Recent Advances in Dynamic Kinetic Resolution by Chiral

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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 reactions are one of the most powerful strategies for the efficient construction of chiral complex molecules with multiple bonds’ powerful strategies for the efﬁcient construction of chiral complex molecules with multiple bonds’ formation and multistereogenic centers’ creation [67,68]. In 2007, Wang and his coworker explored formationthe novel and thio-Michael–aldol multistereogenic reaction, centers’ which creation empl [67oyed,68]. 2-mercaptobenzaldehydes In 2007, Wang and his coworker and maleimides explored theas novel template thio-Michael–aldol substrates and ligand reaction, 3 as catalyst. which employed With the standard 2-mercaptobenzaldehydes conditions, excellent yield and maleimidesand good asstereoselectivity template substrates was achieved and ligand (90%3 yield,as catalyst. 84% ee, With 10:1 thedr). standardFurther examination conditions, of excellentthe scope yieldproved and goodthat stereoselectivity this new methodology was achieved was a general (90% yield, approach 84% ee,to 10:1the preparation dr). Further of examination a range of substituted of the scope provedthiochromanes that this new (Scheme methodology 2) [67]. was a general approach to the preparation of a range of substituted thiochromanes (Scheme2)[67]. Molecules 2016, 21, 1327 3 of 14 Molecules 2016, 21, 1327 3 of 14 Molecules 2016, 21, 1327 3 of 14

Molecules 2016, 21, 1327 3 of 14

SchemeScheme 2. 2. AsymmetricAsymmetric thio-Michael–aldol cascade cascade reaction reaction of 2-mercaptobenzaldehydes of 2-mercaptobenzaldehydes with with maleimides catalyzed by 3. maleimidesScheme 2. catalyzed Asymmetric by 3 thio-Michael–aldol. cascade reaction of 2-mercaptobenzaldehydes with maleimides catalyzed by 3. InScheme 2008, 2.Wang Asymmetric and coworkers thio-Michael–aldol developed cascade a highly reaction stereoselective of 2-mercaptobenzaldehydes thio-Michael-Michael with cascade In 2008,maleimides Wang catalyzed and coworkers by 3. developed a highly stereoselective thio-Michael-Michael cascade reactionIn 2008, of trans Wang-3-(2-mercaptophenyl)-2-prope and coworkers developed noica highly acid ethylstereoselective ester and thio-Michael-Michaeltrans-β-nitrostyrene catalyzed cascade trans trans β reactionreactionby a cinchona of of trans-3-(2-mercaptophenyl)-2-propenoic alkaloid-derived-3-(2-mercaptophenyl)-2-prope thiourea (1), whichnoic acid afforded ethyl ester esterchiral and and thiochromanes trans-β--nitrostyrene-nitrostyrene with three catalyzed catalyzed new In 2008, Wang and coworkers developed a highly stereoselective thio-Michael-Michael cascade bybystereogenic a cinchonaa cinchona centers alkaloid-derived alkaloid-derived through one-pot thioureathiourea access ((11 in),), whichexcellen afforded affordedt efficiency chiral chiral and thiochromanes stereoselectivity thiochromanes with (Scheme with three three 3,new up new reaction of trans-3-(2-mercaptophenyl)-2-propenoic acid ethyl ester and trans-β-nitrostyrene catalyzed stereogenicstereogenicto dr > 30:1, centers centers 99% throughee, through 99% one-potyield) one-pot [68]. access access The in generalityin excellent excellen oft efﬁciency efficiency this cascade and and stereoselectivity reactionstereoselectivity was very (Scheme(Scheme wide, and3 3,, upup a to by a cinchona alkaloid-derived thiourea (1), which afforded chiral thiochromanes with three new drtoseries > 30:1,dr >of 99%30:1, nitroalkenes ee,99% 99% ee, yield) 99%can proceedyield) [68]. The[68]. well. generality The In addition,generality of this this of cascade thiscascade cascade reaction reaction reaction was involved very waswide, verythe DKR wide, and process, a and series a of stereogenic centers through one-pot access in excellent efficiency and stereoselectivity (Scheme 3, up nitroalkenesserieswhich of has nitroalkenes canmade proceed great can contributions well. proceed In addition, well. to this In thisaddition, transformation. cascade this reaction cascade involvedreaction involved the DKR the process, DKR process, which has to dr > 30:1, 99% ee, 99% yield) [68]. The generality of this cascade reaction was very wide, and a madewhich great has contributions made great contributions to this transformation. to this transformation. series of nitroalkenes can proceed well. In addition, this cascade reaction involved the DKR process, which has made great contributions to this transformation.

