Enantioselective hydrogenation of β-keto sulfones with chiral Ru(II)- catalysts: Synthesis of enantiomerically pure butenolides and γ- butyrolactones

Article abstract of DOI:10.1016/S0957-4166(99)00113-5

A series of β-hydroxy sulfones were synthesized with high enantioselectivities via a new enantioselective ruthenium-catalyzed hydrogenation using MeO-BIPHEP as a ligand. Some β-hydroxy sulfones were used in the synthesis of optically active butenolides and γ-butyrolactones with high yields and enantioselectivities over 95%.

Full text of DOI:10.1016/S0957-4166(99)00113-5

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1369–1380
Enantioselective hydrogenation of β-keto sulfones with chiral
Ru(II)-catalysts: synthesis of enantiomerically pure butenolides
and γ-butyrolactones
P. Bertus,a P. Phansavath,a V. Ratovelomanana-Vidal,a J.-P. Genêt,a,∗ A. R. Touati,b T. Homri b
and B. Ben Hassine b
aLaboratoire de Synthèse Sélective Organique et Produits Naturels, Associé au C.N.R.S., Ecole Nationale Supérieure de
Chimie de Paris, 11 rue P. et M. Curie, 75231 Paris Cedex 05, France
bFaculté des Sciences, Laboratoire de Synthèse Organique et Photochimie, Avenue de l’Environnement, 5000 Monastir,
Tunisia
Received 5 March 1999; accepted 25 March 1999
Abstract
A series of β-hydroxy sulfones were synthesized with high enantioselectivities via a new enantioselective
ruthenium-catalyzed hydrogenation using MeO-BIPHEP as a ligand. Some β-hydroxy sulfones were used in the
synthesis of optically active butenolides and γ-butyrolactones with high yields and enantioselectivities over 95%.
© 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Recent investigations in this laboratory have focused on the development of asymmetric catalysts
for the enantioselective hydrogenation of prochiral olefins and keto groups.1 Initial work in this area
resulted in the first general method1 for the preparation of chiral Ru(II)-catalysts and their uses in
the asymmetric hydrogenation of a wide range of prochiral keto groups.2 The chiral Ru(II)-catalysts,
readily prepared in situ from commercially available CODRu(methylallyl)2 and the chiral diphosphine
by addition of methanolic HBr, are highly effective catalysts for the enantioselective hydrogenation of
functionalized ketones containing sulfur groups.1 Because of the potential usefulness of optically active
hydroxy sulfones as chiral synthons in organic synthesis, their preparation in enantiomerically pure
form has stimulated a great deal of interest.3,4 These compounds have been used in the synthesis of
optically active γ-butyrolactones5 and δ-valerolactones.15 They are also key intermediates in obtaining
∗
Corresponding author. E-mail: genet@ext.jussieu.fr
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00113-5

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enantiomerically pure 2,5-disubstituted tetrahydrofuran units or chiral epoxides containing an electron-
withdrawing sulfonyl group at the β-position.7 The alkylation of β-hydroxy sulfones with electrophilic
reagents has also been reported, leading to enantiomerically enriched allylic alcohols8 (Scheme 1).
Scheme 1.
One of the most practical routes to enantiomerically enriched sulfones is the baker’s yeast-mediated
reduction of β-keto sulfones.9 However, the corresponding β-hydroxy sulfones were prepared in enan-
tiomeric excesses depending on the substrate: 1-(phenylsulfonyl)propan-2-one was reduced to the (S)-
alcohol in 98% yield and 95% e.e. If the pentyl or phenyl analogues were submitted to microbial trans-
formation instead, the corresponding hydroxy sulfones were obtained in 10 and 15% e.e., respectively
(Scheme 1, R=n-C5H11 or Ph), and this is one critical limitation of this reduction.6,9,10 The kinetic
resolution of β-hydroxy sulfones has been described with porcine pancreatic lipase (PPL) with moderate
selectivities.11 A tartaric acid-modified Raney nickel reagent has been employed to perform the chemical
reductions of β-keto sulfones in moderate (70%) e.e.12 This report describes the ruthenium-catalyzed
asymmetric hydrogenation of β-keto sulfones as a new application of our simple in situ preparation of
chiral Ru(II)-catalysts1 and a practical route to optically active lactones.
