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.