Enantioselective synthesis of the polyketide antibiotic (3 R ,4 S )‐(−)‐citrinin

The fungal metabolite (−)‐citrinin ( 1 ) was synthesized for the first time. Reaction of the Grignard reagent of 2,4‐bis(benzyloxy)‐6‐bromotoluene ( 3 ) with (2 S )‐ trans ‐(−)‐2,3‐dimethyloxirane ( 6 ) in the presence of 1,5‐cyclooctadienecopper(I) chloride as catalyst leads to the formation of (2 S ,3 S )‐(−)‐ 7 with erythro configuration. Compound (−)‐ 7 could be transformed into (2 R ,3 S )‐(−)‐ 9 with threo configuration via the formate (1 R ,2 S )‐(+)‐ 8 by a Mitsunobu reaction. Reaction of the Grignard reagent of 3 with the achiral cis ‐2,3‐dimethyl‐oxirane yielded directly (±)‐ 9 . The starting material 3 was readily available from 1,3‐bis(benzyloxy)‐5‐bromobenzene ( 4 ). Formylation of 4 furnished the aldehyde 5 which could be reduced to 3 with borane. Hydrogenolysis of the benzyl ether groups in (−)‐ 9 gave (−)‐ 2 with threo configuration. The remaining steps to produce citrinin [(−)‐ 1 ] from (−)‐ 2 required carboxylation to 11 , formylation and in situ ring closure with ethyl orthoformate to produce the required quinomethide structure. Application of the same reactions to (±)‐ 9 and (±)‐ 2 afforded (±)‐citrinin in 40% overall yield.