Stereoselective synthesis of cis-fused perhydrofuro[2,3-b]furan derivatives from sugar-derived allyl vinyl ethers

Article abstract of DOI:10.1002/ejoc.201200898

A stereoselective methodology has been developed for the construction of cis-fused perhydrofuro[2,3-b]furans, via 3-C-branched glycal derivatives, involving Claisen rearrangement of sugar-derived allyl vinyl ethers, followed by a one-pot ozonolysis and acid-mediated acetalization. The methodology was used for the stereoselective synthesis of the P₂ ligand in the recently FDA approved HIV protease inhibitor darunavir (Prezista). The methodology was also successfully used for the synthesis of cis-fused perhydro-5-oxofuro[2,3-b] furan derivatives.

Full text of DOI:10.1002/ejoc.201200898

Job/Unit: O20898
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Date: 24-09-12 17:04:34
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FULL PAPER
DOI: 10.1002/ejoc.201200898
1
Stereoselective Synthesis of cis-Fused Perhydrofuro[2,3-b]furan Derivatives
from Sugar-Derived Allyl Vinyl Ethers
Perali Ramu Sridhar,*[a] Gadi Madhusudhan Reddy,[a] and Kalapati Seshadri[a]
Keywords: Oxygen heterocycles / Carbohydrates / Cyclization / Sigmatropic rearrangement / Chiral pool
A stereoselective methodology has been developed for the
construction of cis-fused perhydrofuro[2,3-b]furans, via 3-C-
branched glycal derivatives, involving Claisen rearrange-
ment of sugar-derived allyl vinyl ethers, followed by a one-
pot ozonolysis and acid-mediated acetalization. The method-
ology was used for the stereoselective synthesis of the P2 li-
gand in the recently FDA approved HIV protease inhibitor
darunavir (Prezista). The methodology was also successfully
used for the synthesis of cis-fused perhydro-5-oxofuro[2,3-b]-
furan derivatives.
6
11
cially of marine origin, show extremely high activity against
microorganisms and enzymes. In this context, several bioac-
tive natural products contain a cis-fused furo[2,3-b]furan
ring system as an essential component of their architecture.
Such compounds include aflatoxin,[2] sterigmatocystin,[3]
rhyacophiline,[4] clerodin,[5] and asteltoxin,[6] etc. (Figure 1).
On the other hand, the cis-fused perhydro-5-oxofuro[2,3-
b]furan system is also an important structural unit present
in a number of biologically active spongiane diterpenoids.[7]
Such structures include norrisolide[8] (which induces
irreversible vesiculation of Golgi membranes),[9] macfarlan-
din C,[10] spongionellin,[11] dendrillolides A and E,[12] and
cheloviolenes A and B,[13] etc. (Figure 2). Surprisingly, to
the best of our knowledge, the total syntheses of none of
the above-named spongiane diterpenoids was reported, ex-
cept for norrisolide.[14] More recently, sugar-fused γ-butyro-
lactones have been shown to be potential GABAA inhibi-
tors.[15] Despite their wide occurrence, very few methods are
available for the stereoselective synthesis of cis-fused per-
Introduction
16
21
Carbohydrates, the most naturally abundant molecules in
the chiral pool, have played a pivotal role in the enantios-
pecific synthesis of many intricate biologically active molec-
ular frameworks.[1] Fused-ring systems are an integral part
of numerous natural products, and they confer a conforma-
tion on the molecules that can have consequences for their
biological properties. Many linearly fused molecules, espe-
26
31
36
41
Figure 1.Naturalproductspossessingacis-fusedperhydrofuro[2,3-b]-
furan subunit.
[a] School of Chemistry, University of Hyderabad,
Hyderabad 500046, India
Fax: +91-40-2301-2460
E-mail: prssc@uohyd.ernet.in
Homepage: chemistry.uohyd.ernet.in/~prs/index.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200898.
Figure 2. Natural products possessing a cis-fused perhydro-5-oxo-
furo[2,3-b]furan subunit.
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P. R. Sridhar, G. M. Reddy, K. Seshadri
FULL PAPER
hydrofuro[2,3-b]furan[16] and perhydro-5-oxofuro[2,3-b]- as single diastereomers in good yields. Reduction of the al-
furan[17,14b] frameworks. As part of our continuing efforts dehydes to alcohols gave glycal-derived 3-C-branched
towards the development of stereoselective methods for the alcohols 10, 14, 18, and 22. A one-pot ozonolysis and acid-
construction of sugar-fused bicycles and spirocycles,[18] we catalyzed acetalization of these alcohols provided the perhy-
report in this paper a stereoselective synthesis of carbo- drofuro[2,3-b]furan derivatives, the so-called bis-THF moie-
hydrate-derived perhydrofuro[2,3-b]furan derivatives, start- ties, 11, 15, 19, and 23, as single diastereomers (Table 1,
76
81
86
91
96
46
ing from sugar-derived allyl vinyl ethers.
entries 1–4). Allyl vinyl ether 24, in which 4-OH was pro-
tected with a benzyl group, also underwent Claisen re-
arrangement smoothly, and provided 3-C-branched alde-
hyde derivative 25. Reduction of aldehyde 25 to alcohol 26,
Results and Discussion
Ferrier rearrangement[19] of 3,4,6-tri-O-acetyl-d-glucal followed by ozonolysis and cyclization, provided bis-THF
51
56
61
66
71
(1) with 2-(phenylselenyl)ethanol as a nucleophile provided derivative 27 as a single diastereomer (Table 1, entry 5).
2,3-unsaturated glycoside 2,[20] which, upon oxidation with
The important role played by the perhydrofuro[2,3-b]-
NaIO4, gave selenone glycoside 3. Base-mediated thermal furan bicyclic system as an effective P2 ligand in HIV prote-
fragmentation of 3 provided the required allyl vinyl ether ase inhibitors is well documented.[22] The significance of the
derivative 4 in good yield. Claisen [3,3]-sigmatropic re- current methodology was further increased by synthesizing
arrangement of compound 4 effected by heating in nitro- (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol 30,[23] the im-
benzene/N,N-dimethylaniline provided the expected 3-C- portant bis-THF moiety present in the HIV protease inhibi-
branched glucal derivative (i.e., 5). Selective reduction of tor darunavir (Prezista)[24] as well as in brecanavir.[25] Very
the aldehyde functional group using NaBH4 in ethanol at few stereoselective synthetic methods have been reported
5 °C gave alcohol 6. Ozonolysis of the olefin in alcohol 6 to for the preparation of bis-THF 30. To this end, deprotec-
give the dialdehyde, followed by subsequent acid-mediated tion of the acetate in 23 gave alcohol 28, which, upon Mit-
acetalization in one pot, provided perhydrofuro[2,3-b]furan sunobu inversion provided compound 29. Hydrolysis of this
derivative 7 in excellent yield, and with very high diastereo- ester provided target molecule 30 as a single diastereomer
selectivity (Scheme 1). The stereochemistry at the bridge- (Scheme 2).