Scheme 3. Asymmetric thio-Michael–Michel cascade reaction of trans-3-(2-mercapto-aryl)-2-propenoic Schemeacid ethyl 3. estersAsymmetric with nitroolefins thio-Michael–Michel catalyzed bycascade 1. reaction of trans-3-(2-mercapto-aryl)-2-propenoic Scheme 3. Asymmetric thio-Michael–Michel cascade reaction of trans-3-(2-mercapto-aryl)-2-propenoic acid ethyl esters with nitroolefins catalyzed by 1. acidTheScheme ethyl initially esters3. Asymmetric formed with nitroolefins Michael thio-Michael–Michel additi catalyzedon product, by cascade1. through reaction reversible of trans-3-(2-mercapto-aryl)-2-propenoic thia-Michael addition step 1 with acid ethyl esters with nitroolefins catalyzed by 1. strongThe acidity, initially went formed through Michael deprot additionationon product, in the throughpresence reversible of bifunc thia-Michaeltional cinchona addition alkaloid-derived step 1 with thioureaThe initially 1, and formedthen underwent Michaeladdition a DKR process, product, which through is mediated reversible by thia-Michael the chiral bifunctional addition step amine 1 with strongThe acidity, initially went formed through Michael deprot additionationon product, in the throughpresence reversible of bifunc thia-Michaeltional cinchona addition alkaloid-derived step 1 with strongthiourea acidity 1 and, went followed through with deprotonation retro-Michael–Michael–Michae in the presence ofl process, bifunctional providing cinchona chiral alkaloid-derived thiochromane thioureastrong acidity, 1, and wentthen throughunderwent deprot a DKRonation process, in the which presence is mediated of bifunc bytional the cinchonachiral bifunctional alkaloid-derived amine product (Scheme 4). Moreover, this hypothesis was confirmed by the treatment of racemic first Michael thioureathioureathiourea1, 1 and1 ,and and then followed then underwent underwent with retro-Michael–Michael–Michae a a DKR DKR process, process, whichwhich is mediated l process, by by providing the the chiral chiral chiral bifunctional bifunctional thiochromane amine amine adduct with catalyst 1 under the standard reaction conditions, affording similar reaction results. thioureaproductthiourea1 (Schemeand 1 and followed followed 4). Moreover, with with retro-Michael–Michael–Michael retro-Michael–Michael–Michae this hypothesis was confirmedl byprocess, process, the treatment providing providing of racemicchiral chiral thiochromane first thiochromane Michael productadductproduct (Scheme with (Scheme catalyst4). 4). Moreover, Moreover, 1 under thisthe this standard hypothesis hypothesis reaction waswas confirmedco conditionsnfirmed by , affording the treatment treatment similar of of racemicreaction racemic first results. first Michael Michael adductadduct with with catalyst catalyst1 under1 under the the standard standardreaction reaction conditions,conditions, affording affording similar similar reaction reaction results. results.

Scheme 4. Proposed pathway for asymmetric thio-Michael–Michael cascade reaction. Scheme 4. Proposed pathway for asymmetric thio-Michael–Michael cascade reaction. In 2011, Wang and coworkers established another asymmetric thio-Michael–Michael cascade SchemeScheme 4. 4.Proposed Proposed pathway pathway forfor asymmetricasymmetric thio-Michael–Michael cascade cascade reaction. reaction. reactionIn 2011,of trans Wang-ethyl and 4-mercapto-2-butenoate coworkers established andanothe transr asymmetric-β-nitrostyrene thio-Michael–Michael catalyzed by Takemoto cascade′s reactionbifunctionalIn 2011,of amine–thioureatrans Wang-ethyl and 4-mercapto-2-butenoate coworkers catalyst (3 ),established and the functionalized andanothe transr asymmetric-β-nitrostyrene chiral trisubstituted thio-Michael–Michael catalyzed tetrahydrothiophene by Takemoto cascade′s bifunctionalproductsreactionIn 2011, bearingof amine–thioureatrans Wang three-ethyl andstereogenic 4-mercapto-2-butenoate catalyst coworkers centers (3), and established through the functionalized and sequential trans another-β-nitrostyrene chiralC–S asymmetricand trisubstituted C–C catalyzedbond thio-Michael–Michael tetrahydrothiopheneformation by Takemoto with high′s cascadeproductsenantio-bifunctional reaction andbearing amine–thiourea diastereoselectivity ofthreetrans stereogenic-ethyl catalyst (Scheme 4-mercapto-2-butenoate centers (3), and 5,through the up functionalizedto >30:1sequential dr, 97% andchiralC–S ee, andtrans trisubstituted93% C–C- βyield)-nitrostyrene bond [69]. tetrahydrothiopheneformation Various catalyzed with aromatic high by Takemoto’senantio-nitroolefinsproducts and bearing bifunctional performed diastereoselectivity three stereogenicsmoothly amine–thiourea (Scheme in centers this transformation. 5,through catalyst up to >30:1 sequential (3), dr, and The 97% theC–S heteroaromatic ee, functionalizedand 93% C–C yield) bond and[69]. formation chiral less Various reactive trisubstituted with aromatic highalkyl tetrahydrothiophenenitroolefinstransenantio--β-nitroolefins and performed diastereoselectivity productswere smoothly also bearing well (Scheme in thistolerated. three transformation. 5, stereogenicup Into >30:1addition, centersdr, The 97% an heteroaromatic throughee,unprecedented 93% yield) sequential and[69]. activation lessVarious C–S reactive and aromaticmode C–C alkyl bondof formationtranscooperativenitroolefins-β-nitroolefins with directperformed high stereocontrol enantio- were smoothly also and well diastereoselectivityand in thissimilartolerated. transformation. DKR In processaddition, (Scheme The was an 5heteroaromatic ,identified. upunprecedented to >30:1 dr, and 97% activation less ee, reactive 93% mode yield) alkyl of [ 69 ]. Variouscooperativetrans- aromaticβ-nitroolefins direct nitroolefins stereocontrol were also performed well and similartolerated. smoothly DKR In process inaddition, this transformation. was an identified. unprecedented The heteroaromatic activation mode and of less reactivecooperative alkyl trans direct-β stereocontrol-nitroolefins and were similar also wellDKR tolerated. process was In identified. addition, an unprecedented activation mode of cooperative direct stereocontrol and similar DKR process was identified. Molecules 2016, 21, 1327 4 of 14 Molecules 2016, 21, 1327 4 of 14

