Ready access to the 6,8-dioxabicyclo[3.2.1]octane ring system using asymmetric heterocycloaddition induced by a chiral sulfoxide: Application to the total synthesis of the Mus musculus pheromone

Article abstract of DOI:10.1016/S0957-4166(99)00070-1

A new stereocontrolled total synthesis of the (1R,5S,7R)-exo-6,8- dioxabicyclo[3.2.1]oct-3-ene skeleton of the Mus musculus pheromone has been achieved via an asymmetric intermolecular Diels-Alder reaction and an intramolecular conjugated addition, contro

Full text of DOI:10.1016/S0957-4166(99)00070-1

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1041–1050
Ready access to the 6,8-dioxabicyclo[3.2.1]octane ring system
using asymmetric heterocycloaddition induced by a chiral
sulfoxide: application to the total synthesis of the Mus musculus
pheromone
Patricia Hayes and Christian Maignan ∗
Laboratoire de Synthèse Organique (ESA 6011), Faculté des Sciences, Avenue Olivier Messiaen, 72085 Cedex 9, Le Mans,
France
Received 18 January 1999; accepted 24 February 1999
Abstract
A new stereocontrolled total synthesis of the (1R,5S,7R)-exo-6,8-dioxabicyclo[3.2.1]oct-3-ene skeleton of the
Mus musculus pheromone has been achieved via an asymmetric intermolecular Diels–Alder reaction and an
intramolecular conjugated addition, controlled by a chiral auxiliary. © 1999 Published by Elsevier Science Ltd.
All rights reserved.
1. Introduction
The sulfinyl group has been widely used as a chiral auxiliary in asymmetric syntheses.1 Within
the space of a few years, the synthesis of chiral sulfinyl-1,3-dienes and their use in asymmetric
Diels–Alder reactions has become an important development.1,2 In recent papers,3–6 we have reported
the first examples of intermolecular Diels–Alder reactions using chiral sulfinyloxabuta-1,3-dienes I
(R=H, CH3) and an application of this methodology to the synthesis of both enantiomers of 1,7-
dioxaspiro[5.5]undecane, the pheromone components of the Dacus oleae olive fruit-fly.6 The results
obtained highlighted the great reactivity of these compounds, under extremely mild and non-catalytic
conditions, in inverse electronic demand [4+2] heterocycloadditions. These reactions occur without
selectivity with enol ethers3–5 but with a total selectivity with styrenic dienophiles.5
∗
Corresponding author. Fax: +1-330-243-833-902; e-mail: maignan@aviion.univ-lemans.fr
0957-4166/99/$ - see front matter © 1999 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00070-1

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P. Hayes, C. Maignan / Tetrahedron: Asymmetry 10 (1999) 1041–1050
To complement our work in this field, we investigate here an extension of the cycloadditions of
(+)-(S)-3-p-tolylsulfinylbut-3-en-2-one 1 towards sulfide activated dienophiles II as well as an original
application to the asymmetric 6,8-dioxabicyclo[3.2.1]octane and oct-3-ene ring system, structures widely
found in many naturally occurring compounds,7 with the total synthesis of the Mus musculus (house
mouse) pheromone.8
2. Results and discussion
The results reported here emphasize the high reactivity of (Ss)-3-p-tolylsulfinylbut-3-en-2-one 1 as
a heterodiene. Indeed, cycloadditions of (Ss)-1 with simple enol thioethers were performed without a
catalyst and at room temperature or by refluxing in dichloromethane (Scheme 1).
Scheme 1.
Under these conditions, an interesting selectivity was observed in comparison with the oxygenated
series. Indeed, good yields and diastereomeric excesses equal to, or higher than, 40% were observed.
These new results, extended to a new chiral-sulfide-activated dienophile 7, make it possible to plan an
application for asymmetric access to the 6,8-dioxabicyclo[3.2.1]octane skeleton of brevicomin 5. Our
synthetic analysis is shown in Scheme 2.
The bicyclic structure of compound 6 can be obtained from the sulfinylbutenone 1 and chiral enol
thioether 7. These two compounds can be easily prepared from (Rs)-p-tolylvinylsulfoxide 109 by addition
of the appropriate aldehyde RCHO10 (R=CH3 or CH2CH3) followed by oxidation of the hydroxy group
for R=CH3, or by reduction of the sulfinyl group for R=CH2CH3: this approach offers several advantages:
(i) we start exclusively from (Rs)-p-tolylvinylsulfoxide 10 for access to the heterodiene and to the
dienophile. Indeed, the sulfinyl group is the chiral auxiliary of (Ss)-1 and could be used to build up the
stereogenic center of 7; (ii) during the heterocycloaddition, sulfinyl and sulfide groups act as activating
substituents for the diene and the dienophile, respectively; and (iii) we take advantage of the Michael
acceptor system formed during the intermolecular Diels–Alder reaction to achieve the intramolecular
conjugate addition of the hydroxy group.

