N-acylethanolamine-hydrolyzing acid amidase (NAAA) is a lysosomal enzyme involved in biological deactivation of N-palmitoylethanolamide (PEA), which exerts anti-inflammatory and analgesic effects through the activation of nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR-α). To develop selective and potent NAAA inhibitors, we designed and synthesized a series of derivatives of 1-pentadecanyl-carbonyl pyrrolidine (compound 1), a general amidase inhibitor. Structure activity relationship (SAR) studies have identified a compound 16, 1-(2-Biphenyl-4-yl)ethyl-carbonyl pyrrolidine, which has shown the highest inhibition on NAAA activity (IC50 = 2.12±0.41 µM) and is characterized as a reversible and competitive NAAA inhibitor. Computational docking analysis and mutagenesis study revealed that compound 16 interacted with Asparagine 209 (Asn209) residue flanking the catalytic pocket of NAAA so as to block the substrate entrance. In vitro pharmacological studies demonstrated that compound 16 dose-dependently reduced mRNA expression levels of iNOS and IL-6, along with an increase of intracellular PEA levels, in mouse macrophages with lipopolysaccharides (LPS) induced inflammation. Our study discovered a novel NAAA inhibitor, compound 16, that could serve as a potential anti-inflammatory agent.

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Enantiopure vicinal amino alcohols and derivatives are essential structural motifs in natural products and pharmaceutically active molecules, and serve as main chiral sources in asymmetric synthesis. Currently known asymmetric catalytic protocols for this class of compounds are still rare and often suffer from limited scope of substrates, relatively low regio-or stereoselectivities, thus prompting the development of more effective methodologies. Herein we report a dual catalytic strategy for the convergent enantioselective synthesis of vicinal amino alcohols. The method features a radical-type Zimmerman-Traxler transition state formed from a rare earth metal with a nitrone and an aromatic ketyl radical in the presence of chiral N,N′-dioxide ligands. In addition to high level of enantio-and diastereoselectivities, our synthetic protocol affords advantages of simple operation, mild conditions, high-yielding, and a broad scope of substrates. Furthermore, this protocol has been successfully applied to the concise synthesis of pharmaceutically valuable compounds (e.g., ephedrine and selegiline).

Bis(cyclopentadienyl)titanium(III) chloride (Nugents reagent) [1] is an efficient single-electron reductant and has been used as a versatile tool in organic synthesis, [2,3] owing to the ease of handling, its functional-group compatibility, and a broad array of reactions that can be effected under relatively mild conditions. Today, [Cp 2 TiCl] is used as a catalyst for several types of radical reactions by employing a catalytic amount of [Cp 2 TiCl 2 ] as a catalyst precursor and a metal (such as Mn, Zn, Al, In, Mg, and Sm) [4] as a coreductant in the presence of TMSCl or protic acids. Among the [Cp 2 TiCl]-catalyzed radical reactions, reductive epoxide opening reaction, [5] first demonstrated by Nugent and Rajan-Babu, [1] then by Gansäuer et al., [5b,c] has been the subject of intensive studies and found applications in natural product synthesis. [6] In this reaction, a [Cp 2 TiCl]-initialized homolysis of CÀO bonds is involved. As an extension of this feature, Barrero and co-workers recently described a deoxygenation of alcohols usually mediated by a stoichiometric amount of [Cp 2 TiCl]. In addition, catalytic examples have also been reported. [7] In view of these precedents, the [Cp 2 TiCl]catalyzed dehydroxylative coupling reactions of alcohols and other hydroxy-containing compounds, such as sugars, hemiacetals, and hemiaminals seemed possible.It is known that umpolung of hemiaminals can provide radical carbon intermediates in a position to amino groups through dehydroxylation and one-electron reduction of the corresponding carbenium ions. [8] We have recently developed a SmI 2 -mediated dehydroxylative radical cross-coupling reaction of hemiaminals with activated alkenes [Scheme 1, Eq. (1)], [9] which was assumed to proceed through a SmI 2based single-electron reduction of N-acyliminium ions. This methodology provides a useful and efficient strategy for C À C bond formation at the carbon atoms in a position to amino groups, and can be employed for the synthesis of alkaloids and other pharmaceuticals. [10] Based on these considerations, it would be particularly interesting and valuable to develop transition-metal-catalyzed dehydroxylative radical coupling reactions of hemiaminals under mild conditions, which have not been reported so far. We envisioned that the singular ability of [Cp 2 TiCl] to cleave a CÀO bond might help us to achieve this goal.Herein we report titanocene-catalyzed dehydroxylative radical coupling reactions of hemiaminals with activated alkenes [Scheme 1, Eq. (2)]. This novel reaction was performed by using a [Cp 2 TiCl 2 ] (cat.)/Mg/TMSCl reduction system [11] in the presence of tert-butanol. An application of this radical methodology has been demonstrated by an efficient synthesis of (AE)-9,10-diepi-stemoamide.We began our study with the treatment of hemiaminal 1 [12] and methyl acrylate (2.0 equiv) with [Cp 2 TiCl 2 ] (0.025 equiv), Mg powder (2.0 equiv), and TMSCl (2.0 equiv); the desired cross-coupling product 2 a was obtained in 54 % yield (Table 1, entry 1). The influence of othe...

We report, for the first time, the synthesis of 8-aza-analogues of PGE2. The SmI2-mediated cross coupling reactions of γ-lactam-hemiaminal 9, lactam 2-pyridyl sulfide 17, and lactam 2-pyridyl sulfone 18 with activated alkenes/alkyne were first developed, giving the corresponding γ-lactams in 49-78%, 45-75%, and 75-90%, respectively. The reactions of lactam 2-pyridyl sulfide and 2-pyridyl sulfone proceeded with ≥12:1 trans-diastereoselectivities. This represents the first intermolecular coupling reaction of the γ-lactam N-α-alkyl radicals of types B, B1, and B2 with activated alkenes. Two radical-based mechanisms were suggested. The asymmetric synthesis of the 11-hydroxylated analogue of the highly selective EP4 receptor agonist PF-04475270 (30), the 11-hydroxylated analogue of ocular hypotensive CP-734432 (31), compounds 35 and 36 have been achieved on the basis of this method.

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A series of unsymmetrical thiosulfonates were successfully prepared from sulfonyl hydrazides and disulfides with the assistance of H2O2 (7.0 equiv.) in PEG-400 at 100 °C, releasing N2 and H2O as byproducts. EPR analysis proved the protocol proceeded through a free radical pathway and a plausible mechanism was proposed.

The imino-Nazarov cyclization of the polysubstituted pentan-1,4-diene-3-imines was realized. To this aim, a one-pot procedure involving reductive alkenyliminylation of α,β-unsaturated secondary amides with potassium organotrifluoroborates, followed by acid-catalyzed imino-Nazarov cyclization of the polysubstituted pentan-1,4-diene-3-imine intermediates, was studied systematically. This mild, operationally simple, flexible, and high-yielding protocol efficiently affords polysubstituted pentan-1,4-diene-3-imines, cyclopentenimines, and α-amino cyclopentenones, which are useful scaffolds in organic synthesis. The substituent effect at the C2 position of the polysubstituted pentan-1,4-diene-3-imines was studied by means of density-functional theory calculations. Results suggested that the electron-donating group facilitates the imino-Nazarov cyclization process.