A Boron Scan of Ethyl Acetoacetate Leads to Versatile Building Blocks.

Discovered in the 19th century, ethyl acetoacetate has been central to the development of organic chemistry, including its pedagogy and applications. In this study, we present borylated derivatives of this venerable molecule. A boron handle has been installed at either α ${{\rm \alpha }}$ - or ß ${\beta }$ -position of acetoacetate by homologation of acyl-MIDA (N-methyliminodiacetic acid) boronates with diazoacetates. Either alkyl or boryl groups were found to migrate with regiochemistry being a function of the steric bulk of the diazo species. Boryl ß ${{\rm \beta }}$ -ketoesters can be further modified into borylated pyrazolones and oximes, thereby expanding the synthetic toolkit and offering opportunities for additional modifications.

Light-Driven Sodium Pump as a Potential Tool for the Control of Seizures in Epilepsy.

The marine flavobacterium Krokinobactereikastus light-driven sodium pump (KR2) generates an outward sodium ion current under 530 nm light stimulation, representing a promising optogenetic tool for seizure control. However, the specifics of KR2 application to suppress epileptic activity have not yet been addressed. In the present study, we investigated the possibility of KR2 photostimulation to suppress epileptiform activity in mouse brain slices using the 4-aminopyrindine (4-AP) model. We injected the adeno-associated viral vector (AAV-PHP.eB-hSyn-KR2-YFP) containing the KR2 sodium pump gene enhanced with appropriate trafficking tags. KR2 expression was observed in the lateral entorhinal cortex and CA1 hippocampus. Using whole-cell patch clamp in mouse brain slices, we show that KR2, when stimulated with LED light, induces a substantial hyperpolarization of entorhinal neurons. However, continuous photostimulation of KR2 does not interrupt ictal discharges in mouse entorhinal cortex slices induced by a solution containing 4-AP. KR2-induced hyperpolarization strongly activates neuronal HCN channels. Consequently, turning off photostimulation resulted in HCN channel-mediated rebound depolarization accompanied by a transient increase in spontaneous network activity. Using low-frequency pulsed photostimulation, we induced the generation of short HCN channel-mediated discharges that occurred in response to the light stimulus being turned off; these discharges reliably interrupt ictal activity. Thus, low-frequency pulsed photostimulation of KR2 can be considered as a potential tool for controlling epileptic seizures.

ß-Boron Effect Enables Regioselective and Stereospecific Electrophilic Addition to Alkenes.

Electrophilic addition to alkenes is a textbook-taught reaction, yet it is not always possible to control the regioselectivity of addition to unsymmetrical 1,2-disubstituted substrates. We report the observation and applications of the ß-boron effect that accounts for high regioselectivity in electrophilic addition reactions to allylic MIDA (N-methyliminodiacetic acid) boronates. While the well-established ß-silicon effect bears partial resemblance to the observed reactivity, the silyl group is typically lost during functionalization. In contrast, the boryl moiety is retained in the product when B(MIDA) is used as the nucleophilic stabilizer. Mechanistic studies elucidate the origin of this effect and demonstrate how σ(C-B) hyperconjugation helps stabilize the incipient carbocation. This transformation represents a rare example of the stereospecific hydrohalogenation of secondary allyl MIDA-boronates that proceeds in a syn-fashion.

Delayed Impairment of Hippocampal Synaptic Plasticity after Pentylenetetrazole-Induced Seizures in Young Rats.

Data on the long-term consequences of a single episode of generalized seizures in infants are inconsistent. In this study, we examined the effects of pentylenetetrazole-induced generalized seizures in three-week-old rats. One month after the seizures, we detected a moderate neuronal loss in several hippocampal regions: CA1, CA3, and hilus, but not in the dentate gyrus. In addition, long-term synaptic potentiation (LTP) was impaired. We also found that the mechanism of plasticity induction was altered: additional activation of metabotropic glutamate receptors (mGluR1) is required for LTP induction in experimental rats. This disturbance of the plasticity induction mechanism is likely due to the greater involvement of perisynaptic NMDA receptors compared to receptors located in the core part of the postsynaptic density. This hypothesis is supported by experiments with selective blockades of core-located NMDA receptors by the use-dependent blocker MK-801. MK-801 had no effect on LTP induction in experimental rats and suppressed LTP in control animals. The weakening of the function of core-located NMDA receptors may be due to the disturbed clearance of glutamate from the synaptic cleft since the distribution of the astrocytic glutamate transporter EAAT2 in experimental animals was found to be altered.

