Organocatalysis using aldehydes: the development and improvement of catalytic hydroaminations, hydrations and hydrolyses

Abstract

Organocatalysis has emerged as a powerful approach to facilitate and accelerate various difficult reactions. This Feature article presents recent developments and improvements using aldehydes as catalysts in difficult Cope-type intermolecular hydroamination, hydration and hydrolysis reactions. Most reactions exploit temporary intramolecularity. In catalytic Cope-type hydroaminations of allylic amines, aldehydes act as tethering catalysts, and allow room temperature reactions and high enantio- or diastereoselectivities if chiral aldehydes or reagents are used. Mechanistic studies showed that simpler catalysts such as formaldehyde are more active due to an improved ability to form the temporary tether, which translated in an improved reaction scope. Gratifyingly, improved catalytic efficiency and broad reaction scope were also observed in the aldehyde-catalyzed hydration of α-amino nitriles. Since destabilized aldehydes often favor temporary intramolecularity, this led to a comparison of the catalytic activity of several carbohydrates, and to experiments relevant in the prebiotic "origin of life" chemistry context. Studies on catalytic hydrolysis reactions of organophosphorous reagents are also presented, in which o-phthalaldehyde performs electrophilic activation of phosphinic amides, and other substrates possessing the P([double bond, length as m-dash]O)NH motif. Overall, this Feature article shows that aldehydes can be efficient catalysts in a variety of reactions, and highlights the efficiency of destabilized aldehydes such as formaldehyde and simple carbohydrates in this context.

How Prebiotic Chemistry and Early Life Chose Phosphate

“…The well-known instability of RNA compared to that of DNA precisely lies in the presence of a hydroxyl group at the ribose 2′-position capable of provoking a cleavage of the internucleotidic linkage intramolecularly. This observation supports the importance of intramolecular processes before the advent of enzymes [16,17,18].…”

Enantioselective Carbonyl Catalysis Enabled by Chiral Aldehydes

“…Carbonyl compounds are typically used as reagents in organic synthesis.However, carbonyl compounds can also be used as catalysts by exploiting different activation modes during carbonyl catalysis. [2] Fori nstance,d uring general enamine catalysis,carbonyl 2 will be converted into enamine 3-B through an imine intermediate 3-A,whereby amine 1 acts as ac atalyst (Scheme 1). In contrast, carbonyl catalysis utilizes carbonyl 2 to activate primary amine 1 by forming imine 3-A.T his increases the acidity of the a-H of amine 1 and enables it to react via the formation of the a-amino carbanion 4-A.Upon reaction with an electrophile and hydrolysis of intermediate 4-B, a-functionalized amine product 4 is obtained.…”

Enantioselective Carbonyl Catalysis Enabled by Chiral Aldehydes

“…Carbonyl compounds are typically used as reagents in organic synthesis. However, carbonyl compounds can also be used as catalysts by exploiting different activation modes during carbonyl catalysis . For instance, during general enamine catalysis, carbonyl 2 will be converted into enamine 3‐B through an imine intermediate 3‐A , whereby amine 1 acts as a catalyst (Scheme ).…”