LAUSR

Abstract A new synthesis of both enantiomers of naturally occurring febrifugine ( 1 ) and its analogue halofuginone ( 3 ) are reported. This robust route relies on an enzymatic kinetic resolution (EKR)-cross metathesis (CM) sequence, performed on allylic alcohol 8 . A diastereoselective Lewis acid-mediated cyclisation of resultant enone 6 affords piperidine 12 . In relation to its enantiomeric excess, values of 87 and 88% e.e were obtained for both enantiomers of 12 and for (−)- 12 this was increased to 98% e.e by conducting the resolution process twice. A bromination (featuring an in situ temporary alcohol protection), alkylation and amino-deprotection sequence finally afforded the target compounds (+)- and (−)- 1 , and (+)- and (−)- 3 . Studies demonstrate that, as their ammonium salts, the compounds are stereochemically stable. However, as their free-bases, particularly in chloroform, C-2 isomerisation occurs. This isomerisation has been taken advantage of synthetically to provide enantioenriched (+)-isofebrifugine ( 2 ) and both enantiomers of isohalofuginone ( 14 ).