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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Dideoxypetrosynol A is linear, polyacetylenic target molecule which consist 30 carbon atoms. It’s also C₂-symmetric molecule what is important to planning synthesis, of course. Let’s see structure of dideoxypetrosynol A:

It looks so simple but its spectrum of biological activities is very wide. Dideoxypetrosynol A was isolated from marine sponge (Petrosia sp.) found in Komun islands, Korea. It exhibit anticancer activity aganist ovarian and skin cancer cells. It can also inhibit DNA replication. So, biological properties are interesting but – unfortunately – concentration of dideoxypetrosynol in dry natural source is very poor (just about 23 mg in 14.5 kg dry source). Development of synthesis this target in larger scale is obvious.

There are also some compounds (with interesting biological activity) related to dideoxypetrosynol, for example: duryne 2, petrosynol 3:

Synthesis of such quite simple compounds shouldn’t be very complicated… maybe boring, but in fact – it’s not. Just look at retrosynthesis chart:

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