head position was assigned by observing the characteristic
coupling constant (3J = 5.0 Hz) of an acetal hydrogen as a to the corresponding carboxylic acid, followed by a one-pot
doublet, as well as by a NOESY experiment. ozonolysis and acid-mediated cyclization would provide the
Furthermore, we envisaged that oxidation of aldehyde 5 101
After the successful preparation of 7, the protocol was cis-fused perhydro-5-oxofuro[2,3-b]furan framework. Thus,
extended to synthesize a number of perhydrofuro[2,3-b]- aldehyde 5 was oxidized to acid 31 under Pinnick oxi-
furan systems. Thus, allyl vinyl ethers 8, 12, 16, and 20, dation[26] conditions. Ozonolysis of compound 31 followed 106
synthesized from the corresponding glycals 3,4,6-tri-O- by cyclization in AcOH/MeOH (3:2) provided the expected
acetyl-d-galactal, 3,4-di-O-acetyl-l-rhamnal, 3,4-di-O- perhydro-5-oxofuro[2,3-b]furan derivative (i.e., 32), but in
acetyl-l-arabinal and 3,4-di-O-acetyl-d-arabinal, respec- very low yield (18%). Optimized reaction conditions of
tively,[21] upon Claisen rearrangement, provided the 3-C- catalytic pTsOH in CH2Cl2 resulted in an improvement in
branched aldehyde derivatives 9, 13, 17, and 21, respectively the yield to 48% over three steps (Scheme 3).
111
Scheme 1. Synthesis of glucal-derived cis-fused perhydrofuro[2,3-b]furan. Reagents and conditions: a) PhSeCH2CH2OH, BF3·OEt2, benz-
ene, 0–25 °C, 5 min, 88%; b) NaIO4, NaHCO3, MeOH/H2O (6:1), 1 h; c) DIPA, benzene, reflux, 30 min, 55% over two steps; d) N,N-
dimethylaniline, nitrobenzene, 160 °C, 3 h, 85%; e) NaBH4, EtOH, 5 °C, 30 min, 95%; f) O3, Me2S, CH2Cl2, –78 °C; g) CH3COOH/
MeOH (3:2), reflux, 3 h, 62% over two steps (DIPA = diisopropylamine).
2
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Synthesis of Perhydrofuro[2,3-b]furans
Table 1. Synthesis of cis-fused perhydrofuro[2,3-b]furan derivatives. 13, 17, 21, and 25 were oxidized to the corresponding carb-
oxylic acids (i.e., 33, 35, 37, 39, and 41, respectively). All
the acid derivatives were converted into the corresponding 116
cis-fused perhydro-5-oxofuro[2,3-b]furans (i.e., 34, 36, 38,
40, and 42) with high stereoselectivity and in good yields
(Table 2).
Table 2. Synthesis of cis-fused perhydro-5-oxofuro[2,3-b]furan de-
rivatives.
[a] Isolated yields after column chromatography.
Scheme 2. Stereoselective synthesis of (3R,3aS,6aR)-hexahy-
drofuro[2,3-b]furan-3-ol. a) K2CO3, MeOH room temp., 1 h, 97%;
b) Ph3P, DIAD, PNBA, THF, –10 °C to r.t., 99%; c) NaOMe,
MeOH, 82%. DIAD = diisopropyl azodicarboxylate, PNBA = p-
nitrobenzoic acid.
[a] Yield represents crude product obtained after oxidation.
[b] Yield represents pure compound isolated by column chromatog-
raphy after three steps.
Conclusions
In conclusion, an efficient and stereoselective protocol 121
for the synthesis of cis-fused perhydrofuro[2,3-b]furan de-
rivatives was developed by implementing a Claisen re-
arrangement of 2,3-unsaturated vinyl glycosides and a one-
pot oxidative acetalization as key steps. The generality of
the reaction was investigated by synthesizing a number of 126
Scheme 3. Synthesis of glucal-derived cis-fused perhydro-5-oxo-
furo[2,3-b]furan. a) NaH2PO4·2H2O, NaClO2, 2-methyl-2-butene,
tBuOH, room temp., 30 min; b) (i) O3, Me2S, CH2Cl2, –78 °C.
(ii) pTsOH, CH2Cl2, reflux, 10 h, 48% over three steps.
This methodology could also be used for the synthesis of bis-THF derivatives. The methodology was also successfully
several 3-C-branched carboxylic acids. Thus, aldehydes 9, extended to construct several cis-fused perhydro-5-oxo-
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P. R. Sridhar, G. M. Reddy, K. Seshadri
FULL PAPER
(3R,6R)-6-(Vinyloxy)-3,6-dihydro-2H-pyran-3-yl Acetate (16) and
(3S,6S)-6-(Vinyloxy)-3,6-dihydro-2H-pyran-3-yl Acetate (20): Yield
68% for 16 and 73% for 20. Rf = 0.70 (silica gel, 20% EtOAc in
hexanes). 1H NMR (400 MHz, CDCl3): δ = 6.47 (dd, J = 6.4,
14.0 Hz, 1 H), 6.15 (dd, J = 5.2, 10.0 Hz, 1 H), 6.06 (dd, J = 3.2,
10.4 Hz, 1 H), 5.30 (d, J = 3.2 Hz, 1 H), 4.96 (dd, J = 2.8, 5.2 Hz,
1 H), 4.55 (dd, J = 1.6, 14.0 Hz, 1 H), 4.19 (dd, J = 2.6, 6.8 Hz, 1
H), 4.13 (dd, J = 2.8, 13.2 Hz, 1 H), 3.87 (dd, J = 1.2, 13.2 Hz, 1
H), 2.06 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.3,
furo[2,3-b]furan derivatives. The application of this method
to the stereoselective total synthesis of natural products is
131 in progress.
191
196
201
Experimental Section
General Methods: All reactions were carried out under an inert
atmosphere with dry solvents under anhydrous conditions unless
otherwise stated. Dichloromethane, methanol, and benzene were
intially dried and stored over molecular sieves (4 Å). TLC was run
on silica gel 60 F254 (Merck) plates, and the spots were detected
by staining with H2SO4 in methanol (5%, v/v) or phosphomolybdic
acid in ethanol (5%, w/v) and heating. Silica gel (100–200 mesh)
was used as the stationary phase for column chromatography.
NMR spectra were recorded at 25 °C with Bruker Avance III 400
149.0, 129.3, 125.7, 92.0, 91.7, 62.7, 61.6, 20.9 ppm. IR (neat): ν =
˜
3445, 2920, 1726, 1364, 1232, 1078, 739 cm–1. [α]2D5 = –128.6 (c =
0.60, CHCl3) for 16 and +130.4 (c = 0.67, CHCl3) for 20. HRMS
(ESI): calcd. for C9H12O4Na [M + Na]+ 207.0364; found 207.0364.
136
141
146
(3S,6R)-3-(Benzyloxy)-6-(vinyloxy)-3,6-dihydro-2H-pyran
(24):
Yield. 72%. Rf = 0.70 (silica gel, 15% EtOAc in hexanes). 1H NMR
(400 MHz, CDCl3): δ = 7.37–7.30 (m, 5 H), 6.49 (dd, J = 6.4,
14.0 Hz, 1 H), 6.18 (qd, J = 1.2, 2.8, 10.4 Hz, 1 H), 5.83 (td, J =
2.0, 10.4 Hz, 1 H), 5.23 (d, J = 0.8 Hz, 1 H), 4.66–4.54 (m, 3 H),
4.20 (dd, J = 1.2, 6.4 Hz, 1 H), 4.17–4.13 (m, 1 H), 3.87 (ddd, J =
1.2, 5.6, 10.8 Hz, 1 H), 3.79 (d, J = 9.6 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 149.2, 137.9, 132.4, 128.4, 127.8, 127.6,
1
1
(400 MHz for H and 100 MHz for 13C) or 500 (500 MHz for H
and 125 MHz for 13C) instruments in CDCl3, using residual CHCl3
206
211
(δH = 7.26 ppm) as internal standard for 1H, and CDCl3 (δC
=
77.0 ppm) as internal standard for 13C. Chemical shifts are given
in δ (ppm) and coupling constants (J) in Hz. IR spectra were re-
corded with a JASCO FTIR-5300 instrument. High resolution
mass spectra were recorded with a Bruker maXis ESI-TOF spec-
trometer. A Welsbach Ozonizer was used for all ozonolysis reac-
tions.
