Total synthesis of the indolizidine alkaloid tashiromine

Tashiromine 1 is a naturally occurring indolizidine alkaloid. It has been the subject of thirteen successful total syntheses to date. Our own approach centres on the stereoselective construction of the indolizidine core by capture of an electrophilic acyliminium species by a pendant allylsilane. The key cyclisation precursor is constructed using olefin cross-metathesis chemistry, which has the potential to facilitate both racemic and asymmetric approaches, depending upon the choice of the allylsilane metathesis partner.

The use of the allyltrimethylsilane cross-metathesis approach enables the rapid construction of the key cyclisation precursor 3 (3 steps from commercial materials), which undergoes acid-induced cyclisation to give the desired bicyclic indolizidine skeleton as a 96:4 mixture of diastereomers. Simple functional group interconversions allowed the completion of the total synthesis of racemic tashiromine in six steps (19% overall yield). Three chiral alpha-alkoxyallylsilanes (12,14 and 15) were prepared in enantioenriched form and their cross-metathesis reactions studied as part of a putative asymmetric approach to tashiromine. In the event, alpha-hydroxysilane 12 underwent isomerisation under the reaction conditions to acylsilane 17, while silanes 14 and 15 were unreactive towards metathesis.

A concise, stereoselective total synthesis of racemic tashiromine has been developed. Attempts to translate this into an asymmetric synthesis have thus far been unsuccessful.