Stereoselective synthesis of 2,4-disubstituted butanolides

Article abstract of DOI:10.1007/s11172-007-0021-4

A series of 2,4-disubstituted butanolides was prepared based on the trans-stereoselective electrophilic cyclization of substituted N-(pent-4-enoyl)pyrrolidines. The butanolides may be considered as synthons for this type of natural products. Springer Scie

Full text of DOI:10.1007/s11172-007-0021-4

Russian Chemical Bulletin, International Edition, Vol. 56, No. 1, pp. 130—136, January, 2007
130
Stereoselective synthesis of 2,4ꢀdisubstituted butanolides*
A. V. Lozanova, T. M. Ugurchieva, and V. V. Veselovskyꢀ
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (495) 135 5328. Eꢀmail: ves@ioc.ac.ru
A series of 2,4ꢀdisubstituted butanolides was prepared based on the transꢀstereoselective
electrophilic cyclization of substituted Nꢀ(pentꢀ4ꢀenoyl)pyrrolidines. The butanolides may be
considered as synthons for this type of natural products.
Key words: substituted butanolides, Nꢀ(pentꢀ4ꢀenoyl)pyrrolidines, electrophilic cyclizaꢀ
tion, substituted (tetrahydrofuranꢀ2ꢀylidene)ammonium bromides.
Scheme 1
Substances comprising a fiveꢀmembered lactone ring
are widely spread among natural metabolites (see Ref. 2
and references cited therein), many of them being of inꢀ
terest due to their perspective biological activity. The inꢀ
sect feromones with lactone ring 1 and 2 (see Ref. 3) as
well as compounds 3 (see Ref. 4) and 4 (see Ref. 5) with
cytostatic activity may be mentioned as examples.
X = Cl, Br, I
We chose Nꢀ(2ꢀphenylthiopentꢀ4ꢀenoyl)ꢀ and
Nꢀ(2ꢀphenylsulfonylpentꢀ4ꢀenoyl)pyrrolidines (7 and 8)
as the first subjects of investigation. Our choice was based
on the suggestion (cf. Ref. 8) that such αꢀsubstituents
might have remarkable stereocontrol over process under
investigation. In addition, if we succeeded, such funcꢀ
tionalization might turn out useful for further utilization
of the thus produced substituted butanolides in synthesis
of natural products of the type 1—4.
Phenylthioacetic acid (9) was used as the starting maꢀ
terial, which was transformed by standard methods into
the target amide 7 via amide 10 in total yield 96%
(Scheme 2). We investigated a new procedure of deꢀ
protonation of amide 10 with lithium diisopropylamide
generated in situ in the system Li—HNPri2 (~7 mol.%)—
methylstyrene as an alternative. In this case, the yield of
amide 7 was 75%.
Amide 12, synthesized from phenylsulfonylacetic acid
(11), was subjected to allylation under different condiꢀ
tions as well. The allylation product 8 was obtained in the
highest yield under the action of NaH—AllBr, whereas
Pd0ꢀcatalyzed allylation of 12 with allyl acetate or diallyl
carbonate turned out to be less efficient (cf. Ref. 9).
As it has been reported earlier,1 bromination of allylic
sulfide 7 led to the stereoselective formation of immonium
In recent years, halogenolactonization of γ,δꢀunsaturꢀ
ated carboxylic acids and their derivatives (see, for exꢀ
ample, Ref. 6) has been found to be the most popular
among known methods for the butanolide ring construcꢀ
tion. Earlier, we have reported7 on a new type of ringꢀ
chain tautomerizm, consisting of reversible transformation
of γꢀhalobutyric acid dialkylamides 5 into dialkyl(tetraꢀ
hydrofuranꢀ2ꢀylidene)ammonium halides 6 detected by
1Н NMR spectroscopy (Scheme 1). Taking into account
that immonium salts of type 6 were considered as possible
intermediates in halogenolactonization of γ,δꢀunsaturated
carboxylic acid amides,6c it was of interest to identify
them in this process as well as to investigate the possibility
of their use in stereoselective synthesis of substituted
butanolides.
* For preliminary communication, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 124—129, January, 2007.
1066ꢀ5285/07/5601ꢀ0130 © 2007 Springer Science+Business Media, Inc.

Synthesis of 3,5ꢀdisubstituted butanolides
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 1, January, 2007
131
Scheme 2
Scheme 3
Reagents and conditions: i. SOC12, 35—40 °С, then pyrrolidine,
СН2Cl2, –5 → 20 °С; ii. NaH, DMF, then АllBr, 20 °С or Li,
methylstyrene, HNPri2 (cat.), THF, 20 °С, then AllBr;
iii. NaH, DMF, Pd2(dba)3(CHCl3) (cat., dba is dibenzylꢀ
idenacetone), Ph3P, АllОАс, 25 °C; iv. Pd2(dba)3(CHCl3) (cat.),
Ph3P, (AllO)2CO, DMF, 25 °C.
salt 13 with transꢀarrangement of substituents in the tetraꢀ
1
hydrofuran ring. The H NMR spectrum of the analytiꢀ
cally pure sample of salt 13 in CDCl3 contained no addiꢀ
tional signals, which might have been evidence of its reꢀ
versible transformation into the corresponding openꢀchain
form (cf. Ref. 7).
Reagents and conditions: i. Br2, CНCl3, 0 °C; ii. NBS, aq. THF,
10 → 20 °C; iii. aq. EtOH, refluxing; iv. Н2О2, АсОН, 20 °C;
v. CCl4, refluxing.