125.5, 93.2, 91.5, 71.0, 69.3, 60.9 ppm. IR (neat): ν = 3032, 2922,
˜
2885, 1639, 1454, 1392, 1317, 1168, 1099, 1024, 912, 839, 734,
698 cm–1. [α]2D5 = +53.0 (c = 1.0, CHCl3). HRMS (ESI): calcd. for
C14H16O3Na [M + Na]+ 255.0997; found 255.0997.
151
156
161
General Procedure for the Oxidation and Thermal Fragmentation of
2-(Phenylselenenyl)ethyl Glycosides To Obtain Vinyl Glycosides 4,
8,12,16,20and24:Sodiumperiodate(1.5 equiv.)andsodiumhydrogen
carbonate (1.1 equiv.) were added to a solution of a 2-(phenylse-
lenenyl)ethyl glycoside 2 (2 mmol) in methanol/water (6:1). After
complete trasformation of the starting material (1 h), the suspen-
sion was filtered through a plug of Celite 545, and the filtrate was
concentrated in vacuo. The crude material was dissolved in ethyl
acetate and washed with water, and the organic phase was concen-
trated in vacuo. The crude selenoxide thus obtained was dissolved
in benzene (20 mL), diisopropylamine (5 equiv.) was added, and
the mixture was heated at reflux for 30 min. After the reaction was
complete, the solvent was evaporated, and the crude product was
purified by column chromatography eluting with hexanes and ethyl
acetate to obtain pure vinyl glycoside in good yield.
General Procedure for the Claisen Rearrangement of Vinyl Glycos-
ides To Obtain 3-C-Branched Aldehydes 5, 9, 13, 17, 21, and 25:
N,N-Dimethylaniline (0.2 mL) was added to the vinyl glycoside 4,
8, 12, 16, 20 or 24 (2.4 mmol, 1 equiv.) in nitrobenzene (10 mL),
and the mixture was heated at 150–170 °C until the complete con-
sumption of starting material was observed (5–6 h). The resulting
solution was directly loaded onto a silica gel column, and the prod-
uct was purified eluting with hexanes and ethyl acetate to obtain
the 3-C-branched glycal derivative in good yield.
216
221
[(2R,3R,4S)-3-Acetoxy-4-(2-oxoethyl)-3,4-dihydro-2H-pyran-2-yl]-
methyl Acetate (9): Yield 65%. Rf = 0.40 (30% EtOAc in hexanes).
1H NMR (400 MHz, CDCl3): δ = 9.77 (s, 1 H), 6.41 (dd, J = 1.2,
6.0 Hz, 1 H), 4.83 (s, 1 H), 4.76–4.73 (m, 1 H), 4.21 (d, J = 6.0 Hz,
2 H), 4.08–4.05 (m, 1 H), 2.73–2.70 (m, 1 H), 2.61 (ddd, J = 1.6,
6, 17.2 Hz, 1 H), 2.51 (ddd, J = 1.2, 8.8, 17.2 Hz, 1 H), 2.08 (s, 3
H), 2.07 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 199.4,
170.6, 170.1, 142.9, 101.1, 70.3, 68.9, 62.5, 48.8, 29.9, 20.8,
226
166
171
176
[(2R,3R,6S)-3-Acetoxy-6-(vinyloxy)-3,6-dihydro-2H-pyran-2-yl]meth-
yl Acetate (8): Yield 65%. Rf = 0.70 (silica gel, 30% EtOAc in
hexanes). 1H NMR (400 MHz, CDCl3): δ = 6.50 (dd, J = 6.8,
14.0 Hz, 1 H), 6.22 (dd, J = 5.6, 10.0 Hz, 1 H) 6.08 (dd, J = 3.2,
10.0 Hz, 1 H), 5.38 (d, J = 3.2 Hz, 1 H), 5.07 (dd, J = 2.4, 5.6 Hz,
1 H), 4.59 (dd, J = 1.2, 14.0 Hz, 1 H), 4.36–4.32 (m, 1 H), 4.23 (s,
1 H), 4.22 (dd, J = 1.6, 5.6 Hz, 1 H), 2.08 (s, 3 H), 2.05 (s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 170.5, 170.2, 148.8, 129.2,
20.7 ppm. IR (neat): ν = 3368, 2918, 1741, 1651, 1373, 1232, 231
˜
1043 cm–1. [α]2D5 = +84.6 (c = 0.3, CHCl3). HRMS (ESI): calcd. for
C12H16O6Na [M + Na]+ 279.0845; found 279.0845.
(2S,3R,4R)-2-Methyl-4-(2-oxoethyl)-3,4-dihydro-2H-pyran-3-yl
Acetate (13): Yield 72%. Rf = 0.40 (20% EtOAc in hexanes). 1H
NMR (400 MHz, CDCl3): δ = 9.74 (t, J = 1.2 Hz, 1 H), 6.29 (dd,
J = 2.0, 6.4 Hz, 1 H), 4.93 (t, J = 5.6 Hz, 1 H), 4.57 (dd, J = 3.6,
6.4 Hz, 1 H), 4.06 (t, J = 6.4 Hz, 1 H), 3.10–3.04 (m, 1 H), 2.62
(ddd, J = 1.6, 7.2, 17.6 Hz, 1 H), 2.44 (ddd, J = 1.6, 6.4, 17.6 Hz,
1 H), 2.03 (s, 3 H), 1.25 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 200.2, 169.9, 142.5, 100.1, 70.9, 69.8, 45.2,
236
241
126.1, 92.9, 92.2, 67.3, 62.3, 62.3, 20.7, 20.7 ppm. IR (neat): ν =
˜
3366, 2924, 1736, 1645, 1510, 1458, 1371, 1230, 1049, 829,
756 cm–1. [α]2D5 = –140.8 (c = 0.5, CHCl3). HRMS (ESI): calcd. for
C12H16O6Na [M + Na]+ 279.0845; found 279.0845.
(2S,3R,6R)-2-Methyl-6-(vinyloxy)-3,6-dihydro-2H-pyran-3-yl Acet-
ate (12): Yield 74%. Rf = 0.30 (silica gel, 10% EtOAc in hexanes).
