1-Hydroxymethyl-4-phenylsulfonybutadiene, a versatile building block for the synthesis of 2,3,4-trisusbtituted tetrahydrothiophenes

Article abstract of DOI:10.3390/90500323

A method to synthesize chiral 2,3,4-trisusbtituted tetrahydrothiophenes in both enantiomerically pure forms starting from 1-hydroxymethyl-4- phenylsulfonylbutadiene is described.

Full text of DOI:10.3390/90500323

Molecules 2004, 9, 323–329
molecules
ISSN 1420-3049
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1-Hydroxymethyl-4-phenylsulfonybutadiene, a Versatile
Building Block for the Synthesis of 2,3,4-Trisusbtituted
Tetrahydrothiophenes
David Díez *, M. Templo Benéitez, Isidro S. Marcos, N. M. Garrido, P. Basabe and Julio G.
Urones
Dpto. de Química Orgánica, Universidad de Salamanca. Plaza de los Caídos 1–5, 37008 Salamanca,
Spain. Fax (+34) 923 294574.
* Author to whom correspondence should be addressed; E-mail: ddm@usal.es
Received: 24 February 2004; in revised form: 4 March 2004 / Accepted: 10 March 2004 / Published:
30 April 2004
Abstract: A method to synthesize chiral 2,3,4-trisusbtituted tetrahydrothiophenes in both
enantiomerically pure forms starting from 1-hydroxymethyl-4-phenylsulfonylbutadiene is
described.
Keywords: Sulfonylbutadienes, heterocycles, tetrahydrothiophenes, vinylsulfones,
chiral.
Introduction
Five-membered oxa-, aza- and thia- ring systems are widely distributed in nature and have
attracted the interest of the scientific community, particularly in conjunction with the total synthesis of
polyether natural products [1], pyrrolidines with glycosidase inhibitor activity [2], and 5-thiosugars as
therapeutic agents. This interest is also due to the use of such molecules for understanding the
recognition processes of sugar-binding proteins [3]. Our group is involved in a program seeking to
exploit the reactivity of 1-hydroxymethyl-4-sulfonylbutadiene for the synthesis of highly
functionalized oxygen, nitrogen and sulfur five-membered heterocycles [4]. Chemo- and
.

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enantioselective epoxidation of 1-hydroxymethyl-4-sulfonylbutadiene (1), under Sharpless conditions
[5] gives rise to epoxide 2. In a recent paper we reported the ability of several protecting groups to
provide excellent control of the opening of 2 [6]. In this way, tosylate 3 and acetate 4 could easily be
obtained, starting from the same chiral epoxide 2. Tosylate 3 has been further transformed into
pyrrolidine 5, which possesses glycosidase inhibitory activity, and its oxygen analogue 6 (Scheme 1).
Scheme 1
SO2Ph
HO
1
Sharpless, L(+)-DET
O
SO2Ph
HO
O
2
O
O
O
TsO
AcO
4
3
SO2Ph
SO2Ph
HO
OH
HO
OH
N
O
H
5
6
Results and Discussion
The easy synthesis on a multigram scale of compounds 3 and 4 prompted us to use them for the
synthesis of the sulfur analogs, which interested us due to their biological activities. The most common
procedure for the synthesis of thiosugars, is based on the introduction of a thiol group by a double
nucleophilic replacement of sulfonyloxy groups in the required positions. Other polyhydroxylated
chiral thiolanes have been obtained by introduction the thiol group by conjugate addition, followed by
internal displacement of a sulfonyloxy group [7]. This tandem reaction has been used by us in the
synthesis of pyrrolidines such as 5 [4]. In order to apply the same methodology for the synthesis of
tetrahydrothiophenes, we decided to react 3 with sodium sulfide under the usual conditions, thus
obtaining the tetrahydrothiophene 7 in low yield (8%). The stereochemistry of 7 was established by
NMR studies. In light of this result we decided to transform the tosylate into iodide 8 under the usual
conditions [8] (75% yield) and then allow this compound to react with thiourea [9]. Hydrolysis of the
resulting thiouronium salt gave a 6:4 epimeric mixture of cis:trans tetrahydrothiophenes 9 in good
yield (81%) (Scheme 2).

