Tetrahedron
Tetrahedron
5 years ago

An asymmetric synthesis of febrifugine, halofuginone and their hemiketal isomers

An asymmetric synthesis of febrifugine, halofuginone and their hemiketal isomers
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).

Publisher URL: www.sciencedirect.com/science

DOI: S0040402017307834

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