Obviously, the intermediate formation of salt 13 ocꢀ
curred also upon treatment of amide 7 with Nꢀbromoꢀ
succinimide in aqueous THF. In this case, however, full
conversion of 7 required 2 equiv. of NBS. Vinyl sulfide 14
was isolated from the reaction mixture in good yield. Apꢀ
parently, its formation occurred as a result of sequences
of transformations, including hydrolysis of the intermediꢀ
ate 13 and bromination of the hydrolysis product. This
suggestion was confirmed by the fact that treatment of salt
13 with equimolar amount of NBS in aqueous THF as
well led to vinyl sulfide 14 (Scheme 3).
Some remarks should be made about aforementioned
reaction of amide 7 with bromination agents. It is known
that sulfides readily react with bromine to give the correꢀ
sponding S,Sꢀdibromides. However, a documented exꢀ
ample10 of such reaction for the sulfides with alkene fragꢀ
ments in their structure did not allow us to make a general
conclusion about relative reactivity of these functional
groups toward bromine. In our case, the high yield of
salt 13 (86%) pointed out to the fact that bromination of
the double bond in unsaturated sulfide 7 is much faster
than that of the phenylthio group.
Hydrolysis of salt 13 in aqueous ethanol was accomꢀ
panied by partial epimerization with the formation of a
mixture of lactones transꢀ15a and cisꢀ15b in a ratio
of ~3 : 2. Isolated by column chromatography on SiO2,
individual components of this mixture were further
subjected to controlled oxidation with H2O2 in AcOH
to the corresponding sulfoxides 16 and 17. It turned
out that formation of a new chiral center at the Sꢀatom
proceeded diastereoselectively. Indeed, oxidation of lacꢀ
tones 15a and 15b gave mixtures of two diastereoꢀ
mers 16a,b and 17a,b, respectively, in a ratio of ~2 : 3
(1H NMR data).

132
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 1, January, 2007
Lozanova et al.
The structures of newly synthesized lactones 14—17
Bromination of amide 8 with bromine in CHCl3 also
led to the stereoselective formation of immonium salt 19
with transꢀposition of substituents in the tetrahydrofuran
ring (Scheme 4). The high stereoselectivity in the related
iodolactonization of αꢀsubstituted γ,δꢀunsaturated carbꢀ
oxylic acids (see, for example, Ref. 8) was explained by
preference of the suggested transition state A with pseudoꢀ
axial position of αꢀsubstituent over transition state B in
which this substituent occupied pseudoequatorial posiꢀ
tion and was close to the dialkylamido group.
The given structure of the immonium salt 19, which
was characterized by spectral and analytical data, was
confirmed by its hydrolysis into transꢀlactone 20. This
process, in contrast to hydrolysis of phenyl sulfide anaꢀ
log 13, proceeded almost without epimerization at the
C(3) center. In turn, the relative configuration of subꢀ
stituents in molecule 20 was confirmed by NOESY exꢀ
periment (500.13 MHz), which showed spatial proximity
of αꢀHC(4) proton with protons in CH2Br fragment and
revealed other informative crossꢀpeaks (see Scheme 4).
were confirmed by combination of spectroscopic methods
and elemental analysis. Particularly, the assignment of
tetrahydrofuranꢀ2ꢀones 15 to transꢀ and cisꢀseries was
made based on the characteristic difference between
chemical shifts of signals for αꢀHC(4) and βꢀHC(4) proꢀ
1
tons in H NMR spectrum. Thus for 15a ∆δ = 0.16 ppm,
whereas for 15b this value is equal to 0.73 ppm, which is
consistent with the particularities of the 1H NMR spectra
recorded earlier8 for both stereoisomers of compounds
with structures similar to 15.
In addition, based on literature data8 for the 1H NMR
spectra of enantiomerically pure analogs of lactones 16,
produced by oxidation of transꢀisomer 15a, we could make
suggestions about relative configurations of their chiral
centers. Thus a comparison of measured spinꢀspin couꢀ
pling constant values for the HC(3)—H2С(4) protons and
the differences in chemical shifts for the H2С(4) geminal
protons with the literature data allowed us to assign
3R*,SS*,5S*ꢀconfiguration to stereoisomer 16a and
3R*,SR*,5S* to 16b. Structure of lactones 16 and 17 was
also confirmed by thermolysis of their mixture in CCl4 to
the known butenolide 18 in 90% yield (see Ref. 11).
Experimental
IR spectra were recorded on a Specord Mꢀ80 instrument.
1H and 13C NMR spectra were recorded on a Bruker ACꢀ200
spectrometer with the signal of the solvent as the reference
(CDCl3, δ 7.27 and δ 77.0, respectively). Massꢀspectra (EI,
Scheme 4
H
C
70 eV) were recorded on a Finnigan MAT ITDꢀ700 instrument.
Rf values were determined on Silufol precoated plates with
Silica gel. Melting points were determined with the Kofler apꢀ
paratus. Column chromatography was performed on Silica gel 60
(0.04ꢀ0.06 mm, Fluka).
Solvents used were purified and dried by standard methods.
Br2 was distilled over P2O5. Chemicals such as
Pd2(dba)3(CHCl3), SOCl2, pyrrolidine, NaH, HNPri2, methylꢀ
styrene, and allylbromide were commercially available from
Aldrich.
(Phenylthio)acetic acid (9)12 and (phenylsulfonyl)acetic acid
(11)13 were obtained by known procedures.
Nꢀ[(Phenylthio)acetyl]pyrrolidine (10). To a stirred mixture
of SOCl2 (30 mL) and DMF (0.5 mL) at 35—40 °C (Ar), acid 9
(7.56 g, 45.0 mmol) was added over a period of 15 min. After 1 h
at this temperature, the excess of SOCl2 was removed in vacuo
(30 Torr, 40 °C, water bath). The oily residue was dissolved in
CH2Cl2 (40 mL) and a solution of pyrrolidine (7.11 g, 100 mmol)
in CH2Cl2 (30 mL) was added to the stirred (Ar) solution at
–5—0 °C over a period of 30 min. The reaction mixture was
heated up to 20 °C and stirred for 2 h, then it was quenched with
water (20 mL). The organic layer was separated, washed with
water (2×10 mL) and brine (3×10 mL), dried with Na2SO4, and
concentrated in vacuo. Chromatography of the residue (11.5 g)
on SiO2 with ButOMe as the eluent gave 8.45 g (85%) of amide
10 as colorless crystals, m.p. 78—79 °C (from hexane—ButOMe).