P. Hayes, C. Maignan / Tetrahedron: Asymmetry 10 (1999) 1041–1050
1043
Scheme 2.
Alcohols 8 and 9 were prepared10 by treatment of (Rs)-10 with lithium diisopropylamide followed by
addition of acetaldehyde [(Ss)-8] or propanal [(Ss)-9] in 61 and 57% yields, respectively. Jones oxidation
of the diastereomeric alcohols (Ss)-811 affords (Ss)-1 in a 95% yield. Compound (Ss,R)-9 was isolated
in a diastereomerically pure form (de >98%) by crystallization in diisopropylether.12 Reduction of the
sulfoxide to sulfide was successfully achieved by the P2I4/pyridine system13 in ether after protection of
the hydroxyl with TBDMSCl/imidazole in DMF.14,15 Desilylation with nBu4NF in THF gives (R)-7 in a
61% overall yield from (Ss,R)-9 (Scheme 3).
Scheme 3. Reagents and conditions: (i) LDA/THF, RCHO, 61% (R=CH3) and 57% (R=CH2CH3); (ii) separation by crystalli-
zation, 22%; (iii) Jones reagent, −20°C, acetone, 95%; (iv) CF3SO3SiMe2tBu, 2,6-lutidine, CH2Cl2, 95%; (v) P2I4, pyridine,
ether, 80%; (vi) nBu4NF, THF, 81%
The hetero Diels–Alder reaction between (Ss)-1 and (R)-7 by refluxing in dichloromethane after 5 days
affords cycloadducts (Ss)-11 as a 70:30 diastereomeric mixture (Scheme 4).
Due to the presence of the hydroxy group, the two cycloadducts of compound 11 were readily separated
by chromatography on silica gel. The low polarity of the major isomer can be explained by the existence
of a strong intramolecular hydrogen bond with the suitably orientated proximal hydroxy group. This
phenomenon is associated with enhanced chromatographic mobility due to the consequent reduction in
the effective polarity of the sulfoxide group.16
Thanks to the Michael acceptor system formed during heterocycloaddition, the intramolecular con-
jugated addition of the alcohol in acidic conditions (p-TsOH) allows, in the case of the major isomer
(Ss,2S,R)-11 access to dioxabicyclic structure of compound 6 with three resolved stereogenic centers.
No cyclization occurs for the minor isomer (Ss,2R,R)-11 under the same conditions. This phenomenon

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P. Hayes, C. Maignan / Tetrahedron: Asymmetry 10 (1999) 1041–1050
Scheme 4. Reagents and conditions: (i) CH2Cl2/∆/5 days, 65%; (ii) p-TsOH (0.25 equiv.)/CH2Cl2/RT/15 h
can be explained by the following consideration: each cycloadduct of compound 11 can adopt two
conformations. In the case of the minor isomer, the last result indicates the pseudoequatorial orientation
of the hydroxylated chain, a position which excludes hydrogen bonding and intramolecular cyclization
(Scheme 5).
Scheme 5.
On the other hand, for the major isomer of compound 11, the hydroxylated chain adopts a pseudoaxial
orientation which involves intramolecular hydrogen bonding and allows an intramolecular conjugated
addition. Moreover, according to the conformation IIA or IIB preferably adopted by major cycloadduct
of compound 11, we can obtain either (1S,5R,7R)-endo or (1R,5S,7R)-exo-brevicomin 517,18 after
cyclization and cleavage of the two C–S bonds (Scheme 6). The presence of only 10% of exo-brevicomin
5 was observed by cleavage of the two C–S bonds using lithium in liquid ammonia19 (1H NMR spectra of
the crude product), this result shows the absolute stereochemistry (Ss,1S,4S,5S,7R) of the bicyclic acetal
6 and (Ss,2S,R) for the major cycloadduct of compound 11 (conformation IIB).
Even though the cleavage in one step of the two C–S bonds enables the absolute configuration of the
bicyclic skeleton to be established, the synthesis of the desired bicyclic acetal is not satisfactory. Because
of the low yields we considered accessing these structures via a two-step procedure: (i) thermolytic
elimination of the sulfoxide; and (ii) reductive cleavage of the sulfide group with tri-n-butyltin hydride.