2. Results and discussion
All β-hydroxy sulfones were conveniently prepared through (S)-BINAP or (S)-MeO-
BIPHEP/ruthenium catalyzed hydrogenation of the corresponding β-keto sulfones 1–11 easily
prepared by condensation of the dianion of methyl phenyl sulfone with various acid chlorides or
esters.13 As a preliminary evaluation of the best experimental reaction conditions, we have examined
the ruthenium-promoted hydrogenations of 1-phenylsulfonyl-butan-2-one 1. The screening tests were
carried out on a mmol scale (Table 1). At high pressure (100 bar) and 30°C, a moderate conversion
was obtained (entry 1). In decreasing hydrogen pressure to 75 bar at 50°C, very good conversion and
enantioselectivity were obtained (entry 2). In lowering the hydrogen pressure to 10 bar at a higher
temperature (80°C), the (R)-alcohols were synthesized with excellent enantiofacial discrimination with
(R)-BINAP (entry 3, 92% e.e.) and (R)-MeO-BIPHEP (entry 4, e.e. >95%). Finally, the hydrogenation
reaction was readily carried out using very mild conditions at atmospheric pressure in refluxing methanol
using the (S)-configuration of the ligand to afford alcohol (S)-12 in an enantiomerically pure form (entry
5).

P. Bertus et al. / Tetrahedron: Asymmetry 10 (1999) 1369–1380
1371
Table 1
Ruthenium-catalyzed hydrogenation of 1-(phenylsulfonyl) butan-2-one 1
Hydrogenation reactions of functionalized β-keto sulfones 2–5 were therefore conducted at atmos-
pheric pressure in refluxing methanol using 1 mol% of the chiral ruthenium(II) catalyst. Our results are
summarized in Table 2. 1-(Phenylsulfonyl)propan-2-one 2 was reduced to (R)-1-(phenylsulfonyl)propan-
2-ol 13 with a slightly better enantioselectivity using (R)-MeO-BIPHEP compared to (R)-BINAP (entries
1 and 2). Both enantiomers (R)-13 and (S)-13 were synthesized in enantiomerically pure forms with
(R)- and (S)-MeO-BIPHEP, respectively (entries 2 and 3). However, in the hydrogenation reaction of
1-(phenylsulfonyl) heptan-2-one 3 promoted by ruthenium–BINAP complexes, both the activity and
enantiomeric excess were moderate (entry 4, 82% e.e.) in contrast to the high enantiofacial discrimination
and complete conversion observed with (R)-MeO-BIPHEP (entry 5, e.e. >95%).
When the β-keto sulfone 4 was substituted with a cyclohexyl ring, both (R)-BINAP and (S)-MeO-
BIPHEP led to comparable yields and enantioselectivities (entries 6 and 7, 91% and >95% e.e.). The
ruthenium-mediated hydrogenation of 3-chloro-1-(phenylsulfonyl) propan-2-one 5 proceeded smoothly
to afford (R)-16 with high enantioselectivity (entry 8, 90% e.e.). The ruthenium-mediated hydrogenation
of β-keto sulfones 6, 7 and 8, bearing a long alkyl chain, required 10 bar and 80°C to afford the
corresponding enantiomerically pure β-hydroxy sulfones 17, 18 and 19 with complete conversions
(entries 9 to 13). Finally, the hydrogenation reaction of β-keto sulfones bearing an aromatic substituent
9, 10 and 11 required more drastic conditions: 1-phenyl-2-(phenylsulfonyl)ethan-1-one 9 was not
completely hydrogenated at atmospheric pressure (entry 14). When conducted at 75 bar and 80°C,
the hydrogenation reaction quantitatively yielded the corresponding β-hydroxy sulfone 20 with 88%
e.e. (entry 15). When the temperature was decreased to 40°C (entry 16), a significant increase in the
enantiofacial discrimination was observed, leading to the corresponding β-hydroxy sulfone (S)-20 with
excellent enantioselectivity (over 95%). The influence of the temperature was also observed when the
phenyl ring was substituted with a chlorine or fluorine group in the para-position, and the corresponding
β-hydroxysulfones (R)-21 and (R)-22 were synthesized with high selectivities (entries 17 and 18).

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Table 2
Ruthenium-catalyzed hydrogenation of functionalized sulfones
Butenolides and saturated γ-lactones are incorporated in the structures of a variety of natural com-
pounds such as flavor components and insect pheromones.16,17 Having in hand a highly practical and
enantioselective route to both enantiomers of various β-hydroxy sulfones, we applied this methodology
to the stereoselective synthesis of some butenolides and γ-butyrolactones. All butenolides were con-

P. Bertus et al. / Tetrahedron: Asymmetry 10 (1999) 1369–1380
1373
veniently prepared from the corresponding β-hydroxysulfones via a three-step sequence:18 reaction of
the dianion of the β-hydroxy sulfones 12–14 and 18 with sodium acetate followed by acid catalyzed
lactonization and elimination of phenyl sulfonyl group with triethylamine. The syntheses of (R)- and
(S)-angelica lactone 23, which are interesting synthons for the preparation of natural products bearing
a γ-lactone moiety, were reported for the first time by Font in 11 steps from tartaric acid.19 Since then
a considerable number of syntheses have been described, including a one-step procedure from methyl
trans-3-pentenoate affording (S)-angelica lactone in 78% e.e.20 Thus, we prepared both enantiomers (R)-
and (S)-β-angelica lactone 23, from the corresponding enantiomerically pure β-hydroxysulfones 13, in
equal overall yields (41%) and in almost enantiomerically pure forms (Scheme 2). A butenolide bearing a
long alkyl chain (i.e. γ-tridecylbutenolide 26) was synthesized in 38% overall yield and enantiomerically
pure form. This compound is a key intermediate in the synthesis of the natural lactone fatty acid (−)-
protolichesterinic.18,21
Scheme 2.