IR (KBr), ν/cm–1: 684, 728, 812, 912, 1028, 1068, 1164, 1192,
1228, 1252, 1344, 1416, 1436, 1484, 1572, 1588, 1620, 1636,
2872, 2948, 2968, 3060. MS, m/z (Irel (%)): 222 [M + 1]+ (5),
221 [M]+ (43), 189 (8), 151 (3), 124 (14), 113 (37), 112 (12), 110
(16), 100 (9), 98 (100), 92 (6), 84 (11), 83 (18), 78 (11), 77 (14),
X = I (see Ref. 9), Br
Reagents and conditions: i. Br2, CНCl3, 0 °C; ii. aq. MeCN,
50 °C.

Synthesis of 3,5ꢀdisubstituted butanolides
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 1, January, 2007
133
70 (26), 69 (15), 65 (12), 56 (31), 55 (70). 1H NMR, δ: 1.90 (m,
4 H, 2 CH2); 3.45 (m, 4 H, 2 CH2N); 3.64 (s, 2 H, CH2S); 7.25,
7.45 (both m, 5 H, Harom) (cf. Ref. 1).
added portionwise over a period of 20 min at 10 °C. The reaction
mixture was stirred at 20 °C for 1 h, diluted with 3 mL of water,
and extracted with MeOBut. The organic layer was washed with
water and brine, dried with Na2SO4, and concentrated in vacuo.
Chromatography of the residue on SiO2 with a mixture light
petroleum—ButOMe (10 : 1) as the eluent gave 0.2 g (70%) of
lactone 14 as colorless crystals, m.p. 81—83 °C (from light peꢀ
troleum—MeOBut). Found (%): C, 46.33; H, 3.18; Br, 28.02,
S, 11.24. C11H9BrO2S. Calculated (%): C, 46.44; H, 3.34;
Br, 27.83, S, 11.17. IR (KBr), ν/cm–1: 496, 540, 576, 616, 692,
704, 752, 772, 792, 852, 872, 904, 1004, 1024, 1056, 1160, 1240,
1268, 1316, 1328, 1424, 1476, 1580, 1600, 1760, 2852, 2924,
3024. 3088. The 1H NMR spectral data are given in Table 1.
B. To a stirred solution of salt 13 (0.18 g, 0.43 mmol) in a
mixture of THF (2 mL) and water (1.0 mL), NBS (0.1 g,
0.56 mmol) was added at 10 °C. The reaction mixture was stirred
for 2 h at 20 °C and worked up similarly to the previous proceꢀ
dure to give 0.08 g (65%) of lactone 14, practically identical
(m.p., 1H NMR spectrum) with the sample of this compound
described earlier.
(
)ꢀNꢀ(2ꢀPhenylthiopentꢀ4ꢀenoyl)pyrrolidine (7). А. A 55%
suspension of NaH in mineral oil (0.47 g, 11.0 mmol of NaH)
was added to a stirred solution of amide 10 (2.21 g, 10.0 mmol)
in DMF (10 mL) at 20 °C (Ar) and after 30 min allyl bromide
(1.45 g, 12.0 mmol) was added. The reaction mixture was stirred
at this temperature for 1 h, then it was quenched with water
(30 mL) and extracted with ButOMe. The organic layer was
separated, washed with water and brine, dried with Na2SO4, and
concentrated in vacuo. Chromatography of the residue (2.8 g)
on SiO2 with ButOMe as the eluent gave 2.50 g (96%) of amide 7
as colorless crystals, m.p. 46—47 °C (from light petroleum, b.p.
40—70 °C, which was used hereinafter). 1H NMR, δ: 1.80 (m,
4 H, 2 CH2); 2.45, 2.76 (both m, 2 H, H2C(3)); 3.40 (m, 4 H,
2 CH2N); 3.70 (dd, 1 H, CHS, J = 11 Hz, J = 6 Hz); 5.10 (m,
2 H, H2C=), 5.80 (m, 1 H, HC=); 7.30, 7.50 (both m, 5 H,
H
arom) (cf. Ref. 1).
B. To a stirred suspension of finely cut Li (21 mg, 3 mmol) in
THF (5 mL), amide 10 (0.62 g, 2.8 mmol), methylstyrene (0.19 g,
1.6 mmol), and HNPri2 (20 mg, 0.20 mmol) were added at 20 °C
(Ar). The reaction mixture was stirred at this temperature for
2.5 h (until Li was almost completely dissolved), and then 0.40 g
(3.31 mmol) of allyl bromide was added. After 1 h, the reaction
mixture was quenched with saturated NH4Cl solution and exꢀ
tracted with ButOMe. The extract was washed with water and
brine, dried with Na2SO4, and concentrated in vacuo. Chromaꢀ
tography of the residue (0.8 g) on SiO2 with a mixture of light
petroleum—ButOMe as the eluent gave 0.55 g (75%) of amide 7,
practically identical (m.p., 1H NMR spectrum) with the sample
of this compound described earlier.
N,Nꢀ(Butanꢀ1,4ꢀdiyl)ꢀNꢀ(5S*ꢀbromomethylꢀ3R*ꢀphenylꢀ
thiotetrahydrofuranꢀ2ꢀylidene)ammonium bromide (13). To a
stirred solution of amide 7 (1.30 g, 5.0 mmol) in CHCl3 (15 mL),
a solution of Br2 (0.85 g, 5.3 mmol) in CHCl3 (15 mL) was
added over a period of 20 min at 0 °C (Ar). The reaction mixture
was kept at this temperature for 15 min, then concentrated
in vacuo, and the residue was crystallized from MeCN to give
1.81 g (86%) of salt 13 as colorless crystals, m.p. 131—136 °C.
Found (%): C, 43.16; H, 4.60; Br, 37.48; N, 3.40; S, 7.48.
C15H19Br2NOS. Calculated (%): C, 42.77; H, 4.55; Br, 37.94;
N, 3.33; S, 7.61. IR (KBr), ν/cm–1: 508, 656, 708, 780, 800,
852, 976, 1060, 1128, 1152, 1208, 1248, 1300, 1344, 1404,
1420, 1452, 1692, 2840, 2876, 2948, 3012. MS, m/z (Irel (%)):
421 [M]+ (3), 342 (12), 341 (25), 339 (8), 323 (4), 312 (9), 308
(15), 306 (17), 260 (9), 232 (5), 228 (14), 192 (15), 189 (7), 163
(32), 161 (34), 152 (18), 151 (100), 149 (10), 136 (10), 135 (38),
129 (28), 128 (34), 110 (43), 109 (45), 99 (19), 98 (100), 85 (22),
81 (31), 72 (16), 70 (53), 56 (47), 55 (79). 1H NMR, δ: 1.90—2.35
(m, 4 H, 2 CH2); 2.58 (ddd, 1 H, αꢀHC(4), J = 1.0 Hz, J =
6.4 Hz, J = 13.9 Hz); 3.44 (ddd, 1 H, βꢀHC(4), J = 8.5 Hz, J =
9.8 Hz, J = 13.9 Hz); 3.50—3.70 (m, 2 H, CH2N); 3.69 (dd,
1 H, HCBr, J = 6.3 Hz, J = 10.8 Hz); 3.86 (dd, 1 H, HCBr, J =
7.1 Hz, J = 10.8 Hz); 3.90—4.00 (m, 1 H, HCN); 4.19—4.32
(m, 1 H, HCN); 4.68 (dddd, 1 H, НC(5), J = 6.3 Hz, J =
6.4 Hz, J = 7.1 Hz, J = 9.8 Hz); 5.11 (dd, 1 H, НC(3), J =
1.0 Hz, J = 8.5 Hz); 7.37—7.54 (m, 5 H, Harom).
5S*ꢀBromomethylꢀ3R*ꢀphenylthiotetrahydrofuranꢀ2ꢀone
(15a) and 5R*ꢀbromomethylꢀ3R*ꢀphenylthiotetrahydrofuranꢀ2ꢀ
one (15b). A solution of salt 13 (1.05 g, 2.5 mmol) in 10 mL of
~95% EtOH was refluxed for 1 h, concentrated in vacuo, diluted
with 10 mL of water and extracted with 50 mL of ButOMe. The
organic layer was separated, washed with water and brine, dried
with Na2SO4, and concentrated in vacuo. Chromatography of
the residue (0.72 g) on SiO2 with a mixture of light petroꢀ
leum—ButOMe (3 : 2) as the eluent gave 0.43 g (60%) of lactone
15а and 0.27 g (37%) of 15b in the order of elution.
transꢀIsomer 15a: colorless oil, Rf 0.65 (hexane—MeOBut,
2 : 3). Found (%): C, 45.95; H, 3.96; Br, 27.50; S, 10.87.
C11H11BrO2S. Calculated (%): C, 46.00; H, 3.86; Br, 27.83;
S, 11.16. IR (CНCl3), ν/cm–1: 664, 692, 728, 924, 1012, 1024,
1068, 1092, 1172, 1228, 1296, 1336, 1444, 1480, 1584, 1784,
3016, 3024. MS, m/z (Irel (%)): 288 [M + 1]+ (42), 287 [M]+
(7), 286 (43), 208 (2), 207 (11), 206 (4), 193 (5), 179 (15), 165
(15), 164 (11), 163 (100), 161 (6), 148 (7), 147 (4), 137 (29), 136
(15), 135 (87), 130 (39), 129 (11), 123 (19), 121 (6), 116 (6), 110
(29), 109 (73), 91 (11), 84 (14), 76 (11), 69 (7), 65 (21). The
1H NMR spectral data are given in Table 1. 13C NMR, δ:
33.71, 34.10, 44.79, 76.04, 128.97, 129.35, 130.51, 133.72,
173.80.
cisꢀIsomer 15b: colorless oil, Rf 0.56 (hexane—MeOBut,
2 : 3). Found (%): C, 45.99; H, 3.76; Br, 27.48; S, 10.97.
C11H11BrO2S. Calculated (%): C, 46.00; H, 3.86; Br, 27.83;
S, 11.16. IR (CНCl3), ν/cm–1: 664, 692, 728, 936, 1020, 1092,
1160, 1224, 1340, 1424, 1444, 1584, 1636, 1784, 3016, 3024.
MS, m/z (Irel (%)): 288 [M + 1]+ (44), 287 [M]+ (6), 286 (44),
208 (4), 207 (24), 193 (7), 165 (16), 164 (8), 163 (67), 148 (7),
137 (18), 136 (10), 135 (58), 130 (39), 129 (11), 121 (6), 116 (6),
110 (23), 109 (100), 91 (12), 84 (20), 77 (14), 69 (7), 66 (11),
65 (30). The 1H NMR spectral data are given in Table 1.
13C NMR, δ: 32.48, 33.78, 46.12, 75.86, 128.85, 129.31, 131.48,
133.84, 173.90.