Thermolysis of the sulfinyl group for (Ss,1S,4S,5S,7R)-6 was performed by refluxing in dry benzene
in the presence of a catalytic amount of AIBN and 2 equiv. of Bu3SnH20 and afforded (1S,5S,7R)-12
in 72% yield. After purification by chromatography, (1S,5S,7R)-12 under the same previous conditions
gave, after 4 days, the desired pheromone, (1R,5S,7R)-13 in 42% yield.21 For this last step, it is necessary
to bubble argon through the reaction mixture to achieve the reductive cleavage of the C–S bond22

P. Hayes, C. Maignan / Tetrahedron: Asymmetry 10 (1999) 1041–1050
1045
Scheme 6.
(Scheme 7). The cleavage of the both C–S bonds in one step from compound 6 afforded compound
13 in a lower yield.
Scheme 7.
The enantiomeric purity of (1R,5S,7R)-13 (ee >98%) was determined by gas chromatography using a
1
chiral column (Restek β-DEX, 30 m, helium). The IR, H NMR, mass spectra and specific rotation of
(1R,5S,7R)-13 were in accordance with the reported data.21
3. Conclusion
In summary, asymmetric heterocycloadditions of (Ss)-p-tolylsulfinylbut-3-en-2-one with simple or
chiral-functionalized-sulfide-activated dienophiles were successfully achieved in a high diastereoselec-
tive manner (dr >70:30). This methodology provides an original and convenient route to the optically
active 6,8-dioxabicyclo[3.2.1] skeleton thanks to inter- and intramolecular cyclization reactions.
The absolute stereochemistry of the bicyclic structure and cycloadducts have been established by two
different studies: (i) by chemical correlation by transformation into exo-brevicomin; and (ii) to illustrate
the interest of our work, by the total synthesis of the Mus musculus (house mouse) pheromone. The
mouse pheromone has been synthesized with a high enantiomeric purity and in only a four steps from
(Ss)-3-p-tolylsulfinylbutenone.

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P. Hayes, C. Maignan / Tetrahedron: Asymmetry 10 (1999) 1041–1050
4. Experimental
4.1. General procedures
1
Melting points were determined on a Reichert Thermovar apparatus and are uncorrected. H (400
MHz) and 13C (100 MHz) NMR spectra were recorded on a Bruker AC 400 instrument in CDCl3 using
TMS for 1H spectra and the solvent for 13C spectra as internal reference. Multiplicities in the 13C spectra
were determined by DEPT experiments.
Unless otherwise noted, all reactions were carried out in anhydrous solvents. IR spectra were re-
corded on a Mattson spectrometer. Optical rotations were measured at 25°C with a Perkin–Elmer
model 343 polarimeter. Mass spectra were recorded on a Finnigan instrument. High resolution mass
measurements were performed at the C.R.M.P.O. (Rennes). Enantiomeric excesses were determined on a
Hewlett–Packard HP6890 series GC system equipped with a chiral column (Restek β-DEX). Elemental
analyses were performed at the C.N.R.S. (Gif-sur-Yvette). Flash chromatography was run on SDS silica
gel A.C.C. (230–400 mesh).
4.2. (Ss,)-6-Methyl-5-p-tolylsulfinyl-2-ethylsulfanyl-3,4-dihydro-2H-pyran 2
A solution of (Ss)-1 (208 mg; 1 mmol) and ethyl vinyl sulfide (507 µL; 5 mmol) in dichloromethane
(4 mL) was stirred at ambient temperature for 8 h. After concentration in vacuo, the crude product was
purified by chromatography on silica gel (cyclohexane:ethyl acetate, 8:2) to afford the major isomer of
compound 2 (155 mg) as a white solid and the minor isomer of compound 2 (64 mg) as a colorless oil, in a
74% overall yield. Calcd for C15H20O2S2: C, 60.77; H, 6.79; S, 21.63; found: C, 60.56; H, 6.85; S, 21.09.
