Synthesis of enantiomerically pure perhydrofuro[2,3-b]furans

Article abstract of DOI:10.1016/j.tetasy.2005.06.016

Enantiomerically pure 2,5,6a-trisubstituted perhydrofuro[2,3-b]furans were obtained by the cyclization of bis-alkenylketones, promoted by camphorselenenyl sulfate produced in situ by oxidation of camphor diselenide with ammonium persulfate in a mixture of water and acetonitrile at room temperature. The cyclization reaction proceeded through a double selenohydroxylation of the two double bonds and produced a mixture of the two diastereoisomers trans- and cis-2,5-bis[(camphorseleno)methyl] perhydrofuro[2,3-b]furans. These were separated by medium pressure liquid chromatography and then deselenenylated with triphenyltin hydride and AIBN.

Full text of DOI:10.1016/j.tetasy.2005.06.016

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2429–2435
Synthesis of enantiomerically pure perhydrofuro[2,3-b]furans
Marcello Tiecco,* Lorenzo Testaferri, Luana Bagnoli, Catalina Scarponi,
Valentina Purgatorio, Andrea Temperini, Francesca Marini and Claudio Santi
`
Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Universita di Perugia, 06123 Perugia, Italy
Received 16 May 2005; accepted 15 June 2005
Abstract—Enantiomerically pure 2,5,6a-trisubstituted perhydrofuro[2,3-b]furans were obtained by the cyclization of bis-alkenyl-
ketones, promoted by camphorselenenyl sulfate produced in situ by oxidation of camphor diselenide with ammonium persulfate
in a mixture of water and acetonitrile at room temperature. The cyclization reaction proceeded through a double selenohydroxyla-
tion of the two double bonds and produced a mixture of the two diastereoisomers trans- and cis-2,5-bis[(camphorseleno)methyl]
perhydrofuro[2,3-b]furans. These were separated by medium pressure liquid chromatography and then deselenenylated with tri-
phenyltin hydride and AIBN.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
is encountered in various biologically active natural
products. Important compounds are clerodane-type
diterpenes, which have potential insect antifeedant19
and antibacterial activity,20 and the aflatoxins, which
are important mycotoxins with potent toxicity and car-
cinogenicity that have been detected as contaminants in
different types of food.15 It has been recently reported
that a series of very potent non-peptidyl HIV protease
inhibitors incorporate a bis-tetrahydrofuranyl structure.21
The stereoselective syntheses of substituted cyclic ether1
and perhydrofurofuran derivatives2 have attracted con-
siderable attention since these heterocyclic compounds
are present in several molecules having interesting bio-
logical properties.3,4 In recent years, our research group
has been deeply involved in the synthesis of several types
of heterocyclic compounds in an enantiomerically
enriched or pure form5 using very efficient organoselenium
reagents.6,7 We have recently reported the synthesis of
enantiomerically enriched substituted tetrahydro-
furans8,9 by the cyclization of alkenols promoted by the
electrophilic reagents produced from two sulfur contain-
ing chiral non-racemic diselenides.9,10 On the other
hand, the synthesis of enantiomerically pure substituted
tetrahydrofurans was obtained starting from commer-
cially available enantiopure epoxides11 and using simple
conversions promoted by achiral phenylselenium
reagents. A similar multi-step sequence has been employed
in the synthesis of more complex molecules. Starting
from the commercially available (R)-(+)-2,2-dimethyl-
1,3-dioxolane-4-carboxaldehyde, by means of two
consecutive selenium promoted cyclizations, the tetra-
hydrofuro[3,4-b]pyrans and tetrahydrofuro[3,4-b]furans
can be easily obtained as pure enantiomers.12 The syn-
thesis of related perhydrofuro[2,3-b]furans has also
attracted considerable attention13–21 since this structure
Herein, we report a new and convenient approach for
the synthesis of enantiomerically pure 2,5,6a-trisubsti-
tuted perhydrofuro[2,3-b]furans. As indicated in Scheme
1, this simple method consists of the double cyclization
of bis-alkenylketones promoted by a chiral non-racemic
electrophilic selenenylating reagent in the presence of
water.
SeR*
R*Se+X-
H2O
+
SeR*
O
O
X-
O
R
O:
..
*RSe
SeR*
R
H
R
O
1a: R = Ph
1b: R = Me
Scheme 1.
2. Results and discussion
*
The starting products 1a and 1b were easily prepared
according to the procedure described.22,23 Their
Corresponding author. Tel.: +39 075 5855100; fax: +39 075
5855116; e-mail: tiecco@unipg.it
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.06.016

2430
M. Tiecco et al. / Tetrahedron: Asymmetry 16 (2005) 2429–2435
cyclization reactions were carried out in acetonitrile and
water and most likely proceeded through the initial for-
mation of the seleno-hydroxylation products, which are
then converted into the perhydrofuro[2,3-b]furans by a
double cyclization.22
(NH ) S O , CF SO H
4 2
2
8
3
3
CfSeOSO3H
SeOSO3H
CH CN
3
Se)2
O
O
6
7
Scheme 3.
In order to obtain 2,5-dimethyl derivatives 4a, 4b, 5a,
and 5b (Scheme 2) that were to be used as reference com-
pounds in our investigations, we first carried out the
cyclization reactions of 1a and 1b with the achiral phen-
ylselenenyl chloride and water under the conditions
described for the selenohydroxylation of alkenes.24 As
reported in Scheme 2, these reactions produced 1:1 mix-
tures of the cis- and trans-isomers 2a, 3a and 2b, 3b.
