Efficient synthesis of carbohydrate thionolactones

Article abstract of DOI:10.1016/j.tetlet.2006.03.104

Carbohydrate thionolactones may be efficiently synthesized from the corresponding 1-thio sugars via a two-step procedure involving formation of a glycosyl phenylthiosulfinate by treatment with either phenylsulfinyl chloride or 1-(phenylsulfinyl)piperidine

Full text of DOI:10.1016/j.tetlet.2006.03.104

Tetrahedron Letters 47 (2006) 3517–3520
Efficient synthesis of carbohydrate thionolactones
Kampanart Chayajarus and Antony J. Fairbanks*
Chemistry Research Laboratory, Oxford University, Mansfield Road, Oxford OX1 3TA, UK
Received 13 February 2006; revised 6 March 2006; accepted 15 March 2006
Abstract—Carbohydrate thionolactones may be efficiently synthesized from the corresponding 1-thio sugars via a two-step proce-
dure involving formation of a glycosyl phenylthiosulfinate by treatment with either phenylsulfinyl chloride or 1-(phenylsulfin-
yl)piperidine (BSP), and subsequent thermal elimination in toluene.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Thiocarbonyl compounds are most commonly accessed
by treatment of the corresponding carbonyl compound
with Lawesson’s reagent.1 Although there are a few re-
ports of the conversion of carbohydrate lactones to the
corresponding carbohydrate thionolactones under
these2 or similar reaction conditions,3 Vasella4 con-
cluded some time ago that the process was generally
unreliable, and gave unsatisfactorily low yields. The
findings of Vasella have been subsequently corroborated
by other research groups.5
O
SH
O
S
SMe
BnO
BnO
BnO
BnO
(i)
OBn
OBn
OBn
OBn
2
1
(iii) or (iv)
(ii)
R
O
S
S
O
S
BnO
BnO
BnO
(v)
O
or
(vi)
BnO
OBn
OBn
OBn
As part of an ongoing synthetic program, access was re-
quired to several carbohydrate thionolactones for a vari-
ety of purposes. Initial attempts at thionation of a
variety of carbohydrate lactones with either Lawesson’s
or Belleau’s reagents met with frustration, in line with
the experiences of Vasella, and others (yields typically
ꢀ20%). Attention therefore turned to an approach
developed by Vasella4 and co-workers as a solution to
this synthetic problem. Herein, formation of a glycosyl
disulfide is achieved by treatment of a 1-thio sugar6 with
dimethyl(methylthio)sulfonium tetrafluoroborate. Reg-
ioselective oxidation of this glycosyl disulfide mediated
by MCPBA produces a methyl glycosyl thiosulfinate,
which then undergoes thermal elimination7 to produce
the corresponding thionolactone. This basic approach
was tested with the gluco 1-thio sugar 1 using
dimethyl(methylthio)sulfonium triflate (DMTST)8 to
access disulfide 2 (Scheme 1). The reaction sequence
OBn
3a R=Me
3b R=Ph
4
Scheme 1. Reagents and conditions: (i) DMTST, pyridine, CH2Cl2, rt,
90%; (ii) MCPBA, CH2Cl2, 0 ꢁC, 82%; (iii) MeSOCl, pyridine, Et2O,
0 ꢁC, 91%; (iv) PhSOCl, pyridine, Et2O, 0 ꢁC, 82%; (v) 120 ꢁC,
˚
ꢀ8 mbar, 49% from 3a, 67% from 3b; (vi) 4 A molecular sieves,
toluene, 120 ꢁC, 63% from 3a, 85% from 3b.
did indeed yield the desired thionolactone with a
much-improved yield and in higher purity as compared
to the Lawesson’s reagent approach. However, it was
found in particular that the selective oxidation reaction
of disulfide 2 could be somewhat troublesome and some
methyl thiosulfonate product was inevitably produced9
(typically at least ꢀ15%) in addition to the desired
methyl thiosulfinates such as 3a.
Hoping to optimize the process it was reasoned that
intermediate thiosulfinates such as 3a could in fact be ac-
cessed directly from 1-thio sugars, such as 1, by treatment
with a sulfinyl chloride. Sulfinyl chlorides can be pre-
pared in situ by treatment of the corresponding disulfide
Keywords: Carbohydrates; 1-Thio sugars; Thionolactones; Thiosul-
finates.
*
Corresponding author. Fax: +44 1865 275674; e-mail addresses:
kampanart.chayajarus@wolfson.oxford.ac.uk; antony.fairbanks@
chem.ox.ac.uk
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.104