(3R*,SS*5S*)ꢀ (16a) and (3R*,SR*5S*)ꢀ5ꢀBromomethylꢀ3ꢀ
phenylsulfinyltetrahydrofuranꢀ2ꢀones (16b). To a stirred solution
of sulfide 15a (0.35 g, 1.2 mmol) in AcOH (3 mL), a 30% H2O2
solution (1.36 g, 12 mmol) was added at 20 °C. The reaction
mixture was stirred for 3 h, diluted with 15 mL of water, and
extracted with 50 mL of CHCl3. The organic layer was sepaꢀ
5ꢀBromomethylꢀ3ꢀphenylthiofuranꢀ2(5H )ꢀone (14). A. To a
stirred solution of amide 7 (0.26 g, 1.0 mmol) in a mixture of
THF (2 mL) and water (0.5 mL), NBS (0.36 g, 2.0 mmol) was

134
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 1, January, 2007
Lozanova et al.
Table 1. 1Н NMR spectra of compounds 14—18 and 20
Comꢀ
poꢀ
δ (J/Hz)
HC(3)
(dd, 1 H)
HC(4)
(ddd, 1 H)
HC(5)
(dddd, 1 H)
HCBr
(dd, 1 H)
Harom
(m, 5 H)
und
14
—
6.53 (d, J = 1.8)
5.14 (ddd, J = 1.8,
J = 4.7, J = 6.2)
4.58 (J = 4.9,
J = 4.9, J = 7.0, J = 7.1)
4.57 (m)
3.46 (J = 6.2, J = 10.8);
3.56 (J = 4.7, J = 10.8)
3.43, 3.44 (both d,
7.44—7.58
7.27—7.64
7.27—7.60
7.56—7.73
7.54—7.72
7.52—7.70
7.54—7.73
—
15a
15b
16a
16b
17a
17b
18
4.00 (J = 4.8,
J = 8.9)
3.96 (J = 9.5,
J = 9.5)
4.24 (J = 3.4,
J = 10.2)
3.86 (J = 6.5,
J = 10.2)
3.81 (J = 8.4,
J = 10.2)
4.37 (J = 7.1,
J = 10.5)
6.27 (J = 1.8,
J = 5.7)
4.22 (J = 4.1,
J = 10.4)
2.41 (J = 4.8, J = 7.1, J = 14.0);
2.57 (J = 7.0, J = 8.9, J = 14.0)
2.10 (J = 8.0, J = 9.5, J = 13.7);
2.83 (J = 6.7, J = 9.5, J = 13.7)
2.44 (J = 7.3, J = 10.2, J = 15.1);
2.89 (J = 3.4, J = 7.7, J = 15.1)
2.01 (J = 4.7, J = 10.2, J = 14.6);
2.94 (J = 6.5, J = 8.4, J = 14.6)
2.22 (J = 7.3, J = 10.2, J = 14.2);
2.60 (J = 7.0, J = 8.4, J = 14.2)
2.37 (J = 6.2, J = 7.1, J = 14.7);
2.73 (J = 8.1, J = 10.5, J = 14.7)
7.56 (dd, J = 1.7, J = 5.7)
1 H each, J = 4.9)
3.25 (J = 7.2, J = 10.7);
3.46 (J = 4.8, J = 10.7)
3.40 (J = 4.2, J = 11.1);
3.46 (J = 4.9, J = 11.1)
3.51 (J = 3.2, J = 11.3);
3.63 (J = 4.7, J = 11.3)
3.53 (J = 8.0, J = 10.3);
3.63 (J = 5.3, J = 10.3)
2.62 (J = 7.9, J = 10.5);
3.08 (J = 5.0, J = 10.5)
3.45 (J = 7.3, J = 10.6);
3.68 (J = 4.6, J = 10.6)
3.58 (J = 3.5, J =11.3);
3.65 (J = 5.2, J = 11.3)
3.94 (J = 4.2, J = 4.9,
J = 7.3, J = 7.7)
4.89 (J = 3.2, J = 4.7,
J = 4.7, J = 8.4)
4.71 (J = 5.3, J = 7.0,
J = 7.3, J = 8.0)
4.65 (J = 5.0, J = 6.2,
J = 7.9, J = 8.1)
5.25 (J = 1.7, J = 1.8,
J = 4.6, J = 7.3)
4.98 (J = 3.5, J = 5.2,
J = 7.3, J = 7.4)
20
2.62 (J = 7.3, J = 10.4, J = 14.9);
3.19 (J = 4.1, J = 7.4, J = 14.9)
7.58—8.02
rated, washed with water and brine, dried with Na2SO4, conꢀ
centrated in vacuo, and additionally kept under vacuum (2 Torr)
for 1 h at 40 °C. A mixture of diastereomers 16a and 16b (~1 : 1.5,
1H NMR data) (0.36 g, ~100%) was obtained. Double crystalliꢀ
zation of the obtained product from CHCl3—Et2O (1 : 1) afꢀ
forded isomer 16a as colorless crystals, m.p. 133—135 °C. The
mother liquor was concentrated in vacuo, and triple crystallizaꢀ
tion of the residue from Et2O afforded isomer 16b as colorless
crystals, m.p. 101—103 °C.
Sulfoxide 16a. Found (%): C, 43.85; H, 3.70; Br, 26.34;
S, 10.57. C11H11BrO3S. Calculated (%): C, 43.58; H, 3.66;
Br, 26.36; S, 10.57. IR (KBr), ν/cm–1: 648, 684, 740, 928, 1020,
1056, 1072, 1104, 1220, 1368, 1456, 1772, 2872ꢀ3076. MS,
m/z (Irel (%)): 304 [M + 1]+ (9), 302 (9), 288 (2), 179 (20), 177
(22), 163 (4), 148 (35), 146 (30), 135 (10), 127 (24), 126 (80),
125 (100), 110 (41), 109 (59), 97 (77), 83 (98), 78 (97), 77 (72),
69 (42), 65 (44), 57 (20), 55 (69), 51 (60). The 1H NMR spectral
data are given in Table 1. 13C NMR, δ: 26.41, 34.13, 63.35,
76.97, 124.82, 129.34, 132.30, 139.18, 168.50.