The major cycloadduct of compound (+)-2 (71%): [α]D +229 (c 1; CH2Cl2). IR (neat): 3048, 2925, 1645,
1232, 1085, 1037, 848 cm−1. 1H NMR δ 1.28 (t, J=7.4 Hz, 3H); 1.58–1.62 (m, 1H); 1.89–1.96 (m, 1H);
2.06–2.15 (m, 1H); 2.23 (s, 3H); 2.3–2.4 (m, 1H); 2.41 (s, 3H); 2.64–2.80 (m, 2H); 5.38 (t, J=3.6 Hz,
1H); 7.3–7.48 (AA0BB0 system, J=8.2 Hz, 4H). 13C NMR δ 14.11 (t); 15.07 (q); 17.78 (q); 21.26 (q);
24.59 (t); 26.85 (t); 81.11 (d); 113.86 (s); 124.29 (d); 129.58 (d); 139.95 (s); 140.26 (s); 157.39 (s). The
minor cycloadduct of compound (−)-2 (29%): [α]D −415 (c 1.07; CH2Cl2). IR (neat): 3048, 2925, 1645,
1232, 1085, 1037, 848 cm−1. 1H NMR δ 1.68 (t, J=7.4 Hz, 3H); 1.49–1.58 (m, 1H); 1.85–1.93 (m, 1H);
1.94–2.02 (m, 1H); 2.25 (s, 3H); 2.36 (s, 3H); 2.41–2.49 (m, 1H); 2.62–2.77 (m, 2H); 5.02 (dd, J=8 and
3 Hz, 1H); 7.23–7.37 (AA0BB0 system, J=8.2 Hz, 4H). 13C NMR δ 12.67 (t); 15.31 (q); 17.78 (q); 21.24
(q); 25.03 (t); 26.98 (t); 80.91 (d); 113.67 (s); 124.48 (d); 129.6 (d); 139.26 (s); 140.09 (s); 156.65 (s).
4.3. (Ss,)-6-Methyl-5-p-tolylsulfinyl-2-phenylsulfanyl-3,4-dihydro-2H-pyran 3
A solution of (Ss)-1 (104 mg; 0.5 mmol) and phenyl vinyl sulfide (55 µL; 1.1 equiv.) in dichlorome-
thane (2 mL) was refluxed for 6 days. After cooling and concentration in vacuo, the crude product was
purified by chromatography on silica gel (eluent: cyclohexane:ethyl acetate, 9:1) to give partly separated
(Ss)-3 (124 mg; 70%) as a white solid. Calcd for C19H20O2S2: 344.09047; found: 344.0905. IR (KBr):
1
3052, 2923, 1643 (C_C), 1076, 1031 (S_O) cm−1. The major cycloadduct of compound 3 (78%): H
NMR δ 1.42–1.63 (m, 1H); 1.94–2.06 (m, 2H); 2.29 (s, 3H); 2.39 (s, 3H); 2.46–2.55 (m, 1H); 5.23 (dd,
J=8 and 3 Hz, 1H); 7.28–7.52 (m, 9H, Harom). 13C NMR δ 14.53 (t); 17.84 (q); 21.3 (q); 27.37 (t); 83.59
(d); 114.09 (s); 124.33 (2d); 128.09 (2d); 128.99 (2d); 129.66 (2d); 132.84 (2d); 139.92 (s); 140.37 (s);
157.27 (s). The minor cycloadduct of compound 3 (22%): 1H NMR δ 1.56–1.64 (m, 1H); 1.05–2.17 (m,
2H); 2.23 (s, 3H); 2.35 (s, 3H); 2.37–2.42 (m, 1H); 5.56 (t, J=3.5 Hz, 1H); 7.23–7.42 (m, 9H, Harom). 13
C

P. Hayes, C. Maignan / Tetrahedron: Asymmetry 10 (1999) 1041–1050
1047
NMR δ 12.21 (t); 17.69 (q); 21.17 (q); 27.09 (t); 83.60 (d); 114.10 (s); 124.36 (2d); 127.52 (2d); 128.94
(2d); 129.59 (2d); 131.57 (2d); 139.14 (s); 140.14 (s); 156.23 (s).
4.4. (Ss)-2-(6-Methyl-2-p-tolylsulfanyl-5-p-tolylsulfinyl-3,4-dihydro-2H-pyran-2-yl)-propan-2-ols 4
Adducts 4 were prepared in the same way as adducts 3 from (Ss)-1 (52 mg; 0.25 mmol) and 2-
methyl-3-p-tolylsulfanylbut-3-en-2-ol (78 mg; 0.37 mmol) by refluxing in dichloromethane for 5 days.
