Proline and its Derivatives as Organocatalysts for Multi‐ Component Reactions in Aqueous Media: Synergic Pathways to the Green Synthesis of Heterocycles

Abstract

Proline is a non‐toxic and inexpensive natural amino acid that is readily available in both enantiomeric forms and was one of the very first compounds to be studied as an organocatalyst. Proline can engage in several modes of organocatalysis, as it can behave both as a Brønsted acid or a Brønsted base, and it can also easily generate the iminium or enamine intermediates that are typical of covalent organocatalysis. In view of the importance of diminishing the generation of residues formed by volatile organic solvents, the development of synthetically useful reactions that can be performed in aqueous environments is of increasing significance. The synergic combination of the advantages of water as a reaction medium with the efficiency associated to reactions that are able to generate several bonds in one operation is particularly relevant from the point of view of sustainable chemistry. In this review we critically summarize the use of proline and proline derivatives as catalysts of multi‐component reactions performed in aqueous media and leading to synthetically and biologically relevant heterocycles, a very important class of compounds that constitutes over 60% of drugs and agrochemicals.

Enabling protein-hosted organocatalytic transformations

“…In fact, taking into account the aqueous reaction medium, physiological pH (near 7.4) and temperature (near 37 C), 20 many of the reported organocatalysts do not function under biocompatible conditions. 8,10,17,[21][22][23][24][25][26][27][28][29][30][31] These boundaries vastly narrow the number of organocatalytic reactions applicable and, in response, efforts have been made to overcome limitations related to biocompatibility. 17,32,33 The use of proteins to host organocatalysts To enhance the biocompatibility of organocatalysis, biomolecules including DNA, RNA and proteins can be used to host the reactions.…”

“…In fact, taking into account the aqueous reaction medium, physiological pH (near 7.4) and temperature (near 37 °C), 20 many of the reported organocatalysts do not function under biocompatible conditions. 8 , 10 , 17 , 21 – 31 These boundaries vastly narrow the number of organocatalytic reactions applicable and, in response, efforts have been made to overcome limitations related to biocompatibility. 17 , 32 , 33 …”

Synthesis and structural anomaly ofxyloketals‐uniquebenzoxacycles: A review

“…Over the last few decades, the search for natural products has aggrandized its range from land to marine in order to reveal new leads for drug candidates. Natural products are being used in the modern modes of organic synthesis as chiral ligands [ 1a–n ] and organo‐catalysts. [ 1o–q ] The impressively diverse structural skeleta that bountiful nature continues to spawn have never ceased to amaze an organic chemist who continues to draw inspiration from such diversity to bring these molecules within the purview of synthesis.…”

“…Natural products are being used in the modern modes of organic synthesis as chiral ligands [ 1a–n ] and organo‐catalysts. [ 1o–q ] The impressively diverse structural skeleta that bountiful nature continues to spawn have never ceased to amaze an organic chemist who continues to draw inspiration from such diversity to bring these molecules within the purview of synthesis. Such diversity has included complex heterocycles with labile and sensitive functionalization, usually from which the synthetic chemistry will stay away.…”

“…Such diversity has included complex heterocycles with labile and sensitive functionalization, usually from which the synthetic chemistry will stay away. Narrowing down to somewhat simpler benzoxacyclic systems, the aflatoxins [Figure 1 ( 1 )] [ 1(i)–(xxi) ] with a central linear benzofuranofuran system are a group of compounds possessing a labile internal ketal fragment, similarly, semiglabrin [Figure 1 ( 2 )] [ 2 ] also belongs to such family and shows anticoagulant and antimalarial activity. [ 2 ] The chemistry and the syntheses of these mycotoxins have attracted one of the most intensive pursuits in the synthesis to ensure the intact survival of the labile internal ketal system for more than four decades.…”