METEDIT

Catalytic olefin metathesis is a transformative transformation with many unique attributes, one being the possibility of converting a ring to a modifiable acyclic diene by ring-opening cross-metathesis (ROCM). However, the existing methods are rare and limited to those that generate E-enoates. To the best of our knowledge, there are no available methods for ROCM reactions that can be used to access Z-alkenes from reactions involving five- to eight-membered rings. To address this, we will develop a ROCM method for converting the small rings to readily alterable acyclic dienes efficiently and in high Z:E ratios. On the basis of preliminary (unpublished) results, a set of molybdenum alkylidene complexes recently designed by the host group will be utilized. We will investigate and develop a method for ROCM of cyclohexene with several commercially available Z- and E-alkenyl halides. The strategy will then be extended to five-, seven- and eight-membered ring alkenes. The diene products can be used for rapid synthesis of bioactive compounds, such as antitumor tetrahydrosiphonodiol, and their specifically altered analogs. Another notable aspect of the project will be application to precise skeletal alterations of polycyclic bioactive compounds. We will exploit the presence of an olefin within a bioactive compound as the launching point for brief sequences leading to various specific modifications. This will obviate the need for lengthy and tedious de novo synthesis of each analog. More specifically, we will develop the open ring modify close ring (OMC) strategy, and by using it prepare an assortment of specifically modified analogs of androstadiene and vindoline. Through collaboration with experts, these compounds will be tested for in vitro bioactivity. Catalyst and method development will thus be applied to accessing formerly uncharted chemical space, which is central to new lead discovery and drug development.