A concise synthesis of highly functionalised 4-thiosugar derivatives

Article abstract of DOI:10.1055/s-2008-1078027

Cyclisation of a sulfenic acid and an alkene to generate 4-thiosugars has been developed. The first example of the cyclisation of a sulfenic acid and a vinyl chloride is included. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078027

2158
LETTER
A Concise Synthesis of Highly Functionalised 4-Thiosugar Derivatives
C
oncise
S
.
ynthesis of
H
M
ighly Functionalised 4
i
-Thios
k
ugar
D
erivati
e
ves Southern,*a Ian A. O’Neil,*b Peter Kearnsb
a
Centre for Synthesis and Chemical Biology and School of Chemistry, University of Dublin, Trinity College, Dublin 2, Ireland
E-mail: southerj@tcd.ie
Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Crown St, Liverpool L69 7ZD, UK
E-mail: ion@liv.ac.uk
b
Received 28 May 2008
Dedicated to Professor Sir Jack Baldwin FRS on the occasion of his 70th birthday
rated. Heating the sulfoxide 9 in octane resulted in elimi-
Abstract: Cyclisation of a sulfenic acid and an alkene to generate
4-thiosugars has been developed. The first example of the cyclisa-
tion of a sulfenic acid and a vinyl chloride is included.
nation of isobutene to generate the intermediate sulfenic
acid 11. This underwent cyclisation in situ to give two
diastereoisomeric sulfoxides 13 and 14 in a 6.5:1 ratio in
Key words: sulfoxides, cyclisation, epoxides, heterocycles
O
NH2
N
Et
H
4-Thiosugars and their nucleoside derivatives are en-
dowed with a wide range of significant biological activi-
ty.1 For example, compound 1 exhibits potent antiviral
activity,2 4¢-thionucleoside 2 shows pronounced antitu-
mor properties3 and salacinol (3)4 and kotalanol (4) are re-
cently isolated 4-thiosugars derivatives which are
glycosidase inhibitors (Figure 1). Interestingly, the nitro-
gen analogue of salacinol does not possess any significant
biological activity.5 In addition, chiral sulfides based on
tetrahydrothiophenes have been used as catalysts in a
number of asymmetric transformations.6
N
HO
N
HO
N
O
O
S
S
F
OH
OH
1 antiviral activity
2 antitumour activity
OH OH
OH OH OH
HO
HO
S
HO
OSO–3 OH OH
–
+
+
S
HO
OSO3
Considerable effort has been spent on developing viable
synthetic routes to 4-thiosugars. Many of these are based
on the manipulation of sugar starting materials.1 In addi-
tion, several routes have been developed which do not rely
on the use of carbohydrates.7 However, most of these
routes are lengthy and inefficient and there is still a need
for a concise and flexible route to this important family of
compounds. We have recently reported the synthesis of
dihydrothiophenes using a novel tin Pummerer reaction.8
Herein we disclose a highly efficient synthesis of 4-thio-
sugars from non-carbohydrate-based starting materials
utilising the cyclisation of functionalised unsaturated
sulfenic acids. Jones and co-workers have previously used
the cyclisation of unsaturated sulfenic acids in the synthe-
sis of a number of cyclic sulfoxides;9 however their exam-
ples were limited to relatively simple substrates. More
recently, Grainger has utilised a sulfenic acid cyclisation
onto a 1,4 diene in the diastereoselective synthesis of cis-
fused perhydrobenzothiophene S-oxides.10
OH
3 salacinol
OH
4 kotalanol
Figure 1 Biologically active 4-thiosugars
OH
RO
RO
t-BuSLi, THF
–78 °C to r.t.
MCPBA, CH2Cl2
O
K2CO3, –78 °C to r.t.
S
5 R = H
6 R = Bn
7 R = H 99%
8 R = Bn 97%
OH
RO
OH
RO
octane
∆
S
+
O–
S
H
O
9 R = H 89%
10 R = Bn 95%
11 R = H
12 R = Bn
Our synthetic sequence is illustrated in Scheme 1. The
readily available epoxide 511 was treated with lithium tert-
butylthiolate to give the thioether 7 in excellent yield. Ox-
idation of the thioether 7 with mCPBA gave the sulfoxide
9 as a mixture of diastereoisomers which were not sepa-
RO
OH
RO
OH
13/14 = 6.5:1, 71%
15/16 = 7.5:1, 81%
+
S
O–
S
+
O –
+
13 R = H
15 R = Bn
14 R = H
16 R = Bn
SYNLETT 2008, No. 14, pp 2158–2160
2
2
.0
8
.2
0
0
8
Advanced online publication: 05.08.2008
DOI: 10.1055/s-2008-1078027; Art ID: D17708ST
Scheme 1
© Georg Thieme Verlag Stuttgart · New York

