Dithin Antiinfective Agents

Truong etal, US Patent 5,668,168 (September 16, 1997) Assignee Shaman Pharmaceuticals, Inc. 

Utility Antifungal Agents Caused by Candida albicans. Cryptococcus 

A reactor was charged with 40 ml DMF, 1 ml water, and KOH (0.3 g). To this was added benzylthiol (22mmol), the reaction stirred 10 minutes, and l,6-dihydroxy-2,4-hexadiyne (10 mmol) added. The resulting exotherm was cooled in a water bath, the reaction stirred 3 hours, and poured into 150 ml water. The mixture was extracted with EtOAc, once with 200 ml and once with 100 ml, washed with water and brine, dried, and concentrated. The residue was re-crystallized in hexanes/chloroform/EtOAc and the product isolated in 65% yield, mp = 121.5-123 °C. 

A reactor was charged with 10 ml liquid ammonia at —78°C to which was added lithium (4 eq) and the product from Step 1 (53 mg) in 4 ml THF. The mixture was stirred and a blue color appeared an additional amount of lithium was added to maintain the color of the mixture. The mixture was stirred 1 hour at —78°C, several drops of methyl alcohol added until the blue color disappears, and the mixture warmed to ambient temperature and concentrated. The residue was treated with 6 ml water and 10 ml diethyl ether, cooled to 0°C, then treated with iodine (3.00 mmol) dissolved in 15 ml 20% aqueous KL The 

To the product from Step 2 (20 mg) dissolved in 1.0 ml pyridine was added 0.13 ml benzoyl chloride and the reaction stirred in the dark overnight. The mixture was subsequently diluted with 10ml diethyl ether then partitioned between 20ml 3.0M H3PO4 and 5.0ml diethyl ether. The ether layer was subsequently washed with 20 ml saturated NaHC03, dried, and concentrated. The oily residue was purified by chromatography on silica gel using diethyl ether/hexanes, 1 3, and the product isolated as a red oil. H-NMR data supplied. 

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