1H NMR (400 MHz, CDCl3): δ = 6.47 (dd, J = 6.4, 14.0 Hz, 1 H),
5.92 (d, J = 10.0 Hz, 1 H), 5.83 (td, J = 2.4, 10.4 Hz, 1 H), 5.24 (s,
1 H), 5.06 (dd, J = 1.6, 9.2 Hz, 1 H), 4.54 (dd, J = 1.6, 14.0 Hz, 1
H), 4.17 (dd, J = 1.2, 6.4 Hz, 1 H), 3.97–3.90 (m, 1 H), 2.06 (s, 3
26.9, 20.7, 16.8 ppm. IR (neat): ν = 3468, 2982, 2939, 1732, 1649,
˜
1377, 1238, 1051, 750 cm–1. [α]2D5 = –130.8 (c = 2.0, CHCl3). HRMS
181
186
(ESI): calcd. for C10H14O4Na [M + Na]+ 221.0790; found 221.0790.
(3R,4S)-4-(2-Oxoethyl)-3,4-dihydro-2H-pyran-3-yl Acetate (17) and
H), 1.20 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): (3S,4R)-4-(2-Oxoethyl)-3,4-dihydro-2H-pyran-3-yl Acetate (21): 246
δ = 170.3, 149.1, 130.6, 126.3, 93.4, 91.6, 70.4, 65.4, 20.9, 17.7 ppm. Yield 82% for 17 and 80% for 21. Rf = 0.50 (20% EtOAc in hex-
1
IR (neat): ν = 2982, 2934, 1743, 1641, 1375, 1236, 1101, 1033, 916,
anes). H NMR (400 MHz, CDCl3): δ = 9.76 (s, 1 H), 6.39 (dd, J
= 1.6, 6.0 Hz, 1 H), 4.80 (dd, J = 5.6, 8.0 Hz, 1 H), 4.65 (dd, J =
3.6, 6.0 Hz, 1 H), 3.96 (dd, J = 2.8, 11.2 Hz, 1 H) 3.88 (dd, J =
˜
842 cm–1. [α]2D5 = –98.2 (c = 1.0, CHCl3). HRMS (ESI): calcd. for
C10H14O4Na [M + Na]+ 221.0790; found 221.0790.
4
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Synthesis of Perhydrofuro[2,3-b]furans
251 6.6, 11.2 Hz, 1 H), 2.80 (d, J = 2.8 Hz, 1 H), 2.60 (dd, J = 1.2,
6.0 Hz, 1 H), 2.56 (dd, J = 1.2, 6.0 Hz, 1 H), 2.07 (s, 3 H) ppm.
(3R,4S)-4-(2-Hydroxyethyl)-3,4-dihydro-2H-pyran-3-yl Acetate (18)
and (3S,4R)-4-(2-Hydroxyethyl)-3,4-dihydro-2H-pyran-3-yl Acetate
13C NMR (100 MHz, CDCl3): δ = 199.9, 170.1, 143.7, 100.8, 69.2, (22): Yield 95% for 18 and 92% for 22. Rf = 0.5 (40% EtOAc in
1
64.0, 48.2, 30.4, 20.8 ppm. IR (neat): ν = 3430, 2876, 2728, 1736,
hexanes). H NMR (400 MHz, CDCl3): δ = 6.34 (d, J = 6.4 Hz, 1
H), 4.79 (s, 1 H), 4.65 (t, J = 4.8 Hz, 1 H), 3.90 (dd, J = 4.0,
11.6 Hz, 1 H), 3.84 (d, J = 11.2 Hz, 1 H), 3.73–3.61 (m, 2 H), 2.76
(s, 1 H), 2.23 (s, 1 H), 2.02 (s, 3 H), 1.61–1.46 (m, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 170.9, 142.9, 102.0, 69.9, 63.5, 59.3,
316
˜
1643, 1364, 1250, 1090, 1046, 964, 926 cm–1. [α]2D5 = +120 (c = 0.55,
CHCl3) for 17 and –116.5 (c = 0.52, CHCl3) for 21. HRMS (ESI):
calcd. for C9H12O4Na [M + Na]+ 207.0634; found 207.0634.
256
2-[(3S,4S)-3-(Benzyloxy)-3,4-Dihydro-2H-pyran-4-yl]acetaldehyde
(25): Yield 81%. Rf = 0.60 (20% EtOAc in hexanes). 1H NMR
(400 MHz, CDCl3): δ = 9.76 (t, J = 1.6 Hz, 1 H), 7.36–7.29 (m, 5
37.5, 32.0, 20.9 ppm. IR (neat): ν = 3398, 2924, 1736, 1649, 1373, 321
˜
1240, 1043 cm–1. [α]2D5 = +113.2 (c = 0.68, CHCl3) for 18 and –111.5
(c = 0.65, CHCl3) for 22. HRMS (ESI): calcd. for C9H14O4Na [M
+ Na]+ 209.0790; found 209.0790.
261 H), 6.35 (dd, J = 2.0, 6.0 Hz, 1 H), 4.63 (d, J = 12.0 Hz, 1 H), 4.59
(dd, J = 3.6, 6.0 Hz, 1 H), 4.52 (d, J = 11.6 Hz, 1 H), 3.91 (d, J =
5.2 Hz, 2 H), 3.84 (dd, J = 4.8, 10.0 Hz, 1 H), 3.09–3.04 (m, 1 H), 2-[(3S,4S)-3-(Benzyloxy)-3,4-dihydro-2H-pyran-4-yl]ethanol
(26):
2.79 (ddd, J = 1.2, 7.6, 17.6 Hz, 1 H), 2.42 (ddd, J = 1.2, 6.0,
17.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 201.2, 143.7,
137.7, 128.4, 127.8, 127.7, 101.56, 71.3, 71.1, 63.7, 45.2, 30.0 ppm.
Yield 91%. Rf = 0.40 (30% EtOAc in hexanes). 1H NMR
326
331
336
(400 MHz, CDCl3): δ = 7.35–7.29 (m, 5 H), 6.32 (dd, J = 2.0,
6.0 Hz, 1 H), 4.70 (d, J = 11.6 Hz, 1 H), 4.62 (dd, J = 4.0, 6.0 Hz,
1 H), 4.58 (d, J = 12.0 Hz, 1 H), 4.00 (dd, J = 6.8, 11.2 Hz, 1 H),
3.91–3.88 (m, 1 H), 3.80–3.76 (m, 1 H), 3.72–3.62 (m, 2 H), 2.61–
2.58 (m, 1 H), 1.99 (s, 1 H), 1.95–1.86 (m, 1 H), 1.62–1.53 (m, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 142.9, 137.8, 128.4,
266
IR (neat): ν = 3481, 3414, 2926, 2883, 1720, 1647, 1454, 1242, 1091,
˜
916, 738, 698 cm–1. [α]2D5 = +53.0 (c = 1.0, CHCl3). HRMS (ESI):
calcd. for C14H16O3Na [M + Na]+ 255.0997; found 255.0997.
General Procedure for the Reduction of the Aldehyde Functionality
127.7, 102.2, 72.0, 70.9, 63.8, 60.6, 33.9, 32.1 ppm. IR (neat): ν =
˜
271 To Obtain Alcohols 6, 10, 14, 18, 22 and 26: NaBH4 (1.45 mmol,
1.2 equiv.) was added to a solution of aldehyde 5, 9, 13, 17, 21 or
25 (1.20 mmol, 1 equiv.) in absolute ethanol (5 mL) at 0–5 °C, and
the mixture was stirred for 15 min. After complete disappearance of
the starting material, the reaction was quenched by adding aqueous
3408, 2928, 2878, 1647, 1454, 1240, 1089, 1028, 738, 698 cm–1.
