Ligand‐Enabled β‐C(sp³)−H Lactamization of Tosyl‐Protected Aliphatic Amides Using a Practical Oxidant

Abstract

The development of C(sp3)−H functionalization reactions that use common protecting groups and practical oxidants remains a significant challenge. Herein we report a monoprotected aminoethyl thioether (MPAThio) ligand‐enabled β‐C(sp3)−H lactamization of tosyl‐protected aliphatic amides using tert‐butyl hydrogen peroxide (TBHP) as the sole oxidant. This protocol features exceedingly mild reaction conditions, reliable scalability, and the use of practical oxidants and protecting groups. Further derivatization of the β‐lactam products enables the synthesis of a range of biologically important motifs including β‐amino acids, γ‐amino alcohols, and azetidines.

Collaboration as a Key to Advance Capabilities for Earth-Abundant Metal Catalysis

“…Yu, Blackmond, and Engle, spanning palladium and EAMs such as copper and nickel. Our collaboration with the Yu lab has focused on innovation aimed toward new reaction methodology, mainly mediated by palladium, with a lens toward our discovery team . Multiple transition-metal-catalyzed mechanistic interrogations have been completed with the Blackmond lab, for example impacting the process route to fostemsavir through investigation of an Ullmann coupling and building understanding of stereospecificity in a rhodium- or ruthenium-catalyzed hydrogenation relevant to our portfolio.…”

Stereoselective synthesis of β-lactams: recent examples

“…Yu and coworkers reported the mono-selective synthesis of a series of β-lactams using a related strategy, the β-C(sp 3 )-H lactamization of amides having commonly used protecting groups (tosyl, 4-nitrobenzenesulphonyl, 4-cianobenzenesulfonyl, 2-trimethylsilylethanesulfonyl and mesyl) instead of quinoline-based substituents, thus diversifying the range of products that can be obtained through C(sp 3 )-H lactamization of amides. 51 Huang and colleagues reported a novel palladium-catalyzed double C-H bond activation synthetic approach to access β-lactams via carbonylative formal cycloaddition. 52 Thus, the authors carried out the reaction of alkylarenes 36 and aldimines 37 in the presence of carbon monoxide, using Pd(CH 3 CN) 2 Cl 2 as the catalyst, Xantphos as the ligand, di-tertbutyl peroxide (DTBP) as the oxidant and 1,2,2,6,6-pentamethylpiperidine (PMP) as the base (Scheme 7).…”

“…3 But the development of new synthetic methodologies has allowed to obtain these bioactive molecules in several ways. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Progress in the preparation of β-lactams ran parallel with the development of stereoselective synthetic methodologies, allowing to access to the different isomers (cis or trans) and also to obtain enantioenriched products. [22][23][24][25][26] This review is focused on recent advances towards the stereoselective synthesis of β-lactams, dividing the manuscript into three main sections: (i) metal-free cycloaddition reactions; (ii) transition metal-catalysis; and (iii) base-promoted synthesis.…”

“…3 But the development of new synthetic methodologies has allowed to obtain these bioactive molecules in several ways. 4–21…”

Ligand-Enabled Pd(II)-Catalyzed Enantioselective β-C(sp3)-H Arylation of Aliphatic Tertiary Amides

“…To this end, monodentate amide directing groups with various structural modifications have been employed (Figure 1b). For instances, Yu and co-workers used N-methoxyl amides, [9] N-perfluroaryl amides, [9c, 10] and Ntosyl amides [11] in the Pd-catalyzed aliphatic C-H functionalization as substrates and achieved the first enantioselective case in this chemistry; [10b] the Yu [12] and Gong [13] groups independently developed enantioselective C-H arylation of thioamides at the α-position of the N-aliphatic substituent; more recently, Gong and coworkers achieved enantioselective β-C-H arylation of thioamides. [14] On the other hand, simple amide without special structural motif as the directing group in C-H functionalization would be more demanding.…”