Molecules 2016, 21, 1327 4 of 14

Scheme 5. Asymmetric thio-Michael–Michael cascade reaction of trans-ethyl 4-mercapto-2-butenoate SchemeMolecules 5. Asymmetric2016, 21, 1327 thio-Michael–Michael cascade reaction of trans-ethyl 4-mercapto-2-butenoate4 of 14 with nitroolefins catalyzed by amine–thiourea 3. with nitroolefins catalyzed by amine–thiourea 3. Scheme 5. Asymmetric thio-Michael–Michael cascade reaction of trans-ethyl 4-mercapto-2-butenoate In 2013, Lattanzi and coworkers successfully disclosed an efficient cascade double Michael with nitroolefins catalyzed by amine–thiourea 3. In 2013,reaction Lattanzi of trans-α and-cyano- coworkersα,β-unsaturated successfully ketone with disclosedtrans-4-mercapto-2-butenoate an efficient cascade to construct double chiral Michael trisubstitutedScheme 5. tetrahydrothiophenes Asymmetric thio-Michael–Michael catalyzed by cascade amino reaction thiourea of 5trans with-ethyl excellent 4-mercapto-2-butenoate results (Scheme 6, up reaction of transIn 2013,-α-cyano- Lattanziα,β and-unsaturated coworkers successfully ketone with ditranssclosed-4-mercapto-2-butenoate an efficient cascade double to Michael construct chiral to 12:1with dr, nitroolefins >99% ee, 98% cataly yield)zed by [70]. amine–thiourea The tetrahydro 3. thiophene products contained three stereocenters, trisubstitutedreaction tetrahydrothiophenes of trans-α-cyano-α,β-unsaturated catalyzed ketone by with amino trans-4-mercapto-2-butenoate thiourea 5 with excellent to construct results chiral (Scheme 6, andtrisubstituted one challenging tetrahydrothiophenes all-carbon quaternary catalyzed stereocenter by amino thiourea was successfully 5 with excellent created. results (Scheme 6, up SchemeIn 2013, 5. LattanziAsymmetric and thio-Michael–Michael coworkers successfully cascade di reactionsclosed of an trans efficient-ethyl 4-mercapto-2-butenoate cascade double Michael up to 12:1to dr, 12:1 >99% dr, >99% ee, ee, 98% 98% yield) yield) [70 [70].]. TheThe tetrahydro tetrahydrothiophenethiophene products products contained contained three stereocenters, three stereocenters, reactionwith of nitroolefins trans-α-cyano- catalyαzed,β-unsaturated by amine–thiourea ketone 3. with trans-4-mercapto-2-butenoate to construct chiral and oneand challenging one challenging all-carbon all-carbon quaternary quaternary stereocenter stereocenter was was successfully successfully created. created. trisubstituted tetrahydrothiophenes catalyzed by amino thiourea 5 with excellent results (Scheme 6, up to 12:1In dr,2013, >99% Lattanzi ee, 98% and yield) coworkers [70]. The successfullytetrahydrothiophene disclosed products an efficient contained cascade three double stereocenters, Michael reactionand one ofchallenging trans-α-cyano- all-carbonα,β-unsaturated quaternary ketone stereocenter with trans was-4-mercapto-2-butenoate successfully created. to construct chiral trisubstituted tetrahydrothiophenes catalyzed by amino thiourea 5 with excellent results (Scheme 6, up to 12:1 dr, >99% ee, 98% yield) [70]. The tetrahydrothiophene products contained three stereocenters, and oneScheme challenging 6. Asymmetric all-carbon thio-Michael–Michael quaternary stereocenter cascade wasreaction successfully of trans- αcreated.-cyano-α ,β-unsaturated ketones with trans-4-mercapto-2-butenoates catalyzed by amino thiourea 5. Scheme 6. Asymmetric thio-Michael–Michael cascade reaction of trans-α-cyano-α,β-unsaturated SchemeIn 6. addition,Asymmetric the control thio-Michael–Michael experiment confirmed cascade that reaction the DKR of processtrans-α -cyano-was involvedα,β-unsaturated in this ketones with trans-4-mercapto-2-butenoates catalyzed by amino thiourea 5. ketonesasymmetric with trans cascade-4-mercapto-2-butenoates reaction (Scheme 7). catalyzedThe racemic by aminomixture thiourea of diastereoisomers5. of the first sulfa-MichaelInScheme addition, 6. product Asymmetric the controlwas treatedthio-Michael–Michael experiment under the confirmed optimized cascade that reaction reaction the DKRconditions of trans process-α-cyano- in the was αpresence, βinvolved-unsaturated of catalystin this 5, andketones the result with wastrans -4-mercapto-2-butenoatesthe same with the trans ca-αtalyzed-cyano- byα, βamino-unsaturated thiourea 5ketone. reacting with trans-4- In addition,asymmetric thecascade control reaction experiment (Scheme 7). confirmedThe racemic mixture that the of DKRdiastereoisomers process of was the involvedfirst in mercapto-2-butenoatesulfa-Michael product wasdirectly. treated under the optimized reaction conditions in the presence of catalyst this asymmetricSchemeIn addition, cascade 6. Asymmetric the reactioncontrol thio-Michael–Michael experiment (Scheme confirmed7). Thecascade racemicthat reaction the DKR mixtureof trans process-α-cyano- of was diastereoisomersα, βinvolved-unsaturated in this of the 5, and the result was the same with the trans-α-cyano-α,β-unsaturated ketone reacting with trans-4- asymmetricketones withcascade trans -4-mercapto-2-butenoatesreaction (Scheme 7). Thecatalyzed racemic by amino mixture thiourea of diastereoisomers5. of the first first sulfa-Michaelmercapto-2-butenoate product directly. was treated under the optimized reaction conditions in the presence sulfa-Michael product was treated under the optimized reaction conditions in the presence of catalyst of catalyst 5,In and addition, the result the wascontrol the experiment same with confirmed the trans that-α-cyano- the DKRα, βprocess-unsaturated was involved ketone in reacting this with 5, and the result was the same with the trans-α-cyano-α,β-unsaturated ketone reacting with trans-4- trans-4-mercapto-2-butenoateasymmetricmercapto-2-butenoate cascade reaction directly. directly. (Scheme 7). The racemic mixture of diastereoisomers of the first sulfa-Michael product wasScheme treated 7. underThe cascade the optimized pathway involving reaction DKRconditions process. in the presence of catalyst 5, and the result was the same with the trans-α-cyano-α,β-unsaturated ketone reacting with trans-4- 2.2. Asymmetric Ring Opening of Azlactones mercapto-2-butenoate directly.Scheme 7. The cascade pathway involving DKR process. Chiral α-amino acids have been widely used for the construction of pharmaceuticals, nature products,2.2. Asymmetric ligands, Ring and Opening organocatalysts of Azlactones [71–74]. The alcoholytic dynamic kinetic resolution of Scheme 7. The cascade pathway involving DKR process. azlactonesChiral hasα-amino beenScheme regardedacids have 7. asThe beenan cascadeattractive widely pathway usedand importantfor involvingthe construction way DKR to generate process.of pharmaceuticals, the enantiomerically nature

