Total Synthesis Blog

You can read here today about total synthesis of (+)-Isofregenedol and, in my opinion, this is the very total synthesis which looks like a magic. In one aspect, at least.

Let’s see our current target molecule:

It looks interestingly. Only one chiral carbon atom, but five-substituted aromatic ring – in other hand. This stuff is a diterpene which was isolated from chilean flower Haplopappus parvifolius by Niemeyer in 1991. (+)-Isofregenedol exhibits important biological activites. It’s – for example – methionine aminopeptidase-2 reversible inhibitor, agonist of glucocorticoid receptor and agonist of serotonin 5-HT₇ receptor. Sounds seriously.

Before you’ll see how this molecule were prepared, I’ll show you my approach to its organic synthesis. First – retrosynthesis:

As you can see, my synthesis would be start with bromoxylene. However, I know that there could be some problems with regioselectivity during Friedel-Crafts acylation step. But see:

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Deja vu? Maybe yes because (+)-Dodoneine is also – similary to hyptolide – α,β-unsaturated δ-lactone. Just look at the structure of (+)-Dodoneine:

It’s not so complicated (it has only two chiral carbon atoms, hyptolide – four) as hyptolide, but synthetic approach to this target is quite different than to previous one.

But now, let’s say something about its biological properties.

(+)-Dodoneine was isolated from methanolic extract from plant called ‘african mistletoe’ with very nice-sounded latin name Tapinathus dodoneifolius. This plants grow somwhere in West Africa. Authors of paper wrote that ‘african mistletoe’ is applied in treatment of wide spectrum of diseases, including cardiovascular and respiratory. It’s also used as remedy aganist cholera, diarrhoea, stomach ache and wounds. It’s possible that (+)-dodoneine could find interesting medical applications.

In my opinion, (+)-Dodoneine can be synthesized analogically like hyptolide. Proposition of retrosynthesis is shown below:

Authors have chosen other synthetic route:

As you can see – only two olefinations and only two stereoselective aldol condesations. Full retrosynthetic analysis is shown below:
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