Convenient and efficient synthesis of functionalized unsymmetrical Z-alkenyl disulfanes

We developed a simple and efficient method for the synthesis of functionalized unsymmetrical Z-alkenyl disulfanes under mild conditions in moderate to good yields. The designed method is based on the reaction of Z-alkenyl thiotosylates with thiols in the presence of base. The developed method allows the preparation of unsymmetrical Z-alkenyl disulfanes bearing additional hydroxy, carboxy, or amino functionalities.


Introduction
Compounds with R-S-S-R structures, where the R groups are alkyl, vinyl or aryl, are known as symmetrical disuldes if the R groups are the same. A large number of unsymmetrical disul-des, in which the R groups are different, are also well known. In the literature, these compounds are oen called organic disuldes; however, the IUPAC recommended nomenclature is disulfanes. 1 The name disulde should only be applied to ionic compounds, such as sodium disulde (Na 2 S 2 ). Moreover, the term disulfane is more widely applicable than disulde because it facilitates naming even when the R groups are acyl and/or phosphoryl groups.
Ajoene was rst isolated by Block 40 in 1984 as an E/Z-mixture of a rearrangement product of allicin produced from freshly crushed garlic. It was established to be an allyl sulfoxide containing an unusual vinyl disulfane functionality, which is rarely seen in the structures of natural products. Z-Ajoene is more active than its E-isomer as an anti-thrombotic agent, 41 and some studies on anticancer treatments have focused primarily on the Z-isomer. 42 Although many different synthetic methods exist for the preparation of unsymmetrical disulfanes, the preparation of unsymmetrical alkenyl disulfanes can be achieved by only two methods. The rst method is based on the reaction of sulfenyl bromide with trityl-alkenyl sulde. 43 The second method involves the low temperature hydroxide-promoted cleavage of an alkenyl thioester followed by sulfenylation with an appropriate S-alkylated p-toluenethiosulfonate to afford vinyl disul-de in high yield aer chromatography. 44 Unfortunately, the methods provide exclusively E or a mixture of Z/E alkenyl disulfanes, respectively. In this context, we set out to investigate the feasibility of a more convenient and experimentally practical diastereoselective method to exclusively access Z-alkenyl disulfanes.

Results and discussion
Our synthetic strategy included the preparation of E-alkenylboronic acid 45 2 from terminal alkyne 1 followed by its conversion to appropriate E-alkenyliodonium salt 46 3 by known methods. Further reaction with sodium p-toluenethiosulfonate provided Z-1-octenyl p-toluenethiosulfonate 4 with inversion of conguration (Scheme 1).
The reaction of Z-1-octenyl p-toluenethiosulfonate 4 with a variety of thiols in the presence of NEt 3 provided Z-alkenyl disulfanes 6 in good or very good yield ( Table 1). All compounds have been fully characterized by 1 H and 13 C NMR spectroscopy (see the ESI †). E/Z-Stereochemistry was assigned based on the vinyl coupling constants in the 1 H NMR spectra; 15 Hz was indicative of the E-isomer and 10 Hz for the Z-isomer.
The reaction proceeded via the nucleophilic substitution of the thiolate anion (generated from 5) at the sulfur atom of thiotosylate 4, and the p-toluenesulnate anion served as the leaving group, which is why the Z geometry of the alkene remained unchanged. The thiolate anion can also be generated in situ from the corresponding thioacetate and sodium methoxide in methanol (entries 11-12). Such an approach is very convenient when a high-purity or stable thiol is not readily available. The developed method seems to be very versatile. The presence of additional functional groups including carboncarbon multiple bonds (entries 10-12) and hydroxy (entry 2), ester (entry 3), azide (entry 4), amino (entry 5) aryl or heteroaryl (entries 6-9 and 15) moieties did not interfere with the formation of Z-alkenyl disulfanes 6. Arylthiol 5disulfane Z-6 exchange reaction was responsible for the formation of corresponding diaryl disulfane and moderate yield of 6f and 6m (entries 6 and 15). The exchange reaction can be limited by the excess of Z-4, what resulted in higher yield of 6f and 6m respectively (entries 7 and 16). L-Cysteine derivatives were also converted to the corresponding Z-alkenyl disulfanes 6k and 6l (entries [13][14]. The biological activities of these compounds are expected to be higher than their E-isomer analogs. 43,44 Conclusions We have developed the rst simple and efficient diastereoselective method for the synthesis of functionalized unsymmetrical Z-alkenyl disulfanes under mild conditions in moderate to good yields. The developed method allows the preparation of unsymmetrical Z-alkenyl disulfanes bearing additional hydroxy, carboxy, or amino functionalities. Anti-fungal and anti-cancer activity studies of the Z-alkenyl L-cysteine disulfane derivatives are in progress.

Experimental
A typical procedure for the preparation of Z-alkenyl disulfanes 6 and representative analytical data A compound Z-4 (0.67 mmol, 200 mg) was dissolved in dry DCM (3 mL) in the round bottom ask. Then a solution of thiol 5 (0.61 mmol) and NEt 3 (0.61 mmol) in dry DCM (2 mL) was added. Reaction was stirred for 15 min. Aer this time solvent was evaporate and Et 2 O (10 mL) was added. Slurry was washed with water (10 mL) and aqueous phase was extracted 2 times with Et 2 O (2 Â 10 mL). Organic layers were dried with MgSO 4 and evaporated. The residue was puried by column chromatography (SiO 2 ).