One-pot synthesis of carbohydrate thionolactones from 1-thiosugars

Article abstract of DOI:10.1016/j.tetlet.2008.05.145

A general and efficient one-pot method for the synthesis of carbohydrate thionolactones from the corresponding 1-thiosugar is described involving the formation of an intermediate glycosyl S-tert-butyl thiosulfinate in situ by treatment of a thiol with com

Full text of DOI:10.1016/j.tetlet.2008.05.145

Tetrahedron Letters 49 (2008) 4941–4943
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Tetrahedron Letters
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One-pot synthesis of carbohydrate thionolactones from 1-thiosugars
*
Brendan L. Wilkinson, Antony J. Fairbanks
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A general and efficient one-pot method for the synthesis of carbohydrate thionolactones from the corre-
sponding 1-thiosugar is described involving the formation of an intermediate glycosyl S-tert-butyl
thiosulfinate in situ by treatment of a thiol with commercially available tert-butylsulfinyl chloride in
toluene at room temperature, followed by thermolysis. The method can also be used to generate reactive
thioaldehydes and thioketones directly from thiols, which can be trapped in situ with a suitable diene.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 14 April 2008
Revised 21 May 2008
Accepted 29 May 2008
Available online 4 June 2008
Keywords:
Carbohydrates
1-Thio sugars
Thiocarbonyl compounds
Thiosulfinates
Non-stabilized thiocarbonyl compounds have been shown to be
useful intermediates in total synthesis1 and also serve as efficient
dienophiles in Diels–Alder [4+2] cycloaddition reactions.2 To date,
synthetic access to thiocarbonyls has relied mainly on the treat-
ment of the corresponding carbonyl compound with a thionation
reagent, such as Lawesson’s or Belleau’s reagents.3 Whilst these
methods have shown broad utility for the preparation of simple
thiocarbonyl compounds, the direct thionation of carbohydrate
O-lactones gives unsatisfactorily low yields of carbohydrate
thionolactones, a finding corroborated by Vasella4 and others.5
As part of an ongoing synthetic programme, access was
required to several carbohydrate thionolactones for a variety of
purposes. Previous efforts at preparation of carbohydrate thiono-
lactones by direct thionation had met with frustration, and atten-
tion had subsequently turned towards more practical methods,
such as the thermolysis of S-methyl thiosulfinates which were
made by oxidation of glycosyl methyl disulfides, as developed by
Vasella and co-workers.4a This synthetic approach did indeed yield
the desired thionolactone with a much-improved yield and in
higher purity as compared with direct thionation of the O-lactone
using Lawesson’s reagent, but was hampered by the undesired for-
mation of glycosyl S-methyl thiosulfonates, either by over-oxida-
tion of the disulfide starting materials or by disproportionation of
methyl thiosulfinates under the prevailing reaction conditions
(typically at least ꢀ15%).6
which are relatively more stable, was developed.7 The two-step
procedure involved treatment of a 1-thiosugar,8 for example, man-
no thiol 1, with a sulfinylating reagent, such as phenylsulfinyl chlo-
ride or benzenesulfinyl piperidine (BSP).9 Subsequent thermolysis
of the isolated S-phenyl thiosulfinate 2 in refluxing anhydrous tol-
uene (110 °C) gave the desired thionolactone 3 in generally good
yield following filtration through CeliteÒ and purification by flash
chromatography (typically 50–75% over the two steps, Scheme 1).
Although this procedure worked well for most 1-thiosugar sub-
strates, and represented an improvement on previous methods,
problems associated with synthesis of the intermediate S-phenyl
thiosulfinates became apparent. In particular, the formation of sta-
ble mixed phenyl and symmetrical glycosyl disulfides, presumably
initiated by reaction of unreacted glycosyl thiols with the phenyl
thiosulfinate products, necessitated additional and often tedious
purification steps, thus lowering the overall yield of thionolactone.
Lowering the temperature used for thiosulfinate formation did
suppress disulfide formation, but meant that considerably longer
reaction times were required (up to 8 h).