enrichedproducts,2.2. Asymmetric α -aminoligands, Ring acid and Opening derivatives organocatalysts of Azlactones (Scheme [71–74]. 8). The azlactThe onesalcoholytic are readily dynamic prepared kinetic by the resolution Erlenmeyer of azlactoneazlactones synthesis has been or regarded fromScheme amino as 7. an The acids attractive cascade by N-acylation pathway and important involving followed way DKR by to process. cyclization–dehydrationgenerate the enantiomerically in the 2.2. AsymmetricChiral Ring α-amino Opening acids of have Azlactones been widely used for the construction of pharmaceuticals, nature presenceenriched αof-amino condensation acid derivatives reagent [75]. (Scheme 8). The azlactones are readily prepared by the Erlenmeyer products, ligands, and organocatalysts [71–74]. The alcoholytic dynamic kinetic resolution of Chiral2.2.azlactone Asymmetricα-amino synthesis Ring acids or Opening from have amino of Azlactones been acids widely by N-acylation used followed for the by constructioncyclization–dehydration of pharmaceuticals, in the azlactones has been regarded as an attractive and important way to generate the enantiomerically presence of condensation reagent [75]. nature products,enrichedChiral α ligands,-amino α-amino acid andacids derivatives organocatalysts have been (Scheme widely 8). [usedThe71– azlact74 for]. th Theonese construction alcoholyticare readily preparedof dynamicpharmaceuticals, by the kinetic Erlenmeyer nature resolution of azlactonesproducts, has been ligands, regarded and organocatalysts as an attractive [71–74]. and The important alcoholytic way dynamic to generate kinetic theresolution enantiomerically of azlactone synthesis or from amino acids by N-acylation followed by cyclization–dehydration in the enrichedazlactonespresenceα-amino of has acidcondensation been derivatives regarded reagent as (Scheme an[75]. attractive 8). The and azlactones important way are to readily generate prepared the enantiomerically by the Erlenmeyer enriched α-amino acid derivatives (Scheme 8). The azlactones are readily prepared by the Erlenmeyer azlactone synthesis or from amino acids by N-acylation followed by cyclization–dehydration in the azlactone synthesis or from amino acids by N-acylation followed by cyclization–dehydration in the presencepresence of condensation of condensation reagent reagent [75 [75].].

Scheme 8. Basis of the DKR of azlactones.

Scheme 8. Basis of the DKR of azlactones. Scheme 8. Basis of the DKR of azlactones. Molecules 2016, 21, 1327 5 of 14

Molecules 2016, 21, 1327 5 of 14 In 2005, Berkessel successfully developed asymmetric ring opening of azlactones with alcohol via the DKRIn process2005, Berkessel catalyzed successfully by bifunctional developed amine asymmetric urea catalyst ring opening4 (Scheme of azlactones9)[ 76], with which alcohol demonstrated via theMoleculesthe effective DKR 2016 process, hydrogen-bonding 21, 1327 catalyzed by bifunctional activation amine of urea the (thio)ureacatalyst 4 (Scheme moiety 9) with[76], which the azlactone demonstrated5 of substrates. 14 Thethe NMR-spectroscopic effective hydrogen-bonding studies activation also indicated of the that (thio)urea the catalyst moiety activates with the theazlactone substrate substrates. azlactone by The NMR-spectroscopicIn 2005, Berkessel successfully studies also developed indicated asymmetric that the catalyst ring opening activates of azlactonesthe substrate with azlactone alcohol viaby hydrogen bonding of the (thio)urea moiety directing to the carbonyl oxygen atom. The alcoholysis and thehydrogen DKR process bonding catalyzed of the (thio)urea by bifunctional moiety aminedirectin ureag to catalystthe carbonyl 4 (Scheme oxygen 9) atom.[76], which The alcoholysis demonstrated and α ringthering opening effective opening of hydrogen-bondingof these these substrate substrate azl azlactones—derived activationactones—derived of the (t fromhio)urea from the thealiphaticmoiety aliphatic with α-amino the-amino azlactone acids acidsphenylalanine, substrates. phenylalanine, alanine,Thealanine, NMR-spectroscopic valine, valine, leucine leucine andand studies terttert-leucine, also indicated and and the thethat aromatic aromaticthe catalyst α-aminoα-amino activates acid acid phenylglycine—proceededthe phenylglycine—proceededsubstrate azlactone by efﬁcientlyhydrogenefficiently with bondingwith good good of enantioselectivities theenantioselec (thio)ureativities moiety catalyzed catalyzeddirecting by to by aminethe amine carbonyl urea urea 4 oxygen (72%–87%4 (72%–87% atom. ee). The ee). alcoholysis and ring opening of these substrate azlactones—derived from the aliphatic α-amino acids phenylalanine, alanine, valine, leucine and tert-leucine, and the aromatic α-amino acid phenylglycine—proceeded efficiently with good enantioselectivities catalyzed by amine urea 4 (72%–87% ee).