These results were in good agreement with those
reported in the literature.22,25,26 The two pairs of the dia-
stereoisomers were separated by medium pressure liquid
chromatography and then submitted to reductive
deselenenylation with Ph3SnH and AIBN.11,12 Yields
of isolated products are indicated (Scheme 2). The single
products 4a,27 4b, 5a, and 5b were examined by GC–MS
using a Chirasildex column. As expected, cis-isomers 4a
and 4b appeared as a single peak, while trans-isomers 5a
and 5b appeared as two peaks with the same integrated
area corresponding to the two enantiomers.
H
H
O
O
O
O
CfSe
CfSe
SeCf
Ph
Ph
8a (2S,5S) (21%)
oil, [α]= -2.73
5a (2R,5R) (89%)
oil, [α]= +29.61
H
H
O
O
O
O
SeCf
Ph
Ph
ent-5a (2S,5S) (70%)
oil, [α]= -28.15
9a (2R,5R) (25%)
oil, [α]= +9.31
H
O
Ph
1a
O
O
H
CfSe
SeCf
Ph
10a (2S ,5R) (26%)
m.p. 51-53°C, [α]= -1.26
O
O
Ph
H
4a (2R,5S) (99% from 10a)
(70% from 11a)
m.p. 60-62°C, [α] = 0
H
H
O
O
CfSe
SeCf
Ph
PhSeCl
+
11a (2R,5S) (8%)
m.p. 75-77°C, [α]= -27.83
O
O
O
O
CH3CN/H2O
SePh
SePh
SePh
SePh
O
R
R
R
2a,b (2S*, 5R*) (30%)
3a,b (2R*, 5R*) (30%)
3a oil, 3b oil
1a: R = Ph
1b: R = Me
Scheme 4.
2a m.p. 102-103°C, 2b oil
Ph3SnH, AIBN
C6H6, 80°C
Ph3SnH, AIBN
C6H6, 80°C
then submitted to reductive deselenenylation with
Ph3SnH and AIBN. Compounds 8a and 9a afforded
the two enantiomeric trisubstituted perhydrofuro[2,3-
b]furans 5a and ent-5a, whereas 10a and 11a gave rise
to the same compound 4a.30 Attribution of structure
5a and structure ent-5a to the dextrorotatory and to
the levorotatory enantiomers, respectively, and hence
to 8a and 9a, is only tentative.
H
H
O
O
O
O
R
R
4a,b (2R*, 5S*) (99%)
5a,b (2S*, 5S*) (98%)
5a oil, 5b oil
4a m.p. 60-62°C, 4b oil
Scheme 2.
As indicated in Scheme 5, in the case of compound 1b,
cyclization gave rise to a mixture of the two trans-diaste-
reoisomers 8b and 9b and only one cis-diastereoisomer
10b. The cis-isomer 11b was only present in trace
amounts. The diastereoisomers 8b–10b could be sepa-
rated by medium pressure liquid chromatography. After
reductive deselenylation, 8b and 9b gave the correspond-
ing enantiomerically pure perhydrofuro[2,3-b]furans 5b
and ent-5b. The cis-isomer 10b gave compound 4b. In
this case also the selenides are presented in the same order
in which they are eluted from the chromatographic
column and structural attributions to compounds 5b
and ent-5b, and hence 8b and 9b, are tentative. Yields
of isolated products are indicated in Scheme 5.
The same synthetic sequence was then employed for the
cyclizations of 1a and 1b promoted by the camphor-
selenenyl sulfate 7. This reagent was produced in situ
by oxidation of camphor diselenide 6 with ammonium
persulfate in the presence of a stoichiometric amount
of trifluoromethanesulfonic acid (Scheme 3).28 The cam-
phor diselenide can be easily obtained in a one-pot reac-
tion from (1R)-(+)-camphor and elemental selenium as
described by Back.29
The results of the cyclization of compound 1a are
reported in Scheme 4. This reaction produced a mixture
of the two trans-diastereoisomers 8a and 9a and the two
cis-diastereoisomers 10a and 11a, which could be
separated by medium pressure liquid chromatography.
The selenides are presented in the same order in which
they are eluted from the chromatographic column.
Yields of the isolated products are indicated (Scheme
4). These enantiomerically pure diastereoisomers were
The enantiomeric excesses of the deselenylated products
5a, 5b, ent-5a, and ent-5b were determined by GC–MS
experiments using a Chirasildex column. All these iso-
mers appeared as a single peak (ee >98%). The specific
rotations of these compounds are indicated in Schemes

M. Tiecco et al. / Tetrahedron: Asymmetry 16 (2005) 2429–2435
2431
The cis-isomers of the phenyl derivatives 2a, 10a, 11a,
and 4a were solids, while the corresponding isomers of
the methyl derivatives 2b, 10b, and 4b were liquids. In
H
H
O
O
O
O
SeCf
SeCf
SeCf
1
Me
Me
the H NMR spectra, the hydrogen at the 3a position
5b (2R,5R) (90%)
oil, [α] = -21.72
8b (2S,5S) (21%)
oil, [α] = +5.17
appeared as a multiplet in compounds 2a, 2b, 10a, and
11a and as a triplet of triplets in compounds 10b, 4a,
and 4b. This indicates that in these cis-isomers, the cou-
pling constant between the proton at 3a and the proton
at the 3a or 4a positions is not zero. The relative con-
figurations of some cis-perhydrofuro[2,3-b]furans were
also confirmed by the results of NOESY experiments.