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Scheme 2
O
O
O
O
b
I
TsO
3
8
SO Ph
2
SO Ph
2
c
a
O
O
O
O
S
S
SO Ph
SO Ph
2
2
9
7
a) Na2S, MeOH, 65ºC; b) NaI, acetone, 80ºC;
c) (H2N)2CS, MeOH, 65ºC, then KOH
In order to obtain the enantiomer, starting from the same epoxide 2, and to simultaneously test the
use of bromide as a leaving group, the acetoxy derivative 4 (obtained from 2 as described previously
[6]) was reduced with DIBAL to the alcohol 10 in 89% yield and then transformed into the bromo
derivative 11 (70%). This compound was submitted to the same conditions as before, providing the
enantiomeric epimeric mixture 12, in this case in a 79% yield (Scheme 3).
Scheme 3
O
O
O
O
O
a
AcO
HO
4
10
SO2Ph
SO2Ph
b
O
O
O
c
Br
S
SO2Ph
SO2Ph
11
12
a) DIBAL, DCM, -78ºC; b) CBr4, Ph3P, DCM, 50ºC;
c) (H2N)2CS, MeOH, 65ºC, then KOH.

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Conclusions
This methodology opens a new way for obtaining chiral 2,3,4-trisubstituted-tetrahydrothiophenes
that could easily be transformed into sugar analogues or biotin derivatives.
Acknowledgments
The authors thank the CICYT (BQU2001-1034) and Junta de Castilla y León (SA13-00B) for
financial support and the Spanish Ministerio de Educación y Ciencia for a doctoral fellowship to
M.T.B.
Experimental
General
Unless otherwise stated, all chemicals were purchased as the highest purity commercially available
and were used without further purification. Melting points were determined with a Kofler hot stage
melting point apparatus and are uncorrected. IR spectra were recorded on a BOMEM 100 FT IR
1
13
spectrophotometer. H- and C-NMR spectra were recorded in deuterochloroform and are referenced
to the residual peak of CHCl3 at δ 7.26 ppm and δ 77.0 ppm, respectively, for 1H- and 13C-, on a Bruker
WP-200 SY or a BRUKER DRX 400 MHz spectrometer. Chemical shifts are reported in ppm on
the δ scale and coupling constants (J) are given in Hz. Mass spectra were performed in a VG-TS 250
spectrometer at a 70 eV ionizing voltage. Results are presented as m/z (% rel. int.). HRMS were
recorded in a VG Platform spectrometer using Electronic Impact (EI) or Fast Atom Bombardment
(FAB) techniques. Optical rotations were determined in a Perkin-Elmer 241 polarimeter in 1 dm cells.
Diethyl ether, THF and benzene were distilled from sodium, and pyridine and dichloromethane (DCM)
were distilled under argon from CaH2.
(2R,3S,4S)-2-Benzenesulfonylmethyl-3,4-isopropylidendioxytetrahydrotiophene (7).
To a solution of 3 (38 mg, 0.08 mmol) in MeOH (1 mL) was added dry Na2S (13 mg, 0.16 mmol).
The mixture was refluxed for 8 h under an argon atmosphere and then the solvent was evaporated. The
crude product was dissolved in water (2 mL) and extracted with AcOEt. The combined organic
extracts were washed with water and brine. After drying and concentration the residue was purified by
20
chromatography (8:2 n-hexane-EtOAc) to give 7 (3 mg, 8%); [α]D = +16.5 (c= 0.30, CHCl3);
1H-NMR (200 MHz): 7.97-7.42 (5H, m, Ar), 4.83 (1H, dt, J= 2.4 and 5.2 Hz, H-4), 4.69 (1H, dd, J=
4.0 and 5.2 Hz, H-3), 3.77 (1H, dd, J= 6.2 and 14.0 Hz, HA-1’), 3.55 (1H, dt, J= 4.0, and 6.2 Hz, H-2),
3.30 (1H, dd, J= 6.2 and 14.0 Hz, HB-1’), 2.86 (2H, d, J= 2.4 Hz, 2H-5), 1.44 (Me-acetonide), 1.25
(Me-acetonide); 13C-NMR (50.3 MHz): 139.4 (C-ipso), 134.2 (CH-para), 129.5 (2CH-meta), 128.4