[α]2D5
= +41.0 (c = 1.0, CHCl3). HRMS (ESI): calcd. for
C14H18O3Na [M + Na]+ 257.1154; found 257.1154.
General Procedure for the One-Pot Ozonolysis and Acid-Mediated
Acetalization of Alcohols To Obtain cis-Fused Perhydrofuro[2,3,b]fu-
ran Derivatives 7, 11, 15, 19, 23 and 27: CH2Cl2 (20 mL) was added
to the alcohol 6, 10, 14, 18, 22 or 26 (0.46 mmol) in a two-necked
round-bottomed flask with a gas outlet on one neck and a gas inlet
on the other neck. The solution was cooled to –78 °C using an
EtOAc/liquid nitrogen bath. Ozone was bubbled through the gas
inlet into the solution until the pale blue color persisted. Then,
oxygen followed by nitrogen were passed through the inlet until the
pale blue color disappeared. Dimethyl sulfide (0.5 mL) was added
to the reaction mixture at –78 °C, which was then allowed to warm
to 25 °C. The solvent was evaporated in vacuo to obtain the crude
formate ester, which was used in the next step without purification.
276
NH4Cl (1 mL), and the mixure was filtered through Celite. The
filtrate was concentrated in vacuo and purified by column
chromatography over silica gel eluting with hexanes and ethyl acet-
ate to obtain the alcohol in excellent yield.
341
346
[(2R,3S,4S)-3-Acetoxy-4-(2-hydroxyethyl)-3,4-dihydro-2H-pyran-2-
281 yl]methyl Acetate (6): Yield 95%. Rf = 0.25 (40% EtOAc in hex-
1
anes). H NMR (400 MHz, CDCl3): δ = 6.28 (dd, J = 2.0, 6.0 Hz,
1 H), 5.07 (t, J = 6.0 Hz, 1 H), 4.66 (dd, J = 4.0, 6.0 Hz, 1 H),
4.26–4.22 (m, 1 H), 4.17–4.11 (m, 2 H), 3.69–3.62 (m, 2 H), 2.61–
2.58 (m, 1 H), 2.05 (s, 3 H), 2.04 (s, 3 H), 1.75–1.66 (m, 1 H), 1.51–
286
1.42 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.7, 170.1,
141.5, 101.5, 71.7, 67.5, 62.4, 59.8, 33.3, 28.8, 20.7, 20.6 ppm. IR
(neat): ν = 3449, 2947, 1743, 1649, 1437, 1373, 1234, 1045,
The crude formate ester was dissolved in AcOH/MeOH (3:2, 5 mL)
and heated at reflux for 3 h. After complete consumption of the
starting material, the solvent was evaporated in vacuo and the
crude residue was partitioned between diethyl ether and aqueous
NaHCO3. The organic phase was washed with H2O and dried with
anhydrous Na2SO4. Evaporation of the solvent followed by purifi-
cation by column chromatography wluting with hexanes and ethyl
acetate gave the cis-fused perhydrofuro[2,3-b]furan derivative in
good yield over two steps.
˜
738 cm–1. [α]2D5 = +137.3 (c = 0.67, CHCl3). HRMS (ESI): calcd.
351
356
for C12H18O6Na [M + Na]+ 281.1001; found 281.1001.
291
296
301
[(2R,3R,4S)-3-Acetoxy-4-(2-hydroxyethyl)-3,4-dihydro-2H-pyran-2-
yl]methyl Acetate (10): Yield 92%. Rf = 0.25 (40% EtOAc in hex-
anes). 1H NMR (400 MHz, CDCl3): δ = 6.41 (d, J = 6.0 Hz, 1 H),
4.88 (s, 1 H), 4.72 (t, J = 6.0 Hz, 1 H), 4.20 (d, J = 2.0 Hz, 1 H),
4.18, (s, 1 H), 4.02 (t, J = 6.0 Hz, 1 H), 3.82–3.76 (m, 1 H), 3.72–
3.67 (m, 1 H), 2.60 (s, 1 H), 2.27 (br. d, J = 5.2 Hz, 1 H), 2.06 (s,
6 H), 1.61 (q, J = 6.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): [(2R,3S,3aR,6aS)-3-Acetoxyperhydrofuro[2,3-b]furan-2-yl]methyl
δ = 171.0, 170.6, 142.4, 102.4, 69.9, 69.5, 63.1, 59.4, 37.7’ 32.6,
Acetate (7): Yield 62%. Rf = 0.70 (50% EtOAc in hexanes). 1H
20.9, 20.6 ppm. IR (neat): ν = 3447, 2926, 1739, 1651, 1373, 1232,
NMR (500 MHz, CDCl3): δ = 5.76 (d, J = 5.0 Hz, 1 H), 4.98 (t, J 361
= 8.0 Hz, 1 H), 4.29 (dd, J = 3.0, 12.0 Hz, 1 H), 4.16–4.12 (m, 1
H), 4.07 (dd, J = 5.5, 12.0 Hz, 1 H), 3.99 (dt, J = 3.5, 8.5 Hz, 1
H), 3.93 (dt, J = 6.5, 9.5 Hz, 1 H), 3.21–3.16 (m, 1 H), 2.10 (s, 3
H), 2.07 (s, 3 H), 1.98–1.93 (m, 1 H), 1.91–1.83 (m, 1 H) ppm. 13C
˜
1041, 754 cm–1. [α]2D5 = +60.0 (c = 0.31, CHCl3). HRMS (ESI):
calcd. for C12H18O6Na [M + Na]+ 281.1001; found 281.1001.
(2S,3R,4R)-4-(2-Hydroxyethyl)-2-methyl-3,4-dihydro-2H-pyran-3-yl
Acetate (14): Yield 96%. Rf = 0.30 (30% EtOAc in hexanes). 1H
NMR (400 MHz, CDCl3): δ = 6.21 (dd, J = 1.6, 6.4 Hz, 1 H), 4.84
(t, J = 4.8 Hz, 1 H), 4.54–4.51 (m, 1 H), 4.10–4.04 (m, 1 H), 3.65–
NMR (100 MHz, CDCl3): δ = 170.6, 170.0, 108.6, 78.9, 73.3, 69.2,
366
63.5, 44.8, 25.5, 20.7 ppm. IR (neat): ν = 2957, 2924, 1739, 1452,
˜
1371, 1228, 1039, 927 cm–1. [α]2D5 = +78.0 (c = 1.0, CHCl3). HRMS
306 3.60 (m, 2 H), 2.75 (s, 1 H), 2.83 (dd, J = 2.8, 4.8 Hz, 1 H), 2.03
(s, 3 H), 1.69–1.61 (m, 1 H), 1.50–1.43 (m, 1 H), 1.20 (d, J = 6.4 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.6, 141.3, 100.6,
(ESI): calcd. for C11H16O6Na [M + Na]+ 267.0845; found 267.0845.
