C–H Bond Functionalization via Hydride Transfer: Formation of α-Arylated Piperidines and 1,2,3,4-Tetrahydroisoquinolines via Stereoselective Intramolecular Amination of Benzylic C–H Bonds

We here report a study of the intramolecular amination of sp³ C–H bonds via the hydride transfer cyclization of <i>N</i>-tosylimines (HT-amination). In this transformation, 5-aryl aldehydes are subjected to <i>N</i>-toluenesulfonamide in the presence of BF₃·OEt₂ to effect imine formation and HT-cyclization, leading to 2-arylpiperidines and 3-aryl-1,2,3,4-tetrahydroisoquinolines in a one-pot procedure. We examined the reactivity of a range of aldehyde substrates as a function of their conformational flexibility. Substrates of higher conformational rigidity were more reactive, giving higher yields of the desired products. However, a single substituent on the alkyl chain linking the <i>N</i>-tosylimine and the benzylic sp³ C–H bonds was sufficient for HT-cyclization to occur. In addition, an examination of various arenes revealed that the electronic character of the hydridic C–H bonds dramatically affects the efficiency of the reaction. We also found that this transformation is highly stereoselective; 2-substituted aldehydes yield <i>cis</i>-2,5-disubstituted piperidines, while 3-substituted aldehydes afford <i>trans</i>-2,4-disubstituted piperidines. The stereoselectivity is a consequence of thermodynamic control. The pseudoallylic strain between the arene and tosyl group on the piperidine ring is proposed to rationalize the greater stability of the isomer with the aryl ring in the axial position. This preferential placement of the arene is proposed to affect the observed stereoselectivity

C–H Bond Functionalization via Hydride Transfer: Formation of α-Arylated Piperidines and 1,2,3,4-Tetrahydroisoquinolines via Stereoselective Intramolecular Amination of Benzylic C–H Bonds

We here report a study of the intramolecular amination of sp³ C–H bonds via the hydride transfer cyclization of <i>N</i>-tosylimines (HT-amination). In this transformation, 5-aryl aldehydes are subjected to <i>N</i>-toluenesulfonamide in the presence of BF₃·OEt₂ to effect imine formation and HT-cyclization, leading to 2-arylpiperidines and 3-aryl-1,2,3,4-tetrahydroisoquinolines in a one-pot procedure. We examined the reactivity of a range of aldehyde substrates as a function of their conformational flexibility. Substrates of higher conformational rigidity were more reactive, giving higher yields of the desired products. However, a single substituent on the alkyl chain linking the <i>N</i>-tosylimine and the benzylic sp³ C–H bonds was sufficient for HT-cyclization to occur. In addition, an examination of various arenes revealed that the electronic character of the hydridic C–H bonds dramatically affects the efficiency of the reaction. We also found that this transformation is highly stereoselective; 2-substituted aldehydes yield <i>cis</i>-2,5-disubstituted piperidines, while 3-substituted aldehydes afford <i>trans</i>-2,4-disubstituted piperidines. The stereoselectivity is a consequence of thermodynamic control. The pseudoallylic strain between the arene and tosyl group on the piperidine ring is proposed to rationalize the greater stability of the isomer with the aryl ring in the axial position. This preferential placement of the arene is proposed to affect the observed stereoselectivity

C–H Bond Functionalization via Hydride Transfer: Formation of α-Arylated Piperidines and 1,2,3,4-Tetrahydroisoquinolines via Stereoselective Intramolecular Amination of Benzylic C–H Bonds

We here report a study of the intramolecular amination of sp³ C–H bonds via the hydride transfer cyclization of <i>N</i>-tosylimines (HT-amination). In this transformation, 5-aryl aldehydes are subjected to <i>N</i>-toluenesulfonamide in the presence of BF₃·OEt₂ to effect imine formation and HT-cyclization, leading to 2-arylpiperidines and 3-aryl-1,2,3,4-tetrahydroisoquinolines in a one-pot procedure. We examined the reactivity of a range of aldehyde substrates as a function of their conformational flexibility. Substrates of higher conformational rigidity were more reactive, giving higher yields of the desired products. However, a single substituent on the alkyl chain linking the <i>N</i>-tosylimine and the benzylic sp³ C–H bonds was sufficient for HT-cyclization to occur. In addition, an examination of various arenes revealed that the electronic character of the hydridic C–H bonds dramatically affects the efficiency of the reaction. We also found that this transformation is highly stereoselective; 2-substituted aldehydes yield <i>cis</i>-2,5-disubstituted piperidines, while 3-substituted aldehydes afford <i>trans</i>-2,4-disubstituted piperidines. The stereoselectivity is a consequence of thermodynamic control. The pseudoallylic strain between the arene and tosyl group on the piperidine ring is proposed to rationalize the greater stability of the isomer with the aryl ring in the axial position. This preferential placement of the arene is proposed to affect the observed stereoselectivity

C–H Bond Functionalization via Hydride Transfer: Formation of α-Arylated Piperidines and 1,2,3,4-Tetrahydroisoquinolines via Stereoselective Intramolecular Amination of Benzylic C–H Bonds

