Synthesis of Morphinans through Anodic Aryl‐Aryl Coupling

Abstract

The morphinans are an important class of structurally fascinating and physiologically important natural products as exemplified by the famous opium alkaloids of the morphine family. Although this class of secondary metabolites from the juice of the opium poppy capsule was already used for medicinal purposes thousands of years ago, chemical modifications are still being applied to the core structure today in order to achieve the most specific effect on the various receptor subtypes possible with the fewest possible side effects. The unusual architecture of the morphinan core has also proven to be a highly challenging target for total synthesis. This review highlights electrosynthetic approaches towards natural and semisynthetic morphinan alkaloids. The historical progress in applying anodic aryl‐aryl couplings to the construction of the morphinan framework is described in chronological order while particular benefits and challenges concerning the electrochemical transformations are grouped together, including the influence of substitution patterns, protecting groups, and reaction conditions.

Flow Conditions‐Controlled Divergent Oxidative Cyclization of Reticuline‐Type Alkaloids to Aporphine and Morphinandienone Natural Products

“…In this work, we followed a reverse strategy since we capitalized on previously reported mechanistic investigations [13,31,32] to establish pathways depicted in Scheme 3 and to design experimental conditions that regioselectively lead to either glaucine (13) or sebiferine (3). We reasoned that compound 11 obtained by a two electrons oxidation of laudanosine ( 6) is a common intermediate to glaucine (13) and sebiferine (3). In this frame we also assumed that 11 can rearrange to glaucine (13) through the erythrinadienone intermediate 12.…”

“…Identifying the limits. From laudanosine (6) we identified two robust flow processes leading to either glaucine (13) with PIFA/ BF 3 .Et 2 O in HFIP or sebiferine (3) in PIDA/TMSOTf in CH 3 CN. In order to establish a first structure-reactivity relationship and to assess the current limits of such oxidative processes, we prepared a series of variously substituted reticuline-type alkaloids.…”

“…Traditionally, reaction mechanisms are established following the determination of the optimal experimental conditions. In this work, we followed a reverse strategy since we capitalized on previously reported mechanistic investigations [13,31,32] to establish pathways depicted in Scheme 3 and to design experimental conditions that regioselectively lead to either glaucine (13) or sebiferine (3). We reasoned that compound 11 obtained by a two electrons oxidation of laudanosine ( 6) is a common intermediate to glaucine (13) and sebiferine (3).…”

“…Synthesis of sebiferine (3). For the synthesis of sebiferine (3) which shares the morphinandienone backbone we followed the same conceptual approach than the one developed for glaucine (13).…”

“…Biogenetic-type intramolecular oxidative coupling of reticulinetype alkaloids [1] is a long-standing issue that continues to stimulate intense research works [2,3] since it leads to a number of iconic natural products such as (+)-corytuberine (1) and (À )morphine (5) (Scheme 1B). The difficulty in achieving such transformations is related to the possibility of forming four regioisomers (Scheme 1A).…”