Maternal Hyperhomocysteinemia Produces Memory Deficits Associated with Impairment of Long-Term Synaptic Plasticity in Young Rats.

Maternal hyperhomocysteinemia (HCY) is a common pregnancy complication caused by high levels of the homocysteine in maternal and fetal blood, which leads to the alterations of the cognitive functions, including learning and memory. In the present study, we investigated the mechanisms of these alterations in a rat model of maternal HCY. The behavioral tests confirmed the memory impairments in young and adult rats following the prenatal HCY exposure. Field potential recordings in hippocampal slices demonstrated that the long-term potentiation (LTP) was significantly reduced in HCY rats. The whole-cell patch-clamp recordings in hippocampal slices demonstrated that the magnitude of NMDA receptor-mediated currents did not change while their desensitization decreased in HCY rats. No significant alterations of glutamate receptor subunit expression except GluN1 were detected in the hippocampus of HCY rats using the quantitative real-time PCR and Western blot methods. The immunofluorescence microscopy revealed that the number of synaptopodin-positive spines is reduced, while the analysis of the ultrastructure of hippocampus using the electron microscopy revealed the indications of delayed hippocampal maturation in young HCY rats. Thus, the obtained results suggest that maternal HCY disturbs the maturation of hippocampus during the first month of life, which disrupts LTP formation and causes memory impairments.

α-Aminoboronates: recent advances in their preparation and synthetic applications.

α-Aminoboronic acids and their derivatives are useful as bioactive agents. Thus far, three compounds containing an α-aminoboronate motif have been approved by the Food and Drug Administration (FDA) as protease inhibitors, and more are currently undergoing clinical trials. In addition, α-aminoboronic acids and their derivatives have found applications in organic synthesis, e.g. as α-aminomethylation reagents for the synthesis of chiral nitrogen-containing molecules, as nucleophiles for preparing valuable vicinal amino alcohols, and as bis-nucleophiles in the construction of valuable small molecule scaffolds. This review summarizes new methodology for the preparation of α-aminoboronates, including highlights of asymmetric synthetic methods and mechanistic explanations of reactivity. Applications of α-aminoboronates as versatile synthetic building blocks are also discussed.

Acylboronates in Polarity-Reversed Generation of Acyl Palladium(II) Intermediates.

We report a catalytic cross-coupling process between aryl (pseudo)halides and boron-based acyl anion equivalents. This mode of acylboronate reactivity represents polarity reversal, which is supported by the observation of tetracoordinated boronate and acyl palladium(II) species by 11B, 31P NMR, and mass spectrometry. A broad scope of aliphatic and aromatic acylboronates has been examined, as well as a variety of aryl (pseudo)halides.

Interrupted reactions in chemical synthesis.

Interrupted reactions reroute established processes to new and often unanticipated end points. Of particular interest are the cases in which a known reactive intermediate takes on a new reaction pathway, either because this pathway is lower in energy or because the conventional pathway is no longer available. Through analysis of documented cases, we aim to dissect the known interrupted reactions and trace their mechanistic origins. As new chemical processes are being discovered at a seemingly ever-increasing pace, it is likely that new interrupted reactions will continue to emerge. Our hope is that the cases considered in this Review will help identify new classes of these fascinating transformations.

Carboxyboronate as a Versatile In Situ CO Surrogate in Palladium-Catalyzed Carbonylative Transformations.

The application of carboxy-MIDA-boronate (MIDA=N-methyliminodiacetic acid) as an in situ CO surrogate for various palladium-catalyzed transformations is described. Carboxy-MIDA-boronate was previously shown to be a bench-stable boron-containing building block for the synthesis of borylated heterocycles. The present study demonstrates that, in addition to its utility as a precursor to heterocycle synthesis, carboxy-MIDA-boronate is an excellent in situ CO surrogate that is tolerant of reactive functionalities such as amines, alcohols, and carbon-based nucleophiles. Its wide functional-group compatibility is highlighted in the palladium-catalyzed aminocarbonylation, alkoxycarbonylation, carbonylative Sonogashira coupling, and carbonylative Suzuki-Miyaura coupling of aryl halides. A variety of amides, esters, (hetero)aromatic ynones, and bis(hetero)aryl ketones were synthesized in good-to-excellent yields in a one-pot fashion.