Scheme 9. Asymmetric ring opening of azlactones with allyl alcohol by catalyst 4. Scheme 9. Asymmetric ring opening of azlactones with allyl alcohol by catalyst 4. Based on their previous studies, Berkessel and coworkers envisioned that the reactivity and enantioselectivityBased onScheme their of previous this9. Asymmetric transformation studies, ring opening Berkesselcould beof azlactonesgreatly and coworkersimproved with allyl byalcohol envisioned reasonable by catalyst modified that 4. the thiourea reactivity and enantioselectivitycatalyst [77]. The of initial thistransformation catalyst-screening could resu belts greatlyof Takemoto-type improved bifunctional by reasonable organocatalysts modiﬁed thiourea catalystdemonstratedBased [77]. on The thattheir initial increasing previous catalyst-screening thestudies, steric Berkessel hindrance results and of thecoworkers of Takemoto-typeadditional envisioned chiral center bifunctional that themay reactivity contribute organocatalysts and to demonstratedenantioselectivityenhancement thatof enantioselectivity.of increasing this transformation the stericTheref couldore, hindrance bethey greatly synthesized of improved the additional a seriesby reasonable of chiral the tert modified center-leucine may thiourea amide- contribute tocatalystderived enhancement catalysts,[77]. The ofand initial enantioselectivity. catalyst catalyst-screening 6 was identified Therefore, resu to belts the of best theyTakemoto-type one. synthesized Various azlactonesbifunctional a series derived organocatalysts of theboth tertfrom-leucine demonstratednatural and non-natural that increasing α-amino the acids steric were hindrance investigated of the to additional examine the chiral generality center ofmay substrates contribute in the to amide-derived catalysts, and catalyst 6 was identiﬁed to be the best one. Various azlactones derived enhancementpresence of catalyst of enantioselectivity. 6, and the enantioselectivity Therefore, theywas upsynthesized to 95% (Scheme a series 10). of They the successfully tert-leucine realizedamide- both from natural and non-natural α-amino acids were investigated to examine the generality of derivedclean stereoinversion catalysts, and of catalystnatural 6and was non-natural identified to α be-amino the best acids one. through Various this azlactones organocatalytic derived bothDKR. from substratesnatural and in non-natural the presence α-amino of catalyst acids were6, investigated and the enantioselectivity to examine the generality was up of substrates to 95% (Schemein the 10). Theypresence successfully of catalyst realized 6, and the clean enantioselectivitystereoinversion wasof naturalup to 95% and (Scheme non-natural 10). Theyα -aminosuccessfully acids realized through this organocatalyticclean stereoinversion DKR. of natural and non-natural α-amino acids through this organocatalytic DKR.

Scheme 10. Asymmetric ring opening of azlactones with allyl alcohol by catalyst 6.

(Thio)urea-based organocatalysts, to some extent, existed hydrogen-bonded aggregates, which led to realizationScheme that 10. the Asymmetric reactivity ring and opening enantios ofelectivity azlactones were with allylgreatly alcohol dependent by catalyst on 6 concentration. Scheme 10. Asymmetric ring opening of azlactones with allyl alcohol by catalyst 6. and temperature of reactions [78–80]. The enantioselectivity always dramatically decreased when the concentration(Thio)urea-based was increased, organocatalysts, and this was to some not conducive extent, existed to their hydrogen-bonded practical application. aggregates, In 2012, which Song ledand(Thio)urea-based to coworkers realization reported that organocatalysts,the thatreactivity C2-symmetric and enantios to some bis-cinchona-alkalelectivity extent, existedwereoid-based greatly hydrogen-bonded dependent thiourea 7on was concentration aggregates, applied to which ledand to realizationtemperature that of reactions the reactivity [78–80]. and The enantioselectivityenantioselectivity always were dramatically greatly dependent decreased on when concentration the andconcentration temperature was of increased, reactions and [78 this–80 ].was The not enantioselectivity conducive to their practical always application. dramatically In 2012, decreased Song when theand concentration coworkers reported was increased, that C2-symmetric and this wasbis-cinchona-alkal not conduciveoid-based to their thiourea practical 7 was application. applied to In 2012, Molecules 2016, 21, 1327 6 of 14