[(2R,3R,3aR,6aS)-3-Acetoxyperhydrofuro[2,3-b]furan-2-yl]methyl
Acetate (11): Yield 65%. Rf = 0.70 (50% EtOAc in hexanes). 1H
NMR (500 MHz, CDCl3): δ = 5.82 (d, J = 5.0 Hz, 1 H), 5.11 (d,
J = 3.5 Hz, 1 H), 4.32–4.29 (m, 1 H) 4.21 (dd, J = 4.5, 11.5 Hz, 1
H), 4.12 (dd, J = 7.5, 12.0 Hz, 1 H), 3.90–3.81 (m, 2 H) 2.81–2.77
71.3, 70.3, 59.8, 33.2, 27.8, 20.8, 16.9 ppm. IR (neat): ν = 3449,
371
˜
2939, 2885, 1734, 1649, 1439, 1377, 1238, 1138, 1049, 815,
311
736 cm–1. [α]2D5 = –98.7 (c = 2.0, CHCl3). HRMS (ESI): calcd. for
C10H16O4Na [M + Na]+ 223.0947; found 223.0947.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20898
/KAP1
Date: 24-09-12 17:04:34
Pages: 9
P. R. Sridhar, G. M. Reddy, K. Seshadri
FULL PAPER
(m, 1 H), 2.21–2.13 (m, 1 H), 2.03 (s, 3 H), 2.02 (s, 3 H), 1.85–1.80 ture was allowed to warm to 25 °C. The solvent was evaporated in
376
(m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.5, 170.0, vacuo to obtain the crude formate ester, which was used in the next
108.3, 78.7, 78.3, 67.7, 62.2, 50.0, 28.6, 20.7, 20.6 ppm. IR (neat):
step without purification.
ν = 2968, 2885, 1741, 1452, 1373, 1232, 1045, 931 cm–1. [α]25
=
˜
D
p-Toluenesulfonic acid (0.3 equiv.) was added to the crude formate
ester in dry CH2Cl2 (10 mL), and the mixture was heated at reflux
for 10 h. After complete consumption of the starting material was
observed, the solvent was evaporated in vacuo and the residue was
dissolved in diethyl ether. The solution was washed with aqueous
NaHCO3 and H2O, and then dried with anhydrous Na2SO4. The
solvent was removed using a rotary evaporator, and the residue was
purified by column chromatography eluting with hexanes and ethyl
acetate to give the fused perhydro-5-oxofuro[2,3-b]furan derivative
in good yield over three steps.
+11.1 (c = 2.0, CHCl3). HRMS (ESI): calcd. for C11H16O6Na [M
441
446
+ Na]+ 267.0845; found 267.0845.
381
386
(2S,3R,3aS,6aR)-2-Methyl-perhydrofuro[2,3-b]furan-3-yl Acetate
(15): Yield 64%. Rf = 0.50 (30% EtOAc in hexanes). 1H NMR
(400 MHz, CDCl3): δ = 5.69 (d, J = 5.2 Hz, 1 H), 4.67 (t, J =
8.4 Hz, 1 H), 4.00–3.86 (m, 3 H), 3.19–3.13 (m, 1 H), 2.09 (s, 3 H),
1.95–1.88 (m, 1 H), 1.86–1.78 (m, 1 H), 1.25 (d, J = 6.0 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 170.2, 107.8, 78.3, 76.5,
69.3, 44.8, 25.4, 20.7, 18.3 ppm. IR (neat): ν = 3414, 2978, 1741,
˜
1616, 1375, 1236, 1043, 937 cm–1. [α]2D5 = –94.7 (c = 1.0, CHCl3).
HRMS (ESI): calcd. for C9H14O4Na [M + Na]+ 209.0790; found
209.0790.
2-[(2R,3S,4S)-3-Acetoxy-2-(acetoxymethyl)-3,4-dihydro-2H-pyran-
4-yl]acetic Acid (31): Yield 97% (crude). Rf = 0.40 (1% MeOH in
EtOAc). 1H NMR (400 MHz, CDCl3): δ = 9.60 (s, 1 H), 6.32 (d, J
= 6.0 Hz, 1 H), 5.18 (t, J = 5.6 Hz, 1 H), 4.68 (t, J = 4.4 Hz, 1 H),
4.68 (t, J = 4.4 Hz, 1 H), 4.31 (dd, J = 5.6, 11.6 Hz, 1 H), 4.17–
4.07 (m, 2 H), 2.9 (s, 1 H), 2.5 (dd, J = 7.6, 16.4 Hz, 1 H), 2.05 (s,
3 H), 2.02 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.3,
170.8, 169.7, 142.6, 100.8, 71.1, 66.6, 62.1, 35.7, 29.3, 20.6,
451
456
391
396
401
(3R,3aR,6aS)-Perhydrofuro[2,3-b]furan-3-yl Acetate (19) and
(3S,3aS,6aR)-Perhydrofuro[2,3-b]furan-3-yl Acetate (23): Yield 55%
for 19 and 67% for 23. Rf: 0.45 (30% EtOAc in hexanes). 1H NMR
(500 MHz, CDCl3): δ = 5.80 (d, J = 5.0 Hz, 1 H), 5.01 (d, J =
3.5 Hz, 1 H), 4.01 (dd, J = 4.0, 11.0 Hz, 1 H), 3.91 (dd, J = 11.0,
15.0 Hz, 1 H), 3.87 (dd, J = 5.0, 8.5 Hz, 1 H), 3.82–3.77 (m, 1 H),
2.83 (q, J = 4.0, 9.5 Hz, 1 H), 2.20–2.11 (m, 1 H), 2.02 (s, 3 H),
1.83–1.77 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.4,
20.5 ppm. IR (neat): ν = 3292, 2926, 1741, 1651, 1375, 1099, 1099,
˜
1039, 760 cm–1. HRMS (ESI): calcd. for C12H16O7Na [M + Na]+
295.0794; found 295.0794.
108.7, 79.6, 72.5, 67.7, 49.0, 28.9, 20.9 ppm. IR (neat): ν = 3449,
˜
2-[(2R,3R,4S)-3-Acetoxy-2-(acetoxymethyl)-3,4-dihydro-2H-pyran-
4-yl]acetic Acid (33): Yield 97% (crude). Rf = 0.40 (1% MeOH in
EtOAc). 1H NMR (400 MHz, CDCl3): δ = 9.89 (s, 1 H), 6.40 (d, J
= 6.0 Hz, 1 H), 4.91 (s, 1 H), 4.77 (t, J = 4.4 Hz, 1 H), 4.18 (d, J
= 6.0 Hz, 2 H), 4.10–4.03 (m, 1 H), 2.56 (s, 1 H), 2.48 (dd, J = 6.8,
461
2926, 1739, 1371, 1240, 1018, 979 cm–1. [α]2D5 = +44.5 (c = 1.0,
CHCl3) for 19 and –45.3 (c = 1.0, CHCl3) for 23. HRMS (ESI):
calcd. for C8H12O4Na [M + Na]+ 195.0634; found 195.0634.
(3S,3aR,6aS)-3-(Benzyloxy)-perhydrofuro[2,3-b]furan (27): Yield
58%. Rf = 0.60 (20% EtOAc in hexanes). 1H NMR (400 MHz,
CDCl3): δ = 7.38–7.30 (m, 5 H), 5.71 (d, J = 5.2 Hz, 1 H), 4.57 (q,
J = 11.6 Hz, 2 H), 4.21 (dd, J = 8.0, 15.2 Hz, 1 H), 4.00–3.89 (m,
3 H), 3.66 (t, J = 8.4 Hz, 1 H), 2.95–2.89 (m, 1 H), 2.36–2.30 (m,
1 H), 1.91–1.81 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
137.6, 128.4, 127.8, 127.5, 109.2, 77.8, 72.1, 70.5, 69.6, 44.6,
15.6 Hz, 1 H), 2.34 (dd, J = 8.4, 15.6 Hz, 1 H), 2.05 (s, 3 H), 2.05 466
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.3, 170.8,
169.8, 142.6, 100.9, 71.1, 66.7, 62.1, 35.7, 29.3, 20.6, 20.5 ppm. IR
406
411
(neat): ν = 3553, 2926, 1742, 1375, 1227, 1095, 1041, 756 cm–1.
