Late-Stage C-H Activation of Drug (Derivative) Molecules with Pd(ll) Catalysis.

This review comprehensively analyses representative examples of Pd(II)-catalyzed late-stage C-H activation reactions and demonstrates their efficacy in converting C-H bonds at multiple positions within drug (derivative) molecules into diverse functional groups. These transformative reactions hold immense potential in medicinal chemistry, enabling the efficient and selective functionalization of specific sites within drug molecules, thereby enhancing their pharmacological activity and expanding the scope of potential drug candidates. Although notable articles have focused on late-stage C-H functionalization reactions of drug-like molecules using transition-metal catalysts, reviews specifically focusing on late-stage C-H functionalization reactions of drug (derivative) molecules using Pd(II) catalysts are required owing to their prominence as the most widely utilized metal catalysts for C-H activation and their ability to introduce a myriad of functional groups at specific C-H bonds.

Empirical Guidelines for the Development of Remote Directing Templates through Quantitative and Experimental Analyses.

The ability to differentiate and selectively activate remote C-H bonds represents a perennial challenge in the field of C-H activation. Since its first report in 2012, a now-established "directing template" (DT) approach remains demonstrably effective for the functionalization of remote C-H bonds. As selectivity is hypothesized to be principally determined by the optimal positioning of the reactive catalyst to a target C-H bond, a DT's spatial factors are particularly important toward achieving high selectivity, though a systematic study on its requisite factors remain unelucidated.

Catalytic Asymmetric Darzens-Type Epoxidation of Diazoesters: Highly Enantioselective Synthesis of Trisubstituted Epoxides.

Highly enantioselective Darzens-type epoxidation of diazoesters with glyoxal derivatives was accomplished using a chiral boron-Lewis acid catalyst, which facilitated asymmetric synthesis of trisubstituted α,β-epoxy esters. In the presence of a chiral oxazaborolidinium ion catalyst, the reaction proceeded in high yield (up to 99 %) with excellent enantio- and diastereoselectivity (up to >99 % ee and >20:1 dr, respectively). The synthetic potential of this method was illustrated by conversion of the products to various compounds such as epoxy γ-butyrolactone, tertiary β-hydroxy ketone and epoxy diester.

Enantioselective Carbonyl 1,2- or 1,4-Addition Reactions of Nucleophilic Silyl and Diazo Compounds Catalyzed by the Chiral Oxazaborolidinium Ion.

Boron Lewis acid catalysis has a long history and has become one of the most powerful methods for organic synthesis. In addition to achiral boron catalysts such as BX (X = F, Cl, Br) and B(CF), chiral boron catalysts are also significant synthetic tools used by organic chemists in academic laboratories and industry. Since first reported by Corey et al.

Asymmetric Synthesis of Cyclobutanone via Lewis Acid Catalyzed Tandem Cyclopropanation/Semipinacol Rearrangement.

Chiral Lewis acid catalyzed asymmetric formation of cyclobutanones from α-silyloxyacroleins and α-alkyl or α-aryl diazoesters has been developed. In the presence of a chiral oxazaborolidinium ion catalyst, various α-silyloxycyclobutanones possessing a chiral β-quaternary center were synthesized in high yield (up to 91%) with excellent enantio- and diastereoselectivity (up to 98% ee and up to >20:1 dr) through tandem cyclopropanation/semipinacol rearrangement. The synthetic potential of this method was illustrated by conversion of the product to various cyclic compounds such as γ-lactone, cyclobutanol, and cyclopentanone.

Catalytic Enantioselective Synthesis of 2,5-Dihydrooxepines.

A Michael addition initiated cyclopropanation/retro-Claisen rearrangement tandem reaction was developed for the enantioselective synthesis of highly functionalized 2,5-dihydrooxepines. In the presence of a chiral oxazaborolidinium ion (COBI) catalyst, the reaction proceeds to give good yields and high enantioselectivity.

Enantioselective Cyclopropanation with α-Alkyl-α-diazoesters Catalyzed by Chiral Oxazaborolidinium Ion: Total Synthesis of (+)-Hamavellone B.

Chiral oxazaborolidinium ion-catalyzed asymmetric cyclopropanation of α- or α,β-substituted acroleins with α-alkyl-α-diazoesters has been developed. With this methodology, chiral functionalized cyclopropanes containing a quaternary stereogenic center were obtained with high to excellent enantioselectivities (up to >99% ee). The synthetic utility of optically enriched functionalized cyclopropane was demonstrated in the first total synthesis of (+)-hamavellone B, which establishes the absolute configuration of natural (+)-hamavellone B.

Highly stereoselective oxazaborolidinium ion catalyzed synthesis of (Z)-silyl enol ethers from alkyl aryl ketones and trimethylsilyldiazomethane.

Highly stereoselective (Z)-silyl enol ethers were prepared from alkyl aryl ketones and trimethylsilyldiazomethane (TMSD) using an oxazaborolidinium ion catalyst. In addition, ring-expanded silyl enol ethers were successfully constructed from cyclic ketones. Their synthetic utilities were shown by sequential Mukaiyama aldol and [2 + 2]-cycloaddition reactions.