Highly Enantioselective Catalytic Synthesis of Neurite Growth-Promoting Secoyohimbanes

Natural products endowed with neuromodulatory activity and their underlying structural scaffolds may inspire the synthesis of novel neurotrophic compound classes. The spirocyclic secoyohimbane alkaloid rhynchophylline is the major component of the extracts of Uncaria species used in Chinese traditional medicine for treatment of disorders of the central nervous system. Based on the structure of rhynchophylline, a highly enantioselective and efficient organocatalyzed synthesis method was developed that gives access to the tetracyclic secoyohimbane scaffold, embodying a quaternary and three tertiary stereogenic centers in a one-pot multistep reaction sequence. Investigation of a collection of the secoyohimbanes in primary rat hippocampal neurons and embryonal stem cell-derived motor neurons led to discovery of compounds that promote neurite outgrowth and influence the complexity of neuronal network formation. [Display omitted] •The secoyohimbane scaffold was obtained by highly enantioselective organocatalysis•Synthesis of a collection of complex natural product-inspired compounds was developed•Neurite outgrowth-promoting activity was investigated•A class of neurotrophic compounds was discovered Antonchick et al. develop a practical method for the tetracyclic secoyohimbane scaffold synthesis in one-pot multi-step reaction sequence. From resulting compounds they identified a class of neurotrophic molecules that promote neurite outgrowth and influence the complexity of neuronal network formation.