Song and coworkers reported that C2-symmetric bis-cinchona-alkaloid-based thiourea 7 was applied Molecules 2016, 21, 1327 6 of 14 to catalyze the DKR of racemic azlactones available from N-protected racemic amino acids in one pot, affordingcatalyze various the DKR chiral of non-naturalracemic azlactonesα-amino available esters from (Scheme N-protected 11, up racemic to 95% amino yield, acids 91% in ee) one [81 pot,]. The steric bulkinessaffording of the various two chiral alkaloid non-natural moieties α-amino of catalyst esters (Scheme7 can prevent11, up to 95% their yield, self-aggregation 91% ee) [81]. The andsteric exhibited bulkinessMolecules 2016of the, 21 ,two 1327 alkaloid moieties of catalyst 7 can prevent their self-aggregation and exhibited6 of 14 concentration-independent enantioselectivity in this transformation. Moreover, the experimental and concentration-independent enantioselectivity in this transformation. Moreover, the experimental and NMR-spectroscopicNMR-spectroscopiccatalyze the DKR studies studiesof racemic and andsingle azlactonessingle crystal available X-ray X-ray an fr analysisalysisom N-protected confirmed conﬁrmed thatracemic these that amino kinds these acidsof kinds bifunctional in one of bifunctional pot, organocatalystsorganocatalystsaffording various do notdo notchiral establish establish non-natural hydrogen-bonded hydrogen-bonded α-amino esters self-aggregates (Scheme self-aggregates 11, up in to ei 95%ther in yield, either solution 91% solution or ee) solid [81]. or state.The solid steric state. bulkiness of the two alkaloid moieties of catalyst 7 can prevent their self-aggregation and exhibited concentration-independent enantioselectivity in this transformation. Moreover, the experimental and NMR-spectroscopic studies and single crystal X-ray analysis confirmed that these kinds of bifunctional organocatalysts do not establish hydrogen-bonded self-aggregates in either solution or solid state.

SchemeScheme 11.11. One-pot procedure procedure for forthe DKR theDKR reactions. reactions. 2.3. Atropo-Enantioselective Transesterification 2.3. Atropo-Enantioselective Transesterification Asymmetric synthesis of axially chiral biaryl compounds emerged as a challenging and attractive Scheme 11. One-pot procedure for the DKR reactions. Asymmetricresearch area, synthesiswhere they of were axially found chiral to have biaryl broad compounds applications emerged for constructing as a challenging various natural and attractive products, drugs, bioactive molecules, and chiral ligands [82–86]. There are numerous excellent synthetic research2.3. area, Atropo-Enantioselective where they were Transesterification found to have broad applications for constructing various natural products,methodologies drugs, bioactiveto efficiently molecules, build chiral and biaryl chiral skeletons, ligands such [82 as– 86chiral]. There auxiliaries, are numerousasymmetric excellent transformations,Asymmetric asymmetric synthesis oxidationof axially chiralhomo biarylcouplings, compounds and asymmetric emerged asSuzuki–Miyaura a challenging and couplings attractive synthetic methodologies to efficiently build chiral biaryl skeletons, such as chiral auxiliaries, [87–92].research DKR area, of configurationally where they were labile found biaryl to havelactones broad was applications a powerful and for outstandingconstructing transformation various natural asymmetricto products,produce transformations, such drugs, chiral bioactive compounds asymmetric molecules, and and continues oxidation chiral lig toands receive homo [82–86]. increasing couplings, There attentionare and numerous asymmetric now excellent[93–98]. Suzuki–Miyaura Owingsynthetic couplingsto methodologiesgreat [87 versatile–92]. DKRapplication to efficiently of configurationally and highlybuild chiraleffective biaryl labileactiva sktion biaryleletons, mode lactones suchof bifunctional as waschiral achiralauxiliaries, powerful thiourea asymmetric and catalyst, outstanding transformationthetransformations, combination to produceof DKRasymmetric and such organocatalysis oxidation chiral compoundshomo is an coupattractivelings, and way and continues to asymmetric build chiral to Suzuki–Miyaura biaryl receive compounds. increasing couplings attention now [93[87–92].–98]. Owing DKR of toconfigurationally great versatile labile application biaryl lactones and was highly a powerful effective and activationoutstanding modetransformation of bifunctional to produce such chiral compounds and continues to receive increasing attention now [93–98]. Owing chiral thiourea catalyst, the combination of DKR and organocatalysis is an attractive way to build to great versatile application and highly effective activation mode of bifunctional chiral thiourea catalyst, chiral biarylthe combination compounds. of DKR and organocatalysis is an attractive way to build chiral biaryl compounds.

Scheme 12. DKR of biaryl lactones via bifunctional amine thiourea (1)-catalyzed atropo-enantioselective transesterification.

Scheme 12. DKR of biaryl lactones via bifunctional amine thiourea (1)-catalyzed atropo-enantioselective Scheme 12. DKR of biaryl lactones via bifunctional amine thiourea (1)-catalyzed atropo-enantioselective transesterification. transesteriﬁcation. Molecules 2016, 21, 1327 7 of 14 Molecules 2016, 21, 1327 7 of 14

Recently, WangWang and and coworkers coworkers realized realized highly highly atropo-enantioselective atropo-enantioselective transesteriﬁcation transesterification of biaryl of lactonesbiaryl lactones catalyzed catalyzed by chiral by bifunctionalchiral bifunctional amine amine thiourea thiourea1 provided 1 provided enantioenriched enantioenriched axially axially chiral biarylchiral biaryl compounds compounds with awith wide a wide substrate substrate scope scop undere under mild mild reaction reaction conditions conditions (Scheme (Scheme 12, 12, up up to quantitativeto quantitative yield, yield, 99% 99% ee) ee) [99 [99].]. Additionally, Additionally, this this asymmetric asymmetric transformation transformation involvedinvolved aa highly enantioselective DKR process, which was owing to synergisticsynergistic activation of the biaryl lactones and alcohols/phenols by by the the thiourea thiourea 11 andand amine amine groups groups (Scheme (Scheme 12).12).