Following the same general sequence (Scheme 2) with an additional hydrogenation step (Scheme 3),
we achieved the synthesis of optically pure (R)-hexanolide, a component of the pheromone secreted by
the female dermestid beetle Trogoderma glabrum L.5,22
Scheme 3.
The trans tetrahydro-4-methyl-5-pentylfuran-2-one 28, identified as an aroma component of cognac,
was obtained from the pure butenolide 25 (Scheme 2) by conjugate addition of lithium dimethyl cuprate
in 65% yield (Scheme 4).23
Scheme 4.

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3. Conclusion
When comparing the present results of reductions of the β-keto sulfones to those using baker’s yeast,
the following comments can be made: in the case of baker’s yeast mediated reductions, an increase in the
number of carbon atoms adjacent to the carbonyl group decreases the e.e. values. Enzymatic reduction
and ruthenium-catalyzed hydrogenation give similar yields and enantioselectivities for compound 2.9
However, the ruthenium-promoted hydrogenation reaction of β-keto sulfones can be conducted at
atmospheric pressure and gives, in most cases, more satisfactory e.e. values compared to those using
baker’s yeast9 and this was the most efficient method. Our technique is advantageous for several reasons,
i.e. its wide scope and predictable absolute configurations of the chiral β-hydroxy sulfones because of
the ready availability of the chiral Ru(II)-catalyst in either enantiomeric forms. Furthermore, this simple
process gives high yields and a practical route to enantiomerically pure butenolides and γ-lactones.
4. Experimental
4.1. General
All NMR spectra were measured in CDCl3 using a Bruker AC 200 or 400 instrument, and chemical
shifts are expressed in ppm relative to internal CHCl3 (7.26 ppm). Infrared spectra were recorded on a
Perkin–Elmer 783 spectrometer. Optical rotations were measured on a Perkin–Elmer 241 polarimeter.
Enantiomeric excesses were determined by 1H NMR with Eu(tfc)3.
4.2. General procedure for the preparation of 2-ketosulfones13b
Butyllithium (11.2 mL of a 2.5 M solution, 28 mmol) was added slowly under argon to a solution of
methyl phenyl sulfone (2.0 g, 13 mmol) in 40 mL of anhydrous THF at −30°C. After 30 min, the acid
chloride (15 mmol) was slowly added by syringe. Subsequently, the reaction mixture was poured into 150
mL of a saturated NH4Cl solution and stirred. The β-keto sulfone was extracted with dichloromethane
and the organic phase was washed with a saturated NaCl solution, dried with magnesium sulfate, filtered
and concentrated. Recrystallization from CCl4 or column chromatography of the crude product afforded
the β-keto sulfones 1, 3, 4 and 6–9.
1-(Phenylsulfonyl)propan-2-one 2 is commercially available from Aldrich. Compound 5 was prepared
by condensation of methylphenylsulfone with ethyl chloroacetate13a while syntheses of 10 and 11 were
performed in two steps according to a literature procedure.13c
4.2.1. (Phenylsulfonyl)butan-2-one 1
1
A white solid (2.0 g, 73%): mp 48°C. IR (CHCl3): 1720, 1330, 1150 cm−1. H NMR (200 MHz,
CDCl3) δ 1.08 (3H, t, J=7.2 Hz), 2.75 (2H, q, J=7.2 Hz), 4.17 (2H, s), 7.54 (3H, m), 7.85–7.95 (2H, m).
13C NMR (50 MHz, CDCl3) δ 7.3, 37.8, 66.7, 128.2, 129.3, 134.2, 138.7, 198.6. MS (EI): m/e=212 (14,
M+), 183 (18), 141 (27).
4.2.2. (Phenylsulfonyl)heptan-2-one 3
1
A pale yellow solid (1.75 g, 73%): mp 38°C. IR (CHCl3): 1710, 1310, 1150 cm−1. H NMR (200
MHz, CDCl3) δ 0.88 (3H, t, J=6.6 Hz), 1.15–1.35 (4H, m), 1.55 (2H, quint, J=7.2 Hz), 2.69 (2H, t, J=7.2

P. Bertus et al. / Tetrahedron: Asymmetry 10 (1999) 1369–1380
1375
Hz), 4.15 (2H, s), 7.53–7.73 (3H, m), 7.86–7.90 (2H, m). 13C NMR (50 MHz, CDCl3) δ 13.8, 22.3, 22.7,
30.9, 44.3, 66.7, 128.2, 129.3, 134.2, 138.7, 198.2. MS (EI): m/e=255 (10, M+H), 198 (19), 141 (42).
