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.

This is a sesquiterpene isolated from the roots of Psacalium decompositum and it exhibit some interesting biological properties including antihyperglycemic, anti-inflammatory, antimicrobial and antioxidant activities. Authors of paper didn’t mention anything about biological activity of single enantiomers of Cacalol.

Retrosynthesis chart (not very good-looking…) is shown below:

Synthesis of target molecule isn’t more complicated than retrosynthesis.

As you can see, total synthesis starts with p-methylanisole 2 which is converted to its organolithium derivative 3 by ortho-lithiation reaction. 3 is then alkylated by 5-iodo-pent-1-ene. In next step intramolecular Friedel-Crafts reaction occur which provides bicyclic product 6. Next, we have formylation which gives two regioisomers 8a and 8b (and 8a is main product). These regioisomers seemed to be inseparable by flesh chromatogrphy. So, Baeyer-Villiger oxidation followed by hydrolysis were undergone and resulting phenols 9a and 9b could by purified by chromatography.

9a was converted to 11 in reaction with chloroacetone under Williamson conditions. By acting of concentrated sulfuric acid on 11, tricyclic product 12 was formed. Deprotection of 12 gives racemic Cacalol.

For more see:

B. L. Kadrowski, R. W. Hoppe, J. Chem. Org., 2008, 73, 5177.

When I was preparing to my summer Natural Product Exam and when I was admiring how Nature ‘do’ such big molecules by biosynthetic routes I just wanted to know how R. B. Woodward could synthesize such complex molecule like cholesterol. Well, it was more complicated than I expected. By the way – articles from 1950s are so difficult to read… there are no chemical equations and no schemes in some of them.

But let’s see how Woodward did his synthesis, but first let’s remind designation of steroids fused-ring system:

The first interesting thing is that Woodward started his synthesis with ring designated as C. Next he built something like pre-ring D and then he constructed rings B and A respectively. Then he converted pre-ring D into true ring D. Let’s see some steps:

As you can see, synthesis starts with some quinone derivatives 1 which is converted to 3 in Diels-Alder reaction. Stereochemistry of resulting bicyclic molecule is cis and switching it into trans is possible by forming enolate 4. Protolysis of 4 gives desired product 5 (configuration trans).

Next steps involve reduction quinone moiety, hydrolysis and de-hydroxylation α-hydroxy ketone. Seems to be quite obvious.

Here, we have formation of ring B. It’s interesting that intermediate 9b is favoured product of first step (Woodward wrote nothing about 9a, but it’s very likely that 9a and 9b exist in equlibrium although – 9a occur in very small amount). Conversion 9b -> 12 involve Michael reaction, cyclization and deformylation reactions. I’d like to know what is mechanism of deformylation (free radical?… in such solvent?). And what was first: cyclization or deformylation?

In next stages, Woodward underwent cis-dihydroxylation (osmium tetraoxide-mediated) reaction. Resulting two isomers converted to isomeric acetonides which one of them was stable and was used in following steps.

These steps involve formation of A ring. To achive this goal Woodward prepared adduct with N-methylaniline, to protect the most sensitive on base attack centre. In spite of this – there was still three active sites of molcules, but attack of acrylonitrile was succesful… In such way 19 was formed.

19 was then converted into β-enol lactone 20 and by acting methylmagnesium bromide on it 21 was formed with established ring A. Mechanism of this transformation is simple. First methylmagnesium bromide attack lactone carbonyl group and lactone ring opens. Then intramolecular aldol-like reaction occurs.

Next acetonide moiety is deprotected and six-membered pre-D ring is oxidized to two aldehyde groups. Then Dieckmann-like reaction happens and five-membered ring D is formed.

Steroid fused ring system is finished. Now, in few steps cholestanol was prepared. And because route form cholestanol to cholesterol was previously known, Woodward could say: total synthesis is done.

For more see:

R. B. Woodward, F. Sondheimer, D. Taub, K. Heusler, W. M. MacLamore, J. Am. Chem. Soc., 1952, 74, 4223.