Question

The terpene palictaxel is highly functionalized, so much so that it is difficult to recognize it as a terpene.

a) state the origin of these polar substituents(how they got there).

b) state the polar substituents are essential (what roles do they play).

Answer 1

Paclitaxel (Taxol) is a chemotherapy drug used to treat many types of tumors such as breast, ovarian, lung, esophageal, etc. Paclitaxel is an ester and the taxol backbone consists of an eight membered ring, a six membered ring and a four membered ring. Attached to these rings are several functional groups including OH group, two benzoyl groups, an acetyl group and an oxetane ring. It has 11 stereocenters having the N-benzoylphenyl-isoserine group attached at C13 and an extra oxetane D ring attached at C4 and C5.

The ketone was converted into β-patchouline oxide which was epoxidised and treated with a Lewis acid, which induced a skeletal rearrangement, providing tertiary alcohol. This alcohol was again epoxidised, and underwent a fragmentation reaction to create the A and B rings of taxol. The C- ring was introduced using the Robinson-Stork annulation methodology.

Taxol’s molecular structure is based on the A, B, and C rings that harbor two hydroxyl groups, two acetyl groups, one benzoyl group and an oxetane ring. The side chain A ring together with the benzoyl group at C2 and the oxetane ring are responsible for Taxol’s anti-cancer activity. The C3 amide-acyl group in the C12 chain maintains this activity and the hydroxyl group at C2 enhances it. The C2' hydroxyl group is also necessary for maintaining taxol's activity. Protection as an ester results in a loss of activity in terms of microtublin stabilisation but not in its cytotoxicity.