Fragment-Based Discovery of a Novel, Brain Penetrant, Orally Active HDAC2 Inhibitor.

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.

Gold-Catalyzed Anti-Markovnikov Selective Hydrothiolation of Unactivated Alkenes.

Despite the widespread use of transition-metal catalysts in organic synthesis, transition-metal-catalyzed reactions of organosulfur compounds, which are known as catalyst poisons, have been difficult. In particular, the transition-metal-catalyzed addition of organosulfur compounds to unactivated alkenes remains a challenge. A novel gold-catalyzed hydrothiolation of unactivated alkenes is presented, which proceeds effectively to give the anti-Markovnikov-selective adducts in good yields and in a regioselective manner.

Palladium-Catalyzed Markovnikov-Selective Hydroselenation of N-Vinyl Lactams with Selenols Affording N,Se-Acetals.

The highly regioselective hydroselenation of N-vinyl lactams has been revealed to successfully afford the corresponding N,Se-acetals as Markovnikov adducts. In the case of terminal N-vinyl lactams, Markovnikov-selective hydroselenation proceeds efficiently in the absence of any catalyst (or additive), owing to the acidity of the selenols. In contrast, the self-promoted hydroselenation is inefficient with internal N-vinyl lactams. In the presence of palladium diacetate (Pd(OAc)2), however, the desired hydroselenation of internal N-vinyl lactams proceeds efficiently to afford the corresponding N,Se-acetals.

Selective Thiolative Lactonization of Internal Alkynes Bearing a Hydroxyl Group with Carbon Monoxide and Organic Disulfides Catalyzed by Transition-Metal Complexes.

Although many transition-metal catalysts are ineffective for the addition and carbonylative addition of organic disulfides to internal alkynes, dicobalt octacarbonyl and palladium complexes such as Pd(PPh3)4 and Pd(OAc)2 were found to exhibit excellent catalytic activity for the thiolative lactonization of internal alkynes bearing a hydroxyl group. In the presence of the cobalt or palladium catalyst, internal alkynes bearing a hydroxy group, such as homopropargyl alcohol derivatives, successfully undergo thiolative carbonylation with carbon monoxide and an organic disulfide regio- and stereoselectively to afford the corresponding thio group bearing-lactones in good yields. In the Co-catalyzed reaction, the cobalt-alkyne complex from dicobalt octacarbonyl and internal alkyne acts as a key species, making it possible to attain thiolative lactonization of internal alkynes with a hydroxyl group. In the Pd-catalyzed reaction, the coordination of the hydroxy group to the palladium catalyst plays an important role for the thiolative lactonization.

Regioselective hydrothiolation of alkenes bearing heteroatoms with thiols catalyzed by palladium diacetate.

In sharp contrast to many examples of transition-metal-catalyzed hydrothiolation of alkynes, the corresponding catalytic addition of thiols to alkenes has remained undeveloped. However, a novel Pd-catalyzed addition of thiols to alkenes bearing a heteroatom, such as oxygen and nitrogen, is found to proceed under mild conditions to give the corresponding Markovnikov adducts, regioselectively, in good yields.