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:

I think it can work.

Ok, let’s leave this and deal with real organic synthesis of (+)-Isofregenedol done by authors of paper. Their total synthesis has a few more steps than my, but theirs really was done So let’s look at retrosynthetic plan:

Lots of disconnections. And one of more important disconnection here is gold(I)-catalyzed benzannulation. This is that magic about which I write. Some details are shown below:

Initially authors wanted to complete synthesis in very effective way. They wanted to perform benzannulation of highly substituted cyclohexane ring (obtained from geraniol as chiral building block), but unfortuantely such reaction gave no product. So plans had to change. Modified approach is shown below in all its details:

Total synthesis of (+)-Isofregenedol starts with cyclohexene epoxide 2. 2 is undergone epoxide ring opening reaction with vinyl Grignard reagent and followed by Swern oxidation to give 3. Next, addition of alkynyl Grignard reagent to ketone 3 occurs and tertiary propargyl alcohol 4 is formed. Everything is ready to carry out gold(I)-catalyzed benzannulation reaction:

Yield of the reaction is 69%, but in this step aromatic ring with four substituent is created. But how it really works? One of possible mechanisms is drawn below:

When I look at this mechanism then everything becomes so clear

Ok, so we have already tetrahydronaphtalene core 5 of (+)-Isofregenedol, now we have to link to it all lacking substituents.

Conversion of 5 to 7 maybe very elegant. Probably regioselctivity of benzylic oxidation isn’ very good. But addition of dimethylzinc in the presence of TiCl₄ as a Lewis acid looks nice. And in such way we have dimethyl derivative 7 as major product (under standard condition we rather would expect tertiary alcohol). Now, 7 is converted with high yield (excellent regioselectivity) to 8 and then Stille coupling is performed (some microwave chemistry aspect) and vinylbenzene 9 is formed. In next step double bond of 9 reacts with 9-BBN in hydroboration reaction to give intermediate 10.

This intermediate is combined with iododerivative 11 under Suzuki coupling conditions. Compound 12 is formed and it’s reduced with DIBAL-H to give allylic alcohol 13. In next step enantioselective Sharpless epoxidation is undergone (with excellent yield and high enantiomeric excess) and epoxide 14 is formed. In next two steps which include formation of iododerivative and epoxide ring opening (+)-Isofregenedol is obtained. And total synthesis (consisting of 13 steps and where no protecting groups was needed) is completed.

Fore more – as always see:

M. Riou, L. Barriault, J. Org. Chem., 2008, 73, 7436.