Enantiodivergent chemoenzymatic synthesis of 4-hydroxypiperidine alkaloids

An efficient chemoenzymatic synthesis of both enantiomers of fagomine, as well as of cis and trans-4-hydroxypipecolic acid is reported. The synthesis starts from commercial δ-valerolactam which, after a Pd-catalyzed methoxycarbonylation of the corresponding vinyl phosphate, is subjected to allylic oxidation to give a racemic 4-hydroxytetrahydropyridine derivative in 57% overall yield. This product is resolved by an enzyme-catalyzed esterification using immobilized lipases from Candida antarctica (Novozym 435) and Burkholderia cepacia (lipase PS Amano IM). The latter provides the corresponding R esters and the S alcohol in 95 and 94% ee, respectively. The S alcohol is then converted into L-fagomine by a stereoselective hydroboration/oxidation as key steps and the cis-(2R,4S)-4-hydroxypipecolic acid by stereoselective hydrogenation. The corresponding D-fagomine and cis-(2S,4R)-4-hydroxypipecolic acid, as well as trans-(2R,4R)-4-hydroxypipecolic acid can be prepared by the same strategy after hydrolysis of the R ester obtained by kinetic resolution.