˜
HRMS (ESI): calcd. for C12H16O7Na [M + Na]+ 295.0794; found
295.0794.
471
2-[(2S,3R,4R)-3-Acetoxy-2-methyl-3,4-dihydro-2H-pyran-4-yl]acetic
Acid (35): Yield 89% (crude). Rf = 0.35 (1% MeOH in EtOAc). 1H
NMR (400 MHz, CDCl3): δ = 9.53 (s, 1 H), 6.29 (dd, J = 2.0,
6.0 Hz, 1 H), 4.97 (t, J = 5.6 Hz, 1 H), 4.59 (dd, J = 3.2, 6.0 Hz, 1
24.8 ppm. IR (neat): ν = 3449, 2955, 2879, 1722, 1454, 1099, 1024,
˜
923, 698 cm–1. [α]2D5 = +40.2 (c = 2.0, CHCl3). HRMS (ESI): calcd.
for C13H16O3Na [M + Na]+ 243.0997; found 243.0997.
General Procedure for the One-Pot Oxidation to Obtain 31, 33, 35,
37, 39 and 41, Ozonolysis and Acid-Mediated Cyclization of Alde-
hydes To Obtain Perhydro-5-oxofuro[2,3-b]furan Derivatives 32, 34,
36, 38, 40 and 42: Aqueous NaH2PO4 (3.4 mL, 2.7 mmol, 5 equiv.)
and aqueous NaClO2 (3.4 mL, 1.65 mmol, 3 equiv.) were added to
a vigorously stirred solution of aldehyde 5, 9, 13, 17, 21 or 25
(0.55 mmol, 1 equiv.) and 2-methyl-2-butene (6.15 mmol, 11 equiv.)
in tBuOH (7.16 mL) at 30 °C, and the mixture was stirred for
30 min at room temp. After complete consumption of starting ma-
terial was observed, aqueous NaCl (10 mL) was added, and the
solvent was removed by freeze drying. The resulting solid residue
was dissolved in MeOH (25 mL) and filtered through Celite 545.
The filtrate was concentrated in vacuo. Thus crude residue was dis-
solved in EtOAc (25 mL) and filtered through Celite 545. The fil-
trate was concentrated in vacuo to obtain the pure acid derivative,
which was used without further treatment in the next step.
H), 4.12–4.04 (m, 1 H), 2.98–2.93 (m, 1 H), 2.50 (dd, J = 7.6, 476
16.4 Hz, 1 H), 2.37 (dd, J = 7.2, 16.4 Hz, 1 H), 2.05 (s, 3 H), 1.25
(d, J = 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.8,
170.4, 142.4, 100.1, 70.8, 69.9, 35.6, 28.6, 20.7, 16.8 ppm. IR (neat):
416
421
426
ν = 3470, 2924, 1732, 1376, 1230, 1041, 980, 735 cm–1. HRMS
˜
(ESI): calcd. for C10H14O5Na [M + Na]+ 237.0739; found 237.0739.
481
2-[(3R,4S)-3-Acetoxy-3,4-dihydro-2H-pyran-4-yl]acetic Acid (37)
and 2-[(3S,4R)-3-Acetoxy-3,4-dihydro-2H-pyran-4-yl]acetic Acid
(39): Yield 93 % (crude). Rf = 0.40 (1 % MeOH in EtOAc). 1H
NMR (400 MHz, CDCl3): δ = 9.33 (s, 1 H), 6.39 (d, J = 6.0 Hz, 1
H), 4.85 (s, 1 H), 4.71 (dd, J = 3.6, 5.2 Hz, 1 H), 3.94–3.87 (m, 2
H), 2.65 (s, 1 H), 2.50 (dd, J = 6.4, 15.6 Hz, 1 H), 2.35 (dd, J = 8.0,
15.6 Hz, 1 H), 2.08 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 177.0, 170.6, 143.9, 100.8, 69.25, 63.9, 38.9, 32.4, 20.9 ppm. IR
486
491
(neat): ν = 2924, 1734, 1707, 1648, 1375, 1231, 1043, 928, 874 cm–1.
˜
HRMS (ESI): calcd. for C9H12O5Na [M + Na]+ 223.0583; found
223.0583.
CH2Cl2 (20 mL) was added to the acid derivative (0.50 mmol) in a
two-necked round-bottomed flask with a gas outlet on one neck
and a gas inlet on the other neck. The solution was cooled to
–78 °C using a EtOAc/liquid nitrogen bath. Ozone was bubbled
through the gas inlet into the solution until the pale blue color
persisted. Then, oxygen followed by nitrogen were passed through
the inlet until the pale blue color disappeared. Dimethyl sulfide
(0.5 mL) was added to the reaction mixture at –78 °C, and the mix-
2-[(3S,4S)-3-(Benzyloxy)-3,4-dihydro-2H-pyran-4-yl]acetic Acid
(41): Yield 95 % (crude). Rf = 0.70 (1 % MeOH in EtOAc): IR
431
436
(neat): ν = 3412, 2928, 1732, 1454, 1051, 740, 698 cm–1. HRMS
˜
(ESI): calcd. for C14H16O4Na [M + Na]+ 271.0947; found 271.0947.
496
[(2R,3S,3aR,6aR)-3-Acetoxy-5-oxo-perhydrofuro[2,3-b]furan-2-yl]-
methyl Acetate (32): Yield 48%. Rf = 0.60 (50% EtOAc in hexanes).
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20898
/KAP1
Date: 24-09-12 17:04:34
Pages: 9
Synthesis of Perhydrofuro[2,3-b]furans
1H NMR (400 MHz, CDCl3): δ = 6.1 (d, J = 5.2 Hz, 1 H), 5.09
(dd, J = 6.4, 8.4 Hz, 1 H), 4.37 (dd, J = 3.2, 12.0 Hz, 1 H), 4.30–
501 4.27 (m, 1 H), 4.19 (dd, J = 4.4, 12 Hz, 1 H), 3.47–3.40 (m, 1 H),
2.65 (s, 1 H), 2.63 (d, J = 0.8 Hz, 1 H), 2.13 (s, 3 H), 2.09 (s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 173.6, 170.4, 69.9, 106.8,
G. M. R. and K. S. gratefully acknowledge the CSIR for senior re-
search fellowships.
[1] a) K. C. Nicolaou, H. J. Mitchell, Angew. Chem. 2001, 113,
1624–1672; Angew. Chem. Int. Ed. 2001, 40, 1576–1624; b) G.- 561
J. Boons, K. J. Hale, Organic Synthesis with Carbohydrates,
Sheffield Academic Press Ltd., England, 2000, part B, p. 175–
333.
80.0, 72.0, 62.5, 41.3, 28.7, 20.7, 20.5 ppm. IR (neat): ν = 3470,
˜
2961, 2928, 1786, 1739, 1425, 1371, 1228, 1024, 798 cm–1. [α]2D5
=
506
+41.4 (c = 0.84, CHCl3). HRMS (ESI): calcd. for C11H14O7Na [M
+ Na]+ 281.0368; found 281.0368.
