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Totally Synthetic by Paul H. Docherty, 6 September 2009

Total Synthesis of Minfiensine


S. B. Jones, B. Simmons, D. W. C. MacMillan, J. Am. Chem. Soc. 2009, 131, 13606-13607.

DOI: 10.1021/ja906472m

Minfiensine is a popular target with syntheses by both Qin and Overman (and a total synthesis of the related vincorine by Qin). These total syntheses contain some really nice chemistry. However, the approach by MacMillan is incredibly concise, containing only nine steps, and starting with a commercially available indole. To get to the key cyclisation precursor, a process of carbonylating the C-2 position by lithiation and addition of DMF, followed by a Horner-Wadsworth-Emmons olefination provided the required diene.

Now it's time for [4+2] cycloaddition, using propargyl aldehyde and a imidazolidinone catalyst. The organocatalyst and the aldehyde form an imine and a subsequent Diels-Alder reaction with the acetylene generates an enamine intermediate. This is of course in tautomeric equilibrium with an indolinium imine ion, that reacts with the pendant amine: two new rings and two stereocenters with a high yield and stereochemical control.

Completion of the target took another five steps - some protecting group transformations and a reductive amination provided the carbon skeleton. The approach here was very interesting; they had two sulfides, one of which was propargylic. Treatment with t-butyl tin hydride promoted radical formation on the cyclohexene, and addition to the alkyene in a 6-exo-dig manner, loosing the extraneous thiol to give an allene. Not a bad yield, although they had to use a near-stoichiometric amount of the initiator.

Completion of the target from here required only loss of the protecting groups and a reduction of the allene - providing a selectivity issue. However, palladium on carbon catalysed a regioselective and diastereoselective reduction in a hydrogen atmosphere, providing the required exocyclic trans-ethylidene in over 90%, 20:1 d.r.