A more direct and efficient route to thionolactones was sought,
the ultimate aim being the development of an efficient one-pot
method for the direct conversion of 1-thio sugars to the corres-
ponding thionolactone, which could perhaps also be more gener-
ally applied to access other thiocarbonyl compounds directly
from thiols. Although it is well known that thiocarbonyl com-
pounds can be generated by the syn elimination of thiosulfinates,10
there are, to the best of our knowledge, no examples in the
literature that describe the generation of thiocarbonyl compounds
directly from thiols.
In order to circumvent these problems, the synthesis of thiono-
lactones via the corresponding glycosyl S-phenyl thiosulfinates,
The approach developed for the one-pot conversion of 1-thio-
sugars to thionolactones involved the generation of S-tert-butyl
* Corresponding author. Tel.: +44 1865 275647; fax: +44 1865 275674.
E-mail address: antony.fairbanks@chem.ox.ac.uk (A. J. Fairbanks).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.145

4942
B. L. Wilkinson, A. J. Fairbanks / Tetrahedron Letters 49 (2008) 4941–4943
Scheme 1. Reagents and conditions: (i) PhS(O)Cl, pyridine, Et2O, 0 °C, 80%; (ii) BSP, CF3CO2H, CH2Cl2, rt, 89%; (iii) 4 Å molecular sieves, toluene, 110 °C, 69%.
thiosulfinates11 in situ using the commercially available tert-butyl-
sulfinyl chloride, and then immediate thermolysis (Scheme 2). It
was envisaged that these more sterically encumbered S-tert-butyl
thiosulfinates would be less prone to the competing processes that
had been observed in the phenyl series.
Table 1
Entry
a
Thiol
Thionolactone
Yield (%)
87
OBn
O
OBn
BnO
BnO
BnO
BnO
BnO
BnO
O
Initial screening of reaction conditions focussed on variation of
the identity and stoichiometry of the added base, and the use of
S
S
1
3
SH
different heat sources for the thermolysis. Reaction of the D-manno
OBn
O
OBn
O
1-thiosugar 1 with excess N,N-diisopropyl diethylamine (DIPEA,
1.5 equiv) and tert-butylsulfinyl chloride (1.0 equiv) followed by
conventional heating produced a somewhat complex mixture by
t.l.c; the desired thionolactone 3 was isolated in only modest yield
BnO
BnO
BnO
BnO
b
85
SH
BnO
4 (α:β, 1:6)
BnO
5
(42%), and in addition the unexpected D-gluco configured thiono-
OBn
O
OBn
O
BnO
BnO
BnO
lactone 5 (10%) was also produced. Interestingly, a similar reaction
that used microwave heating (300 W, 110 °C, 5 min) produced only
the gluco product 5, although in a modest yield (48%). The forma-
tion of the D-gluco configured thionolactone 5 from the a-D-man-
nosyl thiol 1, which was the exclusive product in the case of
c
55
62
SH
BnO
BnO
6
BnO
7
S
O
O
SH
microwave heating, undoubtedly occurs by base catalyzed epimer-
S
BnO
BnO
BnO
ization of the thionolactone at the position
a to the thiocarbonyl, to
d
BnO
8 (α:β, 1:1)
OBn
BnO
OBn
form the more thermodynamically stable equatorial gluco config-
ured product.
However, the use of triethylamine (1.0 equiv) as the added
base, together with a slight excess of tert-butylsulfinyl chloride
(1.2 equiv), followed by conventional heating was found to pro-
9
SH
S
O
O
BnO
e
f
84
BnO
BnO
10
OBn
duce the desired D-manno thionolactone 3 in an excellent 87% yield
OBn
11
following purification by filtration and flash chromatography. With
seemingly optimized reaction conditions in hand (Scheme 2),12
attention was focused on the preparation of a panel of carbo-
hydrate thionolactones,13 as summarized in Table 1.
