Blistering Barnacles – Bryostatin 2

Bryostatin 2Harvard University chemists have devised the first synthetic route to the potential anticancer drug bryostatin 2, which could also make it easier to produce the archetypal member of the group bryostatin 1 made as a defense chemical by marine barnacles.

The first bryostatin was discovered by George Pettit and his team at Cancer Research Institute at Arizona State University in 1982. Since then, it has been found to have potent anti-tumor activity and in vivo it is active against mouse leukemia, B- cell lymphoma, reticulum cell sarcoma, ovarian carcinoma, and melanoma and is in 23 clinical trials David Evans and his colleagues at Harvard realized that bryostatin 1 has remained a rare and costly substance and so began to look for a simple synthesis to make its chemical cousin bryostatin 2. This compound shares the basic skeleton of all the bryostatins having several distinctive features such as three pyran rings, a 20-membered lactone, two exocyclic unsaturated esters, one trans olefin and an unusual octadienyl ester side chain.

Evans’ synthesis uses several new synthetic methods to create a forty- reaction-step path to the compound, including a convergent coupling of the three intact tetrahydropyran rings, followed by macrocyclization and late- stage installation of the two enoate functional groups. Despite its length, the synthesis should allow the chemists to create simpler analogues of the parent compound for biological testing. Several critical functional groups are added at a late stage, explains team member David Smith-Boyle, which means ‘the synthesis offers the opportunity to selectively functionalize the bryostatin “core” and thereby systematically probe the importance of each functional “appendage”,’ he explains. Understanding the effect of each group could allow novel versions with desirable properties.

He adds that, “Since bryostatin 2 is routinely converted to bryostatin 1 via a three step sequence after the commercial isolation process, this synthesis also serves as a formal synthesis of bryostatin 1.”

J.Am.Chem.Soc, 1999, 121, 7540–7552