4.2.3. Cyclohexyl-2-phenylsulfonyl-ethan-1-one 4
1
A white solid (2.4 g, 69%): mp 89°C. IR (CHCl3): 1710, 1310, 1150 cm−1. H NMR (200 MHz,
CDCl3) δ 1.10–1.40 (5H, m), 1.60–1.90 (5H, m), 2.50–2.70 (1H, m), 4.20 (2H, s), 7.5–7.7 (3H, m), 7.88
(2H, d, J=7.0 Hz). 13C NMR (50 MHz, CDCl3) δ 25.2, 25.5, 27.8, 51.4, 64.7, 128.3, 129.2, 134.1, 138.9,
201.2. MS (EI) m/e=267 (4, M−H+), 141 (18), 124 (66).
4.2.4. Chloro-1-phenylsulfonyl-propan-2-one 5
1
A white solid (1.4 g, 60%): mp 48°C. IR (CHCl3): 1720, 1310, 1160 cm−1. H NMR (200 MHz,
CDCl3) δ 4.39 (4H, s), 7.58–7.78 (3H, m), 7.89–7.94 (2H, m). 13C NMR (50 MHz, CDCl3) δ 48.7, 64.1,
128.3, 129.5, 134.6, 138.1, 190.2. MS (EI): m/e=232 (9, M+), 183 (35), 141 (85).
4.2.5. (Phenylsulfonyl)tridecan-2-one 6
1
A white solid (2.2 g, 50%): mp 74°C. IR (CHCl3): 1725, 1320, 1160 cm−1. H NMR (200 MHz,
CDCl3) δ 0.87 (3H, t, J=6.3 Hz), 1.23 (18H, s), 1.57 (2H, m), 2.69 (2H, t, J=7.2 Hz), 4.14 (2H, s),
7.53–7.72 (3H, m), 7.85–7.90 (2H, m). 13C NMR (50 MHz, CDCl3) δ 14.0, 22.6, 23.0, 28.7, 29.2, 29.5,
31.8, 44.4, 66.7, 128.2, 129.2, 134.2, 138.5, 198.0.
4.2.6. (Phenylsulfonyl)pentadecan-2-one 7
1
A white solid (2.5 g, 52%): mp 75°C. IR (CHCl3): 1710, 1320, 1160 cm−1. H NMR (200 MHz,
CDCl3) δ 0.87 (3H, t, J=6.4 Hz), 1.24 (2H, s), 1.54 (22H, m), 2.69 (2H, t, J=7.2 Hz), 4.14 (2H, s),
7.53–7.72 (3H, m), 7.85–7.90 (2H, m). 13C NMR (50 MHz, CDCl3) δ 14.1, 22.6, 23.1, 28.8, 29.3, 29.6,
32.0, 44.4, 66.7, 128.2, 129.3, 134.2, 138.7, 198.2.
4.2.7. (Phenylsulfonyl)heptadecan-2-one 8
1
A white solid (4.2 g, 41%): mp 77°C. IR (CHCl3): 1710, 1320, 1160 cm−1. H NMR (200 MHz,
CDCl3) δ 0.87 (3H, t, J=6.5 Hz), 1.25 (25H, s), 1.57 (2H, m), 2.69 (2H, t, J=7.2 Hz), 4.14 (2H, s),
7.53–7.72 (3H, m), 7.85–7.90 (2H, m). 13C NMR (50 MHz, CDCl3) δ 14.0, 22.6, 23.0, 28.7, 29.2, 29.6,
31.8, 44.4, 66.7, 128.2, 129.2, 134.2, 138.6, 198.2.
4.2.8. Phenyl-2-phenylsulfonyl-ethan-1-one 9
1
A white solid (2.6 g, 76%): mp 100°C. IR (CHCl3): 1700, 1320, 1160 cm−1. H NMR (200 MHz,
CDCl3) δ 4.77 (2H, s), 7.47–7.74 (6H, m), 7.90–8.00 (4H, m). 13C NMR (50 MHz, CDCl3): δ 63.2,
128.4, 128.7, 129.1, 134.1, 134.2, 135.5, 138.6, 187.9. MS (EI): m/e=260 (0.5, M+), 196 (45), 105 (100).
4.2.9. p-Chlorophenyl-2-phenylsulfonyl-ethan-2-one 10
A white solid: mp 118°C. IR (CHCl3): 1690, 1330, 1170 cm−1. 1H NMR (200 MHz, CDCl3) δ 4.73
(2H, s), 7.28–7.70 (5H, m), 7.87–7.94 (4H, m). 13C NMR (50 MHz, CDCl3) δ 63.5, 128.4, 129.2, 130.6,
133.9, 134.3, 138.5, 141.0, 186.7. MS (EI): m/e=294 (0.9, M+), 139 (100), 77 (54).