3518
K. Chayajarus, A. J. Fairbanks / Tetrahedron Letters 47 (2006) 3517–3520
with sulfuryl chloride and acetic anhydride.10 Indeed
treatment of 1 with methyl sulfinyl chloride, prepared
in situ from dimethyl disulfide, did produce the required
methylthiosulfinate 3a smoothly in an excellent 91%
yield. In his original letter, Vasella4 reported that thermal
elimination of methyl glycosyl thiosulfinates was
achieved most efficiently by heating under reduced pres-
sure in the absence of solvent. In our hands, this solvent-
free procedure always resulted in appreciable amounts of
decomposition, and a correspondingly reduced product
yield (e.g., 49% yield of 4 from 3a). An alternative proce-
dure consisting of heating the thiosulfinate in toluene in
smoothly produced the required phenyl thiosulfinate
3b (82% yield).12 Thermal elimination of 3b was then
performed by again heating in toluene at 120 ꢁC in the
˚
presence of 4 A molecular sieves for 15 min, and resulted
in the formation of the thionolactone 4 in a substantially
improved 85% yield, with little or no decomposition
(Scheme 1).
With seemingly optimal conditions in hand, the two-step
procedure of formation of the glycosyl phenylthiosulfi-
nate and thermal elimination was applied to a variety
of 1-thio sugars (Table 1). In all cases, the starting thiols
5a–d were smoothly converted into the desired phenyl
thiosulfinates 6a–d.13 Thermal elimination14 to produce
thionolactones 7a–d15 also occurred smoothly and gen-
erally in high yields, though in the rhamno case some lac-
tone side product was formed alongside the desired
thionolactone 7d, resulting in a somewhat reduced yield.
˚
the presence of 4 A molecular sieves was investigated.
This procedure proved to be the method of choice; heat-
ing methylthiosulfinate 3a to 120 ꢁC in toluene in the
˚
presence of 4 A molecular sieves for 15 min resulted in
transformation to the corresponding thionolactone 4 in
an improved, although still modest, 63% yield.
Previous experiences of the chemistry of the correspond-
ing thiosulfonate11 derivatives had pointed out the
advantages of using aryl rather than alkyl substituted
intermediates, both in terms of product yield and inter-
mediate stability. Attention was therefore turned to the
synthesis and use of the corresponding glycosyl phenyl-
thiosulfinates in order to develop an improved synthetic
procedure. Treatment of 1-thio sugar 1 with phenyl sul-
finyl chloride, prepared in situ by reaction of diphenyl-
disulfide with sulfuryl chloride and acetic anhydride,
Recently, it was reasoned that perhaps the intermediate
glycosyl thiosulfinates may in fact be more conveniently
synthesized directly from the corresponding thiols by
treatment with 1-(phenylsulfinyl)piperidine 8, commonly
referred to as BSP (benzenesulfinyl piperidine), a com-
mercially available and shelf-stable reagent introduced
recently by Crich16 and co-workers for the activation
of thioglycosides. Pleasingly treatment of the manno
thiol 5a with BSP 8 produced the corresponding phenyl
thiosulfinate 6a smoothly in an excellent 89% yield; thio-
Table 1.
Entry
Thiol
Phenyl thiosulfinate
Thionolactone
Ph
O
O
S
O
SH
BnO
BnO
O
S S
BnO
BnO
BnO
OBn
7a
OBn
a
BnO
OBn
OBn
OBn
OBn
6a
5a
69%
80%
Ph
O
O
S
O
S
S
BnO
O
SH
BnO
BnO
BnO
BnO
BnO
OBn
7b
OBn
OBn
b
OBn
OBn
6b
OBn
5b
86%
87%
O
Ph
O
BnO
S
O
BnO
S
S
O
BnO
SH
BnO
OBn
c
BnO
OBn
BnO
OBn
7c
6c
5c
78%
84%
Ph
O
O
S
O
S S
O
SH
OBn
BnO
OBn
BnO
OBn
d
BnO
OBn
OBn
OBn
7d
6d
5d
61%a
76%
a Lactone was also produced (ꢀ20% yield) in addition to the desired thionolactone.

