Mirogabalin besilate is an α₂δ ligand that is developed by Daiichi Sankyo as a drug for the treatment of neuropathic pain. This compound has an intricate and highly strained bicyclo[3.2.0]-heptane skeleton having three consecutive asymmetric centers on the ring, and therefore, it presents formidable synthetic challenges. In this study, we present a highly efficient manufacturing process for mirogabalin, employing an organocatalytic kinetic resolution of a racemic bicyclic ketone as a key step. This synthesis commences with the efficient construction of the racemic ketone via Claisen rearrangement and intramolecular [2+2] cycloaddition, using readily available butyraldehyde as the starting material. Subsequently, the racemic ketone was subjected to the kinetic resolution through an aldol reaction with p-formylbenzoic acid in the presence of an asymmetric organocatalyst. This reaction is designed so that the desired enantiomer can be easily purified and isolated with a high enantiomeric purity from the crude product by simple liquid-liquid separation and distillation. Finally, an efficient process from the optically active ketone to mirogabalin besilate is also developed, relying on Ti-mediated Knoevenagel condensation, highly diastereoselective cyanation to construct the quaternary asymmetric center, and cascade reaction of semi-hydrolysis and decarboxylation. This newly developed process provides mirogabalin besilate in good yield and high purity in an efficient and inexpensive manner. Consequently, this process has been routinely utilized for the production of this drug at industrial scale, representing one of the pioneering examples where an asymmetric organocatalytic reaction is utilized for pharmaceutical production.

Chloropupukeananin was isolated as a natural product with inhibitory activity against HIV-1 replication and antitumor activity. The isolation of its analogues, chloropestolides, chloropupukeanolides, and chlorotheolides, were subsequently reported. These compounds are characterized by highly oxidized multi-functional groups arrayed on a chlorinated bicyclo[2.2.2]octane or tricyclo[4.3.1.0^3,7]decane skeleton. The biosynthesis of the family of chloropupukeananin natural products starts with intermolecular Diels-Alder reactions using (+)-iso-A82775C and (−)-maldoxin as precursors. Subsequent carbonyl-ene reactions and other transformations further elaborate the complex structures. These unique chemical structures and biosynthetic pathways have prompted us to initiate synthetic studies. In this manuscript, we will present our synthetic studies of chloropupukeananin and related compounds.

For long years, meroterpenoids derived from Ganoderma family have received a great deal of attention due to their unique biological activities. Applanatumol compounds or lucidumone were isolated from G. applanatum or G. lucidum, featuring dihydroquinone motif fused to terpenoid structure. This article describes collective synthesis of applanatumol compounds and asymmetric synthesis of lucidumone. Applanatumol A, having a spiro [benzofranbicyclo[3.2.2]nonane] framework with four stereogenic centers, was synthesized via a tandem cascade cyclization using TBD to form tetracyclic skeleton. Applanatumol B was synthesized in 14 steps by employing an intramolecular cyclization and lactonization for quick construction of the tricyclic skeleton with desired stereochemistry. The key step includes efficient epimerization of α-position of the ketone under acidic condition. Lucidumone is a unique 6/5/6/6/5 polycyclic molecule with six contiguous stereogenic centers on a bicyclo[2.2.2]octane skeleton. The racemic total synthesis was accomplished in 10 steps through one-pot preparation of the tetracyclic core framework by Claisen rearrangement followed by an intramolecular aldol reaction. The intramolecular aldol reaction allowed for the stereocontrolled construction of the bicyclo[2.2.2]octane skeleton fused to an indanone structure. The enantioselective total synthesis of lucidumone was also described via a chiral transfer strategy in the Claisen rearrangement. Our work communicated here provides novel strategy for convenient and short-step synthesis of meroterpenoids using tandem reaction or one-pot reaction.

Imines are one of the key intermediates for syntheses of N-containing pharmaceutical molecules, and catalytic green oxidation reactions of amines to imines have been energetically investigated over the past decades. Transition-metal-catalyzed reactions have been effective for the conversion of amines to imines under atmospheric oxygen. However, in order to directly utilize the products for further reactions, metal residues from the catalysts, stoichiometric or excess amounts of reagents, and byproducts must be strictly removed from the final products. Therefore, the development of one-pot and green methods for the synthesis of N-containing pharmaceutical scaffolds has been highly demanded. Recently, the authors have developed a novel method for the oxidation of benzylamines to imines with atmospheric oxygen using 4,6-dihydroxysalicylic acid as an organocatalyst. In this article, we describe our recent work on the development of one-pot synthesis methods for the green oxidation of amines to pharmaceutical molecules using salicylic acid as an organocatalyst. Furthermore, based on the results concerning the tolerance of this method to multi-component and multi-step reactions and the refinement of the catalytic system for industrial manufacturing, we also discuss the efficacy of this method in the synthesis of advanced pharmaceutical platform molecules and its future prospects.

Chemical reactions based on photoexcitation of molecules allow unusual modes that are not available via thermal pathways. Recent photoredox catalysis enable generation of carbon-centered radicals under mild conditions, which previously required harsh conditions. However, the redox process of the catalyst must be involved in the design of the catalytic pathways. As a result, photo-redox reactions undergo multi-step energy and electron transfer, often leading to loss of reaction efficiency. In this context, we have designed and developed boron-ate complexes that can be directly excited under visible-light irradiation. The excited alkyl boron-ate complexes produce alkyl radicals, accompanied by cleavage of carbon-boron bonds. Due to their ability of high single-electron reduction, the radical process proceeds without the photoredox catalysts. This property has been used to develop a new type of photocaged molecule that enables caging/uncaging on carbon.

In the synthesis of natural products, epimerization serves as a powerful tool when undesired stereochemistry is obtained. This short review introduces the total synthesis of Securinine alkaloids and Pleurotin utilizing epimerization through hydrogen atom transfer (HAT) reaction with photoredox catalysts, reported by Han group and Sorensen group. HAT enable epimerization at untraditional positions, as they proceed dependently on the bond dissociation energy of C-H bonds.