Sulfoxide 16b. Found (%): C, 43.89; H, 3.91; Br, 26.28;
S, 10.54. C11H11BrO3S. Calculated (%): C, 43.58; H, 3.66;
Br, 26.36; S, 10.57. IR (KBr), ν/cm–1: 656, 688, 744, 876, 972,
1000, 1044, 1088, 1160, 1188, 1216, 1268, 1304, 1340, 1444,
1480, 1780, 2856—3064. MS, m/z (Irel (%)): 304 [M + 1]+ (4),
302 (4), 179 (15), 177 (15), 148 (16), 146 (14), 126 (62), 125
(100), 110 (30), 109 (30), 97 (57), 83 (84), 78 (93), 77 (65), 69
(31), 65 (36), 55 (77), 51 (62). The 1H NMR spectral data are
given in Table 1. 13C NMR, δ: 22.65, 35.21, 64.61, 77.04, 123.84,
129.62, 131.75, 141.38, 170.88.
from sulfide 15b (0.2 g, 0.70 mmol). Crystallization of the thus
obtained product from CHCl3—Et2O (1 : 1) afforded isomer
17a as colorless crystals, m.p. 147—150 °C. The mother liquor
was concentrated in vacuo, and the isomer 17b was obtained as
colorless crystals, m.p. 123—126 °C, by double crystallization of
the residue from Et2O.
Sulfoxide 17a. Found (%): C, 43.78; H, 3.54; Br, 26.46;
S, 10.81. C11H11BrO3S. Calculated (%): C, 43.58; H, 3.66;
Br, 26.36; S, 10.57. IR (KBr), ν/cm–1: 644, 684, 740, 828, 928,
1036, 1064, 1104, 1184, 1228, 1292, 1368, 1464, 1496, 1780,
2944, 3048. MS, m/z (Irel (%)): 304 [M + 1]+ (3), 302 (3), 179
(10), 177 (8), 148 (17), 146 (18), 135 (5), 127 (13), 126 (70), 125
(100), 110 (20), 109 (38), 97 (55), 83 (75), 78 (85), 77 (64), 69
(32), 65 (28), 55 (90), 51 (55). The 1H NMR spectral data are
given in Table 1. 13C NMR ((CD3)2SO), δ: 22.22, 34.26, 64.07,
77.27, 124.07, 129.64, 131.51, 141.23, 171.07.
Sulfoxide 17b. Found (%): C, 43.88; H, 3.73; Br, 26.23;
S, 10.72. C11H11BrO3S. Calculated (%): C, 43.58; H, 3.66;
Br, 26.36; S, 10.57. IR (KBr), ν/cm–1: 644, 692, 756, 984,
1040, 1084, 1160, 1180, 1216, 1332, 1380, 1452, 1480, 1760,
2956—3060. MS, m/z (Irel (%)): 304 [M + 1]+ (3), 302 (3), 179
(7), 177 (11), 163 (4), 148 (18), 146 (15), 127 (9), 126 (56), 125
(100), 110 (22), 109 (32), 97 (40), 83 (87), 78 (82), 77 (56), 69
(23), 65 (25), 55 (77), 51 (55). The 1H NMR spectral data are
given in Table 1. 13C NMR, δ: 25.34, 31.41, 62.78, 76.75, 125.37,
129.40, 132.33, 138.84, 168.73.
5ꢀBromomethylfuranꢀ2(5H )ꢀone (18). A suspended mixture
of isomeric sulfoxides 16 and 17 (1.51 g, 5 mmol) (obtained by
oxidation of a mixture of sulfides 15a,b similarly to the proceꢀ
dure described above for individual stereoisomers) in CCl4
(25 mL) was refluxed for 6 h. The reaction mixture was concenꢀ
trated in vacuo, and the residue was chromatographed on SiO2.
Elution with CH2Cl2 gave 0.8 g (90%) of lactone 18 as colorless
oil, Rf 0.35 (CH2Cl2). The 1H NMR spectral data are given in
Table 1 (cf. Ref. 11).
5R*ꢀBromomethylꢀ3R*ꢀphenylsulfinyltetrahydrofuranꢀ2ꢀ
onesꢀ 17a и 17b. Similarly, a mixture of isomeric sulfoxides 17a
and 17b (~1.5 : 1, 1H NMR data) (0.21 g, ~100%) was obtained
ꢀ The relative configurations at SOPh asymmetrical centers of
stereoisomers 17a,b have not been established.

Synthesis of 3,5ꢀdisubstituted butanolides
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 1, January, 2007
135
Nꢀ[(Phenylsulfonyl)acetyl]pyrrolidine (12). To a stirred mixꢀ
ture of SOCl2 (15 mL) and DMF (0.3 mL), acid 11 (3.21 g,
16.0 mmol) was added over a period of 20 min at 50 °C (Ar).
After 2 h at this temperature, the excess of SOCl2 was removed
in vacuo (30 Torr, 40 °C, water bath). The oily residue was
dissolved in CH2Cl2 (15 mL), and a solution of pyrrolidine
(2.49 g, 35 mmol) in CH2Cl2 (10 mL) was added to the solution
under stirring (Ar) over a period of 30 min at –5—0 °C. The
reaction mixture was heated up to 20 °C and stirred for 12 h,
then it was diluted with CH2Cl2 (45 mL), washed with water and
brine, dried with Na2SO4, and concentrated in vacuo. Chromaꢀ
tography of the residue on SiO2 with EtOAc as the eluent gave
2.55 g (63%) of amide 12 as colorless crystals, m.p. 119—121 °C
(EtOAc). 1H NMR, δ: 1.78—2.05 (m, 4 H, 2 CH2); 3.41, 3.61
(both t, 4 H, 2 CH2N, J = 6.7 Hz); 4.12 (s, 2 H, CH2S); 7.60,
7.92 (both m, 5 H, HCarom) (cf. Ref. 11).
added over a period of 20 min at 0 °C (Ar). The reaction mixture
was kept at this temperature for 15 min and concentrated
in vacuo. The residue was crystallized from CHCl3—MeOBut
mixture to give 1.17 g (70%) of salt 19 as colorless crystals, m.p..
