Organic Chemistry Portal
Reactions >> Total Syntheses

Totally Synthetic by Paul H. Docherty, 5 March 2008

Total Synthesis of Minfiensine


A. B. Dounay, P. G. Humpreys, L. E. Overman, A. D. Wrobleski, J. Am. Chem. Soc. 2008, 130, 5368-5377

DOI: 10.1021/ja800163v

Minfiensine is a small target but with a very interesting architecture. Although the biological activity of this natural product isn’t mentioned, similar natural products are found in traditional medicines. Overman's retrosynthesis is fairly ambitious, with a plan to use palladium couplings to complete two of the rings as part of a pair of tandem reactions.

The interesting chemistry starts early, with their asymmetric Heck coupling of the aryl triflate onto the cyclohexadiene. The reaction performed reasonably under thermal conditions, but improved considerably in the microwave, allowing lowering of both the catalyst loading and the reaction times. Addition of TFA initiated the desired iminium-ion cyclization, completing both five-member rings in excellent yield and control.

A substrate-controlled epoxidation, replacement of the Boc by an Alloc group and a PhSeNa promoted opening of the epoxide followed by elimination gave the desired allylic alcohol. A mild deprotection of the nitrogen followed by an alkylation gave a vinyl iodide substrate for a palladium catalysed cascade reaction. They hoped that the palladium would oxidatively insert into the vinyl iodide, add to the cyclohexene in a Heck-type reaction to form a new carbon-palladium bond. This would then be trapped by carbon monoxide, completing the carbon skeleton of the natural product. However, the actual product from this reaction was quite surprising - a third five-member ring. They suggested that an alkenylpalladium species had inserted into the allylic C-H bond - but they postulate a far more reasonable mechanism in which the aminal moiety cleaves, rearranges the cyclohexene via an iminium ion and then performs a more traditional 5-exo-trig Heck cyclisation. Dissapointing for them, but interesting…

A revised strategy allowed them to complete the molecule, but they recognized that the tandem palladium chemistry wouldn’t work. Instead as stepwise approach prevailed, starting with a palladium-catalysed intramolecular enolate/vinyl iodide coupling. The cyclohexanone product was then converted to a triflate, and a palladium catalysed carbonylation in the presence of methanol gave the unsaturated ester.

This is an awesome read - lots of detail for each transformation, and a logical discussion of the problems they encountered.