In the majority of cases examined, treatment of the 1-thiosugar
with tert-butylsulfinyl chloride in the presence of triethylamine re-
sulted in highly efficient conversion to the thiosulfinate intermedi-
ate after 10 min at room temperature, as observed by t.l.c and ESI-
MS, with little or no disulfide formation detected. An exception
OBn
O
OBn
O
BnO
BnO
82
O
SH
O
BnO
BnO
S
12 (α:β, 1:5)
13
Ph
Ph
O
O
BnO
O
O
O
O
74a
SH
g
BnO
BnO
S
BnO
was the
symmetrical glycosyl disulfide were also detected by t.l.c. In this
case the desired -galacto thionolactone 7 was ultimately isolated
D-galactosyl thiol 6 in which significant amounts of the
15
14
Contaminated with ca. 20% di-tert-butylthiosulfinate by-product by 1H NMR.
a
D
in a more modest yield (55%). The reaction time required for com-
plete thermolysis, which was usually in the order of 10 min, did
vary slightly depending on the relative stabilities of the intermedi-
sugars with different protecting group patterns was also investi-
gated,14 such as the 3-O-allyl protected
D-glucosyl thiol 12 and
ate thiosulfinates. Thermolysis of
D-glucosyl and D-galactosyl
the 4,6-O-benzylidine protected
D-glucosyl 14 (Table, entries f
S-tert-butylthiosulfinates (Table, entries b and c, respectively)
required longer reaction times (ꢀ20 min). Encouragingly, the pre-
and g). The corresponding thionolactones 13 and 15, respectively,
were readily prepared using the one-pot method, and were both
isolated in good yields (82% and 74%,15 respectively).
viously described somewhat unstable D
-arabino thionolactone 93
and L
-rhamno thionolactone 117 were both isolated in excellent
The final aspect of the study was to investigate the compatibil-
ity of the one-pot method towards non-carbohydrate thiols, in
yields (62% and 84%, respectively), an illustration of the synthetic
advantage of the one-pot method. The reaction of protected 1-thio-
Scheme 2. Reagents and conditions: (i) tert-butylsulfinyl chloride (1.0 equiv), DIPEA (1.5 equiv), 3 Å molecular sieves, toluene, rt; then heat to 110 °C, 3, 42%, 5, 10%; (ii) tert-
butylsulfinyl chloride (1.2 equiv), Et3N (1.0 equiv), 3 Å molecular sieves, toluene, rt; then heat to 110 °C, 3, 87%.

B. L. Wilkinson, A. J. Fairbanks / Tetrahedron Letters 49 (2008) 4941–4943
4943
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. Thiosulfonate side-products may be produced either by direct over-oxidation
of the thiosulfinate or more probably by thiosulfinate disproportionation under
the reaction conditions. See: Kice, J. L.; Cleveland, J. P. J. Am. Chem. Soc. 1974, 95,
109–112.
7. Chayajarus, K.; Fairbanks, A. J. Tetrahedron Lett. 2006, 47, 3517–3520.
8. Thiols were made by treatment of the corresponding glycosyl xanthate with
sodium methoxide. Xanthates were themselves made directly from the
hemiacetal, following the method of Vasella (see Ref. 4a). For a summary of
alternative 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.
9. Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015–9020.
10. (a) Baldwin, J. E.; Lopez, R. C. G. Tetrahedron 1982, 39, 1487–1493; (b) Aslam,
M.; Block, E. Tetrahedron Lett. 1985, 26, 2259–2262.
Scheme 3. Reagents and conditions: (i) tert-butylsulfinyl chloride (1.2 equiv), Et3N
(1.0 equiv), 3 Å molecular sieves, toluene, rt; then anthracene (10 equiv), heat to
110 °C, 65%; (ii) tert-butylsulfinyl chloride (1.2 equiv), Et3N (1.0 equiv), 3 Å mole-
cular sieves, toluene, rt; then 2,3-dimethyl-1,3-butadiene (10 equiv), heat to 110 °C,
43%.
11. The use of commercially available trichloromethanesulfinyl chloride in order
to form trichloromethanethiosulfinates in situ was also investigated, but
significant amounts of by-products were detected by t.l.c and ESI-MS and the
resulting thiosulfinates proved surprisingly stable towards thermolysis.