4.2.10. p-Fluorophenyl-2-phenylsulfonyl-ethan-2-one 11
A white solid: mp 115°C. IR (CHCl3): 1670, 1310, 1160 cm−1. 1H NMR (200 MHz, CDCl3) δ 4.73
(2H, s), 7.14–7.75 (5H, m), 7.89–8.06 (4H, m). 13C NMR (50 MHz, CDCl3) δ 63.5, 128.4, 129.2, 132.0,
132.2, 134.2, 138.5, 186.3. MS (EI): m/e=278 (0.5, M+), 123 (100), 77 (50).

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4.3. Typical procedure for the asymmetric hydrogenation of β-keto sulfones 1–11 to β-hydroxysulfones
12–22
(R)-MeO-BIPHEP (7.0 mg, 0.012 mmol) and CODRu(2-methylallyl)2 (3.2 mg, 0.01 mmol, commer-
cially available from Acros), were placed in a Schlenk tube and dissolved in 1 mL of acetone (degassed
by three cycles of vacuum/argon at room temperature). To this suspension was added 147 µL of a 0.15
N methanolic HBr solution (0.022 mmol) and the mixture was stirred at room temperature for 30 min. A
yellow solid precipitated. The solvent was evaporated under vacuum and keto sulfone (1 mmol) in MeOH
(1 mL) was added to the Ru(II)-catalyst. The resulting mixture was placed under the desired hydrogen
pressure and temperature for 18–35 h. After removal of the solvent, the residue was purified by silica gel
chromatography to afford the hydroxysulfone.
All reactions were run on a 1 mmol scale and led to the corresponding β-hydroxysulfones in
quantitative yields except where specified.
4.3.1. (S)-1-(Phenylsulfonyl)propan-2-ol (S)-13
Starting from 1.4 g (7 mmol) of 2, the reaction yielded 1.4 g (7 mmol, 100%) of 13 as a pale yellow
oil. [α]20=+15 (c 1.6, CHCl3), lit.11 [α]25=+15.1 (c 1.3, CHCl3). IR (CHCl3): 3500, 1310, 1150 cm−1.
D
D
1H NMR (200 MHz, CDCl3) δ 1.25 (3H, d, J=6.4 Hz), 3.13–3.43 (3H, m), 4.27–4.42 (1H, m), 7.47–7.71
(3H, m), 7.93–7.98 (2H, m). 13C NMR (50 MHz, CDCl3) δ 22.6, 62.3, 63.3, 127.9, 129.5, 134.1, 139.13.
MS (EI): m/e=201 (8, M−H+), 141 (39).
4.3.2. (R)-1-(Phenylsulfonyl)butan-2-ol (R)-12
Starting from 414 mg (1.95 mmol) of 1, the reaction yielded 380 mg (1.77 mmol, 91%) of 12 as a white
solid: mp 50°C. [α]20=−22 (c 1.0, CHCl3). IR (CHCl3): 3500, 1300, 1150 cm−1. 1H NMR (200 MHz,
D
CDCl3) δ 0.94 (3H, t, J=7.4 Hz), 1.44–1.67 (2H, m), 3.16–3.32 (2H, m), 3.40 (1H, s, OH), 4.02–4.20
(1H, m), 7.59–7.75 (3H, m), 7.92–7.97 (2H, m). 13C NMR (50 MHz, CDCl3) δ 9.3, 29.4, 61.9, 67.1,
127.8, 129.4, 134.0, 139.2. MS (EI): m/e=214 (15, M−H+), 185 (65), 141 (48).
4.3.3. (R)-1-(Phenylsulfonyl)heptan-2-ol (R)-14
Starting from 1.38 g (5.4 mmol) of 3, the reaction yielded 1.26 g (4.9 mmol, 91%) of 14 as a colorless
oil. [α]20=−15 (c 1.04, CHCl3), lit.12 [α]20=−19.9 (c 5, EtOH). IR (CHCl3): 3450, 1310, 1150 cm−1. 1H
D
D
NMR (200 MHz, CDCl3) δ 0.81–0.95 (3H, m), 1.20–1.80 (8H, m), 3.20–3.40 (3H, m), 4.10–4.25 (1H,
m), 7.51–7.80 (3H, m), 7.90–8.00 (2H, m). 13C NMR (50 MHz, CDCl3) δ 13.9, 22.4, 24.6, 31.4, 36.4,
62.2, 65.9, 127.9, 129.4, 134.0, 139.3. MS (EI): m/e=255 (M−H+), 198 (13), 141 (21).
4.3.4. (R)-1-Cyclohexyl-2-phenylsulfonyl-ethan-1-ol (R)-15
A colorless oil. [α]20=−20 (c 1.0, CHCl3). IR (CHCl3): 3550, 1310, 1150 cm−1. 1H NMR (200 MHz,
D
CDCl3) δ 0.95–1.90 (11H, m), 3.20–3.30 (2H, m), 3.47 (1H, s, OH), 3.91–3.98 (1H, m), 7.55–7.73 (3H,
m), 7.91–7.96 (2H, m). 13C NMR (50 MHz, CDCl3) δ 25.8, 25.9, 26.1, 27.4, 28.4, 43.1, 60.2, 69.7,
127.8, 129.4, 133.9, 139.2. MS (EI): m/e=269 (5, M−H+), 185 (100), 141 (55).
