A new strategy for mixed biaryl synthesis has been developed using the hypervalent iodine(III) reagents. The unique reactivities of the sigma-heteroaryl iodine(III) intermediates generated in situ are the key element for the unusual metal catalyst-free transformations and strict control of the product selectivities.

BSTRACTCdc42 is a key regulator of dynamic actin organization. However, little is known about how Cdc42-dependent actin regulation influences steady-state actin structures in differentiated epithelia. We employed inner ear hair-cell-specific conditional knockout to analyze the role of Cdc42 in hair cells possessing highly elaborate stable actin protrusions (stereocilia). Hair cells of Atoh1-Cre;Cdc42 flox/flox mice developed normally but progressively degenerated after maturation, resulting in progressive hearing loss particularly at high frequencies. Cochlear hair cell degeneration was more robust in inner hair cells than in outer hair cells, and began as stereocilia fusion and depletion, accompanied by a thinning and waving circumferential actin belt at apical junctional complexes (AJCs). Adenovirus-encoded GFP-Cdc42 expression in hair cells and fluorescence resonance energy transfer (FRET) imaging of hair cells from transgenic mice expressing a Cdc42-FRET biosensor indicated Cdc42 presence and activation at stereociliary membranes and AJCs in cochlear hair cells. Cdc42-knockdown in MDCK cells produced phenotypes similar to those of Cdc42-deleted hair cells, including abnormal microvilli and disrupted AJCs, and downregulated actin turnover represented by enhanced levels of phosphorylated cofilin. Thus, Cdc42 influenced the maintenance of stable actin structures through elaborate tuning of actin turnover, and maintained function and viability of cochlear hair cells.

The selection of reward-seeking and aversive behaviors is controlled by two distinct D1 and D2 receptor-expressing striatal medium spiny neurons, namely the direct pathway MSNs (dMSNs) and the indirect pathway MSNs (iMSNs), but the dynamic modulation of signaling cascades of dMSNs and iMSNs in behaving animals remains largely elusive. We developed an in vivo methodology to monitor Förster resonance energy transfer (FRET) of the activities of PKA and ERK in either dMSNs or iMSNs by microendoscopy in freely moving mice. PKA and ERK were coordinately but oppositely regulated between dMSNs and iMSNs by rewarding cocaine administration and aversive electric shocks. Notably, the activities of PKA and ERK rapidly shifted when male mice became active or indifferent toward female mice during mating behavior. Importantly, manipulation of PKA cascades by the Designer Receptor recapitulated active and indifferent mating behaviors, indicating a causal linkage of a dynamic activity shift of PKA and ERK between dMSNs and iMSNs in action selection.in vivo FRET imaging | microendoscope | dorsal striatum | action selection | mating behavior I n changing environments, animals are forced to choose actions among several alternatives to survive and to keep offspring for the next generation. A brain region critical for initiation and selection of actions is the striatum (1-3), and its dysfunction leads to devastating neurological and psychiatric disorders such as Parkinson's disease and drug addiction (4-7). The striatum receives convergent glutamatergic inputs from virtually all cortical areas and the thalamus, and dopaminergic inputs from the substantia nigra pars compacta (SNc) and the ventral tegmental area (8, 9). The glutamatergic inputs convey various sensory, motor, and cognitive information and drive striatal medium spiny projection neurons (MSNs) to fire, whereas the dopaminergic inputs strongly influence synaptic transmission and excitability of MSNs (10, 11). MSNs are divided into two subpopulations, the direct pathway MSN (dMSN) expressing Gs-coupled dopamine D1 receptors and sending axons directly to the internal segment of the globus pallidus (GPi) and the substantia nigra pars reticulata (SNr), and the indirect pathway MSN (iMSN) expressing Gi-coupled D2 receptors and sending axons indirectly to the SNr via the external segment of the globus pallidus (GPe) and subthalamic nucleus (12, 13).Intracellular signaling cascades operating in these two types of MSNs are important for plastic modification of synaptic transmission and excitability (14, 15). Among them, protein kinase A (PKA) and extracellular signal-regulated kinase (ERK) have been shown to be the key molecules in these signaling cascades (10,14,16). PKA is positively and negatively regulated by Gs-coupled D1 and Gi-coupled D2 receptors, respectively, and contributes to the regulation of a wide range of cellular substrates (10,11,16). ERK has been shown to sense coincidental dopaminergic and glutamatergic activations to induce protein synthesis and synaptic modif...

