Shilei Zhang

Differential Roles of NR2A- and NR2B-Containing NMDA Receptors in Activity-Dependent Brain-Derived Neurotrophic Factor Gene Regulation and Limbic Epileptogenesis

Fleeting activation of NMDA receptors (NMDARs) induces long-term modification of synaptic connections and refinement of neuronal circuits, which may underlie learning and memory and contribute to pathogenesis of a diversity of neurological diseases, including epilepsy. Here, we found that NR2A and NR2B subunit-containing NMDARs were coupled to distinct intracellular signaling, resulting in differential BDNF expression and extracellular signal-regulated kinase 1/2 (ERK1/2) activation. Selective activation of NR2A-containing NMDARs increased BDNF gene expression. Activation of NR2B-containing NMDARs led to ERK1/2 phosphorylation. Furthermore, selectively blocking NR2A-containing NMDARs impaired epileptogenesis and the development of mossy fiber sprouting in the kindling and pilocarpine rat models of limbic epilepsy, whereas inhibiting NR2B-containing NMDARs had no effects in epileptogenesis and mossy fiber sprouting. Interestingly, blocking either NR2A- or NR2B-containing NMDARs decreased status epilepticus-induced neuronal cell death. The specific requirement of NR2A and its downstream signaling for epileptogenesis implicates attractive new targets for the development of drugs that prevent epilepsy in patients with brain injury.

Bifunctional Cinchona Alkaloid Thiourea Catalyzed Highly Efficient, Enantioselective Aza‐Henry Reaction of Cyclic Trifluoromethyl Ketimines: Synthesis of Anti‐HIV Drug DPC 083

The aza-Henry reaction is a powerful method for C C bond formation. Moreover, the versatile nitro group can be conveniently transformed into a variety of new functional groups, which are highly valuable in the preparation of related analogues in drug discovery. In recent years, significant efforts have been directed toward the development of catalytic asymmetric aza-Henry reactions. However, the electrophilic substrates have been largely confined to imines derived from aldehydes. The development of an efficient protocol for an enantioselective aza-Henry reaction of ketimines to generate a chiral quaternary center remains elusive because of the lower reactivity of ketimines and difficulties in enantiofacial discrimination. To our knowledge, to date, there has been only one report, by Feng and co-workers, of a chiral N,N’dioxide copper complex (20 mol %) catalyzed asymmetric aza-Henry reaction between acyclic ketimines and nitromethane; this reaction proceeded with good enantioselectivities (71–96 % ee) but generally in poor yields (21–70%). Dihydroquinazolinones, as an important class of heterocyclic compounds are characterized by their broad spectrum of intriguing biological properties, such as antiviral and antiobesity activities, and their use in the treatment of cardiovascular diseases and pain. Notably, among these compounds, drug candidates DPC 083 and DPC 961, bearing a chiral trifluoromethyl moiety, are potent HIV-1 nonnucleoside reverse transcriptase inhibitors (Scheme 1). It is believed that the trifluoromethyl motif plays a pivotal role in the bioactivity. Accordingly, efficient approaches to valuable chiral molecular architectures with sites for functional group diversification are of considerable synthetic and biological importance. Furthermore, catalytic enantioselective syntheses of DPC 083 and DPC 961 are needed. Given the important challenge of the construction of a functionalized quaternary stereogenic center in the dihydroquinazolinone scaffolds, significant efforts have been made but with limited success. The approaches reported to date mainly rely on chiral auxiliaries to control the stereoselectivity. An atom-economical catalytic enantioselective process is more attractive but, to our knowledge, such a method giving a useful level of enantioselectivity (> 90% ee) is an unmet synthetic issue. Herein, we report a novel highly efficient organocatalytic enantioselective aza-Henry reaction for the preparation of the enantioenriched trifluoromethyl dihydroquinazolinones. Notably, a highly efficient hydrogen-bond-mediated enantioselective addition of nitroalkanes to ketimines has been achieved for the first time under mild reaction conditions in high yields using as low as 1 mol% catalyst loading. Furthermore, we also observed that the trifluoromethyl group is critical for not only biological activity, but also for chemical reactivity. Finally, the highly enantioselective synthesis of DPC 083 has been achieved using the aza-Henry reaction as a key step. We envisioned that a catalytic enantioselective aza-Henry reaction could be realized by the reaction of 2(1H)-quinazolinones 1 with versatile nitroalkanes to generate chiral dihydroquinazolinones (Table 1). Accordingly, our investigation began with the model reaction between trifluoromethylquinazolin-2(1H)-one (1a ; 1.0 equiv) and nitromethane (2a ; 2.0 equiv) in the presence of quinine (4a ; 10 mol%) as the catalyst in CH2Cl2 at room temperature (Table 1, entry 1). [11]

Simple cyclohexanediamine-derived primary amine thiourea catalyzed highly enantioselective conjugate addition of nitroalkanes to enones.

