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 article info Article history: 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 abstract 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. Non-stabilized thiocarbonyl compounds have been shown to be useful intermediates in total synthesis 1 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 Vasella 4 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 In order to circumvent these problems, the synthesis of thiono- lactones via the corresponding glycosyl S-phenyl thiosulfinates, 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 Celite Ò 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. The approach developed for the one-pot conversion of 1-thio- sugars to thionolactones involved the generation of S-tert-butyl 0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2008.05.145 * Corresponding author. Tel.: +44 1865 275647; fax: +44 1865 275674. E-mail address: antony.fairbanks@chem.ox.ac.uk (A. J. Fairbanks). Tetrahedron Letters 49 (2008) 4941–4943 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet