Organic Chemistry Portal
Reactions >> Total Syntheses

Totally Synthetic by Paul H. Docherty, 21 March 2007

Total Synthesis of Marcfortine B


B. M. Trost, N. Cramer, H. Bernsmann, J. Am. Chem. Soc. 2007, 129, 3086-3087.

DOI: 10.1021/ja070142u

Marcfortine B certainly has a diverse structure, with a particularly intimidating bicyclo[2.2.2]diazaoctane core; perhaps more usefully, the family it belongs to also has potent anthelmintic activity. With the focus on the spirocyclic cyclopentanone moiety, Trost envisaged that their own TMM (trimethylenemethane) chemistry might produce that complex functionality with ease:

They get to that specific chemistry rather quickly, with the starting material produced from a aldol condensation with acetone. This material was then treated with TMM synthon 3 and palladium catalyst to generate the quaternary spirocyclic cyclopentane in one step - quite an amazing transformation.

This was the first time I have seen this reaction, so I have actually thought that the transformation of carbonate to acid was a typo, and that one of the structures had to be wrong. However, the mechanism of the reaction accounts for this, through a rather involved process:

The palladium actually inserts into the C - O bond, and after loss of MeOTMS rearranges twice to produce the species that is involved in the [3 + 2] cycloaddition. Top stuff! A few less dramatic steps later, they appended a tetrahydropyridine moiety, and were set to cyclise this onto the unsaturated ester. This Michael addition went well, quantitatively generating the complex product as a single isomer. The authors attribute this to shielding of the re face of the Michael-acceptor by the aromatic portion of the molecule.

Next came the exciting radical chemistry: They made the Xanthate ester, allowing radical generation in a Barton-McCombie fashion, which cyclised onto the olefin completing the bicyclo[2.2.2]diazaoctane core. However, rather than picking-up a hydrogen atom and continuing the radical chain reaction in the expected manner, it trapped AIBN and eventually eliminated to give the formal oxidative radical cyclisation product. Thus, they used (super)stoichiometric AIBN and catalytic tributyltin hydride!

As can be seen, they were only a few steps from the end, and completed an interesting synthesis in remarkably few steps.