Skeletal Alteration of Bioactive Polycyclic Molecules by Catalytic Ring-Opening/Cross-Metathesis

Descripción del proyecto

Síntesis química avanzada de compuestos bioactivos

La metátesis olefínica catalítica es una reacción química en la que los dobles enlaces carbono-carbono (olefinas) se rompen y se reforman en una nueva disposición. Esta reacción, facilitada por un catalizador, puede producir una amplia variedad de valiosos productos químicos, como polímeros, productos farmacéuticos y petroquímicos. La metátesis olefínica catalítica ha revolucionado la química orgánica sintética al proporcionar una poderosa herramienta para construir con precisión arquitecturas moleculares complejas. El equipo del proyecto METEDIT, financiado por las Acciones Marie Skłodowska-Curie, pretende superar los retos técnicos asociados a la metátesis olefínica catalítica y crear una estrategia que implique tres sencillos pasos de apertura de anillos. Este método permitirá crear análogos modificados de compuestos bioactivos, lo que contribuirá al desarrollo de nuevos fármacos y al descubrimiento de candidatos.

Objetivo

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 On the basis of preliminary (unpublished) results, a set of molybdenum alkylidene complexes recently designed by the host group will be utilized.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.