Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase, which catalyzes the hydrolysis of the endocannabinoid N-arachidonoylethanolamide to arachidonic acid and ethanolamine. FAAH also hydrolyzes another endocannabinoid, 2-arachidonoylglycerol (2-AG). However, 2-AG has been assumed to be hydrolyzed mainly by monoacylglycerol lipase (MAGL) or a MAGL-like enzyme. Inhibition of FAAH or MAGL activity might lead to beneficial effects in many physiological disorders such as pain, inflammation, and anxiety due to increased endocannabinoid-induced activation of cannabinoid receptors CB1 and CB2. In the present study, a total of 34 novel compounds were designed, synthesized, characterized, and tested against FAAH and MAGL-like enzyme activity. Altogether, 16 compounds were found to inhibit FAAH with half-maximal inhibition concentrations (IC 50 ) between 28 and 380 nM. All the active compounds belong to the structural family of carbamates. Compounds 14 and 18 were found to be the most potent FAAH inhibitors, which may serve as lead structures for novel FAAH inhibitors.

Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) are the main enzymes responsible for the hydrolysis of endogenous cannabinoids N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively. Phenyl alkylcarbamates are FAAH inhibitors with anxiolytic and analgesic activities in vivo. Herein we present for the first time the synthesis and biological evaluation of a series of chiral 3-(2-oxazoline)-phenyl N-alkylcarbamates as FAAH inhibitors. Furthermore, the structural background of chirality on the FAAH inhibition is explored by analyzing the protein-ligand interactions. Remarkably, 10-fold difference in potency was observed for (R)-and (S)-derivatives of 3-(5-methyl-4,5-dihydrooxazol-2-yl)phenyl cyclohexylcarbamate (6a vs. 6b). Molecular modelling indicated an important interaction between the oxazoline nitrogen and FAAH active site.

Aldehydes may be dimerized to symmetric esters via the Tishchenko reaction. This process is traditionally catalyzed by aluminum alkoxides, but a wide variety of different metal catalysts has been explored and implemented, ranging from simple alkali metal compounds to actinoid complexes. The mechanistic key step is a hydride transfer from a hemiacetal intermediate to an aldehyde, both participants being coordinated to the metal catalyst in the transition state. Recent research on the Tishchenko reaction has especially focused on the controlled synthesis of unsymmetrical esters. In the aldol‐Tishchenko variant, an aldol reaction takes place first between two aldehydes, or a ketone and an aldehyde. In the subsequent Tishchenko step, another aldehyde molecule coordinates to the aldol product, forming a hemiacetal intermediate. An intramolecular hydrogen transfer from the hemiacetal to the carbonyl group takes place, giving a 1,3‐diol monoester product. With ‐hydroxy ketone substrates, the reaction is highly diastereoselective towards 1,3‐ anti ‐diols due to a highly organized six‐membered transition state promoted by coordination of a metal catalyst to both the hemiacetal and carbonyl groups. Thus, recent research has strongly focused on the development of direct catalytic asymmetric aldol‐Tishchenko reactions. The Evans‐Tishchenko reaction is a further variant of the aldol‐Tishchenko reaction, being used to reduce preformed ‐hydroxy ketones to anti ‐1,3‐diols under relatively mild conditions. This method is applied to various total syntheses of natural products. Samarium iodide is commonly used as the catalyst, and nearly any aldehyde is suitable as the reducing agent. The reaction has also been exploited in a reverse fashion to oxidize complex aldehydes to carboxylic acids using a simple sacrificial ‐hydroxy ketone as the oxidant. This review covers the literature from the discovery of the Tishchenko reaction in 1887 up to early 2014. Different catalyst systems for both Tishchenko and aldol‐Tishchenko reactions are discussed and compared in the “Scope and Limitations” section, and the state of the art in substrate complexity for the reaction is presented in the “Tabular Survey”.