Chromatography on silica gel (eluent: cyclohexane:ethyl acetate, 9:1; 5:5 then pure ethyl acetate)
afforded the major cycloadduct of compound 4 (40 mg) and minor cycloadduct of compound 4 (17
mg) as white solids in 55% overall yield. IR (KBr): 3305 (OH), 3052 (C_CH), 2919, 1644 (C_C), 1492,
1085 (S_O) cm−1. The major cycloadduct of compound 4 (70%): 1H NMR δ 1.29 (s, 3H); 1.35 (s, 3H);
1.73–1.85 (m, 2H); 1.89 (s, 3H); 1.91–1.97 (m, 1H); 2.21 (br s, 1H, OH); 2.33 (s, 3H); 2.37 (s, 3H);
2.70–2.81 (m, 1H); 7.11–7.35 and 7.25–7.46 (AA0BB0 systems, 4d, J=8 Hz, 8Harom). 13C NMR δ 14.08
(t); 17.22 (q); 21.23 (q); 21.27 (q); 24.49 (q); 25.46 (q); 26.68 (t); 76.68 (s); 94.52 (s); 115.05 (s); 124.25
(2d); 126.79 (s); 129.32 (2d); 129.68 (2d); 137.61 (2d); 139.38 (s); 140.14 (s); 140.32 (s); 155.54 (s).
The minor cycloadduct of compound 4 (30%): m.p. 170–171°C (ether). 1H NMR δ 1.26 (s, 3H); 1.29 (s,
3H); 1.72–1.92 (m, 1H); 1.91–2.15 (m, 2H); 2.01 (s, 3H); 2.29 (s, 3H); 2.31–2.42 (s, 1H); 2.38 (s, 3H);
6.98–7.27 and 7.11–7.35 (AA0BB0 systems, 4d, J=8 Hz, 8Harom). 13C NMR δ 12.32 (t); 17.13 (q); 21.21
(q); 21.36 (q); 24.72 (q); 25.33 (q); 26.78 (t); 76.52 (s); 94.96 (s); 114.79 (s); 124.48 (2d); 127.46 (s);
129.19 (2d); 129.59 (2d); 136.37 (2d); 138.88 (s); 139.07 (s); 140.57 (s); 155.66 (s).
4.5. (Ss,S) and (Ss,R)-2-p-Tolylsulfinylpent-1-en-3-ols 9
To a stirred solution of LDA (22 mmol) in dry THF (80 mL) under a nitrogen atmosphere, at −90°C,
distilled (Rs)-p-tolylvinylsulfoxide 10 (3.34 g; 20 mmol) in THF (40 mL) was slowly added. After 10
min at −90°C, freshly distilled ethanal (4.32 mL; 60 mmol) was added dropwise. The reaction mixture
was maintained at −90°C for 10 min, then a half-saturated aqueous NH4Cl solution (40 mL) was added
at this temperature. Most of the THF was removed under reduced pressure and the residue was finally
extracted with CH2Cl2. After drying over MgSO4 and evaporation of the solvent, the crude oil was
purified by chromatography (eluent: ether:cyclohexane, 7:3 then pure ether) to give the diastereomeric
sulfinylallylic alcohol (Ss)-9 (2.4 g; 57%) as a colorless oil. Crystallization in diisopropylether afforded
diastereomerically pure (Ss,R)-9 (0.987 g; 22%) as a white solid. IR (KBr): 3356 (OH), 1590 (C_C),
1079, 1032 (S_O), 932, 813 cm−1. (Ss,R)-9 (41%): [α]D +195 (c 0.54, ethanol). M.p. 91–92°C (ether).
1H NMR δ 0.84 (t, J=7.3 Hz, 3H); 1.58–1.66 (m, 2H); 2.17 (d, J=5.6 Hz, 1H, OH); 2.38 (s, 3H); 4.03
(m, 1H); 5.81 (s, 1H, Htrans); 6.04 (s, 1H, Hcis); 7.27 and 7.53 (AA0BB0system, 2d, J=7.8 Hz, 4Harom).
1
(Ss,S)-9 (59%): H NMR δ 0.87 (t, J=7.3 Hz, 3H); 1.54–1.65 (m, 2H); 2.39 (s, 3H); 2.92 (d, J=3.5 Hz,
1H, OH); 4.05 (m, 1H); 5.83 (s, 1H, Htrans); 6.05 (s, 1H, Hcis); 7.31 and 7.54 (AA0BB0 system, 2d, J=7.8
Hz, 4Harom).