3. Squaramide Squaramide Organocatalyst Organocatalyst for for DKR DKR Asymmetric organocatalysis organocatalysis employing employing a hydrogen a hydrogen-bonding-bonding activation activation strategy strategy has been has well- been well-establishedestablished for the for thesynthesis synthesis of ofenantioenriche enantioenrichedd compounds. compounds. Chiral Chiral squaramides squaramides have have been identiﬁedidentified as a typetype ofof powerfulpowerful bifunctionalbifunctional hydrogen-bondinghydrogen-bonding catalysts,catalysts, and promotedpromoted numerousnumerous catalytic asymmetric transformations [42–51]. [42–51]. They were also effective for the asymmetric reactions involving the DKR process.process.

3.1. Enantioselective SelenofunctionalizationSelenofunctionalization Reactions Asymmetric selenofunctionalization of of alkenes was regarded as an attractive and challengingchallenging methodology to produce chiral selenide compou compoundsnds in organic synthesi synthesiss [100–106]. [100–106]. Due to the conﬁgurationalconfigurational instabilityinstability ofof seleniraniumseleniranium ions, ions, the the rapid rapid seleniranium seleniranium racemization racemization can can contribute contribute to promotionto promotion of of the the DKR DKR process. process. In In 2014, 2014, Jacobsen Jacobsen and and coworkers coworkers successfullysuccessfully establishedestablished highly enantioselective selenocylization reactions of o-allyl-substituted phenol phenol via via the DKR process of seleniranium ions ions by by chiral chiral squaramide squaramide catalyst catalyst 8 (Scheme8 (Scheme 13, 13up, to up 96% to 96%yield, yield, 92% ee) 92% [107]. ee) [They107]. Theymade madeuse of N-phenylselenyl use of N-phenylselenyl succinimide succinimide (NPSS) as (NPSS) the selenium as the donor, selenium and hydrogen donor, and chloride hydrogen and chloridetris-(dimethylamino)phosphorus and tris-(dimethylamino)phosphorus sulfide (HMPA(S)) sulﬁde (HMPA(S))as cocatalysts. as cocatalysts. The substrates The substrateswith different with differentsubstituent substituent patterns patternsperformed performed smoothly, smoothly, afford affordinging cyclization cyclization products products in inhigh high yield yield and enantioselectivity. However, However, the the ortho substituent of the hydroxyl group substrate obtained poor enantioselectivity, which suggested that the possible interaction between the hydroxyl group and catalyst that may play an important role in the mechanismmechanism of enantioinduction, and such an interaction may be sensitive to the steric environment aroundaround thethe hydroxylhydroxyl group.group.

Scheme 13. Asymmetric selenocyclization via DKR of seleniranium ions by squaramide catalyst 8. Scheme 13. Asymmetric selenocyclization via DKR of seleniranium ions by squaramide catalyst 8.

According to the proposed activation strategy of this asymmetric selenocyclization, cooperative LewisAccording base and toBrønsted the proposed acid activation activation of strategy the electrophilic of this asymmetric selenium selenocyclization,reagent formed a cooperativereactive ion Lewispair (Se-I base), which and Brønsted may be acidassociated activation with of the the squaramide electrophilic catalyst selenium 8. This reagent intermediate formed a reacted reactive with ion pairo-allyl-substituted (Se-I), which mayphenol be associatedsubstrate and with formed the squaramide chiral seleniranium catalyst 8 ions. This (R intermediate, R)-Se-II and reacted (S, S)-Se-II with. o R R S S These-allyl-substituted two seleniranium phenol ions substrate equilib andrated formed very rapidly, chiral seleniranium and subseque ionsntly ( went, )-Se-II throughand cyclizations ( , )-Se-II. Thesewith different two seleniranium rates due to ions the equilibratedassociation with very chiral rapidly, squaramide and subsequently 8, resulting went in formation through cyclizationsof products with differentexcellent ratesenantiosel due toectivities the association (Scheme with 14). chiral squaramide 8, resulting in formation of products with excellent enantioselectivities (Scheme 14). Molecules 2016, 21, 1327 8 of 14 Molecules 20162016,, 2121,, 13271327 88 ofof 1414

O O

R1 R2 R1 N N R2 H H SeAr HCl SeAr HCl SeAr (Me2N)3P=S (Me2N)3P=S O Ph O O Ph O Ph O O O Ph minor enantiomer minor enantiomer major enantiomer N SeAr N SeAr N H

O O O O O

K K K minor R1 R2 K major minor R1 N N R2 major H H OH Ph OH Ph - Cl- ArSe S=P(NMe2)3 O O ArSe+ S=P(NMe2)3 O O O O + O O Se-I

R1 R2 R R R1 N N R2 R 1 N N R 2 NH NH 1 N N 2 H H H H - (Me2N)3P=S (Me N) P=S Cl- (Me2N)3P=S - (Me 2N)3P=S Cl Cl- 2 3 fast SeAr fast SeAr SeAr OH Ph OH Ph OH Ph (R, R)-Se-II (S, S)-Se-II (R, R)-Se-II (S, S)-Se-II Scheme 14. ProposedProposed possible possible catalytic catalytic cycle. cycle.

