Total Synthesis Blog

This time short synthesis of racemic Cacalol:

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.