4.3.5. (S)-1-Phenyl-2-phenylsulfonyl-ethan-1-ol (S)-20
A white solid: mp 112°C. [α]20=+29 (c 1.0, CHCl3). IR (CHCl3): 3450, 1310, 1150 cm−1. 1H NMR
D
(200 MHz, CDCl3) δ 3.35 (1H, dd, J=14.3 and 2.0 Hz), 3.50 (1H, dd, J=14.3 and 9.8 Hz), 3.67 (1H, s,
OH), 5.28 (1H, dd, J=9.8 and 2.0 Hz), 7.25–7.31 (5H, m), 7.50–7.78 (3H, m), 7.94–7.98 (2H, m). 13C

P. Bertus et al. / Tetrahedron: Asymmetry 10 (1999) 1369–1380
1377
NMR (50 MHz, CDCl3) δ 63.9, 68.4, 125.6, 128.0, 128.3, 128.8, 129.5, 134.1, 139.2, 140.6. MS (EI):
m/e=262 (8, M+), 244 (12), 120 (100).
4.3.6. (2R)-1-(Phenylsulfonyl)tridecan-2-ol (R)-17 and (2S)-1-(phenylsulfonyl)tridecan-2-ol (S)-17
A white solid: mp 69°C. [α]20=−11 for (R)-17 or +11 for (S)-17 (c 1.0, CHCl3). IR (CHCl3): 3450,
D
1310, 1150 cm−1. 1H NMR (200 MHz, CDCl3) δ 0.90 (3H, t, J=7.0 Hz), 1.26–1.59 (20H, m), 3.21–3.32
(3H, m), 4.18 (1H, m), 7.59–7.72 (3H, m), 7.96 (2H, m). 13C NMR (50 MHz, CDCl3) δ 14.0, 22.6, 24.9,
29.2, 29.4, 29.5, 30.4, 31.8, 36.4, 62.2, 65.9, 127.8, 129.4, 133.9, 139.2.
4.3.7. (2R)-1-Phenylsulfonylpentadecan-2-ol (R)-18
Starting from 2 g (5.4 mmol) of 7, the reaction yielded 1.8 g (4.8 mmol, 90%) of 18 as a white solid:
mp 78°C. [α]20=−19 (c 1.0, CHCl3), lit.24 [α]32625=−2.0 (c 1.10, MeOH). IR (CHCl3): 3500, 1310, 1160
D
1
cm−1. H NMR (200 MHz, CDCl3) δ 0.89 (3H, t, J=6.8 Hz), 1.20–1.75 (24H, m), 3.21–3.40 (3H, m),
4.18 (1H, m), 7.58–7.71 (3H, m), 7.97 (2H, m). 13C NMR (50 MHz, CDCl3) δ 14.0, 22.6, 24.8, 29.2,
29.4, 29.5, 31.8, 36.3, 62.1, 65.8, 127.8, 129.3, 133.9, 139.2.
4.3.8. (2R)-1-Phenylsulfonylheptadecan-2-ol (R)-19 and (2S)-1-phenylsulfonylheptadecan-2-ol (S)-19
A white solid: mp 84°C. [α]20=−10 for (R)-19 or +10 for (S)-19 (c 1.0, CHCl3). IR (CHCl3): 3500,
D
1310, 1160 cm−1. 1H NMR (200 MHz, CDCl3) δ 0.91 (3H, t, J=7.0 Hz), 1.25–1.58 (28H, m), 3.21–3.35
(3H, m), 4.20 (1H, m), 7.62–7.72 (3H, m), 7.96 (2H, m). 13C NMR (50 MHz, CDCl3) δ 14.1, 22.7, 25.0,
29.3, 29.6, 31.9, 36.4, 62.3, 65.9, 127.9, 129.5, 134.0, 139.3.
4.3.9. (2R)-3-Chloro-1-phenylsulfonyl-propan-2-ol (R)-16
A white solid: mp 93°C. [α]20=+7 (c 1.0, MeOH), lit.18 [α]24=+10.15 (c 1.0, MeOH). IR (CHCl3):
D
D
3450, 1310, 1160 cm−1. 1H NMR (200 MHz, CDCl3) δ 3.39 (3H, m), 3.63 (2H, d, J=5.0 Hz), 4.40 (1H,
s), 7.57–7.72 (3H, m), 7.94–7.98 (2H, m). 13C NMR (50 MHz, CDCl3) δ 47.5, 59.5, 66.1, 127.9, 129.4,
134.2, 138.9.