LETTER
Concise Synthesis of Highly Functionalised 4-Thiosugar Derivatives
2159
HO
BzO
Ph3P, BzOH
t-BuSLi (2 equiv)
O
O
DEAD, benzene
77%
–78 °C to r.t.
THF
99%
5
18
HO
OH
OH
HO
MCPBA, CH2Cl2
S+
O–
K2CO3, –78 °C to r.t.
98%
S
19
20
HO
OH
HO
OH
Figure 2
octane
+
∆
60%
21/22 = 3:2
BnO
OH
+
S
O–
S+
O–
BnO
OH
BH3⋅THF
100%
21
22
S
O–
+
S
Scheme 3
15
17
BnO
1. O3, CH2Cl2, –78 °C
BnO
Scheme 2
O
O
2. Ph3P
t-BuSLi, THF
–
3.
+
–78 °C to r.t.
60%
an excellent combined yield of 71% (96% based on recov-
ered starting material).
Ph3P
Cl
Cl
6
23
40%
The diastereoisomers were readily separable by flash
chromatography. The reaction sequence was repeated on
the O-benzyl-protected epoxy alcohol 6. Again the yields
were excellent and the two diastereoisomeric sulfoxides
15 and 16 were now formed in a 7.5:1 ratio.
OH
BnO
OH
BnO
MCPBA, CH2Cl2
K2CO3, –78 °C to r.t.
80%
S
+
O–
S
Cl
Cl
24
25
The benzyl group served to differentiate between the two
secondary hydroxyl groups on the ring. The sulfoxide
products are convenient precursors for the coupling of nu-
cleoside bases utilising a silicon-mediated Pummerer re-
action.12 In the case of R = H, the major diastereoisomer
13 was crystalline and X-ray analysis confirmed the struc-
ture of the product (Figure 2).13
OH
BnO
BnO
Cl
OH
octane
71%
∆
S+
O–
S
Cl
H
O
26
27
The sulfoxide 15 was readily deoxygenated using borane
to yield the parent thioether 17 in quantitative yield
(Scheme 2).
Scheme 4
40% for the two steps. The vinyl chloride was formed as
an inseparable 5:1 mixture of the Z- and E-isomers. Ring
opening of the epoxide 23 with t-BuSLi proceeded
smoothly to give the thioether 24 in 60% yield. Selective
oxidation of the thioether yielded the sulfoxide 25 as a
mixture of diastereoisomers. Thermolysis of 25 in octane
generated the sulfoxide 27, again via the intermediacy of
sulfenic acid 26. To the best of our knowledge this is the
first example of a sulfenic acid cyclisation onto a vinyl
chloride.14 The product sulfoxide 27 was formed as a sin-
gle diastereoisomer in good yield and the structure of the
product was again confirmed by X-ray analysis
(Figure 3).13
The flexibility of this route is illustrated by the ease with
which diastereoisomeric derivatives can be prepared
(Scheme 3).
Subjecting the epoxide 5 to Mitsunobu conditions gave
the benzoate 18 arising from clean SN2 displacement at
the secondary alcohol. Reaction of 18 with two equiva-
lents of t-BuSLi resulted in concomitant removal of the
benzoate group and ring opening of the epoxide to give
the thioether 19. Oxidation of 19 gave the sulfoxide 20 as
a mixture of diastereoisomers in excellent yield.
Thermolysis of 20 in octane gave the sulfoxides 21 and 22
as an inseparable mixture in a 3:2 ratio. We now wished
to prepare derivatives which bore additional functionality
on the methyl group to enable further synthetic manipula-
tion at this position. Therefore we prepared the vinyl chlo-
ride 25 as shown in Scheme 4.
Thus the epoxy alkene 6 was treated with O3–PPh3 to gen-
erate an intermediate aldehyde, which was not isolated but
converted in situ to the vinyl chloride 23 by treatment with
the chloromethyl phosphonium ylide in an overall yield of
Figure 3
Synlett 2008, No. 14, 2158–2160 © Thieme Stuttgart · New York

