catalysts Review Organocatalysis: A Brief Overview on Its Evolution and Applications Vanessa da Gama Oliveira 1 , Mariana Filomena do Carmo Cardoso 2 and Luana da Silva Magalhães Forezi 2,* 1 Programa de Pós-Graduação em Ciências Aplicadas a Produtos para Saúde, Faculdade de Farmácia, Universidade Federal Fluminense, Niterói 24241-000, RJ, Brazil; [email protected] 2 Programa de Pós-Graduação em Química, Instituto de Química, Universidade Federal Fluminense, Niterói 24210-000, RJ, Brazil; [email protected] * Correspondence: [email protected]; Tel.: +55-21-2629-2345 Received: 20 October 2018; Accepted: 23 November 2018; Published: 3 December 2018 Abstract: The use of small organic molecules as catalysts has gained increasing importance recently. These substances, the so-called organocatalysts, present a lot of advantages, like being less toxic, less polluting, and more economically viable than the organometallic catalysts that dominate asymmetric synthesis. This work intends to briefly show some classic works and recent publications, explaining the advantages of organocatalysis and the different types of compounds used in this field, as well as their course of action. Keywords: organocatalysis; organocatalyst; green chemistry; chiral; asymmetric; proline 1. Introduction A catalyst is a substance that facilitates the course of a reaction without affecting its equilibrium position; it acts by decreasing the activation energy of the process, allowing it to happen under milder conditions [1]. Regarding their chemical composition, catalysts can be metallic, enzymatic, or organic, but for years this area has been dominated by metal catalysts. However, the use of metals or organometallic compounds present some related environmental concerns, mostly owing to their toxicity and the generation of polluting metal waste. In this context, organocatalysis is the use of small organic molecules to activate substrates, whether these substrates are electrophiles or nucleophiles [2,3]. This type of methodology has existed for a long time, and one of the earliest known organocatalyzed described reactions is the use of cinchona alkaloids for the HCN (hydrogen cyanide) addition to aldehydes, published in 1912 by Breding and Fiske. In this synthesis, they observed that enantioselectivity was observed if the reaction media underwent the addition of quinine (1) or quinidine (2) (Scheme1)[4,5]. In addition to the primary advantage of the use of catalysts, which is the reduction of the activation energy of the reaction, organocatalysis is also inserted in the context of green chemistry, since the execution of reactions using catalysis is considered as one of the main points of this expanding area of chemistry [1]. Catalysts 2018, 8, 605; doi:10.3390/catal8120605 www.mdpi.com/journal/catalysts Catalysts 2018, 8, 605 2 of 29 Catalysts 2018, 8, x FOR PEER REVIEW 2 of 29 Catalysts 2018, 8, x FOR PEER REVIEW 2 of 29 Scheme 1. 1 2 Scheme 1. CinchonaCinchonaCinchona alkaloids alkaloidsalkaloidsquinine quininequinine ( ((1)) or or quinidine quinidine ( (),2), used used by by Bredig Bredig and and Fiske Fiske in in the the addition addition of HCN to aldehydes [4,5]. of HCN to aldehydes [4,,5]. Organocatalysis can be greener than traditional catalysis because: Organocatalysis can be greener than traditional catalysis because: − -− TheThe use of catalysts is, itself, a green chemistry principle; − -− ItIt employs employs mild mild conditions, conditions, consequently saving energy; − -− ItIt uses, uses, in in general, general, oxygen-stable oxygen-stable reagents reagents and does not require anhydrous conditions,conditions, reducingreducing thethe cost cost of of the the synthesis synthesis [3]; [3]; − -− ItIt is compatible with several functional groups thatthat couldcould bebe sensitivesensitive toto otherother processes—thisprocesses—this reducesreduces the need for protection groups, loweringlowering thethe totaltotal numbernumber ofof reactionreaction steps;steps; − -− ItIt uses uses less less toxic toxic and and safer substances; − -− ItIt prevents prevents the formation of metallic waste and avoids traces ofof metalsmetals inin thethe products,products, whichwhich isis anan essential feature for applications in medicinal chemistry. 