K. Chayajarus, A. J. Fairbanks / Tetrahedron Letters 47 (2006) 3517–3520
3519
5. (a) Belhadj, T.; Goekjian, P. G. Tetrahedron Lett. 2005,
46, 8117–8120; (b) Hagan, J. P. J. Org. Chem. 1993, 58,
506–508.
6. For a summary of some synthetic routes to 1-thio sugars
see: Horton, D.; Wander, J. D. In The Carbohydrates;
Pigman, W. W., Horton, D., Eds.; Academic Press: New
York, 1980; Vol. IB, pp 799–842.
7. (a) Block, E.; O’Connor, J. J. Am. Chem. Soc. 1974, 96,
3939–3944; (b) Baldwin, J. E.; Lopez, R. C. G. J. Chem.
Soc., Chem. Commun. 1982, 1029–1030; (c) Baldwin, J. E.;
Lopez, R. C. G. Tetrahedron 1983, 39, 1487–1498.
O
S
O
SH
BnO
BnO
+
Ph
N
OBn
OBn
8
5a
(i)
Ph
O
S S
BnO
BnO
O
OBn
OBn
6a
8. Fugedi, P.; Garegg, P. J. Carbohydr. Res. 1986, 149,
¨
C9–C12.
9. Thiosulfonate side product may be produced either by
direct over-oxidation of the thiosulfinate, or more prob-
ably by thiosulfinate disproportionation under the reac-
tion conditions. See: Kice, J. L.; Cleveland, J. P. J. Am.
Chem. Soc. 1974, 95, 109–112.
10. Crich, D.; Smith, M. Org. Lett. 2000, 2, 4067–4069.
11. For a demonstration of the greater merits of glycosyl
phenylthiosulfonate reagents (PTS) over the correspond-
ing methylthiosulfonate (MTS) derivatives see: Davis, B.
G.; Fairbanks, A. J.; Gamblin, D. P.; Garnier, P.;
Oldham, N. J.; Ward, S. J. Org. Biomol. Chem. 2003, 1,
3642–3644.
(ii)
O
S
BnO
BnO
OBn
OBn
7a
Scheme 2. Reagents and conditions: (i) CF3CO2H, CH2Cl2, rt, 89%;
(ii) 4 A molecular sieves, toluene, 120 ꢁC, 69%.
˚
12. Some glycosyl phenyl disulfide (ꢀ12%) was also isolated
sulfinate 6a once again underwent thermal elimination
to give the desired thiolactone 7a (Scheme 2).
from this reaction.
13. Typical experimental procedure: a solution of benz-
enesulfinyl chloride (2 equiv) in dry diethyl ether (10 ml)
was added slowly to a stirred solution of the 1-thioglyco-
pyranose (1 equiv, ꢀ100 mg) and pyridine (1.5 equiv) in
dry diethyl ether (5 ml) under an atmosphere of argon at
room temperature. After 30 min, the mixture was diluted
with diethyl ether, quenched by the addition of dilute 1 M
aqueous H2SO4, washed with saturated aqueous NaHCO3
and brine, dried (MgSO4), filtered and concentrated in
vacuo. The residue was purified by flash column chroma-
tography (typically petrol/ethyl acetate; 5:1 to 2:1) to give
It can be concluded that treatment of 1-thio sugars with
either phenylsulfinyl chloride, or BSP, and subsequent
thermal elimination of the so-formed glycosyl phenyl
thiosulfinates by heating in toluene in the presence of
molecular sieves provides efficient and generally high
yielding access to carbohydrate thionolactones. It is
noteworthy that this two-step procedure effectively
equates to the oxidation of a thiol to a thioketone, a syn-
thetic transformation which it is not particularly
straightforward to achieve. Investigations into the oxi-
dation of thiols to thioketones in this manner, together
with the use of carbohydrate thionolactones for the syn-
thesis of a range of oligosaccharides and spiro-C/O-gly-
coside-containing natural products are currently under
investigation, and the results will be reported in due
course.
the glycosyl phenyl thiosulfinate, as
diastereomers.
a mixture of
14. Typical experimental procedure: a solution of glycosyl
˚
phenyl thiosulfinate (ꢀ100 mg) and 4 A molecular sieves
(ꢀ100 mg) were suspended in anhydrous toluene (1 ml),
and the mixture was heated at 120 ꢁC under an atmo-
sphere of argon. After 15 min, TLC (typically petrol/ethyl
acetate; 5:1) indicated complete reaction. The mixture was
cooled to room temperature, filtered through Celiteꢂ and
concentrated in vacuo. The residue was purified by flash
column chromatography (typically petrol/ethyl acetate,
7:1) to yield the thiolactone.
Acknowledgements
15. All new compounds exhibited spectral data consistent
20
with their structures. Selected data: 7b a yellow oil: ½aꢁD
We gratefully acknowledge financial support from the
Royal Thai Government (studentship to K.C.), and
the use of the Chemical Database Service (CDS) at
Daresbury, UK.
+76 (c 1.0 in CHCl3); dH (400 MHz, C6D6) 3.50 (1H, dd,
J3,4 = 2.5 Hz, J2,3 = 7.8 Hz, H-3), 3.57–3.65 (2H, m, H-6,
60), 3.87 (1H, dd, J4,5 = 1.7 Hz, J3,4 = 2.5 Hz, H-4), 4.08
(1H, td, J4,5 = 1.7 Hz, J5,6 = 5.5 Hz, H-5), 4.12 (1H, d,
J = 11.8 Hz, CH0HPh), 4.20 (1H, d, J = 11.8 Hz,
CHH0Ph), 4.25 (1H, d, J = 12.0 Hz, CHH0Ph), 4.41
(1H, d, J = 11.8 Hz, CHH0Ph), 4.47 (1H, d, J = 11.3 Hz,
CHH0Ph), 4.61 (1H, d, J = 8.1 Hz, CHH0Ph), 4.62 (1H, d,
J = 10.8 Hz, CHH0Ph), 4.81 (1H, d, J = 11.6 Hz,
CHH0Ph), 5.24 (1H, d, J = 10.8 Hz, CHH0Ph), 7.06–7.22
(20H, m, Ar-H); dC (100.6 MHz, C6D6) 67.9 (C-6), 72.9
(C-4), 72.5, 73.5, 74.7, 75.0 (4 · CH2Ph), 80.3 (C-3), 81.7
(C-5), 84.3 (C-2), 127.7, 127.8, 127.9, 128.0, 128.1, 128.4,
128.5, 128.6, 128.8, 138.2, 138.4, 138.5 (Ar-C), 217.9
(C@S); m/z (ES+) 613 (M þ NHþ4 þ MeCN, 100%);
HRMS calcd for C34H34O5NaS (MNa+) 577.2025,
found 577.2020. 7d a yellow oil; dH (400 MHz, C6D6)
References and notes
1. See, for example: Scheibye, S.; Shabana, R.; Lawesson,
S.-O.; Romming, C. Tetrahedron 1982, 38, 993–1001, and
references cited therein.
2. Kahne, D.; Yang, D.; Jin Lim, J.; Miller, R.; Paguaga, E.
J. Am. Chem. Soc. 1988, 110, 8716–8717.
3. For a report on the use of Belleau’s reagent see: Barrett, A.
G. M.; Lee, A. C. J. Org. Chem. 1992, 57, 2818–2824.
4. Hurzeler, M.; Bernet, B.; Vasella, A. Helv. Chim. Acta
¨
1993, 76, 995–1012.

