(+)-Lepadin F

This has been a rough couple of weeks…hence the lack of posts. With my first synthesis test out of the way though, I’m back in the driver’s seat of my life again. Retron of the Week should resume sometime next week. In the meantime though, how about some brand-spanking-new synthetic chemistry from the land of Eric Foreman and the 70’s Show gang?Hsung and co-workers at the University of Wisconsin have tackled an interesting class of cis-aza-decalins known as the lepadins. They all share the same bicyclic ten-membered, cis core, but differ in the identity and stereochemistry of their ring appendages. Hsung and friends setup the central core via a very interesting auxiliary-controlled, aza-6-pi electrocyclization reaction, which merited a paper of its own back in 2002.Dihydroxylation of the less hindered double bond, selective removal of the left-hand OH with a bunch of triethylsilane and TFA, and finally removal of the electrocyclization directing group led to the key intermediate 7.
The next big challenge was hydrogenating the fusing double bond while somehow setting the stereochemisty at the carbonyl carbon. After a couple of failed protocols, they backed up to compound 6, the amine with the chiral directing group still attached. They decided to set up an enone at the carbonyl carbon, then attempt a stereoselective double hydrogenation to establish cis stereochemistry for all four added hydrogens. The plan worked beautifully, although Horner-Wadsworth-Emmons didn’t work to set up the enone, and they had to use Eschenmoser’s sulfide contraction protocol (basically a thio-Wittig) to install it. At any rate, this got them to intermediate 17, which was carried through a number of standard steps to (+)-Lepadin F. I particularly like the substrate-controlled conversion of 18 to 19, which I initially thought would require Mitsunobu conditions. Neat stuff!

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2 Comments

  1. I wish there was an even easier way to prepare these heterocyclic decalins; they’re seemingly so simple-looking (pardon the alliteration). It’s pretty cool, though, to see a convergent synthesis of several analogs out of a central core.

    I imagine that it’s the sort of thing that drug companies would try to buy in a heartbeat (for building libraries if nothing else).

    Reply

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