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. The utilization of Pd-catalyzed C-H activation methodologies demonstrates impressive success in introducing various functional groups, such as cyano (CN), fluorine (F), chlorine (Cl), aromatic rings, olefin, alkyl, alkyne, and hydroxyl groups, to drug (derivative) molecules with high regioselectivity and functional-group tolerance. These breakthroughs in late-stage C-H activation reactions serve as invaluable tools for drug discovery and development, thereby offering strategic options to optimize drug candidates and drive the exploration of innovative therapeutic solutions.

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. Through an in-depth analysis of 119 structurally unique published remote DTs, this report summarizes the key factors that are central toward achieving high selectivity at defined aryl positions, which are experimentally corroborated through the development of new aliphatic meta and para-selective DTs for electronically unbiased arenes. These empirical rules, which summarize key distance and geometric factors, are expected to be useful tools for the future development of site-selective arene C-H activation as well as other reactions that rely on covalent/noncovalent DT-mediated remote regioselection.

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,ß-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 ß-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 BX3 (X = F, Cl, Br) and B(C6F5)3, chiral boron catalysts are also significant synthetic tools used by organic chemists in academic laboratories and industry. Since first reported by Corey et al. in 2002 ( Corey et al. J. Am. Chem. Soc. 2002 , 124 , 3808 ), the chiral oxazaborolidinium ion (COBI), an activated form of proline-derived oxazaborolidine, has been used as a strong Lewis acid catalyst. Although the early examples of asymmetric synthesis through COBI-catalyzed nucleophilic 1,2- or 1,4-carbonyl additions were reported in 2004-2006, Diels-Alder and cycloaddition reactions of various carbonyl compounds were mostly developed over the next several years to afford enantioenriched cyclized products. The power of COBI in catalyzing carbonyl 1,2- or 1,4-addition reactions triggered our interest in developing asymmetric synthetic methodologies to generate versatile enantiomerically enriched compounds. In this Account, we summarize our recent studies on COBI-catalyzed asymmetric nucleophilic carbonyl addition and tandem reactions. Logical mechanistic explanations of asymmetric COBI catalysis are also discussed. The proton-activated COBI catalyst, which can activate various carbonyl compounds such as aldehydes, ketones, acroleins, and enones through Lewis acid-base interactions and synergistic hydrogen bonds, facilitates asymmetric 1,2- or 1,4-carbonyl additions of nucleophiles. Nucleophiles bearing trialkylsilyl groups successfully reacted with aromatic, aliphatic, and α,ß-unsaturated aldehydes through 1,2-addition reactions resulting in chiral ß-hydroxy esters. In addition, efficient asymmetric hydrosilylation of ketones was achieved with a TfOH-activated COBI catalyst. Optically active ß-keto esters and all-carbon quaternary aldehydes were synthesized successfully through asymmetric 1,2-addition of diazo compounds and tandem H- or C-migration, respectively. In some cases, epoxide products were obtained as side products via the Darzens reaction pathway. Solvent and π-π interactions played important roles in favoring C-migration over H-migration. Nucleophilic 1,4-addition of diazo compounds and chemoselective ring-closure afforded an efficient approach to cyclopropanes, and their tandem rearrangements provided four- and seven-membered cyclic compounds with excellent stereoselectivity. After a Michael addition of diazo compounds, the selective ß-hydride shift pathway afforded the ß-substituted cyclic enones with high diastereo- and enantioselectivity. The presence of π-bond(s) in the substituents at the α-position of the diazo compound hindered the ß-hydride shift pathway and, as a result, favored the cyclopropanation pathway. While there still remain challenges to be overcome, these results further understanding of COBI catalysis and open a window for future development of new asymmetric synthetic methods using carbonyl addition and tandem reactions.

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 ß-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,ß-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.