3520
K. Chayajarus, A. J. Fairbanks / Tetrahedron Letters 47 (2006) 3517–3520
1.27 (3H, d, J5,6 = 6.3 Hz Hz, CH3), 3.57 (1H, dd,
C6D6) 19.0 (C-6), 72.0 (C-5), 73.0, 73.3, 78.2 (3 · CH2Ph),
78.3 (C-4), 82.4 (C-3), 83.4, (C-2), 128.2, 128.4, 128.5,
128.6, 137.7, 138.2, 138.5 (Ar-C), 216.3 (C@S); HRMS
calcd for C27H28O4NaS (MNa+) 471.1601, found
471.1600.
J2,3 = 2.5 Hz, J3,4 = 8.0 Hz, H-3), 3.92–4.02 (2H, m, H-
4, 5), 4.13 (1H, d, J = 11.6 Hz, CHH0Ph), 4.26 (1H, d,
J2,3 = 3.0 Hz, H-2), 4.35, 4.46 (2H, ABq, J = 11.6 Hz,
CH2Ph), 4.62 (1H, d, J = 11.8 Hz, CHH0Ph), 4.96 (1H, d,
J = 11.8 Hz, CHH0Ph), 5.25 (1H, d, J = 11.3 Hz,
CHH0Ph), 7.15–7.32 (15H, m, Ar-H); dC (62.9 MHz,
16. Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015–
9020.