Calcium-permeable AMPA receptors are essential to the synaptic plasticity induced by epileptiform activity in rat hippocampal slices.

Abnormal neuronal activity during epileptic seizures alters the properties of synaptic plasticity, and, consequently, leads to cognitive impairment. The molecular mechanism of these alterations in synaptic plasticity is still unclear. In the present study, using a 4-aminopyridine (4-AP) in vitro model, we demonstrated that epileptiform activity in rat hippocampal slices initially causes substantial enhancement of field excitatory postsynaptic potential amplitude. However, the potentiation of CA3-CA1 synapses was temporary and switched to long-term depression (LTD) within an hour. Previous studies showed that transient incorporation of calcium-permeable AMPA receptors (CP-AMPARs) is crucial for the consolidation of long-term potentiation (LTP). We confirmed that, in normal conditions, the blockage of CP-AMPARs prevented the consolidation of LTP induced by theta-burst stimulation (TBS). In contrast, the blockage of CP-AMPARs preserved synaptic potentiation induced by epileptiform activity. One hour after a period of epileptiform activity in the hippocampal slices, synaptic plasticity was substantially altered, and the TBS protocol was unable to produce LTP. Moreover, if CP-AMPARs were blocked, the TBS protocol induced LTD. Our results indicate that CP-AMPARs play an essential role in the molecular mechanism of the disturbances of synaptic plasticity caused by epileptiform activity.

The phosphinoboration of acyl chlorides.

This investigation examines the reactivity of phosphinoboronate esters Ph2PBpin (pin = 1,2-O2C2Me4) and Ph2PBcat (cat = 1,2-O2C6H4), as well as other phosphinoboron species, with various aryl and aliphatic acyl chlorides. These reactions proceed smoothly to give acyl phosphines of the type RC(O)PR'2 along with loss of a boron-chloride compound. In some cases, a second equivalent of the phosphinoboron species can add to the C[double bond, length as m-dash]O double bond at elevated temperatures to give the corresponding diphosphines RC(OBR''2)(PR'2)2. These ambiphilic diphosphines behave like substituted (1,1-bis(diphenylphosphino)methane) derivatives in a reaction of PhC(OBpin)(PPh2)2 (2a) with (η5-C9H7)Rh(η2-coe)2 (coe = cis-cyclooctene) affording the indenyl rhodium complex (η5-C9H7)Rh(PhC(OBpin)(PPh2)2) (3a) where the phosphines are bound to the metal centre in a κ2-P,P bidentate manner.

1,1-Phosphinoboration of diazomethanes.

The reactions of the phosphinoboranes Ph2PBMes2, Ph2PBpin, and Ph2PBcat with the diazomethanes Ph2CN2, C12H8CN2, and EtO2CCHN2 are shown to give products of 1,1-phosphinoboration. The products (1-6) are shown to have PNB linkages with three-coordinate boron centers, whereas the products (EtOOC)CNN(PR2)(Bpin) (R = Ph 7, tBu 8) form zwitterionic heterocycles resulting from chelation of the ester carbonyl to boron. DFT calculations show that the reactions are initiated by N-to-B addition followed by 1,2-phosphinyl shift.

Phosphinoboration of Diazobenzene: Intramolecular FLP Synthon for PN2 B-Derived Heterocycles.

Phosphinoboration of diazobenzene with Ph2 PBR'2 cleanly affords products of the form Ph2 P(PhNNPh)BR'2 (2: R'2 =catechol, cat; 4: R'2 =phenanthrenediol, quin) and shows evidence of Ph2 P(PhNNPh)Bpin 7 (pin: pinacol). The mechanism of these reactions was probed computationally and shown to proceed via intermediates involving a diazobenzene-adduct of the boron center of the PB reagent. The resulting PNNB species 2 and 4 are shown to be frustrated Lewis pairs (FLPs). Despite the presence of weakly Lewis acidic boron centers, these species react with diazobenzene. Additionally, the FLP reactivity of 2 was further probed with 4-phenyl-1,2,4-triazole-3,5-dione, 1,10-phenanthroline-5,6-dione, and benzyl azide to give unique five-, six-, and eight-membered heterocyclic rings. Thus, phosphinoboration provides a new avenue to FLPs in which donor and acceptor sites are linked by nitrogen atoms.

