Chemoenzymatic syntheses of allocedrane and prezizaane-type sesquiterpenes

Abstract

Various genetically modified microorganisms that over-express dioxygenase-type enzymes can be used for the whole-cell biotransformation of a wide range of arenes into the corresponding cis-1,2-dihydrocatechol (c-DHC). These metabolites, which are obtained in essentially enantiopure form, can serve as valuable starting materials in chemical synthesis. This thesis describes the application of certain c-DHCs to the synthesis of biologically active and or synthetically challenging natural products. In particular, it details the use of Type 1 intramolecular Diels-Alder (IMDA) adducts derived from c-DHCs in the synthesis of the tashironins and related compounds belonging to the allocedrane class of natural product. The tashironins possesses complex structures and display interesting biological properties including neurotropic activity. As such they are considered to be useful leads in developing new therapies for treating neurodegenerative afflictions such as Alzheimer's and Parkinson's diseases. In the process of the campaign towards tashironins, several highly oxygenated tri- and tetra-cyclic compounds were prepared. These are described in Chapter Two and Three and are expected to possess similar biological properties to the natural products. Chapter Four of the thesis describes the synthesis of members of prezizaane group of compounds that are biogenetically related to allocedranes, sesquiterpenoids that are highly prized in the flavour and fragrance industry. During the course of preparing the prezizaanes, a novel Wagner-Meerwein rearrangement of the allocedrane system was discovered that afforded a pleasantly smelling compound that is enantiomerically related to the natural product isopipitzol.