Coldham, Burrell, White, Adams and Oram. ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200701943.
Now this looks a little different from the past two syntheses: a nice pentacyclic alkaloid! Another difference is the brevity of the synthetic route: nine steps! When I saw the title, I was sure I’d seen a classic synthesis of the target, and this was confirmed with a reference to the Stork synthesis from 1963. In this paper a key tricyclic ketone was perpared in thirteen steps; in this work, Iain Coldham’s group manage this in six!
The key to this brevity is their formation of an azomethine ylide from an aldehyde and a primary amine, following an in situ N alkylation! The ylide then performs a 1,3-dipolar cyclisation onto the olefin, forming a five-member ring. This type of process was previously developed by Pearson, but Coldham has taken this forward considerably. The substrate for the cyclisation was made very quickly and easily (I like the mono-elimination in the first step), basically doing two alkylations.
The ylide formation / cyclisation went really well forming four new bonds,
three new rings, and three new stereocenters as a single diastereoisomer! Good stuff! I’ve not drawn the reaction transition state, which is “S shaped”, but there is an interesting discussion of this in the paper. To complete the synthesis of the Stork intermediate, all that was required was a deprotection of the ketal, and concomitant epimerisation of the adjacent stereocenter. Three further steps from the literature then completed the target. Nice read.