We here report a study of the intramolecular amination of sp³ C–H bonds via the hydride transfer cyclization of <i>N</i>-tosylimines (HT-amination). In this transformation, 5-aryl aldehydes are subjected to <i>N</i>-toluenesulfonamide in the presence of BF₃·OEt₂ to effect imine formation and HT-cyclization, leading to 2-arylpiperidines and 3-aryl-1,2,3,4-tetrahydroisoquinolines in a one-pot procedure. We examined the reactivity of a range of aldehyde substrates as a function of their conformational flexibility. Substrates of higher conformational rigidity were more reactive, giving higher yields of the desired products. However, a single substituent on the alkyl chain linking the <i>N</i>-tosylimine and the benzylic sp³ C–H bonds was sufficient for HT-cyclization to occur. In addition, an examination of various arenes revealed that the electronic character of the hydridic C–H bonds dramatically affects the efficiency of the reaction. We also found that this transformation is highly stereoselective; 2-substituted aldehydes yield <i>cis</i>-2,5-disubstituted piperidines, while 3-substituted aldehydes afford <i>trans</i>-2,4-disubstituted piperidines. The stereoselectivity is a consequence of thermodynamic control. The pseudoallylic strain between the arene and tosyl group on the piperidine ring is proposed to rationalize the greater stability of the isomer with the aryl ring in the axial position. This preferential placement of the arene is proposed to affect the observed stereoselectivity

C–H Bond Functionalization via Hydride Transfer: Formation of α-Arylated Piperidines and 1,2,3,4-Tetrahydroisoquinolines via Stereoselective Intramolecular Amination of Benzylic C–H Bonds

We here report a study of the intramolecular amination of sp³ C–H bonds via the hydride transfer cyclization of <i>N</i>-tosylimines (HT-amination). In this transformation, 5-aryl aldehydes are subjected to <i>N</i>-toluenesulfonamide in the presence of BF₃·OEt₂ to effect imine formation and HT-cyclization, leading to 2-arylpiperidines and 3-aryl-1,2,3,4-tetrahydroisoquinolines in a one-pot procedure. We examined the reactivity of a range of aldehyde substrates as a function of their conformational flexibility. Substrates of higher conformational rigidity were more reactive, giving higher yields of the desired products. However, a single substituent on the alkyl chain linking the <i>N</i>-tosylimine and the benzylic sp³ C–H bonds was sufficient for HT-cyclization to occur. In addition, an examination of various arenes revealed that the electronic character of the hydridic C–H bonds dramatically affects the efficiency of the reaction. We also found that this transformation is highly stereoselective; 2-substituted aldehydes yield <i>cis</i>-2,5-disubstituted piperidines, while 3-substituted aldehydes afford <i>trans</i>-2,4-disubstituted piperidines. The stereoselectivity is a consequence of thermodynamic control. The pseudoallylic strain between the arene and tosyl group on the piperidine ring is proposed to rationalize the greater stability of the isomer with the aryl ring in the axial position. This preferential placement of the arene is proposed to affect the observed stereoselectivity

Double [3,3]-Sigmatropic Rearrangement in the Enzymatic Dioxygenation of Benzyl Azide: Preparation of Novel Synthetically Valuable Azido-diols

Enzymatic dioxygenation of benzyl azide by toluene dioxygenase produces the expected enantiopure <i>cis</i>-cyclohexadienediol along with an exocyclic diene formed by a spontaneous sequence of two [3,3] sigmatropic shifts. This novel dienediol presents high synthetic potential for natural product synthesis. The sigmatropic rearrangements can be reversed by protection of the diol moiety. An optimized production protocol for either of these valuable diols is presented

A Zn(II) luminescent complex with a Schiff base ligand: solution, computational and solid state studies

<p>A new mononuclear complex of zinc(II), [Zn(HL)₂]∙2DMF (H₂L = (<i>E</i>)-<i>N′</i>-((<i>E</i>)-(hydroxyimino)butan-2-ylidene)salicyloylhydrazide, DMF = <i>N,N</i>-dimethylformamide), was prepared and characterized. Single-crystal X-ray crystallography revealed a six-coordinate zinc(II) surrounded by nitrogen of the oxime function and oxygen and distal nitrogens of the acylhydrazone group. This entity also exists in solution as demonstrated by ¹H-NMR and potentiometric titrations. The computational analysis showed that the molecular orbitals involved in the main electronic transitions of the complex species in solution are centered on the ligand with negligible contribution of the metal ion. The photophysical properties of the complex were evaluated in solution and in the solid state. Luminescence studies showed that the solid has a strong emission at 550 nm with a large Stokes shift with respect to absorption. The solid state fluorescence emission is ascribed to ligand-centered and/or ligand-to-ligand charge transfer transitions, following the DFT results in solution. A comparison with a previously reported mononuclear [Zn(HL)₂] allowed the investigation of the influence of DMF molecules in the structural packing and the luminescence properties.</p