12. Typical experimental procedure: to a stirring suspension of thiol (0.05 M) and
activated 3 Å molecular sieves (ꢀ100 mg) in dry toluene were added
triethylamine (1.0 equiv) and tert-butylsulfinyl chloride (1.2 equiv) at room
temperature. The mixture was stirred at room temperature for 10 min, at
which time t.l.c (typically petroleum spirit 40–60 °C-ethyl acetate; 5:1)
indicated reaction completion. For Table entries a–g, the mixture was then
heated to gentle reflux (110 °C) for 10 min. The mixture was then cooled to
room temperature and filtered through CeliteÒ, eluting with toluene. The
filtrate was then concentrated in vacuo at 20 °C and the resulting crude oil
purified immediately by flash silica chromatography to afford the
thionolactone. For thiosulfinates derived from thiols 16 and 17, excess diene
(10 equiv) was added to the mixture prior to heating, and the reaction mixture
was stirred at reflux (110 °C) for 1 h. After this time t.l.c. indicated reaction
completion. The filtrate was evaporated in vacuo and the resulting oil purified
by flash silica chromatography to afford the cycloadducts.
order to expand its scope and synthetic utility. Treatment of benzyl
mercaptan 16 and cyclohexyl mercaptan 17 with tert-butylsulfinyl
chloride and triethylamine in toluene smoothly produced the
respective S-tert-butyl thiosulfinates as monitored by t.l.c. Thermal
elimination of thiosulfinates gave the respective thiocarbonyl
compounds, which were trapped in situ with an added diene
(10 equiv), to produce the isolated cycloadducts 1810 and 19,16
respectively (Scheme 3).
In conclusion, an efficient method for the synthesis of carbo-
hydrate thionolactones has been developed, in which they may
be accessed directly from the corresponding 1-thiosugars. This
one-pot method represents an improvement on existing methods
in terms of efficiency, product purity and overall yield. Further-
more, this chemistry has been demonstrated to allow access to
thioketones and thioaldehydes directly from thiols, a transforma-
tion that, unlike the oxidation of alcohols to aldehydes and
ketones, is far from trivial. The direct conversion of thiols to thio-
carbonyl compounds may thus serve as a useful entry into the rou-
tine preparation of these synthetically useful compounds.
13. All new compounds exhibited spectral data consistent with their structures.
Selected data: 13 a yellow oil: ½a D20
+82 (c 1.0 CHCl3); mmax (KBr disc) 3087,
ꢁ
3063, 3030, 2907, 2867, 1094, 1496, 1454, 1367, 1177, 1094, 738, 698 cmꢂ1; dH
(500 MHz, C6D6) 3.67–3.71 (2H, m, H-6, OCHH0C@CH2), 3.75 (1H, dd,
J6 -6 ¼ 11:4 Hz, J6 -5 ¼ 1:9 Hz, H-60), 3.86 (1H, ddt, Jgem = 12.9 Hz, Jvic = 5.4 Hz,
J = 1.6 Hz, OCHH0C@CH2), 3.99 (1H, dd, J3ꢂ4 = 4.4 Hz, J3–2 = 2.2 Hz, H-3), 4.13
(1H, dd, J4–5 = 10.1 Hz, J4–3 = 4.4 Hz, H-4), 4.40, 4.49 (2H, ABq, JAB = 12.3 Hz,
CH2Ph), 4.55, 4.72 (2H, ABq, JAB = 11.7 Hz, CH2Ph), 4.65, 4.84 (2H, ABq,
JAB = 12.0 Hz,) 4.77 (1H, d, J2–3 = 2.2 Hz, H-2), 5.03 (1H, dq, JZ = 10.4 Hz,
J = 1.6 Hz, CH@CHEHZ), 5.10–5.14 (2H, m, H-5, CH@CHEHZ), 5.73 (1H, ddt,
CH@CH2), 7.16–7.39 (15H, m, Ar-H); dC (125 MHz, C6D6) 68.1 (C-6), 70.7
(OCH2C@CH2), 71.7 (CH2Ph), 73.1 (CH2Ph), 73.6 (CH2Ph), 77.4 (C-4), 80.8 (C-5),
81.9 (C-3), 83.6 (C-2), 117.3 (CH@CH2), 127.5, 127.8, 127.9, 128.0, 128.1, 128.2,
128.3, 128.6, 128.6, 128.7, (Ar CH), 134.3, 137.5, 138.4, 138.5 (Ar C, CH@CH),
215.1 (C@S); m/z (ES+) 522.2 (M+NH4þ, 100%); HRMS calcd for C30H32NaO5S
0
0
Acknowledgements
(MNa+) 527.1863, found 527.1858. Compound 15 a yellow oil: ½a 2D0
ꢁ
+42 (c 1.0
CHCl3); mmax (KBr disc) 3091, 3044, 2912, 2867, 1497, 1455, 1367, 1302, 1267,
We gratefully acknowledge financial support from the EPSRC
(Project Grant D051495/1).