4.6. Synthesis of (R)-2-p-tolysulfanylpent-3-en-2-ol 7
A solution of (Ss,R)-9 (448 mg; 2 mmol), CF3SO3SiMe2tBu (700 µL; 3 mmol) and 2,6-lutidine (465
µL; 4 mmol) in dichloromethane (2 mL) was stirred for 2 h at ambient temperature. The reaction mixture
was then poured into water (2 mL) and the resulting suspension extracted with petroleum ether (3×6
mL). The organic extracts were combined, dried and concentrated to give the corresponding silylether
1
(693 mg; 95%) as a colorless liquid. H NMR data shown that no purification was necessary. [α]D +43

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P. Hayes, C. Maignan / Tetrahedron: Asymmetry 10 (1999) 1041–1050
(c 0.5, ethanol). IR (film): 3050, 2954, 2929, 1621, 1471, 1081 cm−1. 1H NMR δ −0.31 (s, 3H); −0.16 (s,
3H); 0.79–0.87 (s+t, J=7.5 Hz, 12H); 1.47–1.60 (m, 2H); 2.40 (s, 3H); 4.08 (t, J=5.3 Hz, 1H); 5.89 (s, 1H,
H
trans); 6.05 (s, 1H, Hcis); 7.27 and 7.51 (AA0BB0 system, 2d, J=8 Hz, 4Harom). 13C NMR δ −5.30 (q);
−5.23 (q); 9.04 (q); 17.97 (s); 21.34 (q); 25.61 (q); 31.43 (t); 70.07 (d); 118.53 (t); 125.26 (2d); 129.76
(2d); 139.43 (s); 141.58 (s); 156.81 (s).
To a stirred suspension of P2I4 (1.076 g; 1.9 mmol) in ether (25 mL) was added a solution of silylether
(647 mg; 1.9 mmol) in ether (25 mL) containing pyridine (1.9 mL). The mixture was then stirred for 1 h
at room temperature, quenched by addition of water (15 mL) and extracted with ether (3×30 mL). The
combined ether layers were successively washed with 10% HCl (10 mL); 5% H2SO3 solution and brine.
Drying (MgSO4) and concentration in vacuo gave the sulfide silylether (490 mg; 80%) as a colorless
1
liquid. [α]D −50.3 (c 0.5, ethanol). IR (film): 3023, 2958, 2929, 1604, 1095, 1018 cm−1. H NMR δ
0.026 (s, 3H); 0.043 (s, 3H); 0.88 (t, J=7.4 Hz, 3H); 0.91 (s, 9H); 1.65–1.77 (m, 2H); 2.35 (s, 3H); 4.10
(t, J=5.7 Hz, 1H); 4.74 (d, J=0.68 Hz, 1H, Htrans); 5.32 (d, J=0.68 Hz, 1H, Hcis); 7.14 and 7.33 (AA0BB0
system, 2d, J=8 Hz, 4Harom). 13C NMR δ −5.08 (q); −4.73 (q); 9.38 (q); 18.24 (s); 21.16 (q); 25.82 (q);
30.06 (t); 75.99 (d); 110.48 (t); 128.99 (d); 129.91 (d); 134.06 (s); 138.05 (s); 149.83 (s).
Tetrabutylammonium fluoride (3 mL, 1 molar in THF) was added to a solution of sulfide silylether
(480 mg; 1.49 mmol) in THF (6 mL) at 0°C. After 2 h at room temperature, the solvent was removed
under reduced pressure and the residue purified by chromatography (eluent: ether:petroleum ether, 2:8)
to give (R)-7 as a colorless liquid. (R)-7: [α]D −100 (c 0.5, ethanol). IR (film): 3363, 3035, 2958, 2857,
1
1608, 1492, 1095 cm−1. H NMR δ 0.93 (t, J=7.4 Hz, 3H); 1.69 (dq, J=7.4 and 6.4 Hz, 1H); 1.78 (dq,
J=7.4 and 6.4 Hz, 1H); 1.85 (d, J=4.8 Hz, 1H, OH); 2.33 (s, 3H); 4.12 (q, J=6.4 Hz, 1H); 4.79 (s, 1H,
H
trans); 5.34 (s, 1H, Hcis); 7.13 and 7.33 (AA0BB0 system, 2d, J=8 Hz, 4Harom). 13C NMR δ 9.74 (q);
21.09 (q); 28.88 (t); 75.91 (d); 111.31 (t); 128.41 (s); 130.01 (d); 133.86 (d); 138.25 (s); 149.58 (s).
4.7. (Ss,2R,R) and (Ss,2S,R)-1-(6-Methyl-5-p-tolylsulfinyl-3-p-tolylsulfanyl-3,4-dihydro-2H-pyran-
2-yl)-propan-1-ols 11
A solution of (Ss)-1 (160 mg; 0.77 mmol) and (R)-7 (157 mg; 0.75 mmol) in dichloromethane (10
mL) was refluxed for 5 days. After cooling and concentration under reduced pressure, the residue was
purified by chromatography on silica gel (eluent: ether:petroleum ether, 2:8; 5:5 then pure ether) to
afford (Ss,2S,R)-11 (137 mg; 44%) as a colorless oil and (Ss,2R,R)-11 (66 mg; 21%) as a white solid.
