Prostratin total synthesis

12 May 2008 - Total synthesis

ProstratinSynthesisWender2008  A new total synthesis from the lab of Paul Wender converts phobol to prostratin in 5 easy steps (DOI).

Prostratin is in the picture as a potential drug in the battle against HIV. The diterpene is very efficient in luring the virus out of those places in the hman body where the regular HIV destroyers cannot reach. One of the natural sources for prostratin is the plant Homalanthus nutans which has been known in traditional Samoan medicine for its healing powers for a long time for example in the treatment of hepatitis.

Problem is that the isolable yield is low (up to 50 mg/g). On the other hand, phorbol, the new precursor to prostratin is isolated from widely available croton oil.

The main difference between the two compounds is a hydroxyl group at C12 but all deoxygenation attempts fail without opening the cyclopropane ring next-door to a propenyl group. Rather than resorting to protective groups (increasingly criticized) the researchers opted for restoring the cycloprane ring instead.

Acid hydrolysis of phorbol A gives crotophorbolone B. Addition of hydrazine and acetic acid first gives the hydrazone and then after addition of base (pyridine, DIPEA) the pyrazoline C. Oxidation to the diazene D with lead tetraacetate is accompanied with placement of the acetate group. This step is followed by photolysis with extrusion of nitrogen to prostratin E.