molecules Review Recent Advances in Dynamic Kinetic Resolution by Chiral Bifunctional (Thio)urea- and Squaramide-BasedReview Organocatalysts Recent Advances in Dynamic Kinetic Pan LiResolution1,2, Xinquan Hu 1by, Xiu-Qin Chiral Dong Bifunctional2,* and Xumu Zhang (Thio)urea-2,3,* and 1 CollegeSquaramide-Based of Chemical Engineering, Zhejiang Organocatalysts University of Technology, Hangzhou 310014, Zhejiang, China; [email protected] (P.L.); [email protected] (X.H.) 2 CollegePan Li 1,2 of, Xinquan Chemistry Hu and 1, Xiu-Qin Molecular Dong Sciences, 2,* and Wuhan XumuUniversity, Zhang 2,3,* Wuhan 430072, Hubei, China 3 Department of Chemistry, South University of Science and Technology of China, Shenzhen 518000, 1 College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, Zhejiang, China; Guangdong, China [email protected] (P.L.); [email protected] (X.H.) * Correspondence:2 College of Chemistry [email protected] and Molecular Sciences (X.-Q.D.);, Wuhan University, [email protected] Wuhan 430072, (X.Z.) Hubei, China 3 Academic Department Editor: Raquel of Chemistry, P. Herrera South University of Science and Technology of China, Shenzhen 518000, Guangdong, China Received: 29 August 2016; Accepted: 30 September 2016; Published: 14 October 2016 * Correspondence: [email protected] (X.-Q.D.); [email protected] (X.Z.) Abstract:AcademicThe Editor: organocatalysis-based Raquel P. Herrera dynamic kinetic resolution (DKR) process has proved to be a powerfulReceived: strategy 27 September for the 2016; construction Accepted: 30 ofSeptember chiral compounds. 2016; Published: In date this feature review, we summarized recent progress on the DKR process, which was promoted by chiral bifunctional (thio)urea and Abstract: The organocatalysis-based dynamic kinetic resolution (DKR) process has proved to be a squaramide catalysis via hydrogen-bonding interactions between substrates and catalysts. A wide powerful strategy for the construction of chiral compounds. In this feature review, we summarized range of asymmetric reactions involving DKR, such as asymmetric alcoholysis of azlactones, recent progress on the DKR process, which was promoted by chiral bifunctional (thio)urea and asymmetricsquaramide Michael–Michael catalysis via hydrogen-bonding cascade reaction, interact and enantioselectiveions between substrates selenocyclization, and catalysts. are A wide reviewed and demonstraterange of asymmetric the efficiency reactions of thisinvolving strategy. DKR, The such (thio)urea as asymmetric and squaramide alcoholysis catalysts of azlactones, with dual activationasymmetric would Michael–Michael be efficient for cascade more unmet reaction, challenges and enantioselective in dynamic selenocyclization, kinetic resolution. are reviewed and demonstrate the efficiency of this strategy. The (thio)urea and squaramide catalysts with dual Keywords:activationdynamic would be kinetic efficient resolution; for more unme (thio)urea;t challenges squaramide in dynamic kinetic resolution. Keywords: dynamic kinetic resolution; (thio)urea; squaramide 1. Introduction The1. Introduction synthesis of optically pure compounds is increasingly in demand in the pharmaceutical, fine chemicals,The synthesis and agriculture of optically industries pure compounds [1–8]. Resolutionis increasingly of in racemates demand in is the one pharmaceutical, of the most important fine industrialchemicals, approaches and agriculture to obtain industries enantiomerically [1–8]. Resolution pure compounds of racemates [is9, 10one]. Kineticof the most resolution important (KR) is a processindustrial in which approaches one of to the obtain enantiomers enantiomerically of a racemic pure compounds mixture is [9,10]. transformed Kinetic resolution to the corresponding (KR) is a productprocess faster in which than theone of other the enantiomers one (Scheme of 1a)[ race11mic–13 mixture]. If the is KRtransforme processd to is the efficient, corresponding one of the enantiomersproduct faster of the than racemic the other mixture one (Scheme is completely 1) [11–13 transformed]. If the KR toprocess the desired is efficient, product one of while the the otherenantiomers remains unchanged. of the racemic Therefore, mixture is the completely critical drawback transformed of KRto the process desired is product the maximum while the theoretical other yieldremains of 50%. unchanged. The dynamic Therefore, kinetic the resolution critical drawback (DKR) of process KR process isan is the attractive maximum strategy theoretical without yield this of 50%. The dynamic kinetic resolution (DKR) process is an attractive strategy without this limitation, limitation, which efficiently combines the process of KR and the racemization of the slowly reacting which efficiently combines