Total synthesis of Sceletium alkaloids (±)-joubertinamine, (±)-epijoubertinamine, (±)-tortuosamine and formal synthesis of (±)-mesembrine, (±)-N-formyltortuosamine

Abstract

An efficient collective formal/total synthesis of Sceletium alkaloids achieved by employing the Wittig olefination–Claisen rearrangement protocol.

Progress in the Chemistry of Tetrahydroquinolines

“…Another Hantzsch-like process, allowing the preparation of pyridines from cyclohexanone oxime acetates, was applied to the synthesis of some Sceletium alkaloids containing a fused 5,6,7,8-tetrahydropyridine core …”

Efficient Synthesis of (−)‐Corynoline by Enantioselective Palladium‐Catalyzed α‐Arylation with Sterically Hindered Substrates

“…Chemie with H 2 NMe/Na(OAc) 3 BH completed the asymmetric synthesis of (+ +)-sceletium A-4 (2)i no nly four steps and 37 % overall yield from 7,8-dihydroquinolin-5(6H)-one,inaprocess that was significantly more efficient than reported methods. [4,5] Further hydrogenolysis with Pd/C as the catalyst according to ar eported procedure [16] would also yield (+ +)-tortuosamine (3).…”

“…The Sceletium alkaloid (+ +)-sceletium A-4 (2)h as been obtained through anumber of synthetic efforts. [4,5] However, most current synthetic routes were lengthy and inefficient (> 8steps). We envisioned that the a-arylation could be well suited for an enantioselective synthesis of 2.T hus quinolone 12 was prepared from 7,8-dihydroquinolin-5(6H)-one in one step by allylation.…”

“…The search for asymmetric catalytic methods for the efficient construction of all-carbon quaternary centers continues to be amajor interest in organic synthesis.Inparticular, asymmetric catalytic methods applicable to the synthesis of chiral natural products and therapeutic agents containing all-carbon quaternary centers remain in high demand. [1,2] Chiral 2-alkyl-2aryl-1,2,3,4-tetrahydronaphthalene and quinoline motifs are found in many biologically important natural products and drugs,s uch as the antidepressant (S)-nafenodone (1), [3] the Sceletium alkaloids (+ +)-sceletium A-4 (2) [4] and (+ +)-tortuosamine (3), [5] as well as the acetylcholinesterase inhibitors (+ +)-corynoline (ent-4), [6] (+ +)-DeN-corynoline (ent-5), [7] and corynoloxine (6; Figure 1). [8] Although there has been agreat deal of synthetic effort, efficient asymmetric syntheses,i n particular those based on asymmetric catalytic methods,a re still lacking.…”

Catalytic Function of Cu (I) and Cu (II) in Total Synthesis of Alkaloids

“…Tortuosamine (57), a pyridine based Sceletium alkaloid congener of Sceletium A-4 (58), was isolated from Sceletium species in 1971. [71] An effective formal/total synthesis of Sceletium alkaloids and their seco-congeners has been developed in 2016 by Bhosale et al [72] Total synthesis was commenced from 3,4dimethoxybenzaldehyde 55 that after several steps afforded Oacetylketoxime 56. More conversion of O-acetyl ketoxime 56 to cycloalkenopyridine and debenzoylation with potassium carbonate afforded alcohol over two steps with 66 % yields.…”