143—148 °C. Found (%): C, 39.76; H, 4.39; Br, 34.88; N, 3.39;
S, 6.85. C15H19Br2NO3S. Calculated (%): C, 39.75; H, 4.23;
Br, 35.26; N, 3.09; S, 7.08. IR (KBr), ν/cm–1: 448, 532, 554,
640, 668, 692, 728, 748, 768, 800, 848, 876, 996, 1060, 1084,
1152, 1224, 1248, 1316, 1328, 1408, 1448, 1580, 1692, 1700,
2840, 2980. 1H NMR, δ: 1.90—2.40 (m, 4 H, 2 CH2); 2.63 (dd,
1 H, αꢀHC(4), J = 6.2 Hz, J = 14.4 Hz); 3.36 (ddd, 1 H,
βꢀHC(4), J = 8.6 Hz, J = 9.9 Hz, J = 14.4 Hz); 3.80, 3.95, 4.21,
4.57 (all m, 4 H, 2 CH2N); 3.78 (dd, 1 H, HCBr, J = 6.5 Hz, J =
10.9 Hz); 3.92 (dd, 1 H, HCBr, J = 7.0 Hz, J = 10.9 Hz); 5.51
(dddd, 1 H, НC(5), J = 6.2 Hz, J = 6.5 Hz, J = 7.0 Hz, J =
9.9 Hz); 5.60 (d, 1 H, НC(3), J = 8.6 Hz); 7.63—8.05 (m,
5 H, Harom).
(
)ꢀNꢀ(2ꢀPhenylsulfonylpentꢀ4ꢀenoyl)pyrrolidine (8). A. To
a stirred solution of amide 12 (1.92 g, 7.6 mmol) in DMF
(10 mL), a 55% suspension of NaH in mineral oil (0.36 g,
8.3 mmol of NaH) was added at 10 °C (Ar), and after 30 min,
allyl bromide (1.0 g, 8.3 mmol) was added as well. The reaction
mixture was heated up to 20 °C and stirred at this temperature
for 1 h, then it was quenched with 30 mL of water and extracted
with CHCl3. The organic layer was washed with water and brine,
dried with Na2SO4, and concentrated in vacuo. Chromatography
of the residue (2.5 g) on SiO2 with EtOAc as the eluent gave
1.94 g (87%) of amide 8 as colorless crystals, m.p. 102—104 °C
(from light petroleum—EtOAc). 1H NMR, δ: 1.80—2.04 (m,
4 H, 2 CH2); 2.60—2.72 (m, 2 H, HC(3)); 3.40, 3.73 (both m,
2 H, CH2N); 3.47 (t, 2 H, CH2N, J = 6.7 Hz); 4.16 (dd, 1 H,
CHS, J = 5.4 Hz, J = 9.3 Hz); 5.05 (ddd, 1 H, H2C=C, J =
1.3 Hz, J = 2.5 Hz, J = 10.0 Hz); 5.10 (ddd, 1 H, H2C=C, J =
1.5 Hz, J = 2.5 Hz, J = 17.0 Hz); 5.64 (dddd, 1 H, HC=C, J =
6.9 Hz, J = 6.9 Hz, J = 10.0 Hz, J = 17.0 Hz); 7.50—7.95 (m,
5 H, Harom) (cf. Ref. 9).
B. To a stirred suspension of Pd2(dba)3(CHCl3) (27 mg,
0.025 mmol) in DMF (1 mL), Ph3P (68 mg, 0.26 mmol) was
added at 25 °C (Ar), after 30 min, AllOAc (0.2 g, 2 mmol) was
added, and after another 10 min, the solution was diluted with
DMF (6 mL), and a solution of the sodium derivative of sulꢀ
fone 12 (prepared from 12 (0.51 g, 2 mmol) and 55% suspension
of NaH in mineral oil (87 mg, 2 mmol of NaH) at 25 °C) in
DMF (3 mL) was added in one portion. The reaction mixture
was stirred for 6 h at 25 °C and worked up as described above
to give 0.36 g (60%) of amide 8 as colorless crystals, m.p.
101—103 °C (from light petroleum—EtOAc).
5S*ꢀBromomethylꢀ3R*ꢀphenylsulfonyltetrahydrofuranꢀ2ꢀone
(20). A solution of salt 19 (2.6 g, 6.2 mmol) in a mixture of
MeCN (50 mL) and H2O (10 mL) was stirred at 50 °C for 5 h,
then was concentrated in vacuo, and the residue was extracted
with MeOBut. The extract was washed with water and brine,
dried with Na2SO4 and concentrated in vacuo. Crystallization of
the residue from the EtOAc—light petroleum mixture gave 1.24 g
of lactone 20 as colorless crystals, m.p. of 83—85 °C. By conꢀ
centration in vacuo of the mother liquor and chromatography of
the residue on SiO2 with the mixture of light petroleum—EtOAc
(20%) as the eluent gave additionally 0.41 g of lactone 20 (m.p.
82—84 °C), total yield 84%. Another fraction (0.2 g) was also
isolated, which according to 1Н NMR data turned out to be
a ~2 : 1 mixture of lactone 20 and its cisꢀisomer (~5%), The
latter had signals unoverlapped with the spectrum of the main
isomer 20 at δ 2.77 (ddd 1 H, HC(4), J = 6.5 Hz, J = 8.1 Hz, J =
14.6 Hz); 2.89 (ddd 1 H, HC(4), J = 7.6 Hz, J = 10.5 Hz, J =
14.6 Hz); 4.31 (dd 1 H, HCS, J = 8.1 Hz, J = 10.4 Hz); 4.71 (m,
1 Н, НC(5)).