the process of KR and the racemization of the slowly reacting enantiomer enantiomer in a one-pot system with 100% theoretical yield (Scheme1)[ 14–20]. This powerful strategy in a one-pot system with 100% theoretical yield (Scheme 1) [14–20]. This powerful strategy has been has beenwidely widely applied applied to a great to many a great asymmetric many asymmetric catalytic reactions catalytic for reactionsthe access of for chiral the accesscompounds of chiral compounds[21–29]. [21–29]. fast SR PR SR, SS = substrate enantiomers SR PR SR, SS = substrate enantiomers slow SS PS PR, PS = product enatiomers SS PS PR, PS = product enatiomers Kinetic resolution (KR) Dynamic kinetic resolution (DKR) Scheme 1. Kinetic resolution (KR) and dynamic kinetic resolution (DKR). Scheme 1. Kinetic resolution (KR) and dynamic kinetic resolution (DKR). Molecules 2016, 21, 1327; doi:10.3390/molecules21101327 www.mdpi.com/journal/molecules Molecules 2016, 21, 1327; doi:10.3390/molecules21101327 www.mdpi.com/journal/molecules Molecules 2016, 21, 1327 2 of 14 Molecules 2016, 21, 1327 2 of 14 Asymmetric organocatalysis has been made significant advances in the last decades [30–32], and numerousAsymmetric asymmetric organocatalysis transformations has been made were signif broadlyicant applied advances to in construct the last decades natural [30–32], products and [33 ] andnumerous industrial asymmetric products [transformati34]. Until now,ons were various broadly activation applied strategies to construct have natural been developed,products [33] such and as noncovalentindustrial products catalysis [34]. via Until hydrogen-bonding now, various activa [35],tion Brønsted strategies base have [36, 37been], Brønsteddeveloped, acid such [38 as,39 ], phasenoncovalent transfer [catalysis40], and via covalent hydrogen-bonding catalysis via [35], Lewis Brønsted base [41 base]. Metal [36,37], catalytic Brønsted DKR acid has [38,39], dominated phase in thistransfer research [40], field and during covalent the endcatalysis of the via last Lewis century base [42 [41].], and Metal organocatalytic catalytic DKR asymmetric has dominated reactions in this have reachedresearch maturity field during in recent the yearsend of with the impressivelast century progress[42], and [43organocatalytic–52]. Among asymmetric these chiral reactions organocatalysts, have reached maturity in recent years with impressive progress [43–52]. Among these chiral organocatalysts, chiral bifunctional (thio)ureas and squaramides catalysts have been intensively investigated to promote chiral bifunctional (thio)ureas and squaramides catalysts have been intensively investigated to asymmetric reactions via dual hydrogen-bonding interactions which worked along with a Lewis acid promote asymmetric reactions via dual hydrogen-bonding interactions which worked along with a functional group to achieve the activation of both the nucleophile and the electrophile [53]. Since the Lewis acid functional group to achieve the activation of both the nucleophile and the electrophile [53]. early research of primary amine–thiourea catalyzed the process of DKR in 2006 [54–56], DKR catalyzed Since the early research of primary amine–thiourea catalyzed the process of DKR in 2006 [54–56], DKR bycatalyzed (thio)urea by and (thio)urea squaramide and squaramide has achieved has achiev tremendoused tremendous advances advances [57–66]. [57–66]. The goal The of goal the of present the reviewpresent is toreview cover is the to recentcover the developments recent developmen concerningts concerning chiral (thio)ureas chiral (thio)ureas and squaramides and squaramides (Figure 1) catalytic(Figure reactions 1) catalytic through reactions DKR. through This review DKR. This is subdivided review is subdivided into two sections into two according sections according to the types to of organocatalyststhe types of organocatalysts employed in theseemployed asymmetric in these reactionsasymmetric involving reactions the involving process the of DKR.process of DKR. CF CF 3 N H H 3 N N CF S 3 X Ph H Ph MeO S N N CF3 N N CF3 H H H H NH CF N N 3 1:R=OMe 3:X=S 5 2:R=H 4:X=O O O CF3 tBu N N tBu S H H N N N N N H H N H CF3 Bn N N H O H H S O N N 6 8 N 7 CF3 OMe N OMe N O O H N H N H H OMe H H OMe F3C N N N N H N N H H H N N N N N 11 O O O O Bis-HQN-SQA (9) Bis-HQD-SQA (10) FigureFigure 1. 1.Selected Selected reported reported representativerepresentative (thio)urea and and squaramide squaramide catalysts. catalysts. 2. (Thio)urea Organocatalyst for DKR 2. (Thio)urea Organocatalyst for DKR 2.1. Thio-Michael–Michael Cascade Reaction 2.1. Thio-Michael–Michael Cascade Reaction Asymmetric (thio)urea catalyzed Michael–Michael cascade reactions are one of the most Asymmetric (thio)urea catalyzed Michael–Michael cascade