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Organocatalysis and Beyond catalysts Review OrganocatalysisReview and Beyond: Activating Reactions withOrganocatalysis Two Catalytic and Species Beyond: Activating Reactions with Two Catalytic Species Arianna Sinibaldi 1, Valeria Nori 1, Andrea Baschieri 1, Francesco Fini 2, Antonio Arcadi 1 and ArmandoArianna Sinibaldi Carlone 1,1*, Valeria Nori 1 , Andrea Baschieri 1 , Francesco Fini 2, Antonio Arcadi 1 1, and1 Department Armando of Carlone Physical *and Chemical Sciences, Università degli Studi dell’Aquila, via Vetoio, 1 67100Department L’Aquila, of Italy; Physical arianna.sinibaldi and [email protected] Sciences, Università (A.S.);degli [email protected] dell’Aquila, via Vetoio, (V.N.); [email protected] L’Aquila, Italy; [email protected] (A.B.); [email protected] (A.A.) (A.S.); [email protected] (V.N.); 2 [email protected] of Life Sciences, (A.B.);Università [email protected] degli Studi di Modena (A.A.) e Reggio Emilia, via G. Campi 103, 2 41125Department Modena, of Italy; Life Sciences,[email protected] Università degli Studi di Modena e Reggio Emilia, via G. Campi 103, * Correspondence:41125 Modena, Italy;armando.ca francesco.fi[email protected]@univaq.it; +39-0862-433-036 *Received:Correspondence: 18 October 2019; [email protected]; Accepted: 1 November Tel.:2019;+ Published:39-0862-433-036 date Abstract:Received: 18Since October the beginning 2019; Accepted: of the 1 November millennium, 2019; orga Published:nocatalysis 6 November has been 2019 gaining a predominant role in asymmetric synthesis and it is, nowadays, a foundation of catalysis. Synergistic catalysis, Abstract: Since the beginning of the millennium, organocatalysis has been gaining a predominant combining two or more different catalytic cycles acting in concert, exploits the vast knowledge role in asymmetric synthesis and it is, nowadays, a foundation of catalysis. Synergistic catalysis, acquired in organocatalysis and other fields to perform reactions that would be otherwise combining two or more different catalytic cycles acting in concert, exploits the vast knowledge impossible. Merging organocatalysis with photo-, metallo- and organocatalysis itself, researchers acquired in organocatalysis and other fields to perform reactions that would be otherwise impossible. have ingeniously devised a range of activations. This feature review, focusing on selected Merging organocatalysis with photo-, metallo- and organocatalysis itself, researchers have ingeniously synergistic catalytic approaches, aims to provide a flavor of the creativity and innovation in the area, devised a range of activations. This feature review, focusing on selected synergistic catalytic approaches, showing ground-breaking examples of organocatalysts, such as proline derivatives, hydrogen aims to provide a flavor of the creativity and innovation in the area, showing ground-breaking bond-mediated, Cinchona alkaloids or phosphoric acids catalysts, which work cooperatively with examples of organocatalysts, such as proline derivatives, hydrogen bond-mediated, Cinchona alkaloids different catalytic partners. or phosphoric acids catalysts, which work cooperatively with different catalytic partners. Keywords: organocatalysis; metallocatalysis; photocatalysis; synergistic; cooperative; asymmetric; Keywords: organocatalysis; metallocatalysis; photocatalysis; synergistic; cooperative; asymmetric; catalysis catalysis 1. Introduction 1. Introduction The origins of asymmetric organocatalysis date back to the intuitive experiment of two remarkable The origins of asymmetric organocatalysis date back to the intuitive experiment of two scientists, Bredig and Fiske, during the first decade of the 1900s. They reported the first enantioselective remarkable scientists, Bredig and Fiske, during the first decade of the 1900s. They reported the first addition reaction of HCN to benzaldehyde 1 mediated by Cinchona alkaloids as organocatalyst [1] enantioselective addition reaction of HCN to benzaldehyde 1 mediated by Cinchona alkaloids as (Scheme1). organocatalyst [1] (Scheme 1). Catalyst: H O OH N HCN H * CN HO H Ia 1 2 N Ia Scheme 1. AdditionAddition of of HCN HCN to to benzaldehyde benzaldehyde 1,1, performedperformed by Bredig and Fiske. In hindsight, the results obtained were a breakthrough as it was the first use of a small organic molecule as a catalyst. For several reasons, however, asymmetric organocatalysis was not born; Catalysts 2019, 9, x; doi: FOR PEER REVIEW www.mdpi.com/journal/catalysts Catalysts 2019, 9, 928; doi:10.3390/catal9110928 www.mdpi.com/journal/catalysts Catalysts 2019, 9, x FOR PEER REVIEW 2 of 36 Catalysts 2019, 9, 928 2 of 35 In hindsight, the results obtained were a breakthrough as it was the first use of a small organic