Biomimetic Photocyclization

Photochemical [2+2]-cycloadditions have been used to form cyclobutanes in natural product synthesis for a long time, although biogenetic considerations did not play a major role in most cases. Remarkably, Bielschowskysin (1), which was isolated from the gorgonian octocoral Pseudoptero-gorgia kallos collected from the Southwestern Caribbean Sea in 2003, contains a highly substituted cyclobutane ring which was speculated to be the result of a biogenetic intramolecular photo-[2+2]-cycloaddition. Moreover the molecular architecture of bielschowskysin is unusually complex, featuring a hexacyclic, highly oxygenated diterpene structure which bears two cyclic hemiacetals, two isolated carbon-carbon double bonds, one lactone, one tertiary alcohol and one acetate as functional groups. The compound, whose absolute configuration is unknown, contains 11 stereogenic centers. So far, there is no total synthesis of Bielschowskysin. Biologically, Bielschowskysin exhibits antiplasmoidal activity as it inhibits two chloroquine-sensitive strains and one chloroquine resistant strain of Plasmodium falciparum which causes the most severe forms of malaria. With about 300 million clinical cases and about 2 million deaths a year, malaria is one of the most life-threatening diseases in the world. Furthermore the increasing resistance of the mosquito vector (the female anopheles) against established insecticides as well as the increasing resistance of the parasite against common vaccines strongly emphasize the need for new anti-malaria agents. On this background we decided to embark on a total synthesis of Bielschowskysin, which should be pursued along three different routes converging at a common late stage intermediate 27 (Scheme). This is the substrate for the envisaged photochemical [2+2]-cyclization. The total synthesis will start from readily available and cheap material, should be stereo- and regioselective and try to benefit from our previous work on the related furanocembranolide providencin.

Gorgonian octocorals such as Pseudopterogorgia kallos, are a rich source of structurally interesting diterpenes with significant biological activities. Bielschowsyksin (1) was isolated along with other congeners from this very specimen harvested in the Caribbean Sea. This natural compound has attracted considerable interest from the scientific community not only because of its densely functionalized novel furanocembranoid structure but also because of its cytotoxic properties against two human cancer cell lines and its significant biological activity against the malaria causing protozoan parasite Plasmodium falciparum. The natural source is not suited for the production of larger quantities, and even less to procure important derivatives. These were the reasons why we started a synthetic program towards bielschowskysin all the more so because no total synthesis has been accomplished despite considerable efforts worldwide.Although we could not complete our synthesis we have prepared an intermediate that is far more advanced than any other reported so far. In course of the experiments a lot of novel and useful details on chemical reactions have been uncovered and published.