You might recall my fascination with cocaine (no, not for that reason), which culminated in a total synthesis of its enantiomer, (+)-cocaine, using our 2-azaallyl anion chemistry (Mans and Pearson, 2004, blog post here). Davies and co-workers at Oxford have now published a short and elegant synthesis of (+)-pseudococaine, a diastereomer of natural (-)-cocaine.
The key step is a highly diastereoselective transannular iodoamination with concomitant N-debenzylation by iodide ion to produce the tropane skeleton:
It’s worth pointing out that intramolecular iodoamination reactions of simple primary and secondary amines can be problematic due to N-iodoamine formation and subsequent shenanigans, including potential post-cyclization aziridinium ion formation. Davies’ reaction is well-behaved, since transannular iodoaminations are especially favorable, the amine is tertiary, and the product is not susceptible to aziridinium ion formation.
The cyclization precursor is made by a very nice sequence involving conjugate addition of a chiral lithium amide to an enoate with subsequent in situ trapping of the enolate by a diasteroselective aldol condensation (7% of the other aldol diastereomer is not shown).