Stereodivergent Synthesis of Arylcyclopropylamines by Sequential CH Borylation and Suzuki–Miyaura Coupling

Abstract

A step-economical and stereodivergent synthesis of privileged 2-arylcyclopropylamines (ACPAs) through a C(sp(3))-H borylation and Suzuki-Miyaura coupling sequence has been developed. The iridium-catalyzed C-H borylation of N-cyclopropylpivalamide proceeds with cis selectivity. The subsequent B-cyclopropyl Suzuki-Miyaura coupling catalyzed by [PdCl2(dppf)]/Ag2O proceeds with retention of configuration at the carbon center bearing the Bpin group, while epimerization at the nitrogen-bound carbon atoms of both the starting materials and products is observed under the reaction conditions. This epimerization is, however, suppressed in the presence of O2. The present new ACPA synthesis results in not only a significant reduction in the steps required for making ACPA derivatives, but also the ability to access either isomer (cis or trans) by simply changing the atmosphere (N2 or O2) in the coupling stage.

Ligand‐Promoted Borylation of C(sp3)H Bonds with Palladium(II) Catalysts

“…This C(sp 3 )H borylation reaction is compatible with α‐methyl CH bonds as well as methylene CH bonds in a wide range of cyclic amide substrates, including cyclopropanes, cyclobutanes, cyclopentanes, cyclohexanes, and cycloheptanes. The C(sp 3 )H borylation of this class of substrates has not been demonstrated using other catalytic systems 1k–m. 2d Importantly, Pd II ‐catalyzed C(sp 3 )H borylation proceeds through a reaction mechanism and redox processes that are fundamentally different to those of the Ir‐ and Rh‐catalyzed CH borylation reactions.…”

“…We also performed the borylation of the bicyclo[2.2.2]octanes 5 k and 5 l to rapidly diversify this class of three‐dimensional drug scaffolds. Notably, Ir‐catalyzed C(sp 3 )H borylation of carbocyclic systems has only been demonstrated with cyclopropylamine1m and 2‐cyclohexylpyridine substrates 1k. To further demonstrate the efficiency of this ligand‐promoted borylation reaction, we conducted the reaction of cyclobutyl substrate 5 e with 1–2 mol % of Pd(OAc) 2 [Eq.…”

Drug Design Concepts for LSD1‐Selective Inhibitors

“…The optimization studies of the phenyl ring of the PCPA part of 16d were performed to improve the LSD1 inhibitory activity and anticancer activity of 16d . A series of 16d derivatives were rapidly synthesized using a new synthetic strategy for trans ‐2‐arylcyclopropylamine (ACPA), in which a sequential coupling reaction with C−H borylation and Suzuki coupling reported by Itami and Yamaguchi group was performed . Among the 16d derivatives, M1310 ( 17 ) was identified as a potent and selective LSD1 inhibitor (Figure b).…”

Configurationally stable, enantioenriched organometallic nucleophiles in stereospecific Pd-catalyzed cross-coupling reactions: an alternative approach to asymmetric synthesis

“…Prior to recent efforts, stereospecific Pd-catalyzed cross-coupling reactions of C(sp 3 ) nucleophiles typically required the use of cyclopropyl reagents. 10 However, because cyclopropyl groups undergo uniquely facile transmetallation and cannot undergo β-hydride elimination, such reactions constitute markedly limited examples of stereospecificity in cross-coupling reactions. By comparison, an efficient, general method to employ optically active alkyltin and alkylboron nucleophiles in palladium-catalyzed cross-coupling reactions would constitute a broadly powerful tool for use in organic synthesis.…”