[2] B. M. Trost, F. D. Toste, J. Am. Chem. Soc. 2003, 125, 3090–
3100.
566
571
576
581
586
591
[(2R,3R,3aR,6aR)-3-Acetoxy-5-oxo-perhydrofuro[2,3-b]furan-2-yl]-
methyl Acetate (34): Yield 52%. Rf = 0.60 (50% EtOAc in hexanes).
1H NMR (400 MHz, CDCl3): δ = 6.20 (d, J = 4.8 Hz, 1 H), 5.09
[3] E. Bullock, J. C. Roberts, J. G. Underwood, J. Chem. Soc. 1962,
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511 (d, J = 2.4 Hz, 1 H), 4.40 (dd, J = 3.2, 6.4 Hz, 1 H), 4.36 (dd, J =
4.0, 12.0 Hz, 1 H), 4.26 (dd, J = 7.2, 11.6 Hz, 1 H), 3.15 (t, J =
6.0 Hz, 1 H), 2.99 (dd, J = 11.6, 19.2 Hz, 1 H), 2.61 (dd, J = 3.6,
18.8 Hz, 1 H), 2.10 (s, 3 H), 2.08 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 173.6, 170.5, 169.9, 106.4, 77.9, 77.4, 61.1,
516 46.3, 31.4, 20.7 ppm. IR (neat): ν = 3439, 2926, 1788, 1741, 1236,
˜
1043 cm–1. [α]2D5 = +1.2 (c = 1.0, CHCl3). HRMS (ESI): calcd. for
C11H14O7Na [M + Na]+ 281.0368; found 281.0368.
(2S,3R,3aS,6aS)-2-Methyl-5-oxo-perhydrofuro[2,3-b]furan-3-yl
Acetate (36): Yield 48%. Rf = 0.45 (40% EtOAc in hexanes). 1H
521 NMR (400 MHz, CDCl3): δ = 6.06 (d, J = 5.6 Hz, 1 H), 4.74 (t, J
= 8.4 Hz, 1 H), 4.12 (dd, J = 6.4, 7.6 Hz, 1 H), 3.49–3.42 (m, 1 H),
2.61 (dd, J = 3.6, 4.8 Hz, 2 H), 2.13 (s, 3 H), 1.36 (d, J = 6.4 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.3, 170.0, 106.2,
76.4, 40.7, 28.2, 20.5, 17.4 ppm. IR (neat): ν = 2982, 2935, 1786,
˜
526
1743, 1379, 1238, 1126, 1087, 974 cm–1. [α]2D5 = –80.2 (c = 1.0,
CHCl3). HRMS (ESI): calcd. for C9H12O5Na [M + Na]+ 223.0583;
found 223.0583.
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(3R,3aR,6aR)-5-Oxohexahydrofuro[2,3-b]furan-3-yl Acetate (38)
and (3S,3aS,6aS)-5-Oxo-perhydrofuro[2,3-b]furan-3-yl Acetate (40):
531 Yield 50 %. Rf = 0.55 (50 % EtOAc in hexanes). 1H NMR
(500 MHz, CDCl3): δ = 6.20 (d, J = 5.5 Hz, 1 H), 5.01 (d, J =
3.0 Hz, 1 H), 4.13 (dd, J = 0.5, 12.0 Hz, 1 H), 4.07 (dd, J = 3.5,
11.5 Hz, 1 H), 3.17–3.12 (m, 1 H), 2.97 (dd, J = 11.5, 19.0 Hz, 1
H), 2.57 (dd, J = 4.5, 19.5 Hz, 1 H), 2.08 (s, 3 H) ppm. 13C NMR
536 (100 MHz, CDCl3): δ = 173.9, 170.3, 107.3, 78.7, 71.0, 45.5, 31.6,
[14] a) T. P. Brady, S. H. Kim, K. Wen, C. Kim, E. A. Theodorakis,
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1331–1334; l) C. Su, X. Huang, Adv. Synth. Catal. 2009, 351,
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20.8 ppm. IR (neat): ν = 3456, 2922, 1784, 1736, 1365, 1242, 1176,
˜
1093, 974 cm–1. [α]2D5 = + and –21.1 (c = 1.0, CHCl3). HRMS (ESI):
calcd. for C8H10O5Na [M + Na]+ 209.0426; found 209.0426.
(3aR,4S,6aR)-4-(Benzyloxy)-perhydrofuro[2,3-b]furan-2(6aH)-one
541 (42): Yield 49%. Rf = 0.50 (30% EtOAc in hexanes). 1H NMR
(400 MHz, CDCl3): δ = 7.38–7.29 (m, 5 H), 6.00 (d, J = 5.6 Hz, 1
H), 4.55 (q, J = 12.0 Hz, 2 H), 4.22 (dd, J = 8.0, 14.4 Hz, 1 H),
4.10 (dd, J = 6.4, 9.2 Hz, 1 H), 3.73 (t, J = 9.2 Hz, 1 H), 3.17–3.12
(m, 1 H), 3.05 (dd, J = 3.6, 18.4 Hz, 1 H), 2.54 (dd, J = 10.4,
606
611
616
621
546
18.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.0, 136.9,
128.6, 128.2, 127.7, 107.3, 76.2, 69.4, 40.8, 27.7 ppm. IR (neat): ν
˜
= 3479, 3414, 2924, 1784, 1616, 1456, 1116, 738 cm–1. [α]2D5 = +13.5
(c = 1.0, CHCl3). HRMS (ESI): calcd. for C13H14O4Na [M +
Na]+ 257.0790; found 257.0790.
551 Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H, 13C, and DEPT NMR spectra of all com-
1
pounds, and 2D 1H–1H COSY H–1H NOESY spectra of all bicy-
clic compounds.
Acknowledgments
556
This work was supported by Council of Scientific and Industrial
Research (CSIR), New Delhi (grant number 01(2408)/10/EMR-II).
1999, 1, 1295–1297; f) C. Kim, T. Brady, S. H. Kim, E. A. The- 626
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P. R. Sridhar, G. M. Reddy, K. Seshadri
FULL PAPER
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Received: July 7, 2012
Published Online: ᭿
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Job/Unit: O20898
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Date: 24-09-12 17:04:34
Pages: 9
Synthesis of Perhydrofuro[2,3-b]furans
Oxygen Heterocycles
671
P. R. Sridhar,* G. M. Reddy,
K. Seshadri ....................................... 1–9
Stereoselective Synthesis of cis-Fused Per-
hydrofuro[2,3-b]furan Derivatives from Su-
gar-Derived Allyl Vinyl Ethers
A general protocol for the stereoselective
synthesis of cis-fused perhydrofuro[2,3-b]-
furans has been developed using carbo-
hydrates as chiral-pool starting materials.
Depending on the precursor sugar, this
procedure can provide any stereoisomer of
the bis-THF system in a stereoselective fa-
shion. The extension of the methodology
for the synthesis of perhydro-5-oxo-
furo[2,3-b]furans is also reported.
Keywords: Oxygen heterocycles / Carbo-
hydrates / Cyclization / Sigmatropic re-
arrangement / Chiral pool
676
Eur. J. Org. Chem. 0000, 0–0
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