The protons at the 2 and 5 positions showed a dipolar
effect with the proton at the 3a position in compound
11a while a similar dipolar effect was observed between
the protons at the 3a position and the two protons of the
CH2SeR* group in compound 10a. This suggests that
compounds 11a and 10a have the two cis-configurations
indicated in Scheme 4. The cis-configuration of com-
pound 10b was attributed by analogy. The cis-configura-
tion of compounds 2a,22,25 2b, 4a, and 4b was confirmed
by the fact that the proton and 13C NMR spectra that
resulted were very simple because of the symmetry of
the molecules.
H
H
O
O
O
O
CfSe
CfSe
Me
Me
9b (2R,5R) (20%)
oil, [α] = +17.60
ent-5b (2S,5S) (85%)
oil, [α] = +21.69
H
H
O
Me
1b
O
O
O
O
SeCf
Me
Me
4b (2R,5S) (98%)
10b (2S,5R) (22%)
oil, [α] = +9.07
oil, [α] = 0
H
O
O
SeCf
SeCf
Me
11b (2R,5S) traces
Scheme 5.
4 and 5 and are also reported in the Experimental. Obvi-
ously, compounds 4a and 4b also appeared as single
peaks but were optically inactive.
3. Conclusions
The herein described camphorselenenyl sulfate pro-
moted double cyclization of bis-alkenylketones favor-
ably compares with previously described methods for
the preparation of substituted perhydrofuro[2,3-b]furan
derivatives.14–20 The great advantage of the present
method consists of the use of chiral non-racemic organo-
selenium reagents and hence the preparation of the
perhydrofuro[2,3-b]furans in their enantiomerically pure
forms. This simple procedure could have general appli-
cation since it can be applied to the cyclization of several
bis-alkenylketones thus leading to differently substituted
perhydrofuro[2,3-b]furans. Moreover, the presence of
the organoselenium function in the cyclization products
facilitates the introduction of several other groups to be
easily effected.
All trans-compounds 3a, 3b, 8a, 8b, 9a, 9b, 5a, 5b, ent-
5a, and ent-5b were liquids and in their 1H NMR spectra
the hydrogen at the 3a position appeared as a broad
quartet because the coupling constant with the proton
anti in the 3a position (in compounds 8a, 8b, 5a, and
5b) or in the 4a position (in compounds 3a, 3b, 9a, 9b,
ent-5a, and ent-5b) is nearly zero17 and produces only
a line broadening. Molecular models, in fact, indicate
that the two protons H3a and H3a in compounds 8a,
8b, 5a, and 5b, and the two protons H3a and H4a in com-
pounds 3a, 3b, 9a, 9b, ent-5a, and ent-5b are almost
orthogonal (Fig. 1).
H3
H3a
H4β
H4
β
H3
H3a
α
α
2
5
2
5
4. Experimental
O
O
O
O
*RSe
*RSe
SeR*
R
SeR*
R
1
All new compounds were characterized by MS, H, and
3a, 3b, 9a, 9b, ent-5a, ent-5b
13C NMR spectroscopy. GC analyses and MS spectra
were carried out with an HP 6890 gas chromatograph
(25 m dimethyl silicone capillary column) equipped with
an HP 5973 Mass Selective Detector; for the ions con-
taining selenium only the peaks arising from the sele-
nium-80 isotope are given. GC chiral analyses and MS
spectra were carried out with an HP 5890 gas chromato-
graph (25 m Chirasildex capillary column) equipped
8a, 8b, 5a, 5b
JH3a,H3α = 0
JH3a,H4α = 0
Figure 1.
In the case of 8b, the trans relationship between the two
CH2SeR* groups was confirmed by the results of
NOESY experiments. A strong dipolar effect was in fact
observed between the protons at the 5 and 3a positions.
The trans-configuration of compounds 3a,22,25 3b, 8a,
9a, and 9b was attributed by analogy. It was also impor-
tant that, because of the lack of symmetry, all these
trans-compounds, as well as their deselenenylated deriv-
atives 5a, 5b, ent-5a, and ent-5b, gave proton and 13C
NMR spectra which were more complex than those of
the cis-isomers.
with an HP 5971 Mass Selective Detector. H and 13C
1
NMR spectra were recorded at 400 and 100.62 MHz,
respectively, on a Bruker DRX 400 instrument; unless
otherwise specified, CDCl3 was used as solvent and
TMS as standard. Optical rotations were measured with
a Jasco DIP-1000 digital polarimeter. Elemental analy-
ses were carried out on a Carlo Erba 1106 Elemental
Analyzer.

2432
M. Tiecco et al. / Tetrahedron: Asymmetry 16 (2005) 2429–2435
4.1. Starting products
12.3 Hz), 2.70–2.61 (m, 1H), 1.96–1.88 (m, 4H), 1.51
(s, 3H); 13C NMR: d 132.4 (three carbons), 130.2 (two
carbons), 129.0 (four carbons), 126.8 (three carbons),
117.0, 78.8 (two carbons), 47.3, 39.1 (two carbons),
32.7 (two carbons), 25.1; MS m/z (rel. int.): 468 (23),
297 (100), 279 (12), 207 (27), 157 (28), 121 (29), 91
(28), 77 (17). Anal. Calcd for C21H24O2Se2: C, 54.09;
H, 5.19. Found: C, 54.04; H, 5.03.
