Structure Pattern Recognition: A Catalyst for Methodology Development in Total Synthesis

Application

• Many important biochemical compounds and drugs of natural origin contain spirofuranone ring structures (these structures exist among carbohydrates, terpenoids, vitamins, alkaloids, glycosides and antibiotics). All derived from a simple precursor via intramolecular cascade transformation.
• Numerous studies have led to a wide variety of modern drugs and potential pharmaceutical candidates that share the compact tricyclic systems, as alliacanes, arteannuins, teucrolivins
• These molecules are naturally produced in small quantities, there is great interest in mass-producing them through a synthetic pathway.
• Unfortunately, access to a large number of these target molecules and their structural analogues is either unknown or hindered by their multistep syntheses.

Our Innovation

Novel synthetic methodology that will enable to deliver desired targets via cascade sequence of cyclization reactions from easily accessible key molecule. Our novel approach includes platform technology to synthesize libraries of compounds.

• Effectively synthesizing natural materials that have always been hard to synthesize.
• Faster synthesis process.
• A simplified access to a wide range of spiro-epoxy-fused natural product and their structural analogues.
• Unite the families of described molecular frames under a common synthetic strategy
• Enables scaffolds constructed through simple and straightforward cyclization

Technology

• There are several molecular domains that can be considered as common.
• For example, in natural TPRV1 agonist we focus mainly on the presence of three distinct regions, conceptually similar:
• The Vanilloid scaffold, which consists of the Vanilloid (3-methoxy-4-hydroxy) moiety and is vital for the biological activity.
• The Carbonylic segment which is integrated with the carbonylic moiety, and responsible for specific hydrogen bond interactions between the substrate and the enzyme.
• The lipophilic domain which is significantly different in all agonists, yet crucial for their high potency.
• It also devises a simple means for building the tricyclic skeletons in a rapid and efficient manner.
• In addition, Pd(II)-catalyzed cascade reactions were profitably selected as a key step for the total synthesis of several natural products. Using unprecedented Pd-catalyzed cascade Wacker-Heck lactonization-cyclization sequence, rapid assembly of spiranoid lactones was achieved.

Fig.1 : Natural products from diverse biological origins share tricyclic spiranoid ring systems

Fig. 2: Natural TRPV1 agonists (exo- and endo-Vanilloids): structural difference and similarity

Opportunity

Short synthetic process to be used on families of natural products.

Broad natural diversity of compounds available.

Pain treatment – reducing the hypersensitivity of nociceptors  

Patent Status

Published 3250559; 201727028082