Calcd for C23H29O3S2 [M+H]: 417.1558; found: 417.1556. IR (film): 3388, 3052, 1648, 1492, 1087
1
cm−1. (Ss,2S,R)-11: [α]D +275 (c 0.58, ethanol). H NMR δ 0.96 (t, J=7.4 Hz, 3H); 1.36–1.46 (m,
2H); 1.61–1.72 (m, 2H); 2.00 (ddd, J=14.7, 6.5 and 2 Hz, 1H); 2.21 (s, 3H); 2.38 (s, 3H); 2.41 (s, 3H);
2.56–2.66 (m, 1H); 2.66 (s, 1H, OH); 3.39 (d, J=9.8 Hz, 1H); 7.17–7.37 and 7.30–7.41 (AA0BB0 systems,
4d, J=8 Hz, 8Harom). 13C NMR δ 11.23 (q); 13.85 (t); 17.68 (q); 21.18 (q); 21.22 (q); 22.89 (t); 24.22 (t);
73.98 (d); 93.24 (s); 115.60 (s); 124.17 (d, 2CHAr); 124.41 (s); 129.62 (d, 2CHAr); 129.66 (d, 2CHAr);
137.00 (d, 2CHAr); 139.66 (s); 139.97 (s); 140.35 (s); 154.86 (s). (Ss,2R,R)-11: m.p. 108–112°C (ether).
1
[α]D −429 (c 0.55, ethanol). H NMR δ 0.94 (t, J=7.4 Hz, 3H); 1.19–1.40 (m, 1H); 1.69–1.81 (m, 2H);
2.00–2.05 (m, 2H); 2.14 (td, J=12.9 and 6.2 Hz, 1H); 2.28 (s, 3H); 2.34 (s, 3H); 2.37 (s, 3H); 2.37–2.45
(m, 1H); 3.42 (d, J=10 Hz, 1H); 7.11–7.28 and 7.21–7.48 (AA0BB0 systems, 4d, J=8 Hz, 8Harom). 13C
NMR δ 11.23 (q); 12.23 (t); 17.57 (q); 21.16 (q); 21.22 (q); 23.28 (t); 23.57 (t); 75.55 (d); 91.88 (s);
114.69 (s); 124.45 (d, 2CHAr); 125.14 (s); 129.50 (d, 2CHAr); 129.62 (d, 2CHAr); 136.46 (d, 2CHAr);
138.93 (s); 139.42(s); 140.24 (s); 155.89 (s).

P. Hayes, C. Maignan / Tetrahedron: Asymmetry 10 (1999) 1041–1050
1049
4.8. (Ss,1S,4S,5S,7R)-7-Ethyl-5-methyl-1-p-tolylsulfanyl-4-p-tolylsulfinyl-6,8-dioxabicyclo[3.2.1]-
octane 6
A solution of (Ss,2S,R)-11 (100 mg; 0.24 mmol) and p-toluene sulfonic acid (11.5 mg; 0.06 mmol) in
dichloromethane (12 mL) was stirred at ambient temperature for 12 h. After evaporation of the solvent
in vacuo, the residue was purified by chromatography (eluent: ether:petroleum ether, 2:8 and then 4:6)
to give (Ss,1S,4S,5S,7R)-6 (90 mg, 90%) as a white solid. [α]D +55 (c 0.5, ethanol). M.p. 131–132°C
1
(ether). IR (KBr): 3004, 2989, 2925, 1492, 1380, 1203, 1047, 995, 808, 493 cm−1. H NMR δ 1.02 (t,
J=7.3 Hz, 3H); 1.37 (dd, J=13.5 and 5.9 Hz, 1H); 1.56–1.63 (m, 1H); 1.71 (s, 3H); 1.72–1.81 (m, 1H);
1.90–1.99 (m, 1H); 2.06 (dd, J=14.7 and 6.3 Hz, 1H); 2.18 (td, J=13.5 and 6.3 Hz, 1H); 2.31 (s, 3H);
2.35 (s, 3H); 2.55 (d, J=6 Hz, 1H); 3.96 (dd, J=9.6 and 3 Hz, 1H); 7.13–7.37 and 7.24–7.47 (AA0BB0
systems, 4d, J=8 Hz, 8Harom). 13C NMR δ 10.21 (q); 16.65 (t); 21.21 (q); 21.28 (q); 24.49 (q); 25.37 (t);
31.91 (t); 66.82 (d); 83.44 (d); 93.23 (s); 107.82 (s); 123.89 (d, 2CHAr); 126.35 (s); 129.64 (d, 2CHAr);
129.85 (d, 2CHAr); 134.99 (d, 2CHAr); 138.67 (s); 141.00 (s); 141.70 (s). MS (EI, 70 eV): m/z (%)=417
(M+1, 2), 416 (M+, 5), 399 (12), 339 (25), 277 (13), 218 (26), 189 (14), 165 (15), 153 (11), 124 (28),
123 (29), 111 (34), 95 (100), 91 (50).
