Enantioselective Syntheses of Yohimbine Alkaloids: Proving Grounds for New Catalytic Transformations

Abstract

The total synthesis of bioactive alkaloids is an enduring challenge and an indication of the state of the art of chemical synthesis. With the explosion of catalytic asymmetric methods over the past three decades, these compelling targets have been fertile proving grounds for enantioselective bond forming transformations. We summarize these activities herein both to highlight the power and versatility of these methods and to instill future inspiration for new syntheses of these privileged natural products.

Yeast Platforms for Production and Screening of Bioactive Derivatives of Rauwolscine

“…Following supplementation of sMIA1 to the reporter strains, we observed a 14-fold agonist activity on receptor 5HT4b, compared to MeOH control, and significant antagonist effects on receptors 5HT1A (58), 5HT4b (23), ADRA2A (83), ADRA2B (29), and CHRM3 (20%), measured as percent reduction in reporter output compared to the positive controls which had been stimulated by their cognate ligands serotonin, epinephrine, or acetylcholine (Supplementary Figure 7). However, a modest (19%), yet significant, drop in luminescence in the no-receptor control when adding sMIA1 at 0.5% of the total volume indicates that the sMIA1 content is inhibitory to the luciferase reporter output independent of GPCR signaling (Supplementary Figure 7).…”

“…For these reasons, pharmaceutical interest stemming from the high density of corynanthe-type MIA bioactivities has led to subsequent interest from the synthetic chemistry community. However, the corynanthe-type MIA subgroup is characterized by a stereochemically complex pentacyclic structure and, as such, enantiopure yohimbine-type alkaloid synthesis requires racemate resolution or the use of stoichiometric chiral auxiliaries or starting materials sourced from the chiral pool, which suffer from an inherent efficiency limit of 50%, or require extra steps that further limit the yield . Enantioselective synthesis of (+)-rauwolscine was reported in 2016, and the naturally occurring (−) enantiomer was more recently synthesized with an overall yield of 13% .…”

A Platform for the Synthesis of Corynantheine-Type Corynanthe Alkaloids

“…C orynantheine-type alkaloids are a family of tetracyclic monoterpenoid natural products that possess an unaltered secologanin carbon skeleton fused to an indole-or indole-derived heterocyclic core (Figure 1). 1,2 They are mainly isolated from the Mitragyna speciosa, also commonly known as kratom, and have garnered considerable attention due to their potent G-protein selective agonism of μ-opioid receptors (MORs). 3−5 Of particular interest is that many of these alkaloids exhibit few adverse side effects characteristic of classical MOR agonists such as hyperlocomotion, respiratory depression, and addiction.…”

“…(−)-Corynantheidol (1) was obtained by lithium aluminum hydride reduction in 90% yield (overall 8 steps, 18% yield). 24 Next, we pursued the synthesis of (−)-corynantheidine (2). While conversion of Cook's intermediate 13 to (−)-corynantheidine (2) was a known route, the reported reaction procedures and purification methods proved unreproducible in our hands, providing only low yields and poor E/ Z selectivity.…”

“…Corynantheine-type alkaloids are a family of tetracyclic monoterpenoid natural products that possess an unaltered secologanin carbon skeleton fused to an indole- or indole-derived heterocyclic core (Figure ). , They are mainly isolated from the Mitragyna speciosa , also commonly known as kratom, and have garnered considerable attention due to their potent G-protein selective agonism of μ-opioid receptors (MORs). − Of particular interest is that many of these alkaloids exhibit few adverse side effects characteristic of classical MOR agonists such as hyperlocomotion, respiratory depression, and addiction. − Thus, it has been proposed that understanding the pharmacological properties of corynantheine-type alkaloids can aid in the discovery of novel analgesics devoid of side effects. − Most research to date has relied primarily on the natural abundance of a select few major alkaloids. − As a result, wider investigations of the biological potential of these scaffolds have been significantly restricted, necessitating the development of a reliable platform that provides facile access to corynantheine natural products.…”