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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Today, some nice-looking target – isolated from germinating sunflowers (Helianthus annus L.) – (+)-Sundiversifolide:

Nice structure and nice name (however, I prefer snow ). (+)-Sundiversifolide exhibits some interesting biological properties. For example it can inhibit root growth of some plants. Also it can inhibit (in small concentrations – about 100 μM) germination of some fungi species and therefore it can be used as natural herbicide.

Below I’ve shown my retrosynthetic approach to (+)-Sundiversifolide:

(Click on image to enlarge it)

The key steps involve Diels-Alder cyclization, ring expansion (with use diazo compound) and TPAP-promoted cyclization (see also Total Synthesis of Bruguierol C for other application of that key reaction). I’m waiting for your opinions.

The real retrosynthesis of (+)-Sundiversifolide is shown below:
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