Bis-alkenylation of acetophenone with allyl bromide in
the presence of sodium hydride in tetrahydrofuran gave
rise to 4-benzoylhepta-1,6-diene 1a.22 3-Allylhex-5en-
2-one 1b was obtained by bis-allylation of the ethyl 3-
oxobutanoate and subsequently by hydrolysis and
decarboxylation.23 N-Phenylseleno phthalimide and tri-
phenyltin hydride were commercial products and used
without further purification.
4.2.4. (2R*,5R*)- 6a-Methyl-2,5-bis[(phenylseleno)methyl]-
1
hexahydrofuro[2,3-b]furan, 3b. Oil. H NMR: d 7.55–
4.2. Cyclization reactions promoted by phenylselenenyl
chloride: general procedure
7.45 (m, 4H), 7.35–7.15 (m, 6H), 4.49–4.39 (m, 1H),
4.19–3.99 (m, 1H), 3.13 (dd, 1H, J = 1.9, 12.3 Hz),
3.11 (dd, 1H, J = 2.0, 12.3 Hz), 2.93 (dd, 1H, J = 1.9,
12.3 Hz), 2.91 (dd, 1H, J = 2.0, 12.3 Hz), 2.50 (br q,
1H, J = 9.0 Hz), 2.35 (ddd, 1H, J = 5.5, 9.0, 12.5 Hz),
1.89 (dd, 1H, J = 4.5, 12.5 Hz), 1.75 (ddd, 1H, J = 9.0,
10.5, 12.5 Hz), 1.55–1.43 (m, 1H), 1.47 (s, 3H); 13C
NMR: d 132.4 (four carbons), 129.9 (two carbons),
128.9 (four carbons), 126.8 (two carbons), 116.6, 77.1,
77.0, 47.6, 38.8, 38.2, 32.2, 31.4, 24.6; MS m/z (rel.
int.): 468 (32), 311 (36), 297 (64), 207 (23), 171 (26),
157 (51), 153 (53), 139 (100), 121 (44), 91 (53), 77 (32).
Anal. Calcd for C21H24O2Se2: C, 54.09; H, 5.19. Found:
C, 54.07; H, 5.09.
Phenylselenenylchloride24 (1.5 mmol) was added to a
solution of bis-alkenylketones 1a and 1b (0.5 mmol) in
acetonitrile (5 mL) and water (2 mL). The resulting pale
yellow solution was stirred at room temperature for 4 h.
The progress of the reaction was monitored by TLC.
The reaction mixture was then poured into aqueous
NaHCO3 solution and extracted with dichloromethane.
The combined organic extracts were washed with brine,
dried over sodium sulfate, filtered, and evaporated. The
reaction products were separated by medium pressure
liquid chromatography on a silica gel column (Merck,
LiChroprepÒ Si60, 40–63 lm) using a 1:9 mixture of
diethyl ether and light petroleum as eluant. The prod-
ucts obtained and the reaction yields are reported in
Scheme 2. Physical and spectral data are reported below.
4.3. Cyclization reactions promoted by camphorselenenyl
sulfate: general procedure
Ammonium persulfate (0.75 mmol) and CF3SO3H
(1.5 mmol) were added to a solution of camphor disele-
nide 6 (0.75 mmol) in acetonitrile (4 mL) and the result-
ing red solution stirred at room temperature for 15 min.
A solution of bis-alkenylketones 1a and 1b (0.5 mmol) in
water (2 mL) and acetonitrile (2 mL) was then added
and the mixture stirred at room temperature for 16 h.
The progress of the reaction was monitored by TLC.
The reaction mixture was then poured into aqueous
NaHCO3 solution and extracted with dichloromethane.
The combined organic extracts were washed with brine,
dried over sodium sulfate, filtered, and evaporated. The
reaction products were separated by medium pressure
chromatography on a silica gel column (Merck, LiChro-
prepÒ Si60, 40–63 lm) using a 2:8 mixture of diethyl
ether and light petroleum as eluant. The separation in
a pure form of the two trans-diastereoisomers 8a, 9a
and 8b, 9b was carried out by monitoring the different
4.2.1. (2S*,5R*)-6a-Phenyl-2,5-bis[(phenylseleno)methyl]-
hexahydrofuro[2,3-b]furan, 2a22,25
.
Mp 102–103 °C; 1H
NMR: d 7.70–7.50 (m, 6H), 7.40–7.10 (m, 9H), 4.53–
4.46 (m, 2H), 3.24 (dd, 2H, J = 4.5, 12.3 Hz), 3.05 (dd,
2H, J = 7.4, 12.3 Hz), 2.86–2.79 (m, 1H), 1.98–1.93 (m,
4H); 13C NMR: d 141.7, 132.5 (four carbons), 130.1
(two carbons), 129.0 (four carbons), 127.9 (three car-
bons), 126.9 (two carbons), 125.8 (two carbons), 117.6,
79.8 (two carbons), 50.6, 39.3 (two carbons), 32.4 (two
carbons). Anal. Calcd for C26H26O2Se2: C, 59.10; H,
4.96. Found: C, 59.08; H, 4.94.
4.2.2. (2R*,5R*)-6a-Phenyl-2,5-bis[(phenylseleno)methyl]-
hexahydrofuro[2,3-b]furan, 3a22,25
.
