Deuterated Alkyl Sulfonium Salt Reagents; Importance of H/D Exchange Methods in Drug Discovery.

Deuterated drugs (heavy drugs) have recently been spotlighted as a new modality for small-molecule drugs because the pharmacokinetics of pharmaceutical drugs can be enhanced by replacing C-H bonds with more stable C-D bonds at metabolic positions. Therefore, deuteration methods for drug candidates are a hot topic in medicinal chemistry. Among them, the H/D exchange reaction (direct transformation of C-H bonds to C-D bonds) is a useful and straightforward method for creating novel deuterated target molecules, and over 20 reviews on the synthetic methods related to H/D exchange reactions have been published in recent years. Although various deuterated drug candidates undergo clinical trials, approved deuterated drugs possess CD3 groups in the same molecule. However, less diversification, except for the CD3 group, is a problem for future medicinal chemistry. Recently, we developed various deuterated alkyl (dn-alkyl) sulfonium salts based on the H/D exchange reaction of the corresponding hydrogen form using D2O as an inexpensive deuterium source to introduce CD3, CH3CD2, and ArCH2CD2 groups into drug candidates. This concept summarises recent reviews related to H/D exchange reactions and novel reagents that introduce the CD3 group, and our newly developed electrophilic dn-alkyl reagents are discussed.

Furanyl bis(indolyl)methane as a palladium ion-selective chromogenic agent.

The colorless solution of furan-2-yl bis(indolyl)methane (BIM) is newly revealed to work as a palladium (Pd2+) ion-selective chromogenic agent by turning orange. 5-(N-Methyl-N-phenyl-aminomethyl)-furan-2-yl BIM could be synthesized from 5-chloromethylfurfural as a biorenewable feedstock via one-pot and double functionalization, and a mixture of its solution and Pd2+ ions showed the highest absorbance at 465 nm in UV-Vis analysis. On the other hand, other metal ions (Cu2+, Cr2+, Cr3+, Fe2+, Fe3+, Ni2+, Zn2+, In2+, Pt2+, or Ce3+) exhibited no response.

Impact of multiple H/D replacements on the physicochemical properties of flurbiprofen.

Although deuterium incorporation into pharmaceutical drugs is an attractive way to expand drug modalities, their physicochemical properties have not been sufficiently examined. This study focuses on examining the changes in physicochemical properties between flurbiprofen (FP) and flurbiprofen-d8 (FP-d8), which was successfully prepared by direct and multiple H/D exchange reactions at the eight aromatic C-H bonds of FP. Although the effect of deuterium incorporation was not observed between the crystal structures of FP and FP-d8, the melting point and heat of fusion of FP-d8 were lower than those of FP. Additionally, the solubility of FP-d8 increased by 2-fold compared to that of FP. Calculation of the interaction energy between FP/FP-d8 and water molecules using the multi-component density functional theory method resulted in increased solubility of FP-d8. These novel and valuable findings regarding the changes in physicochemical properties triggered by deuterium incorporation can contribute to the further development of deuterated drugs.

Sulfonium Salt Reagents for the Introduction of Deuterated Alkyl Groups in Drug Discovery.

The pharmacokinetics of pharmaceutical drugs can be improved by replacing C-H bonds with the more stable C-D bonds at the α-position to heteroatoms, which is a typical metabolic site for cytochrome P450 enzymes. However, the application of deuterated synthons is limited. Herein, we established a novel concept for preparing deuterated reagents for the successful synthesis of complex drug skeletons with deuterium atoms at the α-position to heteroatoms. (dn -Alkyl)diphenylsulfonium salts prepared from the corresponding nondeuterated forms using inexpensive and abundant D2 O as the deuterium source with a base, were used as electrophilic alkylating reagents. Additionally, these deuterated sulfonium salts were efficiently transformed into dn -alkyl halides and a dn -alkyl azide as coupling reagents and a dn -alkyl amine as a nucleophile. Furthermore, liver microsomal metabolism studies revealed deuterium kinetic isotope effects (KIE) in 7-(d2 -ethoxy)flavone. The present concept for the synthesis of deuterated reagents and the first demonstration of a KIE in a d2 -ethoxy group will contribute to drug discovery research based on deuterium chemistry.

Arylation of indoles using cyclohexanones dually-catalyzed by niobic acid and palladium-on-carbons.

3-Arylindoles were easily constructed from indoles and cyclohexanone derivatives using a combination of catalytic niobic acid-on-carbon (Nb2O5/C) and palladium-on-carbon (Pd/C) under heating conditions without any oxidants. The Lewis acidic Nb2O5/C promoted the nucleophilic addition of indoles to the cyclohexanones, and the subsequent dehydration and Pd/C-catalyzed dehydrogenation produced the 3-arylindoles. The additive 2,3-dimethyl-1,3-butadiene worked as a hydrogen acceptor to facilitate the dehydrogenation step.

Facile Hydrogenative Deprotection of N-Benzyl Groups Using a Mixed Catalyst of Palladium and Niobic Acid-on-Carbon.

The palladium-on-carbon (Pd/C)-catalyzed hydrogenative deprotection of the N-benzyl-protecting group was effectively facilitated by the combined use of niobic acid-on-carbon (Nb2O5/C). Nb2O5/C is an acidic heterogeneous catalyst prepared from NbCl5 and activated carbon. The catalysts were easily removed from the reaction mixture and reusable. Deprotected amines were obtained in excellent yields without an additional neutralization process. The facilitating effect of Nb2O5/C was also observed during the Pd/C-catalyzed hydrogenative deprotection of the N-benzyloxycarbonyl (Cbz) and O-benzyl groups.

Birch-Type Reduction of Arenes in 2-Propanol Catalyzed by Zero-Valent Iron and Platinum on Carbon.

Catalytic arene reduction was effectively realized by heating in 2-propanol/water in the presence of Pt on carbon (Pt/C) and metallic Fe. 2-Propanol acted as a hydrogen source, obviating the need for flammable (and hence, dangerous and hard-to-handle) hydrogen gas, while metallic Fe acted as an essential co-catalyst to promote reduction. The chemical states of Pt and Fe in the reaction mixture were determined by X-ray absorption near-edge structure analysis, and the obtained results were used to suggest a plausible reaction mechanism, implying that catalytic reduction involved Pt- and Fe-mediated single-electron transfer and the dehydrogenation of 2-propanol.

Stainless Steel-Mediated Hydrogen Generation from Alkanes and Diethyl Ether and Its Application for Arene Reduction.

Hydrogen gas can be generated from simple alkanes (e.g., n-pentane, n-hexane, etc.) and diethyl ether (Et2O) by mechanochemical energy using a planetary ball mill (SUS304, Fritsch Pulverisette 7), and the use of stainless steel balls and vessel is an important factor to generate the hydrogen. The reduction of organic compounds was also accomplished using the in-situ-generated hydrogen. While the use of pentane as the hydrogen source facilitated the reduction of the olefin moieties, the arene reduction could proceed using Et2O. Within the components (Fe, Cr, Ni, etc.) of the stainless steel, Cr was the metal factor for the hydrogen generation from the alkanes and Et2O, and Ni metal played the role of the hydrogenation catalyst.