2160
J. M. Southern et al.
LETTER
(9) (a) Jones, D. N.; Kogan, T. P.; Newton, R. F. J. Chem. Soc.,
Perkin Trans. 1 1982, 1333. (b) Jones, D. N.; Lewton, D. A.
J. Chem. Soc., Chem. Commun. 1974, 457. (c) Adams, H.;
Bell, R.; Cheung, Y. Y.; Jones, D. N.; Tomkinson, N. C. O.
Tetrahedron: Asymmetry 1999, 10, 4129.
RO
OH
RO
OH
DBU, THF
86%
S +
O–
S +
O–
Cl
(10) Grainger, R. S.; Tisselli, P.; Steed, J. W. Org. Biomol. Chem.
27
28
2004, 2, 151.
(11) (a) Wong, C. H.; Romero, A. J. Org. Chem. 2000, 65, 8264.
(b) O’Neil, I. A.; Cleator, E.; Hone, N.; Southern, J. M.;
Tapolczay, D. J. Synlett 2000, 1408. (c) Palmer, A. M.;
Jäger, V. Synlett 2000, 1405. (d) Smith, D. B.; Wang, Z.;
Schreiber, S. L. Tetrahedron 1990, 46, 4793. (e) Katsuki,
T.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237.
(12) O’Neil, I. A.; Hamilton, K. M. Synlett 1992, 791.
(13) X-ray Data: 13: C5H10O3S, M = 150.21, T = 213 (2) K,
monoclinic, P21, a = 6.0330 (15) Å, b = 7.7668 (13) Å, c =
Scheme 5
Treatment of sulfoxide 27 with DBU gave the vinyl sulf-
oxide 28 in 86% yield (Scheme 5). Vinyl sulfoxide 28 is a
flexible intermediate, potentially allowing the introduc-
tion of a wide range of functionality into the methyl side
chain.
7.4105 (19) Å, a = 90º, b = 105.65 (3)º, g = 90º, Z = 2, Dcalcd
=
1.492 Mg/m3, F(000) = 160, absorption coefficient = 0.357
mm–1, independent reflections 2116/1005 [R(int) = 0.0340]
with I ≥ 2s(I) were used in the analysis; qmax = 24.21°, final
R1 = 0.0254, wR2 = 0.0620. 27: C12H15ClO3S, M = 274.75,
T = 213 (2) K, orthorhombic, P212121, a = 8.5497 (17) Å,
b = 9.756 (2) Å, c = 15.067 (3) Å, a = 90°, b = 90°, g = 90°,
Z = 4, Dcalcd = 1.452 Mg/m3, F(000) = 576, absorption
coefficient = 0.463 mm–1, independent reflections 1968
[R(int) = 0.0442] with I ≥ 2s(I) were used in the analysis;
In summary, we have developed a short and efficient route
to highly functionalised chiral cyclic sulfoxides utilising
an intramolecular sulfenic acid cyclisation onto alkenes.
Acknowledgment
Jamie Bickley is thanked for carrying out the X-ray crystallography.
We would like to thank the EPSRC (GR/M13558) and the BBSRC
for financial support. We would also like to thank Dr Luis Castro
formerly of Merck Sharp and Dohme (Terlings Park, UK) for ge-
nerous unrestricted funding.
q
max = 24.16°, final R1 = 0.0400, wR2 = 0.1091. Atomic
coordinates and further crystallographic details have been
deposited at the Cambridge Crystallographic Data Centre;
deposition numbers are CCDC 634841 (13) and CCDC
634842 (27). Copies of these data can be obtained by
applying to CCDC, University Chemical Laboratory,
Lensfield Road, Cambridge CB2 1EW, UK; fax +44
(1223)336033; email: deposit@ccdc.cam.ac.uk.
References and Notes
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J. G.; Jeong, L. S. Curr. Med. Chem. 2004, 11, 2585.
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(14) Preparation of 4-(Benzyloxy)-5-(chloromethyl)-1-
oxotetrahydrothiophen-3-ol (27): A solution of vinyl
chloride 25 (42 mg, 0.21 mmol) in octane (5 mL) was heated
at reflux for 12 h in a nitrogen atmosphere. After cooling the
solvent was removed under reduced pressure. The crude
product was purified by column chromatography on silica
gel (5% MeOH in EtOAc) to yield the title compound as a
white solid (24 mg, 71%); mp 125–127 °C. IR (nujol): 1033
(SO) cm–1. 1H NMR (400 MHz, CDCl3): d = 2.78 [dd, J =
5.0, 15.0 Hz, 1 H, SCHHCH(OH)], 3.28 [m, 1 H, CH(OBn)],
3.41 [dd, J = 2.0, 14.0 Hz, 1 H, CH(OH)], 3.68 (dd, J = 5.0,
11.5 Hz, 2 H, CH2Cl), 4.09 (m, 1 H, SCHCH2Cl), 4.52 [dd,
J = 3.5, 10.0 Hz, 1 H, SCHCH(OH)], 4.57 (s, 2 H, OCH2Ph),
7.27 (m, 5 H, CH2Ph). 13C NMR (100 MHz, CDCl3): d =
37.9, 58.7, 64.6, 70.2, 74.0, 82.9, 128.5, 129.2, 129.3, 136.8.
HRMS (CI, NH3): m/z calcd for C12H16ClO3S: 275.05087;
found: 275.05155.
(2) (a) Su, T. L.; Watanabe, K. A.; Schinazi, R. F.; Fox, J.
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Synlett 2008, No. 14, 2158–2160 © Thieme Stuttgart · New York

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