1209, 1181, 1109, 1014, 750, 698, 642 cmꢂ1; dH (500 MHz, C6D6) 3.45(1H, t,
J4–3 = 10.4 Hz, H-6), 3.85 (1H, dd, J4–3 = 10.1 Hz, J4–5 = 6.6 Hz, H-4), 4.13–4.15
(1H, m, H-3), 4.20 (1H, dd, J6 -6 ¼ 10:4 Hz, J6 -5 ¼ 5:4 Hz, H-60), 4.43 (2H, s,
CH2Ph), 4.55, 4.75 (2H, AB q, JAB = 12.0 Hz, CH2Ph), 4.85 (1H, br s, H-2), 4.91–
4.96 (1H, m, H-5), 5.20 (1H, s, PhCH), 7.17–7.59 (15H, m, Ar-H); dC (125 MHz,
C6D6) 68.1 (C-6), 69.6 (C-5), 71.6 (PhCH2), 71.9, (PhCH2), 80.8 (C-3), 81.1 (C-4),
85.8 (C-2), 101.7 (PhCH), 126.5, 126.6, 126.7, 127.5, 127.9, 128.0, 128.1, 128.3,
128.3, 128.4, 128.5, 128.6, 128.7, 128.7, 129.3, (Ar CH), 137.1, 137.5, 137.8 (Ar
C), 213.9 (C@S); m/z (ES+) 480.2 (M+NH4þ, 100%); HRMS calcd for C27H26NaO5S
(MNa+) 485.1393, found 485.1387.
0
0
References and notes
1. Nicolaou, K. C.; McGarry, D. G.; Somers, P. K.; Kim, B. H.; Ogilvie, W. W.;
Yiannikouros, G.; Prasad, C. V. C.; Veale, C. A.; Hark, R. R. J. Am. Chem. Soc. 1990,
112, 6263–6276.
2. For a comprehensive review concerning the preparation and reactivity of
thiocarbonyl compounds, see: Molina, M. T.; Yáñez, M.; Mó, O.; Notario, R.;
Abboud, J.-L. M. In The Chemistry of Double-bonded functional groupsFunctional
Groups; Patai, S., Ed.; John Wiley and Sons Ltd, 1997; pp 1355–1496.
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.
14. Thionolactones bearing ester protection of the hydroxyl groups undergo ready
b-elimination processes as demonstrated by Vasella. See Ref. 4a.
15. One caveat to the use of this method is that di-tert-butyl thiosulfinate is
produced as the stable thermolysis by-product, and in this case it was found to
contaminate the thionolactone product 15.
4. (a) Hürzeler, M.; Bernet, B.; Vasella, A. Helv. Chim. Acta 1993, 76, 995–1012; (b)
Hürzeler, M.; Bernet, B.; Mäder, T.; Vasella, A. Helv. Chim. Acta 1993, 76, 1779–
1801; (c) Bernet, B.; Mäder, T.; Vasella, A. Helv. Chim. Acta 1997, 80, 1260–1278.
16. Degl’Innocenti, A.; Capperucci, A.; Mordini, A.; Reginato, G.; Ricci, A.; Cerreta, F.
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