Oil. 1H NMR: d
7.60–7.52 (m, 4H), 7.50–7.43 (m, 2H), 7.39–7.20 (m,
9H), 4.65 (ddt, 1H, J = 4.5, 7.8, 10.5 Hz), 4.30 (dddd,
1H, J = 5.4, 6.0, 7.2, 10.3 Hz), 3.38 (dd, 1H, J = 4.5,
12.3 Hz), 3.35 (dd, 1H, J = 5.4, 12.3 Hz), 3.18 (dd, 1H,
J = 7.8, 12.3 Hz), 3.15 (dd, 1H, J = 7.2, 12.3 Hz), 2.94
(br q, 1H, J = 9.0 Hz), 2.45 (ddd, 1H, J = 6.0, 9.0,
12.6 Hz), 2.03 (dd, 1H, J = 4.5, 12.4 Hz), 1.95 (ddd,
1H, J = 9.0, 10.5, 12.4 Hz), 1.65 (ddd, 1H, J = 9.0,
10.3, 12.6 Hz); 13C NMR: d 142.4, 132.7 (two carbons),
132.6, 130.0, 129.1 (four carbons), 128.2 (two carbons),
128.1, 128.0, 127.0, 127.9 (two carbons), 125.5 (two car-
bons), 117.1, 78.9, 77.9, 51.0, 39.3, 38.3, 32.4, 31.3. Anal.
Calcd for C26H26O2Se2: C, 59.10; H, 4.96. Found: C,
59.12; H, 4.94.
1
fractions by H NMR. The products obtained and the
reaction yields are reported in Schemes 4 and 5. Physical
and spectral data are reported below.
4.3.1. (2S,5S)-2,5-Bis[(camphorseleno)methyl]-6a-phenyl-
21
hexahydrofuro[2,3-b]furan, 8a. Oil, ½aꢀ ¼ ꢁ2.73 (c
D
2.76, CHCl3). 1H NMR: d 7.56–7.51 (m, 2H), 7.39–
7.27 (m, 3H), 4.74 (ddt, 1H, J = 4.4, 6.6, 10.1 Hz), 4.38
(ddt, 1H, J = 4.9, 6.1, 10.6 Hz), 3.92 (dd, 1H, J = 1.7,
4.1 Hz), 3.89 (dd, 1H, J = 1.5, 4.1 Hz), 3.28 (dd, 1H,
J = 6.1, 13.0 Hz), 3.21 (dd, 1H, J = 6.6, 12.7 Hz), 3.11
(dd, 1H, J = 4.9, 13.0 Hz), 3.08 (dd, 1H, J = 4.4,
12.7 Hz), 3.01 (br q, 1H, J = 8.6 Hz), 2.52–2.42 (m,
1H), 2.31 (t, 1H, J = 4.1 Hz), 2.15 (t, 1H, J = 4.1 Hz),
2.15–1.99 (m, 2H), 1.92–1.63 (m, 7H), 1.52–1.46 (m,
2H), 1.03 (s, 3H), 0.97 (s, 3H), 0.94 (s, 3H), 0.91 (s,
4.2.3. (2S*,5R*)-6a-Methyl-2,5-bis[(phenylseleno)methyl]-
1
hexahydrofuro[2,3-b]furan, 2b. Oil. H NMR: d 7.62–
7.49 (m, 4H), 7.25–7.18 (m, 6H), 4.42–4.33 (m, 2H),
3.15 (dd, 2H, J = 4.5, 12.3 Hz), 2.96 (dd, 2H, J = 7.3,

M. Tiecco et al. / Tetrahedron: Asymmetry 16 (2005) 2429–2435
2433
3H), 0.90 (s, 3H), 0.75 (s, 3H); 13C NMR: d 218.2, 218.1,
142.8, 128.0 (two carbons), 127.8, 125.6 (two carbons),
117.1, 79.4, 78.4, 58.1 (two carbons), 50.8, 48.4, 48.2,
47.4, 47.2, 46.7, 46.6, 39.1, 38.2, 30.5 (two carbons),
28.9, 27.5, 23.4, 23.2, 19.6, 19.5 (two carbons), 19.4,
9.7 (two carbons). Anal. Calcd for C34H46O4Se2: C,
60.35; H, 6.85. Found: C, 60.21; H, 6.76.
30.4 (two carbons), 28.1, 23.2 (two carbons), 19.6 (three
carbons), 19.1, 9.65 (two carbons). Anal. Calcd for
C34H46O4Se2: C, 60.35; H, 6.85. Found: C, 60.27; H, 6.81.
