) to afford upper isomer 7 (minor)
(0.411 g) and further elution afforded lower isomer 13 (major;
[(2R,2ЈS,4R,5R,5ЈR)-5,5Ј-Bis(chloromercuriomethyl)octahydro-2,2Ј-
bifuran-4-yloxy](tert-butyl)dimethylsilane (15): Upper spot (cis).
1
[α]2D9 = –16.3 (c = 1.0, CHCl3). H NMR (CDCl3, 300 MHz): δ =
4.48 (m, 1 H, CHO), 4.33–4.19 (m, 2 H, 2 CHO), 4.09–3.96 (m, 2
H, 2 CHO), 2.53–2.22 (m, 4 H, 2 ClHgCH2), 2.18–2.10 (m, 2 H,
CH2 of THF rings), 1.89–1.78 (m, 2 H, CH2 of THF rings), 1.68–
1.46 (m, 2 H, CH2 of THF rings), 0.95 (s, 9 H, 3 CH3), 0.13 (s, 3
H, SiCH3), 0.12 (s, 3 H, SiCH3) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 81.0, 80.9, 80.4, 78.8, 73.8, 39.4, 39.1, 36.6, 30.0, 26.2, 29.7,
18.4, –4.5, –4.5 ppm.
1.639 g) as colorless liquids in a 1:4 ratio. Major isomer: [α]2D6
=
1
–5.3 (c = 1.4, CHCl3). H NMR (CDCl3, 300 MHz): δ = 5.84 (m, [(2R,2ЈS,4R,5R,5ЈS)-5,5Ј-Bis(chloromercuriomethyl)octahydro-2,2Ј-
1 H, CH=CH2), 5.76 (d, J = 3.8 Hz, 1 H, OCHO), 5.08–4.93 (m, bifuran-4-yloxy](tert-butyl)dimethylsilane (14): Lower spot (trans).
Eur. J. Org. Chem. 2010, 6263–6268
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6267

D. K. Mohapatra et al.
FULL PAPER
[α]2D6 = +2.6 (c = 0.8, CHCl3). 1H NMR (CDCl3, 300 MHz): δ =
4.42 (m, 1 H, CHO), 4.34–4.19 (m, 2 H, 2 CHO), 4.14 (m, 1 H,
CHO), 3.94 (m, 1 H, CHO), 2.34–2.08 (m, 6 H, 2 ClHgCH2, 1 CH2
of THF rings), 1.88–1.75 (m, 2 H, 1 CH2 of THF rings), 1.60–1.41
(m, 2 H, 1 CH2 of THF rings), 0.95 (s, 9 H, 3 CH3), 0.14 (s, 6 H,
2 SiCH3) ppm. 13C NMR (CDCl3, 75 MHz): δ = 80.5, 80.2, 80.0,
78.4, 73.6, 38.5, 38.1, 36.4, 29.6, 28.1, 26.1, 18.3, –4.4, –4.5 ppm.
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Acknowledgments
P. R. N. and D. S. R. thank the Council of Scientific and Industrial
Research (CSIR), New Delhi, India for the award of research fel-
lowships. We thank Dr. J. S. Yadav, Director, Indian Institute of
Chemical Technology (CSIR), for his constant support and encour-
agement. D. K. M. thanks the CSIR, New Delhi, for a research
grant (INSA Young Scientist Award).
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Received: June 16, 2010
Published Online: September 27, 2010
6268
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Eur. J. Org. Chem. 2010, 6263–6268