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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”.

The asymmetric Michael addition of Meldrum’s acid to nitroalkenes was studied using a novel type of Cinchona alkaloid-based bifunctional thiourea organocatalyst. The functionality of the thiourea catalysts was also probed by preparing and testing thiourea-N-methylated analogues of the well-known bis-(3,5-trifluoromethyl)phenyl-substituted catalyst.

Carbamates are a well-established class of fatty acid amide hydrolase (FAAH) inhibitors. Here we describe the synthesis of meta-substituted phenolic N-alkyl/aryl carbamates and their in vitro FAAH inhibitory activities. The most potent compound, 3-(oxazol-2yl)phenyl cyclohexylcarbamate (2 a), inhibited FAAH with a sub-nanomolar IC(50) value (IC(50)=0.74 nM). Additionally, we developed and validated three-dimensional quantitative structure-activity relationships (QSAR) models of FAAH inhibition combining the newly disclosed carbamates with our previously published inhibitors to give a total set of 99 compounds. Prior to 3D-QSAR modeling, the degree of correlation between FAAH inhibition and in silico reactivity was also established. Both 3D-QSAR methods used, CoMSIA and GRID/GOLPE, produced statistically significant models with coefficient of correlation for external prediction (R(2) (PRED)) values of 0.732 and 0.760, respectively. These models could be of high value in further FAAH inhibitor design.

A highly enantio- and diastereoselective synthesis of 3-aminocyclopenta[b]indoles has been developed through formal [3+2] cycloaddition reaction of enecarbamates and 3-indolylmethanols. This transformation is catalyzed by a chiral phosphoric acid that achieves simultaneous activation of both partners of the cycloaddition. Mechanistic data are also presented that suggest that the reaction occurs through a stepwise pathway.

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”.

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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.

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 (IC50) 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.