Several Generations of Chemoenzymatic Synthesis of Oseltamivir (Tamiflu): Evolution of Strategy, Quest for a Process-Quality Synthesis, and Evaluation of Efficiency Metrics

Four generations of chemoenzymatic approaches to oseltamivir are presented. The first two generations relied on the use of cyclohexadiene-<i>cis</i>-diol derived enzymatically from bromobenzene. The third and fourth generation used the corresponding diol obtained from ethyl benzoate by fermentation with <i>E. coli</i> JM109­(pDTG601a). Oseltamivir was obtained from ethyl benzoate by intersecting intermediate <b>39</b> (third-generation synthesis) and intermediate <b>45</b> (fourth-generation synthesis). Both of these advanced approaches benefited from symmetry considerations and translocation of the acrylate double bond with concomitant elimination of the C-1 hydroxyl. The syntheses are evaluated for overall efficiency by the use of efficiency metrics and compared with other syntheses of oseltamivir (both academic and industrial)

Presentation_1_Ibogaine Acute Administration in Rats Promotes Wakefulness, Long-Lasting REM Sleep Suppression, and a Distinctive Motor Profile.pdf

<p>Ibogaine is a potent psychedelic alkaloid that has been the focus of intense research because of its intriguing anti-addictive properties. According to anecdotic reports, ibogaine has been originally classified as an oneirogenic psychedelic; i.e., induces a dream-like cognitive activity while awake. However, the effects of ibogaine administration on wakefulness (W) and sleep have not been thoroughly assessed. The main aim of our study was to characterize the acute effects of ibogaine administration on W and sleep. For this purpose, polysomnographic recordings on chronically prepared rats were performed in the light phase during 6 h. Animals were treated with ibogaine (20 and 40 mg/kg) or vehicle, immediately before the beginning of the recordings. Furthermore, in order to evaluate associated motor behaviors during the W period, a different group of animals was tested for 2 h after ibogaine treatment on an open field with video-tracking software. Compared to control, animals treated with ibogaine showed an increase in time spent in W. This effect was accompanied by a decrease in slow wave sleep (SWS) and rapid-eye movements (REM) sleep time. REM sleep latency was significantly increased in animals treated with the higher ibogaine dose. While the effects on W and SWS were observed during the first 2 h of recordings, the decrement in REM sleep time was observed throughout the recording time. Accordingly, ibogaine treatment with the lower dose promoted an increase on locomotion, while tremor and flat body posture were observed only with the higher dose in a time-dependent manner. In contrast, head shake response, a behavior which has been associated in rats with the 5HT_2A receptor activation by hallucinogens, was not modified. We conclude that ibogaine promotes a waking state that is accompanied by a robust and long-lasting REM sleep suppression. In addition, it produces a dose-dependent unusual motor profile along with other serotonin-related behaviors. Since ibogaine is metabolized to produce noribogaine, further experiments are needed to elucidate if the metabolite and/or the parent drug produced these effects.</p

DataSheet1_Functionalization of breast implants by cyclodextrin in-situ polymerization: a local drug delivery system for augmentation mammaplasty.PDF

Mammaplasty is a widely performed surgical procedure worldwide, utilized for breast reconstruction, in the context of breast cancer treatment, and aesthetic purposes. To enhance post-operative outcomes and reduce risks (hematoma with required evacuation, capsular contracture, implant-associated infection and others), the controlled release of medicaments can be achieved using drug delivery systems based on cyclodextrins (CDs). In this study, our objective was to functionalize commercially available silicone breast implants with smooth and textured surfaces through in-situ polymerization of two CDs: β-CD/citric acid and 2-hydroxypropyl-β-CD/citric acid. This functionalization serves as a local drug delivery system for the controlled release of therapeutic molecules that potentially can be a preventive treatment for post-operative complications in mammaplasty interventions. Initially, we evaluated the pre-treatment of sample surfaces with O2 plasma, followed by chitosan grafting. Subsequently, in-situ polymerization using both types of CDs was performed on implants. The results demonstrated that the proposed pre-treatment significantly increased the polymerization yield. The functionalized samples were characterized using microscopic and physicochemical techniques. To evaluate the efficacy of the proposed system for controlled drug delivery in augmentation mammaplasty, three different molecules were utilized: pirfenidone (PFD) for capsular contracture prevention, Rose Bengal (RB) as anticancer agent, and KR-12 peptide (KR-12) to prevent bacterial infection. The release kinetics of PFD, RB, and KR-12 were analyzed using the Korsmeyer-Peppas and monolithic solution mathematical models to identify the respective delivery mechanisms. The antibacterial effect of KR-12 was assessed against Staphylococcus epidermidis and Pseudomonas aeruginosa, revealing that the antibacterial rate of functionalized samples loaded with KR-12 was dependent on the diffusion coefficients. Finally, due to the immunomodulatory properties of KR-12 peptide on epithelial cells, this type of cells was employed to investigate the cytotoxicity of the functionalized samples. These assays confirmed the superior properties of functionalized samples compared to unprotected implants.</p