Total Synthesis Blog

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:

Benefits from presence of C₂ symmetry axis are clear. Grignard and Wittig key steps are obvious, but what is the ‘Oxidative coupling of Wittig reagent’? Let’s look at the synthesis to answer this question.

Synthesis starts with 4, TBS-protected terminal alkynol, which is deprotonated by butyllithium in first step and reacted with oxirane in the presence of Me3Al as Lewis acid to give diol 5. Now, free OH group is exchanged to Br and then, by adding triphenylphosphine, phosphonium salt 6 is formed. It’s quite clear. In next step buthyllithium is added again and in next few hours by acting of oxygen from the atmosphere – product 7 is forming. It’s oxidative coupling. Nice reaction.

Next steps are:

and they include deprotection and oxidation to form 8, Wittig olefination to form 9, and Grignard reagent addition to form racemic dideoxypetrosynol 1. Well, racemic.

Finally, racemic product was resolved by enzyme lipase AK:

There are also one feature in this synthesis: why don’t they start their synthesis from 1,4-dichlorobut-2-ene and undergo S_N2 reaction with Grignard reagent derived from corresponding alkyne? Well, actually they wanted to do it in such way but only side products were forming:

For more see:

B. W. Gung, A. O. Omollo, Eur. J. Org. Chem, 2008.