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(2CH-ortho), 111.3 (C-acetonide), 83.1 (CH-3), 83.0 (CH-4), 55.5 (CH2-1’), 46.1 (CH-2), 38.8 (CH2-
5), 25.9 (Me-acetonide), 24.7 (Me-acetonide); IR νmax (film) ν (cm-1): 2986, 1447, 1373, 1308, 1209,
1148, 1049; EIMS, m/z (%): 314 (M+, 5), 299 (20), 172 (80), 115 (83), 77 (100); HRMS (EI) calcd. for
C14H18O4S2: 314.0646, found: 314.0671.
(2R, 3R,4E)-5-Benzenesulfonyl-1-iodo-2,3-isopropylidenedioxypent-4-ene (8).
To a solution of 3 (80 mg, 0.18 mmol) in dry acetone (2.0 mL) was added NaI (81 mg, 0.54 mmol).
The reaction mixture was refluxed overnight. The solvent was evaporated and the residue was
dissolved in water (2mL) and extracted with EtOAc. The combined organic layers were washed with
10% aqueous Na2S2O3, 5% NaHCO3 and brine. The organic phase was dried over Na2SO4.
Concentration followed by flash chromatography on silica gel (85:15 n-hexane-EtOAc) gave
20
1
compound 8 (55 mg, 75 %); [α]D = +14.2 (c = 1.2, CHCl3); H-NMR (400 MHz) 7.94-7.52 (5H, m,
-Ar), 6.99 (1H, dd, J = 4.4 and 15.0 Hz, H-4), 6.66 (1H, dd, J = 1.4 and 15.0 Hz, H-5), 4.85 (1H, m, H-
3), 4.57 (1H, ddd, J = 6.6, 6.6, and 7.8 Hz, H-2), 3.10 (1H, dd, J = 6.6 and 10.2 Hz, HA-1), 2.90 (1H,
dd, J = 7.8 and 10.2 Hz, HB-1), 1.47 (3H, s, Me-acetonide), 1.35 (3H, s, Me-acetonide); 13C-NMR
(50.3 MHz) 140.1 (C-ipso), 139.6 (CH-4), 133.9 (CH-5), 133.4 (CH-para), 129.6 (2CH-meta), 128.1
(2CH-ortho), 110.2 (C-acetonide), 77.9 (CH-3), 76.1 (CH-2), 76.1 (CH2-1), 28.1 (Me-acetonide), 25.5
(Me-acetonide); IR (film) ν (cm-1) 1383, 1148, 1086, 1038, 880, 760; EIMS m/z (%) 408 (M+, 5), 238
(91), 125 (60), 97 (100), 77 (80); HRMS (EI) calcd. for C14H17O4SI: 407.9892, found 407.9921.
(2RS,3S,4R)-2-Benzenesulfonyl-3,4-isopropylidenedioxytetrahydrothiophene (9).
To a solution of 8 (55 mg, 0.13 mmol) in EtOH (1.3 mL) was added thiourea (15 mg, 0.19 mmol).
After stirring at reflux temperature for 5 days the solvent was evaporated and the residue was dissolved
in 0.5 mL of water and added to an aqueous solution of 1 M KOH (0.7 mL). The resulting mixture was
refluxed for 14 h, then the mixture was cooled, neutralized with 3M H2SO4 and extracted with EtOAc.
The combined organic extracts were washed with water and brine. After drying and concentration the
residue was purified by chromatography (85:15 n-hexane-EtOAc) to give a mixture of cis/trans
diastereoisomers 9 (33 mg, 81%) in a ratio of 6:4.
(2R,3S,4E)-5-Benzenesulfonyl-2,3-isopropylidenedioxypent-4-en-1-ol (10).
To a solution of 4 (48 mg, 0.14 mmol) in DCM (1.5 mL) was added 1.5 M DIBAL-H in toluene
(0.2 mL, 0.28 mmol) at -78ºC under an argon atmosphere. The mixture was stirred for 20 minutes,
quenched carefully with water and warmed to room temperature. The reaction mixture was then
diluted with 100 mL of Et2O and 2 M HCl (1.5 mL). After stirring for 1h the mixture was dried over
20
Na2SO4. Filtration followed by concentration afforded 10 (37 mg, 89%); [α]D = -2.6 (c = 0.87,
1
CHCl3); H-NMR (200 MHz): 7.94-7.52 (5H, m, -Ar), 7.02 (1H, dd, J= 4.0 and 14.8 Hz, H-4), 6.68

