Palladium-catalyzed alkenylboration of carbon-carbon double bonds has been achieved using the reaction of chloro(diisopropylamino)boryl ethers of homoallylic alcohols with alkenylzirconium reagents. The reaction may proceed through an initial oxidative addition of the B-Cl bond, intramolecular insertion of the C═C bond into the B-Pd bond, transmetalation from the alkenylzirconium reagent, and reductive elimination of the products. The cyclization proceeds with high diastereoselectivity for the formation of cis-3,5- or trans-3,4-disubstituted-1,2-oxaborolane products. Cross-coupling of the resultant products with aryl iodides proceeds with retention of configuration at the boron-bound secondary carbon atom.

Three-component coupling of bis(dialkylamino)chloroborane, alkynes and organozirconium reagents proceeded in the presence of palladium catalysts, leading to the formation of stereo-defined alkenylborane derivatives via cis-carboboration of carbon-carbon triple bonds.

Persistent epigenetic dysregulation may underlie the pathophysiology of neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here, we show that the inhibition of lysine-specific demethylase 1 (LSD1) enzyme activity normalizes aberrant epigenetic control of gene expression in neurodevelopmental disorders. Maternal exposure to valproate or poly I:C caused sustained dysregulation of gene expression in the brain and ASD-like social and cognitive deficits after birth in rodents. Unexpectedly, a specific inhibitor of LSD1 enzyme activity, 5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide hydrochloride (TAK-418), almost completely normalized the dysregulated gene expression in the brain and ameliorated some ASD-like behaviors in these models. The genes modulated by TAK-418 were almost completely different across the models and their ages. These results suggest that LSD1 enzyme activity may stabilize the aberrant epigenetic machinery in neurodevelopmental disorders, and the inhibition of LSD1 enzyme activity may be the master key to recover gene expression homeostasis. TAK-418 may benefit patients with neurodevelopmental disorders.

There are increasing demands for organoboronic acid derivatives in synthetic organic chemistry because they exhibit remarkable reactivities upon appropriate activation, while being stable, storable, and nonpoisonous. 1 Their applications are spreading over the pharmaceutical and material sciences in recognition of the unique properties of organoboron compounds. Therefore, development of efficient methods for the synthesis of stereodefined, functionalized organoboronic acids is highly desirable.Catalytic borylation reactions have gained much attention with respect to efficiency, selectivity, and functional group compatibility. 2,3 Recent efforts have focused on the additions of boronelement bonds across carbon-carbon multiple bonds, 4 such as diboration 5 and silaboration. 6 Our attention has been focused on the development of catalytic carboboration reactions, in which B-C and C-C bonds are formed concurrently. We have so far reported two distinctive classes of carboborations, i.e., direct 7 and transmetalative 8 carboborations. While direct carboboration involves the activation of B-C bonds of the boron reagents, transmetalative carboboration uses haloborane as the source of the boryl group, with organometallic reagents as the source of the organic group. As the first example of the latter class of carboboration, we recently established that a carbon-carbon triple bond tethered to chlorobound boron underwent nickel-catalyzed carboboration upon use of alkynylstannanes as the transmetalation reagents. 8 In contrast to our mechanism-based assumption, the carboboration proceeded with a trans-addition mode. In this paper, we report a new carboboration system utilizing organozirconium reagents with palladium catalysts. The Pd/Zr system not only allows significant expansion of the substrate scope but also brings about highly stereoselective carboboration with either stereochemical course, which critically depends on the phosphine ligands.After screening various alkenyl organometallics as the transmetalation reagents, we found that reaction of alkenylzirconium reagent 2a with chloroborane 1a, which was tethered to an arylsubstituted alkyne, gave the carboboration product trans-3aa in good yield in the presence of nickel catalysts (Scheme 1). The Ni/Zr system still gave a trans-addition product with high selectivity, as did the Ni/Sn system. However, no carboboration products were obtained in the reaction of terminal or alkyl-substituted alkynes 1b or 1c, even with the Ni/Zr system.We then reexamined the transition metal catalysts for use with the organozirconium reagent. We found that palladium catalysts exhibited high catalytic activity. On using bulky trialkylphosphines such as P t Bu 3 or PCy 3 with palladium complexes such as PdCp-(allyl) or Pd(acac) 2 , the alkenylboration proceeded with high stereoselectivities for the trans-addition product, as observed in the Ni-catalyzed reaction (Table 1, entries 1 and 2). 9 To our surprise, however, the stereochemical course was completely switched to favor cis-addition, whe...