Chemoenzymatic synthesis of complex natural and unnatural products: morphine, pancratistatin, and their analogs

The synthesis of morphine ( 1) and pancratistatin ( 2) have been the subject of intense effort by the synthetic community for many years. Our focus on the total synthesis of these challenging targets resulted in several generations of approaches that combine enzymatic transformations with traditional synthetic protocols in order to provide for maximum efficiency and brevity in attaining the targets. [GRAPHICS] Recombinant strains that express toluene dioxygenase (TDO) are used to provide the homochiral diene cis-diol derived from bromobenzene and containing the structural features of both ring C of morphine and ring C of pancratistatin. Bromocatechol, representing ring A of morphine, is also derived from bromobenzene by fermentation with E. coli JM109 that expresses TDO as well as catechol dehydrogenase. In this fashion twelve of the carbons in morphine originate in the same starting material. One approach is based on the Kazmaier-Claisen rearrangement of glycinate esters, the other on an intramolecular Heck reaction. The route to pancratistatin and to its unnatural analogs is based on the metal-mediated cyclotrimerization of acetylenic substrates of type 3. The core of this Amaryllidaceae constituent has been attained in the initial stages of this project. The details of the synthetic endeavours toward these and other heterocyclic targets will be disclosed with emphasis on practicality, brevity, and efficiency as guiding principles of enviromentally benign manufacturing of relevant compounds.