Enantiospecific synthesis of the phospholipase A2 inhibitor (-)-cinatrin B.
The first enantiospecific synthesis of phospholipase A2 (PLA2) inhibitor (-)-cinatrin B (2) from the D-arabinose derivative 9 is described. The spirolactone system was formed by an Ireland-Claisen rearrangement of the allyl ester 8 followed by hydrolysis and stereoselective iodolactonization. The stereoselectivity of the rearrangement was controlled by the asymmetry in the allylic alcohol fragment. Ester (S)-8 gave the desired rearrangement product 7 and the epimer 13 in high yield as a 73:27 ratio, respectively. The final stereocenter at C2 was introduced via a chelation-controlled addition of the Grignard reagent derived from trimethylsilylacetylene to alpha-hydroxy ketone 6. Transformation of the terminal alkyne into the methyl ester 21 followed by acetal hydrolysis and selective lactol oxidation afforded cinatrin B methyl ester (22). Base hydrolysis and acid-induced relactonization then gave (-)-cinatrin B (2).
Cuzzupe
Anthony N
AN
School of Chemistry, The University of Melbourne, Melbourne, Victoria 3010, Australia.
Di Florio
Romina
R
Rizzacasa
Mark A
MA
D002384:Catalysis; D004951:Esterification; D004952:Esters / Q000737:chemistry; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004952:Esters; D007783:Lactones; C073568:cinatrin B; D010741:Phospholipases A; D054467:Phospholipases A2