4.3.10. (1R)-1-p-Chlorophenyl-2-phenylsulfonyl-ethan-1-ol (R)-21
20
1
A white solid: mp 92°C. [α] =−20 (c 5.0, CHCl3). IR (CHCl3): 3500, 1300, 1143 cm−1. H NMR
D
(200 MHz, CDCl3) δ 3.34 (1H, dd, J=14.3 and 2.4 Hz), 3.51 (1H, dd, J=14.3 and 9.6 Hz), 3.94 (1H, s),
5.28 (1H, dd, J=9.6 and 2.1 Hz), 7.08–7.28 (4H, m), 7.52–7.72 (3H, m), 7.90–8.32 (2H, m). 13C NMR
(50 MHz, CDCl3) δ 63.7, 67.7, 127.0, 127.8, 128.4, 128.8, 129.4, 134.0, 134.1, 139.0. MS (EI): m/e=296
(11, M+), 154 (100), 77 (53).
4.3.11. (1R)-1-p-Fluorophenyl-2-phenylsulfonyl-ethan-1-ol (R)-22
20
1
A white solid: mp 68°C. [α] =−23 (c 3.0, CHCl3). IR (CHCl3): 3510, 1300, 1143 cm−1. H NMR
D
(200 MHz, CDCl3) δ 3.34 (1H, dd, J=14.3 and 2.3 Hz), 3.52 (1H, dd, J=14.3 and 9.7 Hz), 3.80 (1H, s),
5.29 (1H, dd, J=9.7 and 2.3 Hz), 6.93–7.02 (2H, m), 7.23–7.30 (2H, m), 7.54–7.69 (3H, m), 7.91–7.96
(2H, m). 13C NMR (50 MHz, CDCl3) δ 63.7, 67.7, 127.3, 127.5, 127.9, 129.4, 134.1, 136.5, 139.0. MS
(EI): m/e=262 (8, M+), 244 (12), 120 (100).
4.4. General procedure for the preparation of butenolides 23–2618
A solution of n-butyllithium (15.5 mmol) in hexane was added dropwise to a solution of β-hydroxy
sulfone (7 mmol) in tetrahydrofuran (50 mL) at −78°C under an argon atmosphere. After being stirred

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P. Bertus et al. / Tetrahedron: Asymmetry 10 (1999) 1369–1380
at −78°C for 30 min and at −10°C for 2 h, sodium iodoacetate (1.77 g, 8.5 mmol) was added at −78°C.
The resulting mixture was allowed to warm to 0°C with stirring for 15 h, then quenched with aqueous
saturated ammonium chloride (10 mL), and acidified with 10% hydrochloric acid (10 mL). The organic
layer was separated, the aqueous layer extracted with ether (150 mL), and the combined organic phase
dried with magnesium sulfate and concentrated. The residue was dissolved in benzene (80 mL) and a
catalytic amount of p-toluenesulfonic acid was added. The solution was refluxed for 2 h, the water being
removed with a Dean–Stark apparatus. The cooled benzene layer was washed with aqueous 5% sodium
hydrogen carbonate (50 mL), and dried with magnesium sulfate. After filtering off the magnesium sulfate,
triethylamine (2.53 g, 25 mmol) was added to the benzene solution and the resulting mixture was stirred
at room temperature for 15 h, washed with 10% hydrochloric acid (50 mL), and dried with magnesium
sulfate. The solvent was evaporated and the residue purified by column chromatography on silica gel
affording enantiomerically pure butenolides 23–26.
4.4.1. (S)-(+)-Methyl-2(5H)-furanone [(S)-(+)-β-angelica lactone)] 23
A colorless oil (280 mg, 41%). [α]20=+95 (c 0.5, CHCl3), lit.24 [α]20=+93.8 (c 0.5, CHCl3). IR
D
D
1
(CHCl3): 1810, 1570, 1470, 1220 cm−1. H NMR (200 MHz, CDCl3) δ 1.44 (3H, d, J=6.9 Hz), 5.14
(1H, m), 6.08 (1H, dd, J=1.9 and 5.6 Hz), 7.45 (1H, dd, J=1.1 and 5.6 Hz). 13C NMR (50 MHz, CDCl3)
δ 18.7, 79.5, 121.1, 157.3, 173.0.
4.4.2. (R)-5-Ethyl-2(5H)-furanone 24
A colorless oil (82 mg, 41%). [α]20=−94 (c 1.05, CH2Cl2), lit.21a [α]23=−95 (liq. l=1 dm). 1H NMR
D
D
(200 MHz, CDCl3) δ 0.97 (3H, t, J=7.4 Hz), 1.65–1.91 (2H, m), 5.00 (1H, m), 6.11 (1H, dd, J=1.9 and
5.8 Hz), 7.44 (1H, dd, J=1.4 and 5.6 Hz). 13C NMR (50 MHz, CDCl3) δ 8.9, 26.1, 84.2, 121.6, 155.9,
173.0.