Dedicated to Professor Ryoji Noyori on the occasion of his 70th birthdayThe hydration of organonitriles is a reaction of great synthetic significance for the preparation of organoamides (e.g., acrylamide and nicotinamide) in view of its broad industrial and pharmacological applications.[1] For example, hydration of acrylonitrile is used to produce more than 2 10 5 tons of acrylamide per year.[2] Classically the reaction proceeds in a sequence of distinct steps upon treatment with strong inorganic acid or base, but these methods are frequently unable to control overhydrolysis.[1f] Although several pioneering precedents involving molecular [3] and heterogeneous [4] catalysts have been reported, in many cases, drastic conditions including high temperatures (80-180 8C) or high pressure (e.g., 80 psi) are required. As an exception, Co III [3a,d] and Pt II [3e,o] complexes mediate hydration under milder conditions; however, the substrate range applicable under standard or ambient conditions remains unclarified. We report here a notable advance towards expanding the substrate scope, by demonstrating an easier to conduct and milder hydration of organonitriles using a low-valent Rh I -(OMe) species as the molecular catalyst (Scheme 1).The Rh I catalyst was prepared by treatment of commercially available [{Rh(OMe)(cod)} 2 ] (0.01 equiv) with PCy 3 (0.04 equiv) in anhydrous THF at 25 8C for 15 min under argon (cod = cyclooctadiene, Cy = cyclohexyl). After the solvent THF and residual cod had been removed by evaporation in vacuo, oxygen-free, Ar-saturated iPrOH was added. The iPrOH solution of the Rh I OMe/2 PCy 3 catalyst (Rh: 0.04 m) was treated sequentially with benzonitrile (1 a) (1 equiv) and H 2 O (5 equiv) at 25 8C under argon, and the reaction mixture was stirred at 25 8C for 17 h. Subsequent purification by column chromatography on silica gel provided benzamide (2 a) in 90 % yield. The reaction mixture was not contaminated by further hydration and/or alcoholysis products; in contrast, the formation of benzoic acid and/or the ester was frequently the side reaction in several methods previously described.[1f] Use of [{Rh(OH)(cod)} 2 ] in place of [{Rh(OMe)(cod)} 2 ] resulted in a slightly lower yield (74 %). Scant reactivity was observed with other Rh I complexes including [{RhCl(cod)} 2 ] and [Rh(acac)(cod)] (acac = acetylacetonate) under otherwise identical conditions, suggesting that the OR (R = H, Me) component is the critical functional group in facilitating the reaction. When we screened the solvents, we found that protic solvents (MeOH, EtOH, iPrOH, and tBuOH) led to rate enhancement (2 a, 60-99 %: 25 8C, 24 h), whereas aprotic solvents (dimethylacetamide (DMA), dimethyl sulfoxide, and N-methylpyrrolidinone (NMP)) resulted in low conversion (< 10 %). Additional experiments revealed that the yield of benzamide (2 a) depends least on the concentration of the Rh catalyst when the hydration is carried out in iPrOH, so that we chose this solvent for further screening. Two equivalents of PCy 3 per equivalent of Rh ...

We have developed a new and reliable method for the direct construction of biologically important aryl lactones and phthalides from carboxylic and benzoic acids, using a combination of hypervalent iodine(III) reagents with KBr.

Hypervalent iodine(III) reagents mediate the direct cyanating reaction of a wide range of electron-rich heteroaromatic compounds such as pyrroles 1, thiophenes 3, and indoles 5 under mild conditions (ambient temperature), without the need for any prefunctionalization. Commercially available trimethylsilylcyanide is usable as a stable and effective cyanide source, and the reaction proceeds in a homogeneous system. The N-substituent of pyrroles is crucial to avoid the undesired oxidative bipyrrole coupling process, and thus a cyano group was introduced selectively at the 2-position of N-tosylpyrroles 1 in good yields using the combination of phenyliodine bis(trifluoroacetate) (PIFA), TMSCN, and BF3.Et2O at room temperature. In the reaction mechanism, cation radical intermediates of heteroaromatic compounds are involved as a result of single electron oxidation, and the key to successful transformations seems to depend on the oxidation potential of the substrates used. Thus, the reaction was also successfully extended to other heteroaromatic compounds having oxidation potentials similar to that of N-tosylpyrroles such as thiophenes 3 and indoles 5. However, regioisomeric mixtures of the products derived from the reaction at the 2- and 3-positions were obtained in the case of N-tosylindole 5a. Further investigation performed in our laboratory provided insights into the real active iodine(III) species during the reaction; the reaction is induced by an active hypervalent iodine(III) species having a cyano ligand in situ generated by ligand exchange reaction at the iodine(III) center between trifluoroacetoxy group in PIFA and TMSCN, and effective cyanide introduction into heteroaromatic compounds is achieved by means of the high cyano transfer ability of the hypervalent iodine(III)-cyano intermediates. In fact, the reaction of N-tosylpyrrole 1a with a hypervalent iodine(III)-cyano compound (e.g., (dicyano)iodobenzene 8), in the absence of TMSCN, took place to afford the 2-cyanated product 2a in good yield, and an effective preparation of the intermediates is of importance for successful transformation. 1,3,5,7-Tetrakis[4-{bis(trifluoroacetoxy)-iodo}phenyl]adamantane 12, a recyclable hypervalent iodine(III) reagent, was also comparable in the cyanating reactions as a valuable alternative to PIFA, affording a high yield of the heteroaromatic cyanide by facilitating isolation of the cyanated products with a simple workup. Accordingly, after preparing the active hypervalent iodine(III)-CN species by premixing of a recyclable reagent 12, TMSCN, and BF3.Et2O for 30 min in dichloromethane, reaction of a variety of pyrroles 1 and thiophenes 3 provided the desired cyanated products 2 and 4 in high yields. The iodine compound 13, recovered by filtration after replacement of the reaction solvent to MeOH, could be reused without any loss of activity (the oxidant 12 can be obtained nearly quantitatively by reoxidation of 13 using m-CPBA).

We have found that unreactive and insoluble polymeric iodosobenzene [PhIO] n induced aqueous benzylic C-H oxidation to effectively give arylketones, in the presence of KBr and montmorillonite-K10 (M-K10) clay. Water-soluble and reactive species 1 having the unique I(III)-Br bond, in situ generated from [PhIO]n and KBr, was considered to be the key radical initiator during the reactions.

Where and when of memory consolidation Episodic memory is initially encoded in the hippocampus and later transferred to other brain regions for long-term storage. Synaptic plasticity underlies learning and plays a critical role in memory consolidation. However, it remains largely unknown where and when synaptic plasticity occurs and how it shapes the neuronal representation. Goto et al . developed a new tool for controlling early structural long-term potentiation (sLTP). By selectively manipulating sLTP, the authors showed that the local circuitry in hippocampal area CA1 is required for memory formation shortly after the encoding event. The local circuitry is also important for offline memory consolidation within 24 hours. The anterior cingulate cortex, another brain region directly connected with area CA1, is crucial for memory consolidation during sleep on the second night. —PRS