A Rapid, Asymmetric Synthesis of the Decahydrofluorene Core of the Hirsutellones

A Rapid, Asymmetric Synthesis of the Decahydrofluorene Core of the Hirsutellones

S. David Tilley, Keith P. Reber, and Erik J. Sorensen

DOI: http://dx.doi.org/10.1021/ol802768p

Back again, I will present to you an interesting idea coming up from Princeton to access a relatively new family of natural products, the Hirsutellones.

Hirsutellone B:


hirsutellone

It’s said in the paper that this class of natural products exhibits an antimicrobial activity against the bacterias causing Tuberculosis. They didn’t describe herein a complete access but a general one to the decahydrofluorene-core allthough a proposed cascade reaction towards the almost completely functionalised core is presented:


proposed-key-step

To test this retro-Diels-Alder/Diels-Alder/ketene-trapping reaction a core was needed which construction is described in the following steps.

They started with a Seebach-auxiliary controlled asymmetric Diels-Alder reaction with isoprene, followed by a DIBAL-H and Crabtree-reduction to set the first three stereocenters. Some Swern and Wittig completes the first scheme:

Scheme 1

scheme-12

Having the first half of the decahydrofluorene-core in hand, they did a substrate controlled dihydroxylation followed in one pot by another Wittig reaction, which is really a cool idea. The major isomer was isolated and, after some protection/deprotection chemistry, oxidised, using this time Dess-Martin-periodinane, and again reacted with a Wittig-salt.

The resulting intermediate was heated up in a little bit of toluene/methanol to get in really good yield the expected Diels-Alder compound:

Scheme 2

scheme-2

The produced core structure itself exhibits potent activity against the Mycobacterias while the mode of action is not well understood yet.

What catched my eye this time was the nice cascade reaction which I presented first and the highly convergent use of the Wittig-reaction to build up very fast the core structure needed for the cascade reaction. I’m interested to see the synthesis of the main target being realised in the next few months.

That’s it for the moment, again a shorty but I’m a bit busy these days. Next time I will grab a more complex one…

So feel free to post.

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