4.9. (1S,5S,7R)-7-Ethyl-5-methyl-1-p-tolylsulfanyl-6,8-dioxabicyclo[3.2.1]octane 12
A solution of (Ss,1S,4S,5S,7R)-6 (188 mg; 0.45 mmol) in freshly distilled benzene (6 mL) was mixed
with tri-n-butyltin hydride (306 µL; 2 equiv.) and a catalytic amount of azobisisobutyronitrile (AIBN,
2 mg) and refluxed over 48 h. After cooling and concentration under reduced pressure, the residue was
purified by chromatography on silica gel (eluent: petroleum ether) to give (1S,5S,7R)-12 (90 mg; 72%) as
a colorless oil. [α]D −132 (c 0.7, ethanol). Calcd for C16H21O2S [M+H]: 277.1262; found: 277.1255. IR
(neat): 3040, 2923, 2875, 1643, 1492, 1386, 1241, 1201, 1128, 1070, 1020, 991, 872, 812 cm−1. 1H NMR
δ 1.04 (t, J=7.3 Hz, 3H); 1.59 (s, 3H); 1.65–1.83 (m, 2S); 1.92 (ddd, J=17.8, 4.3 and 1.6 Hz, 1H); 2.33
(s, 3H); 2.50 (ddd, J=17.8, 2.3 and 2.3 Hz, 1H); 3.92 (dd, J=9.7 and 3.4 Hz); 5.63 (ddd, J=9.4, 4.3 and
2.4 Hz, 1H); 5.76 (ddd, J=9.4, 2.4 and 1.8 Hz, 1H); 7.12–7.48 (AA0BB0 systems, 4d, J=8.2 Hz, 4Harom).
13C NMR δ 11.02 (t); 21.20 (t); 21.48 (q); 24.67 (q); 38.39 (t); 84.38 (d); 90.88 (s); 103.46 (s); 125.95
(d); 128.78 (d); 131.08 (d); 135.32 (s); 135.45 (d); 138.70 (s).
4.10. exo-(1R,5S,7R)-(7-Ethyl-5-methyl-6,8-dioxabicyclo[3.2.1]oct-3-ene 13
A solution of (1S,5S,7R)-12 (81 mg; 0.29 mmol) in freshly distilled benzene (1 mL) was mixed with
tri-n-butyltin hydride (195 µL; 0.72 mmol) and a solution of azobisisobutyronitrile (1% in benzene, 200
µL). The mixture was degassed with a stream of argon for 30 min and then placed into a preheated
oil bath (90–100°C). The solution was heated at 80°C for 4 days. Removal of the solvent and column
chromatography of the residue (eluent: petroleum ether) afforded pure exo-(1R,5S,7R)-13 (19 mg; 42%)
as a colorless liquid. [α]D −88 (c 0.5, CHCl3) (lit.21: [α]D −90.5 (c 0.95, CHCl3); [α]D −71 (c 2.5,
1
ether)). IR (neat): 3060, 2980, 1640, 1425, 1395, 1380, 1255, 1200, 1150, 1130, 1115 cm−1. H NMR
δ 0.94 (t, J=7.5 Hz, 3H); 1.53 (s, 3H); 1.55–1.65 (m, 2H); 1.85 (ddd, J=17.9, 4.3 and 1.8 Hz, 1H); 2.64
(dddd, J=17.9, 4.4, 2.3 and 2.3 Hz); 3.79 (td, J=6.3 and 1.6 Hz, 1H); 4.24 (m, 1H); 5.71 (dddd, J=9.5,
4.4, 2.2 and 1.8 Hz); 5.82 (ddd, J=9.6, 2.3 and 1.8 Hz, 1H). MS (EI, 70 eV): m/z (%)=154 (M+, 1.89);
137 (1.4); 125 (8); 111 (20); 95 (34); 83 (17); 67 (13); 57 (18); 43 (100).

1050
P. Hayes, C. Maignan / Tetrahedron: Asymmetry 10 (1999) 1041–1050
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