2.2. Amines as Organocatalysts OneOne of theof the main main purposes purposes of of organocatalysis organocatalysis is is the the execution execution of of stereoselectivestereoselective reactionsreactions [6]. [6]. L AA classicclassic exampleexample isis thethe useuse ofof LL-proline-proline ((66),), anan aminoacid,aminoacid, donatingdonating aa protonproton andand functioningfunctioning asas aa BrønstedBrønsted acid.acid. Being Being a secondary a secondary amine, amine, this aminoacid this aminoacid can form can enamines form withenamines carbonyl with compounds; carbonyl L bycompounds; having its by amine having group its amine inserted group into inserted a cyclic system,into a cyclicL-proline system, (6) hasL-proline rigidity (6) andhas canrigidity be used and incan sub-stoichiometric be used in sub-stoichiometric amounts to induce amountsamounts the toto formation induceinduce thethe of formationformation one enantiomer ofof oneone overenantiomerenantiomer the other overover in the carbonylthe otherother additioninin carbonylcarbonyl reactions. additionaddition reactions.reactions. L TheThe first first reported reported use use of Lof-proline L-proline (6 )(6 as) as a catalysta catalyst was was in in the the process process developed developed by by HajosHajos andand Parrish,Parrish, whichwhich waswas patentedpatented inin 19711971 andand publishedpublished inin 1974.1974. This synthesis involves the useuse ofof organocatalysisorganocatalysis toto obtainobtain aa chiralchiral alcoholalcohol ((88)) (Scheme(Scheme2 2))[ [1,7–9].1,7–9]. TheThe use of different different chiralchiral aminoacidsaminoacids waswas alsoalso extensivelyextensively studiedstudied byby Eder,Eder, Sauer,Sauer, andand WiechertWiechert forfor thethe synthesissynthesis ofof chiralchiral fusedfused bicyclesbicycles fromfrom prochiralprochiral centerscenters [[10].10]. Scheme 2. Hajos and Parrish synthesis of fused bicyclic compounds using L-proline as a catalyst. SchemeScheme 2. 2.HajosHajos and and Parrish Parrish synthesis synthesis of of fused fused bicyclic bicyclic compounds compounds using using L-prolineL-proline as as a acatalyst. catalyst. InIn thisthis reaction,reaction, prolineproline ((66)) initiallyinitially actsacts as a nucleophile, addi addingng to the terminal carbonyl carbonyl group. group. TheThe formed enamine enamine 1212 reactsreactsreacts withwith with oneone one ofof ofthethe the ringring ring carbonylscarbonyls carbonyls inin anan in aldolaldol an aldol condensationcondensation condensation reaction,reaction, reaction, withwith with100% 100% yield yield of the of cis the additionadditioncis addition productproduct product ((13). ( Thereafter,13). Thereafter, the catalyst the catalyst is regenerated, is regenerated, being being available available for fora new a new catalytic catalytic cycle cycle (Scheme (Scheme 3) [2,7–9].3)[2,7– 9]. Catalysts 2018, 8, x FOR PEER REVIEW 3 of 29 Catalysts 2018, 8, 605 3 of 29 Catalysts 2018, 8, x FOR PEER REVIEW 3 of 29 Catalysts 2018, 8, x FOR PEER REVIEW 3 of 29 Scheme 3. Adapted mechanism for the L-proline-catalyzed aldol condensation reaction [2]. SchemeScheme 3. 3. Adapted mechanism for the L-proline-catalyzed aldol condensation reaction [2]. Scheme 3.Adapted Adapted mechanism mechanism forfor thethe L-proline-catalyzed aldol aldol cond condensationensation reaction reaction [2]. [2 ]. Recently, Xu et al. showed that aminoacids are not the only molecules capable of inducing Recently,Recently, XuXu etet al. al. showed showed that thataminoacids aminoacids are not are the notonly themolecules only moleculescapable of capableinducing of chirality in organic reactions. Using a primary amine 17 as a chiral catalyst, the Hajos-Parrish-Eder- inducingchirality chiralityin organic in reactions. organic Using reactions. a primary Using amine a 17 primary as a chiral amine catalyst,17 asthe aHajos-Parrish-Eder- chiral catalyst, the Sauer-Wiechert reaction was made in a “one-pot” fashion with excellent enantiomeric excesses (ee) Hajos-Parrish-Eder-Sauer-WiechertSauer-Wiechert reaction was made in reaction a “one-pot was” fashion made with in a excellent “one-pot” enantiomeric fashion withexcesses excellent (ee) (Scheme 4) [11]. enantiomeric(Scheme 4) [11]. excesses (ee) (Scheme4)[11]. Scheme 4. A Hajos-Parrish-Eder-Sauer-Wiechert reaction catalyzed by amine 17. SchemeScheme 4. 4. A A Hajos-Parrish-Eder-Sauer-Wiechert Hajos-Parrish-Eder-Sauer-Wiechert reaction reactionreaction catalyzed catalyzedcatalyzed by byby amine amineamine 17 17.17 .. There are also reports of a proline-pyrrolidine-oxyimide organocatalyst (21) being used in the ThereThereThere areare are alsoalso also reportsreports reports ofof of a aa proline-pyrrolidine-oxyimide proline-pyrrolidine-oxyimideproline-pyrrolidine-oxyimide organocatalyst organocatalystorganocatalyst (21 (21) being)) beingbeing used usedused in inthein thethe asymmetric Michael addition of ketones (22) to nitroolefins (23) (Scheme 5). This catalyst allowed the asymmetricasymmetricasymmetric MichaelMichael Michael additionaddition addition ofof of ketones ketonesketones ((2222)) tototo nitroolefinsnitroolefinsnitroolefins ( (23(2323)) )(Scheme (Scheme(Scheme 5).5 5).). This This This catalyst catalyst catalyst allowed allowed allowed the the the