4.3.5. (2S,5S)-2,5-Bis[(camphorseleno)methyl]-6a-methyl-
17
hexahydrofuro[2,3-b]furan, 8b. Oil, ½aꢀ ¼ þ5.2 (c 3.83,
D
CHCl3). 1H NMR: d 4.42 (ddt, 1H, J = 5.5, 5.6,
10.6 Hz), 4.03 (ddt, 1H, J = 5.8, 5.9, 10.6 Hz), 3.98
(dd, 1H, J = 1.1, 4.7 Hz), 3.88 (dd, 1H, J = 1.7,
4.5 Hz), 3.03 (dd, 1H, J = 5.9, 12.3 Hz), 2.97 (dd, 1H,
J = 5.5, 12.3 Hz), 2.94 (dd, 1H, J = 5.6, 12.3 Hz), 2.90
(dd, 1H, J = 5.8, 12.3 Hz), 2.59 (br q, 1H, J = 9.0 Hz),
2.35 (ddd, 1H, J = 5.6, 9.0, 12.7 Hz), 2.23–2.15 (m,
2H), 1.93–1.75 (m, 6H), 1.70–1.60 (m, 2H), 1.59–1.47
(m, 1H), 1.42–1.35 (m, 2H), 1.41 (s, 3H), 0.98 (s, 6H),
0.89 (s, 9H), 0.86 (s, 3H); 13C NMR: d 218.8, 218.7,
117.5, 79.1, 79.0, 59.1, 59.0, 49.3, 49.1, 48.6, 48.5, 48.4,
47.7, 47.6, 39.9, 39.5, 31.5, 31.4, 29.8, 28.7, 25.7, 24.2,
24.1, 20.6 (two carbons), 20.5 (two carbons), 10.6 (two
carbons). Anal. Calcd for C29H44O4Se2: C, 56.67; H,
7.22. Found: C, 56.61; H, 7.19.
4.3.2. (2R,5R)-2,5-Bis[(camphorseleno)methyl]-6a-phenyl-
24
D
hexahydrofuro[2,3-b]furan, 9a. Oil, ½aꢀ ¼ þ9.3 (c 2.65,
1
CHCl3) H NMR: d 7.66–7.49 (m, 2H), 7.46–7.19 (m,
3H), 4.68 (ddt, 1H, J = 5.4, 5.7, 10.6 Hz), 4.34 (ddt,
1H, J = 5.3, 6.2, 10.0 Hz), 4.05 (dd, 1H, J = 1.4,
4.7 Hz), 4.03 (dd, 1H, J = 1.5, 4.7 Hz), 3.23 (dd, 1H,
J = 6.2, 12.6 Hz), 3.20–3.12 (m, 2H), 3.10 (dd, 1H,
J = 5.7, 12.6 Hz), 3.01 (br q, 1H, J = 8.6 Hz), 2.52–
2.45 (m, 1H), 2.27 (t, 1H, J = 4.7 Hz), 2.23 (t, 1H,
J = 4.7 Hz), 2.14 (ddd, 1H, J = 8.6, 10.6, 12.1 Hz), 2.03
(dd, 1H, J = 5.3, 12.1 Hz), 1.91–1.83 (m, 4H), 1.78–
1.65 (m, 3H), 1.55–1.40 (m, 2H), 1.06 (s, 3H), 1.05 (s,
3H), 0.96 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H), 0.72 (s,
3H); 13C NMR: d 217.9 (two carbons), 142.6, 128.0
(two carbons), 127.8, 125.6 (two carbons), 117.1, 79.8,
78.8, 58.1 (two carbons), 50.9, 48.4, 48.0, 47.7, 47.4,
46.8, 46.6, 39.4, 38.6, 30.3 (two carbons), 28.8, 27.2,
23.3, 23.1, 19.6 (three carbons), 19.3, 9.7 (two carbons).
Anal. Calcd for C34H46O4Se2: C, 60.35; H, 6.85. Found:
C, 60.31; H, 6.78.
4.3.6. (2R,5R)-2,5-Bis[(camphorseleno)methyl]-6a-methyl-
19
hexahydrofuro[2,3-b]furan, 9b. Oil, ½aꢀ ¼ þ17.6 (c
D
3.35, CHCl3). 1H NMR: d 4.52–4.49 (m, 1H), 4.17–
4.09 (m, 1H), 3.87 (dd, 1H, J = 1.1, 4.7 Hz), 3.77 (dd,
1H, J = 1.7, 4.5 Hz), 3.10–2.87 (m, 4H), 2.58 (br q,
1H, J = 8.6 Hz), 2.45–2.30 (m, 1H), 2.25–2.19 (m, 2H),
1.90–1.57 (m, 10H), 1.49 (s, 3H), 1.48–1.38 (m, 1H),
4.3.3. (2S,5R)-2,5-Bis[(camphorseleno)methyl]-6a-phenyl-
0.99 (s, 3H), 0.98 (s, 3H), 0.88 (s, 6H), 0.87 (s, 3H),
0.86 (s, 3H);
19
D
13
hexahydrofuro[2,3-b]furan, 10a. Mp 51–53 °C; ½aꢀ
¼
C NMR: d 217.9, 217.8, 116.6, 77.8,
1
ꢁ1.3 (c 3.74, CHCl3) H NMR: d 7.60–7.58 (m, 2H),
7.33–7.30 (m, 3H), 4.78–4.65 (m, 2H), 4.02 (dd, 1H,
J = 1.1, 4.6 Hz), 3.85 (dd, 1H, J = 1.4, 4.1 Hz), 3.22
(dd, 1H, J = 6.0, 12.7 Hz), 3.18 (dd, 1H, J = 6.5,
12.7 Hz), 3.11 (dd, 1H, J = 4.5, 12.7 Hz), 3.02 (dd, 1H,
J = 5.4, 12.7 Hz), 3.01–2.94 (m, 1H), 2.25–2.22 (m,
2H), 2.17–2.12 (m, 3H), 1.90–1.65 (m, 7H), 1.50–1.40
(m, 2H), 1.03 (s, 3H), 1.01 (s, 3H), 0.94 (s, 3H), 0.93
(s, 3H), 0.84 (s, 3H), 0.78 (s, 3H); 13C NMR: d 217.6,
217.5, 141.9, 127.7 (three carbons), 125.8 (two carbons),
117.4, 81.1, 80.2, 57.9 (two carbons), 50.3, 48.1, 47.9,
47.0, 46.6 (two carbons), 39.5, 39.1, 30.4 (three carbons),
28.6, 28.3, 23.2 (two carbons), 19.4 (three carbons), 19.3,
9.6 (two carbons). Anal. Calcd for C34H46O4Se2: C,
60.35; H, 6.85. Found: C, 60.23; H, 6.75.