molecule as a catalyst. For several reasons, however, asymmetric organocatalysis was not born; it was it was probably only at the beginning of the new millennium that the field was mature enough to probably only at the beginning of the new millennium that the field was mature enough to bloom. bloom. This is testified by the fact that two ground breaking pioneers in the field of organic chemistry, This is testified by the fact that two ground breaking pioneers in the field of organic chemistry, Benjamin List [2] (Scheme2a) and David MacMillan [ 3] (Scheme2b), simultaneously reported two Benjamin List [2] (Scheme 2a) and David MacMillan [3] (Scheme 2b), simultaneously reported two different, albeit complementary, activations with aminocatalysts, giving birth to a “Gold Rush” in different, albeit complementary, activations with aminocatalysts, giving birth to a “Gold Rush” in organocatalysis [4]. In particular, their studies highlighted the possibility of carrying out asymmetric organocatalysis [4]. In particular, their studies highlighted the possibility of carrying out asymmetric reactions with organocatalysts based on enamine or iminium ion or activation. reactions with organocatalysts based on enamine or iminium ion or activation. Scheme 2. (a) Ketone activation via aminocatalysis, performed by List; and (b) aldehyde activation via Scheme 2 (a) Ketone activation via aminocatalysis, performed by List; and (b) aldehyde activation via aminocatalysis, performed by MacMillan. aminocatalysis, performed by MacMillan. The main advantage of using organocatalysts derives from their user-friendliness: No anhydrous conditionsThe main are required; advantage they of are using highly organocatalysts stable in a broad derives range of temperaturesfrom their user-friendliness: and in most common No anhydrouschromatographic conditions and reactionare required; conditions; they are and highly moreover, stable their in a wastebroad disposal range of operation temperatures has aand lower in mostenvironmental common impactchromatographic respect to other and catalysts.reaction conditions; and moreover, their waste disposal operationInspired has bya lower this new environmental technology platform,impact respect several to scientists other catalysts. discovered a large variety of catalysts, whichInspired directly by came this from new the technology chiral pool platform, or undergo seve syntheticral scientists modifications discovered to generatea large analogousvariety of catalysts,compounds which positively directly impacting came from the the economy chiral po ofol the or entireundergo process, synthetic thanks modifications to the availability to generate and analogousaffordability compounds of the starting positively materials impacting [5]. the economy of the entire process, thanks to the availabilityAn incredible and affordability range of organocatalysts of the starting capable materials of promoting [5]. enantioselective reactions were found, enablingAn incredible transformations range of thanks organocatalysts to different activations,capable of promoting via iminium enantioselective ion or enamine reactions activation were [6], viafound, protonation enabling or transformations deprotonation (chiralthanks basic to diff [1] orerent acidic activations, catalysts [via7]), coordinationiminium ion viaor hydrogenenamine activationbond [8,9], [6], and via via protonation steric hindrance or deprotonation [6,10,11] (Figure (chi1ral). The basic combination [1] or acidic of catalysts the di fferent [7]), activationscoordination in viaone hydrogen catalyst to bond interact [8,9], with and di viafferent steric reaction hindrance partners [6,10,11] is noteworthy; (Figure 1).a The bifunctional, combination or multifunctional, of the different activationscatalyst is ain molecule one catalyst which to interact exhibits with more differ thanent one reaction functional partners group is noteworthy; capable of interacting a bifunctional, and ororientating multifunctional, with two catalyst different is a substrates molecule duringwhich aexhibits catalytic more process than [ 12one]. functional group capable of interacting and orientating with two different substrates during a catalytic process [12]. Catalysts 2019, 9, 928 3 of 35 Catalysts 2019, 9, x FOR PEER REVIEW 3 of 36 Figure 1. Different methods of substrate activation. Figure 1. Different methods of substrate activation. With the purpose of imitating the perfect performance of enzymes, chemists began to synthesize a With the purpose of imitating the perfect performance of enzymes, chemists began to synthesize few bifunctional catalysts able to bring together the different reaction partners. a few bifunctional catalysts able to bring together the
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