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(1H, dd, J= 1.8 and 14.8 Hz, H-5), 4.84 (1H, ddd, J= 1.8, 4.0 and 6.0 Hz, H-3), 4.40 (1H, dt, J= 5.8 and
6.0 Hz, H-2), 3.57 (2H, d, J= 5.8 Hz, 2H-1), 1.46 (3H, s, Me-acetonide), 1.36 (3H, s, Me-acetonide);
13C-NMR (50.3 MHz): 141.3 (CH-4), 140.2 (C-ipso), 133.8 (CH-5), 132.0 (CH-para), 129.6 (2CH-
meta), 128.1 (2CH-ortho), 110.0 (C-acetonide), 78.1 (CH-3), 75.3 (CH-2), 61.6 (CH2-1), 27.7 (Me-
acetonide), 25.2 (Me-acetonide); IR νmax (film) ν (cm-1): 3500 (wide), 2930, 1447, 1148, 1086.
(2R,3S,4E)- 5-Benzenesulfonyl-1-bromo-2,3-isopropylidenedioxypent-4-ene (11).
To a solution of 10 (37 mg, 0.12 mmol) in DCM (1.5 mL) was added PPh3 (31 mg, 0.12 mmol) and
CBr4 (40 mg, 0.12 mmol). The mixture was heated at 50ºC for 12 h under an argon atmosphere. The
reaction mixture was then quenched with water and extracted with EtOAc. The combined organic
extracts were washed with water and brine. After drying and concentration the residue was purified by
20
chromatography (9:1 n-hexane-EtOAc) to give 11 (30 mg, 70%); [α]D = -4.6 (c= 0.82, CHCl3);
1H-NMR (200 MHz): 7.94-7.52 (5H, m, -Ar), 7.06 (1H, dd, J= 4.4 and 15.0 Hz, H-4), 6.67 (1H, dd, J=
1.8 and 15.0 Hz, H-5), 4.88 (1H, ddd, J= 1.8, 4.4 and 6.2 Hz, H-3), 4.54 (1H, ddd, J= 5.4, 6.2 and 8.0
Hz, H-2), 3.30 (1H, dd, J= 5.4 and 10.2 Hz, HA-1), 3.10 (1H, dd, J= 8.0 and 10.2 Hz, HB-1), 1.47 (3H,
13
s, Me-acetonide), 1.35 (3H, s, Me-acetonide); C-NMR (50.3 MHz): 140.1 (C-ipso), 139.4 (CH-4),
133.9 (CH-5), 133.1 (CH-para), 129.6 (2CH-meta), 128.1 (2CH-ortho), 110.3 (C-acetonide), 77.9
(CH-3), 75.9 (CH-2), 29.5 (CH2-1), 27.9 (Me-acetonide), 25.4 (Me-acetonide); IR νmax (film) ν (cm-1):
1750, 1319, 1148, 1086, 1047.
(2RS,3R,4S)-2-Benzenesulfonyl-3,4-isopropylidenedioxy-tetrahydrothiophene (12).
To a solution of 11 (30 mg, 0.08 mmol) in EtOH (1 mL) was added thiourea (9 mg, 0.12 mmol).
Following an identical procedure to that described for the preparation of 9 a 6:4 (cis/trans) mixture of
diastereoisomers 12 was obtained (19 mg, 79%).
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Sample availability: Available from the authors.
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