77.5, 58.0 (two carbons), 48.3, 48.2, 47.7, 47.3, 47.2,
46.7 (two carbons), 38.5, 38.1, 30.4 (two carbons),
28.9, 28.0, 24.8, 23.2 (two carbons), 19.6 (two carbons),
19.5 (two carbons), 9.6 (two carbons). Anal. Calcd for
C29H44O4Se2: C, 56.67; H, 7.22. Found: C, 56.58; H, 7.20.
4.3.7. (2S,5R)-2,5-Bis[(camphorseleno)methyl]-6a-methyl-
20
D
hexahydrofuro[2,3-b]furan, 10b. Oil, ½aꢀ ¼ þ9.1 (c 3.16,
1
CHCl3). H NMR: d 4.53–4.45 (m, 2H), 4.01 (dd, 1H,
J = 1.8, 4.9 Hz), 3.83 (dd, 1H, J = 1.9, 4.6 Hz), 3.05 (dd,
1H, J = 6.4, 12.7 Hz), 2.99 (dd, 1H, J = 5.6, 12.7 Hz),
2.92 (dd, 1H, J = 5.6, 12.7 Hz), 2.91 (dd, 1H, J = 4.2,
12.7 Hz), 2.70 (tt, 1H, J = 2.5, 8.9 Hz), 2.25–2.22 (m,
2H), 2.12–1.94 (m, 3H), 1.86–1.82 (m, 3H), 1.80–1.62
(m, 4H), 1.52 (s, 3H), 1.50–1.40 (m, 2H), 1.03 (s, 3H),
1.02 (s, 3H), 0.94 (s, 3H), 0.93 (s, 3H), 0.90 (s, 6H); 13C
NMR: d 218.0 (two carbons), 116.9, 79.9, 79.3, 58.0
(two carbons), 48.3, 48.0, 47.3, 47.1 (two carbons), 46.6
(two carbons), 39.2, 38.9, 30.4 (two carbons), 29.1, 28.8,
24.9, 23.2, 23.1, 19.5 (three carbons), 19.4, 9.6 (two car-
bons). Anal. Calcd for C29H44O4Se2: C, 56.67; H, 7.22.
Found: C, 56.63; H, 7.17.
4.3.4. (2R,5S)-2,5-Bis[(camphorseleno)methyl]-6a-phenyl-
20
D
hexahydrofuro[2,3-b]furan, 11a. Mp 75–77 °C; ½aꢀ
¼
1
ꢁ27.8 (c 2.63, CHCl3). H NMR: d 7.77–7.65 (m, 2H),
7.42–7.28 (m, 3H), 4.77–4.65 (m, 2H), 4.02 (dd, 1H,
J = 1.1, 4.1 Hz), 3.92 (dd, 1H, J = 1.6, 4.4 Hz), 3.32
(dd, 1H, J = 6.6, 12.9 Hz), 3.22 (dd, 1H, J = 6.6,
12.9 Hz), 3.18 (dd, 1H, J = 4.8, 12.9 Hz), 3.16–3.15 (m,
1H), 3.06 (dd, 1H, J = 5.1, 12.9 Hz), 2.78 (ddd, 2H,
J = 5.2, 7.7, 13.1 Hz), 2.59 (dd, 1H, J = 10.3, 13.1 Hz),
2.44 (dd, 1H, J = 10.3, 13.1 Hz), 2.31 (t, 1H,
J = 4.4 Hz), 2.25 (t, 1H, J = 4.1 Hz), 1.96–1.15 (m,
8H), 1.05 (s, 3H), 1.00 (s, 3H), 0.95 (s, 3H), 0.94 (s,
3H), 0.86 (s, 3H), 0.80 (s, 3H); 13C NMR: d 217.8,
217.4, 139.0, 128.5, 127.6 (two carbons), 127.3 (two car-
bons), 118.1, 79.8, 78.8, 58.0 (two carbons), 57.8, 49.3,
49.2, 48.5, 48.2, 48.1, 47.1, 47.0, 46.7 (two carbons),
4.4. Reductive deselenenylations: general procedure
Triphenyltin hydride (2.5 mmol) and a catalytic amount
of AIBN were added to a solution of compounds 8a–11a
and 8b–10b (0.5 mmol) in dry benzene (5 mL) and the
mixture was stirred and refluxed for 1 h. The solvent
was then removed under reduced pressure. The per-
hydrofuro[2,3-b]furans 4a, 5a, ent-5a, 4b, 5b, ent-5b were
purified by column chromatography on silica gel using

2434
M. Tiecco et al. / Tetrahedron: Asymmetry 16 (2005) 2429–2435
a 2:8 mixture of diethyl ether and light petroleum as elu-
ant. The reaction yields are reported in Schemes 4 and 5.