Double Phosphinoboration of CO2 : A Facile Route to Diphospha-Ureas.

The reactions of CO2 with a series of phosphinoboranes, including R2 PBpin (R=Ph, tBu; pin=pinacol), R2 PBMes2 (R=Ph, tBu; Mes=2,4,6-Me3 -C6 H2 ), and R2 PBcat (R=Ph, tBu, Mes; cat=catechol) are described. Although R2 PBpin and R2 PBMes2 afford products of the form R2 PCO2 Bpin (R=Ph 1, tBu 4) and R2 PCO2 BMes2 (R=Ph 2, tBu 3), respectively, R2 PBcat lead to further reaction affording the diphospha-ureas, (R2 P)2 CO (R=Ph 5, tBu 6, Mes 7), together with O(Bcat)2 . Computational studies provide insight into the mechanism, revealing an intermediate derived from double phosphinoboration of CO2 .

Transient Switching of NMDA-Dependent Long-Term Synaptic Potentiation in CA3-CA1 Hippocampal Synapses to mGluR1-Dependent Potentiation After Pentylenetetrazole-Induced Acute Seizures in Young Rats.

The mechanisms of impairment in long-term potentiation after status epilepticus (SE) remain unclear. We investigated the properties of LTP induced by theta-burst stimulation in hippocampal slices of rats 3 h and 1, 3, and 7 days after SE. Seizures were induced in 3-week old rats by a single injection of pentylenetetrazole (PTZ). Only animals with generalized seizures lasting more than 30 min were included in the experiments. The results revealed that LTP was strongly attenuated in the CA1 hippocampal area after PTZ-induced SE as compared with that in control animals. Saturation of synaptic responses following epileptic activity does not explain weakening of LTP because neither the quantal size of the excitatory responses nor the slopes of the input-output curves for field excitatory postsynaptic potentials changed in the post-SE rats. After PTZ-induced SE, NMDA-dependent LTP was suppressed, and LTP transiently switched to the mGluR1-dependent form. This finding does not appear to have been reported previously in the literature. An antagonist of NMDA receptors, D-2-amino-5-phosphonovalerate, did not block LTP induction in 3-h and 1-day post-SE slices. An antagonist of mGluR1, FTIDS, completely prevented LTP in 1-day post-SE slices; whereas it did not affect LTP induction in control and post-SE slices at the other studied times. mGluR1-dependent LTP was postsynaptically expressed and did not require NMDA receptor activation. Recovery of NMDA-dependent LTP occurred 7 day after SE. Transient switching between NMDA-dependent LTP and mGluR1-dependent LTP could play a role in the pathogenesis of acquired epilepsy.

Changes in Functional Properties of Rat Hippocampal Neurons Following Pentylenetetrazole-induced Status Epilepticus.

Pathophysiological remodeling processes following status epilepticus (SE) play a critical role in the pathophysiology of epilepsy but have not yet been not fully investigated. In the present study, we examined changes in intrinsic properties of pyramidal neurons, basal excitatory synaptic transmission, and short-term synaptic plasticity in hippocampal slices of rats after SE. Seizures were induced in 3-week-old rats by an intraperitoneal pentylenetetrazole (PTZ) injection. Only animals with generalized seizures lasting more than 30 min were included in the experiments. We found that CA1 pyramidal neurons became more excitable and started firing at a lower excitatory input due to a significant increase in input resistance. However, basal excitatory synaptic transmission was reduced in CA3-CA1 synapses, thus preventing the propagation of excitation through neural networks. A significant increase in paired-pulse facilitation 1 d after SE pointed to a decrease in the probability of glutamate release. Increased intrinsic excitability of neurons and decreased synaptic transmission differentially affected the excitability of a neural network. In terms of changes in seizure susceptibility after SE, we observed a significant increase in the maximal electroshock threshold 1 day after SE, suggesting a decrease in seizure susceptibility. However, after 1 week, there was no difference in seizure susceptibility between control and post-SE rats. The effects of SE on functional properties of hippocampal neurons were transient in the PTZ model, and most of them had recovered 1 week after SE. However, some minor alterations, such as smaller amplitude field potentials, were observed 1 month after SE.