A highly enantioselective conjugate addition of nitroalkanes to enones has been developed. The process is efficiently catalyzed by a simple chiral cyclohexanediamine-derived primary amine thiourea with a broad substrate scope.

A Simple Primary Amine Thiourea Catalyzed Highly Enantioselective Conjugate Addition of α,α-Disubstituted Aldehydes to Maleimides

Conjugate addition reactions are powerful and versatile processes for the formation of C C bonds in organic synthesis as a result of a wide variety of substances that can serve as electrophiles and nucleophiles and, consequently, a diverse array of products can be generated. Notably, in recent years, organocatalytic, enantioselective conjugate reactions have been subject to intensive investigations. The general observation is that enals, enones, and nitroolefins are often used as Michael acceptors. In sharp contrast, the use of maleimides 2, for C C bond formation remains elusive, despite the broad synthetic and biological utilities of chiral a-branched succinimides 3 (Scheme 1). To the best

An Organocatalytic Cascade Approach toward Polysubstituted Quinolines and Chiral 1,4‐Dihydroquinolines–Unanticipated Effect of N‐Protecting Groups

A matter of protection: The outcome of a divergent organocatalytic aza-Michael/aldol cascade process toward quinolines and 1,4-dihydroquinolines depends on the choice of the N-protecting group (see scheme; TEA = triethylamine, TMS = trimethylsilyl). Use of an electron-donating sulfonyl group results in an unanticipated aza-Michael/aldol/aromatization cascade to give polysubstituted quinolines (right). In contrast, chiral 1,4-dihydroquinolines are obtained with an electron-withdrawing sulfonyl group (left).

An organocatalytic approach to the construction of chiral oxazolidinone rings and application in the synthesis of antibiotic linezolid and its analogues.

An efficient, catalytic asymmetric approach to antibacterial agent linezolid has been developed. The route features organocatalytic, highly enantioselective aldol and Beckman rearrangement reactions. The strategy has also been successfully applied for the preparation of new alpha-substituted analogues with high enantio- and diastereoselectivity.

Total Synthesis of Polyene Natural Product Dihydroxerulin by Mild Organocatalyzed Dehydrogenation of Alcohols

Polyene synthesis: An efficient approach to the total synthesis of polyene natural product dihydroxrulin (1) is described. A novel, mild, direct organocatalytic IBX-mediated dehydrogenation process of simple alcohols to enals has been developed, which serves as a key step in the synthesis (see scheme).

Synthesis of benzoxazoles via an amine-catalyzed [4 + 1] annulation.

An unprecedented simple pyrrolidine catalyzed [4 + 1] annulation reaction of ynals with N-protected-2-aminophenols is reported. The utilization of the unique property and reactivity of the C≡C triple bond in ynals leads to two consecutive conjugate addition reactions at the same β-position with pyrrolidine via iminium activation. The powerful cascade process affords a new alternative approach to biologically and synthetically important benzoxazoles in high yields (83-95%).

An enantioselective synthesis of (+)-(S)-[n]-gingerols via the L-proline-catalyzed aldol reaction

An enantioselective approach to (+)-(S)-[n]-gingerols (1a-c) has been developed. The requisite stereogenic centers of target molecules are facilely constructed by the proline-catalyzed cross-aldol reaction from readily available achiral starting materials.

Facile Installation of 2‐Reverse Prenyl Functionality into Indoles by a Tandem N‐Alkylation–Aza‐Cope Rearrangement Reaction and Its Application in Synthesis

An unprecedented tandem N-alkylation-ionic aza-Cope (or Claisen) rearrangement-hydrolysis reaction of readily available indolyl bromides with enamines is described. Due to the complicated nature of the two processes, an operationally simple N-alkylation and subsequent microwave-irradiated ionic aza-Cope rearrangement-hydrolysis process has been uncovered. The tandem reaction serves as a powerful approach to the preparation of synthetically and biologically important, but challenging, 2-reverse quaternary-centered prenylated indoles with high efficiency. Notably, unusual nonaromatic 3-methylene-2,3-dihydro-1H-indole architectures, instead of aromatic indoles, are produced. Furthermore, the aza-Cope rearrangement reaction proceeds highly regioselectively to give the quaternary-centered reverse prenyl functionality, which often produces a mixture of two regioisomers by reported methods. The synthetic value of the resulting nonaromatic 3-methylene-2,3-dihydro-1H-indole architectures has been demonstrated as versatile building blocks in the efficient synthesis of structurally diverse 2-reverse prenylated indoles, such as indolines, indole-fused sultams and lactams, and the natural product bruceolline D.