Physical and spectral data are reported below.
4.4.7.
(2R,5R)-2,5,6a-Trimethylhexahydrofuro[2,3-b]-
21
furan, 5b. Oil, ½aꢀ ¼ ꢁ21.7 (c 1.20, CHCl3). Spectral
D
date are identical to those of the racemic sample. Anal.
Calcd for C9H16O2: C, 69.19; H, 10.32. Found: C, 69.12;
H, 10.27.
4.4.1.
(2R*,5S*)-2,5-Dimethyl-6a-phenylhexahydro-
1
furo[2,3-b]furan, 4a. Mp 60–62 °C. H NMR: d 7.60–
7.45 (m, 2H), 7.30–7.10 (m, 3H), 4.45 (dq, 2H, J = 5.8,
10.3 Hz), 2.78 (tt, 1H, J = 1.9, 9.2 Hz), 1.89 (ddd, 2H,
J = 1.9, 5.8, 12.7 Hz), 1.80 (ddd, 2H, J = 9.2, 10.3,
12.7 Hz), 1.32 (d, 6H, J = 5.8 Hz); 13C NMR: d 142.6,
127.8 (two carbons), 127.6, 125.8 (two carbons), 116.8,
76.7 (two carbons), 51.4, 41.3 (two carbons), 21.3 (two
carbons); MS m/z (rel. int.): 218 (15), 203 (42), 174
(69), 105 (100), 77 (31). Anal. Calcd for C14H18O2: C,
77.03; H, 8.31. Found: C, 77.06; H, 8.35.
4.4.8.
(2S,5S)-2,5,6a-Trimethylhexahydrofuro[2,3-b]-
21
furan, ent-5b. Oil, ½aꢀ ¼ þ21.7 (c 1.05, CHCl3). Spec-
D
tral date are identical to those of the racemic sample.
Anal. Calcd for C9H16O2: C, 69.19; H, 10.32. Found:
C, 69.15; H, 10.30.
Acknowledgements
Financial support from MIUR, National Projects
PRIN2003, FIRB2001 and Consorzio CINMPIS is
gratefully acknowledged.
4.4.2. (2S*,5S*)-2,5-Dimethyl-6a-phenylhexahydrofuro-
1
[2,3-b]furan, 5a. Oil. H NMR: d 7.65–7.50 (m, 2H),
7.40–7.20 (m, 3H), 4.55–4.45 (m, 1H), 4.15 (m, 1H),
2.92 (br q, 1H, J = 9.0 Hz), 2.39 (ddd, 1H, J = 5.8, 9.0,
12.4 Hz), 1.90 (dd, 1H, J = 4.4, 12.4 Hz), 1.85–1.74 (m,
1H), 1.55–1.45 (m, 1H), 1.44 (d, 3H, J = 6.0 Hz), 1.43
(d, 3H, J = 6.0 Hz); 13C NMR: d 143.3, 129.3 (two car-
bons), 128.0, 125.5 (two carbons), 116.4, 75.5, 74.2, 51.8,
41.3, 40.4, 20.6, 19.5; MS m/z (rel. int.): 218 (7), 203 (34),
174 (58), 105 (100), 77 (27). Anal. Calcd for C14H18O2:
C, 77.03; H, 8.31. Found: C, 77.01; H, 8.33.
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4.4.3. (2R,5R)-2,5-Dimethyl-6a-phenylhexahydrofuro[2,3-b]-
25
D
furan, 5a. Oil, ½aꢀ ¼ þ29.6 (c 2.47, CHCl3). Spectral
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4.4.4.
(2S,5S)-2,5-Dimethyl-6a-phenylhexahydrofuro-
25
[2,3-b]furan, ent-5a. Oil, ½aꢀ ¼ ꢁ28.15 (c 1.91, CHCl3).
D
Spectral date are identical to those of the racemic sample.
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77.02; H, 8.30.
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furan, 4b. Oil. 1H NMR: d 4.32 (ddq, 2H, J = 5.4,
6.0, 10.2 Hz), 2.65 (tt, 1H, J = 1.8, 9.0 Hz), 1,87 (ddd,
2H, J = 1.8, 5.4, 12.6 Hz), 1.76 (ddd, 2H, J = 9.0, 10.2,
12.6 Hz), 1.54 (s, 3H) 1.25 (d, 6H, J = 6.0 Hz); 13C
NMR: d 115.0, 75.9 (two carbons), 47.9, 41.3 (two car-
bons), 25.4, 21.0 (two carbons); MS m/z (rel. int.): 156
(2), 155 (6), 141 (100), 112 (76), 97 (37), 81 (40), 71
(23), 69 (24), 55 (15). Anal. Calcd for C9H16O2: C,
69.19; H, 10.32. Found: C, 69.05; H, 10.12.
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3.80 (m, 1H), 2.56 (br q, 1H, J = 9.0 Hz), 2.25 (ddd,
1H, J = 5.1, 9.0, 12.3 Hz), 1.69 (dd, 1H, J = 4.3,
12.3 Hz), 1.56 (ddd, 1H, J = 7.9, 9.0, 12.3 Hz), 1.46 (s,
3H), 1.28 (d, 3H, J = 5.9 Hz), 1.27 (d, 3H,
J = 6.0 Hz), 1.27–1.19 (m, 1H); 13C NMR: d 115.6,
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