Lactone 20. Found (%): C, 41.55; H, 3.39; Br, 24.81; S, 9.96.
C
11H11BrNO4S. Calculated (%): C, 41.40; H, 3.47; Br, 25.03;
S, 10.04. IR (KBr), ν/cm–1: 428, 496, 568, 576, 628, 644, 692,
716, 736, 764, 780, 836, 880, 928, 980, 1004, 1044, 1088, 1152,
1176, 1196, 1236, 1316, 1424, 1452, 1484, 1588, 1656, 1772.
MS, m/z (Irel (%)): 319 [M]+ (2), 257 (3), 256 (37), 258 (34),
239 (8), 225 (6), 179 (9), 163 (6), 161 (8), 149 (3), 143 (18), 142
(25), 141 (83), 133 (9), 126 (8), 125 (64), 118 (9), 109 (3), 98
(4), 97 (32), 82 (19), 81 (16), 80 (77), 77 (47), 76 (100), 69 (5),
65 (10), 56 (5), 55 (72). The 1H NMR spectral data are given in
Table 1.
C. To a solution of catalyst, prepared as described above
from Pd2(dba)3(CHCl3) (27 mg, 0.025 mmol) and Ph3P (68 mg,
0.26 mmol) in DMF (1 mL) for 5 min at 25 °C, a solution of
sulfone 12 (0.51 g, 2 mmol) and diallyl carbonate (0.35 g,
2.46 mmol) in DMF (3 mL) was added. After stirring for 2 h
another 0.2 g (1.4 mmol) of diallyl carbonate was added to the
reaction mixture, and after additional 2 h of stirring the reaction
mixture was worked up as described in the preceding experiꢀ
ments. Amide 8 (0.3 g, 52%) was obtained, practically identical
(m.p., 1H NMR spectrum) to the samples of this compound
described above.
The authors thank Yu. A. Strelenko (Institute of Orꢀ
ganic Chemistry, RAS) for carrying out the NOESY exꢀ
periment on a Bruker DRXꢀ500 spectrometer.
This work was financially supported by the Russian
Foundation for Basic Research (Project No 06ꢀ03ꢀ32238).
References
N,Nꢀ(Butanꢀ1,4ꢀdiyl)ꢀNꢀ(5S*ꢀbromomethylꢀ3R*ꢀphenylꢀ
sulfonyltetrahydrofuranꢀ2ꢀylidene)ammonium bromide (19). To a
stirred solution of amide 8 (1.08 g, 3.7 mmol) in CHCl3 (15 mL),
a solution of Br2 (0.64 g, 4.0 mmol) in CHCl3 (10 mL) was
1. А. V. Lozanova, Т. М. Ugurchieva, М. V. Zlokazov, A. V.
Stepanov, and V. V. Veselovsky, Mendeleev Commun.,
2006, 15.

136
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 1, January, 2007
Lozanova et al.
2. (a) S. S. С. Koch and A. R. Chamberlin, in Studies in Natuꢀ
ral Products Chemistry, Ed. AttaꢀurꢀRahman, Elsevier,
Amsterdam, 1995, Vol. 16, pp. 687—725; (b) S. S. C. Koch
and A. R. Chamberlin, J. Org. Chem., 1993, 58, 2725.
3. K. Mori, in The Total Synthesis of Natural Products,
Ed. J. ApSimon, J. Wiley and Sons, New York, 1992, Vol. 9.
4. V. Popsavin, I. Krstic, and M. Popsavin, Tetrahedron Lett.,
2003, 44, 8897.
8. V. Blot, V. Reboul, and P. Metzner, J. Org. Chem., 2004,
69, 1196.
9. A. V. Lozanova, Т. М. Ugurchieva, and V. V. Veselovsky,
Izv. Akad. Nauk, Ser. Khim., 2006, 2024 [Russ. Chem. Bull.,
Int. Ed., 2006, 55, 2103].
10. K. Praefcke and C. Weichsel, Liebigs Ann. Chem., 1979, 784.
11. J. Cardellach, С. Estopa, J. Font, М. Morenoꢀmanas, R. M.
Ortuno, F. SanchezꢀFerrando, S. Valle, and L. Vilamajo,
Tetrahedron, 1982, 38, 2377.
12. D. J. Pasto and R. Kent, J. Org. Chem., 1965, 30, 2684.
13. A. N. Mirskova, Yu. I. Kryukova, G. G. Levkovskaya, S. A.
Guseva, and M. G. Voronkov, Zh. Org. Khim., 1984, 20, 602
[J. Org. Chem. USSR, 1984, 20 (Engl. Transl.)].
5. S. R. V. Kandula and P. Kumar, Tetrahedron Lett., 2003,
44, 6149.
6. (a) M.ꢀX. Wang and S. M. Zhao, Tetrahedron Asymmetry,
2002, 13, 1695; (b) J. A. Macritchie, T. M. Peakman,
A. Silcock, and C. L. Willis, Tetrahedron Lett., 1998, 39,
7415; (c) G. Robin and G. Rousseau, Tetrahedron, 1998,
54, 13681.
7. M. V. Zlokazov, A. V. Lozanova, and V. V. Veselovsky,
Mendeleev Commun., 2003, 242; M. V. Zlokazov, A. V.
Lozanova, and V. V. Veselovsky, Izv. Akad. Nauk, Ser. Khim.,
2004, 521 [Russ. Chem. Bull., Int. Ed., 2004, 53, 547].
Received August 28, 2006;
in revised form November 20, 2006