Chemo-enzymatic synthesis of (R,R)-(-)-Pyrenophorin

A chemo-enzymatic approach to (R,R)-(-)-pyrenophorin starting from commercially available 6-methyl-5-hepten-2-one is described. Firstly, (R)-6-methyl-5-hepten-2-ol (sulcatol) was prepared by interface-bioreactor mediated asymmetric reduction of the corresponding ketone by a yeast, Pichia farinosa IAM 4682 (51% yield, 90%e.e.). The sequential carbon-chain elongation via Horner-Emmons olefination of protected aldehyde and cyanation afforded all of carbon skeleton in the seco acid with a desired β,γ-(E)-double bond. By the aid of a microorganism, Rhodococcus rhodochrous IFO15564, the nitrile was efficiently hydrolyzed to give the corresponding carboxylic acid, (R,E)-7-hydroxy-3-octenoate, the key synthetic intermediate without affecting the position and configuration of the double bond (90% yield). Dimeric lactone structure was obtained by utilizing a lipase-catalyzed lactonization. While Pseudomonas cepacia lipase-catalyzed reaction worked in a moderate efficiency, higher yield of desired dimeric lactone (44%) was obtained by the use of an immobilized form of Candida antarctica lipase. The lactonization was accelerated in the presence of molecular sieves 4A. (R,R)-(-)-Pyrenophorin was obtained from this dimeric lactone (Seebach's intermediate) by the subsequent chemical transformation.