Total Synthesis Blog

Do you know snowdrops? It’s well-known that bulbs of these flowers (latin name is Galanthus nivalis) contain many alkaloids and galantamine (or galanthamine) is one of them:

This is an important natural product because of its biological properties and phamacological applications – it’s used in treatment of mild Alzheimer’s disease. So there are many approaches to total synthesis of galantamine and here I’ll try to show most recent of them (I think so).

Authors of the paper on which I base developed new interesting reaction: DMCRC – what means Double Michael-Claisen Reaction Cascade. The reaction allows to synthesise quickly highly substituted cyclohexenones which can be used in total syntheses of many ‘sterically congested’ natural products and galantamine is only one of several examples mentioned in paper (the others are aspidospermidone, lycoramine and  mesembrine).

Let’s look at retrosynthetic analysis:

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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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