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.

We describe the structure-activity relationship of various arylcyclopropylamines (ACPAs), which are potent LSD1 inhibitors. More than 45 ACPAs were synthesized rapidly by an unconventional method that we have recently developed, consisting of a C-H borylation and cross-coupling sequence starting from cyclopropylamine. We also generated NCD38 derivatives, which are known as LSD1 selective inhibitors, and discovered a more effective inhibitor compared to the original NCD38.

Hydroboration of alkenes is a classical reaction in organic synthesis, in which alkenes react with boranes to give alkylboranes, with subsequent oxidation resulting in alcohols. The double bond (π-bond) of alkenes can be readily reacted with boranes owing to its high reactivity. However, the single bond (σ-bond) of alkanes has never been reacted. To pursue the development of σ-bond cleavage, we selected cyclopropanes as model substrates since they present a relatively weak σ-bond. Herein, we describe an iridium-catalyzed hydroboration of cyclopropanes, resulting in β-methyl alkylboronates. These unusually branched boronates can be derivatized by oxidation or cross-coupling chemistry, accessing "designer" products that are desired by practitioners of natural product synthesis and medicinal chemistry. Furthermore, mechanistic investigations and theoretical studies revealed the enabling role of the catalyst. Recently, several chemists including our group reported an iridium-catalyzed C-H borylation of cyclopropanes [19-21]. In one report, cyclopropanes were reacted with iridium complexes with a nitrogen bidentate ligand, 3,4,7,8-tetramethylphenanthroline (3,4,7,8-tetraMephen), which engendered a cyclopropane carbonhydrogen activation to afford borylated cyclopropanes (Fig. 1B). With the aim of achieving cyclopropane carbon-carbon activation, we forged a blueprint for selective bond activation. If an appropriate ligand were used, it might be possible to perform a "chemoselectivity switch" from C-H (intermediate A) to CC (intermediate B) bond activation in which the selectivity of CC activation could be achieved by reaction of the catalyst with the sterically less hindered Cb-Cg bond [22-24]. With these goals in mind, we conducted an extensive screening of ligands, and by using 2-[4-(1,1-dimethylethyl)-4,5-dihydro-2-oxazolyl]quinoline (t-Bu-Quinox), we achieved the first iridium-catalyzed σ-bond hydroboration of cyclopropanes (Fig. 1C). We initiated our study by finding a suitable ligand for the target reaction, consisting of N-cyclopropylpivalamide (1a) as a model mono-substituted cyclopropane. 1a was reacted with pinacolborane (H-Bpin: 1.5 equiv) in the presence of Ir dimer [Ir(OMe)(cod)]2 (5 mol%) and ligands (5 mol%) in THF at 80 ºC under nitrogen atmosphere. After an extensive screening of ligands (see Supplementary Materials), it was found that t-BuQuinox (L1) effects the cleavage of the σ-bond and forms hydroboration product 2a in 62% yield

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Fragment-based ligand discovery was successfully applied to histone deacetylase HDAC2. In addition to the anticipated hydroxamic acid- and benzamide-based fragment screening hits, a low affinity (∼1 mM) α-amino-amide zinc binding fragment was identified, as well as fragments binding to other regions of the catalytic site. This alternative zinc-binding fragment was further optimized, guided by the structural information from protein–ligand complex X-ray structures, into a sub-μM, brain penetrant, HDAC2 inhibitor (17) capable of modulating histone acetylation levels in vivo.