4.4.3. (R)-5-Pentyl-2(5H)-furanone 25
A colorless oil (320 mg, 44%). [α]20=−84 (c 1.30, CHCl3), lit.23a [α]20=−85 (c 1.36, CHCl3). IR
D
D
(CHCl3): 1760, 1620, 1310, 1160 cm−1. 1H NMR (200 MHz, CDCl3) δ 0.89 (3H, t, J=6.6 Hz), 1.22–1.79
(8H, m), 5.04 (1H, m), 6.10 (1H, dd, J=1.9 and 5.8 Hz), 7.45 (1H, dd, J=1.4 and 5.6 Hz). 13C NMR (50
MHz, CDCl3) δ 13.8, 22.3, 24.5, 31.3, 33.0, 83.3, 121.4, 156.2, 173.1.
4.4.4. (R)-5-Tridecyl-2(5H)-furanone 26
A white solid (370 mg, 38%): mp 50°C. [α]20=−49 (c 2.0, dioxane), lit.21b [α]25=−51.7 (c 2.0,
D
D
dioxane). IR (CHCl3): 1750, 1610, 1580, 1170 cm−1. 1H NMR (200 MHz, CDCl3) δ 0.88 (3H, t, J=6.4
Hz), 1.10–1.76 (24H, m), 5.04 (1H, m), 6.11 (1H, dd, J=1.9 and 5.6 Hz), 7.44 (1H, dd, J=1.4 and 5.6 Hz).
13C NMR (50 MHz, CDCl3) δ 14.0, 22.5, 24.8, 29.2, 29.4, 29.5, 31.8, 33.0, 83.3, 121.3, 156.3, 173.0.
4.5. Preparation of γ-lactones 27–28
4.5.1. (R)-(+)-4-Hexanolide 27
To a degassed solution of 24 (63 mg, 0.56 mmol) in MeOH (5 mL) was added 10% Pd/C (100 mg). The
resulting mixture was placed under a hydrogen atmosphere and stirred overnight. After filtration through
Celite and removal of the solvent, the residue was purified by silica gel chromatography to afford 27 as a
colorless oil (38 mg, 60%). [α]20=+50 (c 1.7, MeOH), lit.22b [α]24.2=+48.8 (c 1.72, MeOH). 1H NMR
D
D
(200 MHz, CDCl3) δ 1.01 (3H, t, J=7.5 Hz), 1.65–1.96 (3H, m), 2.24–2.40 (1H, m), 2.50–2.58 (2H, m),
4.44 (1H, quint, J=6.4 Hz). 13C NMR (50 MHz, CDCl3) δ 9.3, 27.4, 28.4, 28.7, 82.1, 177.2.

P. Bertus et al. / Tetrahedron: Asymmetry 10 (1999) 1369–1380
1379
4.5.2. (4S,5R)-Methyl-5-pentyl-4,5-dihydro-2(3H)-furanone [(+)-trans-cognac lactone] 28
A solution of 25 (100 mg, 0.65 mmol) in Et2O (6 mL) was added dropwise to a stirred solution of
lithium dimethyl cuprate [3.25 mmol, prepared from addition of a solution of methyllithium (1.4 M)
in ether (4.1 mL, 6.5 mmol) to a suspension of CuI (619 mg, 3.25 mmol) in Et2O (8.3 mL) at −20°C]
at −60°C. The reaction mixture was then stirred for 2 h at the same temperature. After the addition of
10% HCl (6 mL), the mixture was stirred for 30 min then filtered through Celite, and the organic layer
was separated. The aqueous solution was extracted with Et2O, the combined organic layers were dried
with magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography
(cyclohexane:AcOEt, 3:1) affording 28 (72 mg, 65%) as a colorless oil. [α]20=+72, lit.23 [α]25=+75 (c
D
D
1
1.0, CH2Cl2). IR (CHCl3): 2930, 2870, 1780, 1200, 1170 cm−1. H NMR (200 MHz, CDCl3) δ 0.89
(3H, t, J=7.0 Hz), 1.13 (3H, d, J=6.5 Hz), 1.26–1.70 (8H, m), 2.15–2.24 (2H, m), 2.63–2.70 (1H, m),
4.01 (1H, dt, J=7.9 and 4.1 Hz). 13C NMR (50 MHz, CDCl3) δ 13.9, 17.4, 22.4, 25.3, 31.5, 33.9, 36.0,
37.0, 87.4, 176.5.
Acknowledgements
We are grateful to the CMCU (Comité Mixte Franco-Tunisien pour la Coopération Universitaire) for
grants to A.R.T. and T.H. and we wish to thank Dr. R. Schmid (Hoffmann La Roche) for samples of (R)-
and (S)-MeO-BIPHEP=(R)-(+)-6,60-dimethoxy-2,20-bis(diphenylphosphino)-1,10 -biphenyl.
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