3.2. Asymmetric Asymmetric Ring Opening of Azlactones Numerous thiourea-organocatalytic DKRs of racemic azlactones azlactones have have been been widely widely investigated, investigated, but few examples concerning DKR of racemicracemic azlactonesazlactones promotedpromoted byby squaramide-organocatalystssquaramide-organocatalystsramide-organocatalysts were reported.reported. Song Song and coworkers developed a a novel catalytic DKR ofof ring-openingring-opening reactions of racemicracemic azlactones azlactones with with variousvarious alcoholsalcohols byby thethethe bifunctionalbifunctional squaramide-basedsquaramide-based dimericdimeric cinchonacinchona alkaloid catalysts 9 andand 1010 (Scheme(Scheme(Scheme 15)15)15)[ [108].[108].108]. TheseThese These catalystscatalysts catalysts dispdisp displayedlayedlayed unprecedentedunprecedented unprecedented catalyticcatalytic catalytic activity,activity, activity, as wellwell asas enantioselectivity enantioselectivity in in the the DKR DKR reaction reaction of aof broad a broad range range of racemic of racemic azlactones azlactones (up to (up 99% toyield, 99% yield,97% ee). 97% The ee). recyclability The recyclability of the of catalysts the catalysts was examined, was examined, and the and enantioselectivity the enantioselectivity and activity and activity were werenot decreased not decreased even aftereven ﬁfthafter run. fifth run.

Scheme 15. DKR of the racemic azlactones with alcohols by squaramide-based dimeric cinchona Scheme 15. DKRDKR of of the racemic azlactones with alcoho alcoholsls by squaramide-based dimeric cinchona alkaloid catalysts. alkaloid catalysts.

InspiredInspired byby thethe aforementionedaforementioned results,results, SongSong anand coworkers further employed this protocol for Inspired by the aforementioned results, Song and coworkers further employed this protocol for thethe preparationpreparation ofof α-carbon-carbon deuterium-labeleddeuterium-labeled α-amino-amino acidsacids withwith EtODEtOD asas aa nucleophilenucleophile asas wellwell asas the preparation of α-carbon deuterium-labeled α-amino acids with EtOD as a nucleophile as well as a deuterium source catalyzed by bifunctional squaramide-basedramide-based dimericdimeric cinchonacinchona alkaloidalkaloid catalystcatalyst 9 a deuterium source catalyzed by bifunctional squaramide-based dimeric cinchona alkaloid catalyst 9 (Scheme(Scheme 16)16) [109].[109]. VariousVarious α-deuterated-deuterated aminoamino estersesters werewere affordafforded with good enantioselectivities (Scheme 16)[109]. Various α-deuterated amino esters were afforded with good enantioselectivities and yields (up to 88% yield, 88% ee). In addition, most of the N-protected-protected α-deuterated-deuterated aminoamino esterester and yields (up to 88% yield, 88% ee). In addition, most of the N-protected α-deuterated amino ester products were obtained with a deuterium content greater than 95%, and their optical purity can be products were obtained with a deuterium content greater than 95%, and their optical purity can be improvedimproved toto >99% ee after a single recrystallization. improved to >99% ee after a single recrystallization. Molecules 2016,, 21,, 13271327 9 of 14 Molecules 2016, 21, 1327 9 of 14

Scheme 16. Catalytic DKR of various azlactones with ethanol-d. Scheme 16. Catalytic DKR of various azlactones with ethanol-dd.. 3.3. Cascade Sulfur-Michael–Michael Reaction 3.3. Cascade Sulfur-Michael–Michael Reaction Chroman is a kind of fundamental heterocyclic skeleton and widely found in natural products and Chromanmedical molecules isis aa kind kind of ofwith fundamental fundamental great importance heterocyclic heterocyclic [110–112]. skeleton skeleton andOrganocatalytic and widely widely found found cascade in natural in natural reactions products products were and medicalregardedand medical molecules as amolecules straightforward with greatwith importancegreat and efficientimportance [110 method–112 [1].10–112]. Organocatalytic to construct Organocatalytic chiral cascade chroman reactionscascade framework reactions were regarded [113].were asInregarded a2013, straightforward Duas a andstraightforward coworkers and efﬁcient developedand method efficient to an construct method efficient chiral to asymmetricconstruct chroman chiral frameworkcascade chroman sulfa-Michael/Michael [113 framework]. In 2013, Du [113]. and coworkersadditionIn 2013, ofDu developed thiosalicylates and coworkers an efﬁcient with developed asymmetricnitroalkene an cascadeenoate efficients sulfa-Michael/Michaelto buildasymmetric chiral chromanscascade addition sulfa-Michael/Michael catalyzed of thiosalicylates by a chiral withbifunctionaladdition nitroalkene of thiosalicylatessquaramide-tertiary enoates to buildwith chiralnitroalkene amine chromans catalyst enoate 11 catalyzed (Schemes to build by 17, a chiral chiral 98% yield,chromans bifunctional 95:5 dr,catalyzed squaramide-tertiary 95% ee) by [114]. a chiral The aminehighlybifunctional catalystfunctionalized squaramide-tertiary11 (Scheme chiral 17chro, 98% manamine yield, products catalyst 95:5 contained dr,11 (Scheme 95% ee) three 17, [114 98% cont]. The yield,iguous highly 95 stereocenters,:5 dr, functionalized 95% ee) [114].including chiral The chromanonehighly quaternary functionalized products center. contained chiral Based chro on threeman the contiguousproductsresults of contained co stereocenters,ntrol experiments, three cont includingiguous they stereocenters, oneproposed quaternary a reasonable including center. Basedreactionone quaternary on pathway the results center. of sulfa-Michael/retro-sulfa-Michael/sulfa-Michael/Michael of Based control on experiments,the results of theycontrol proposed experiments, a reasonable they proposed reactions reaction involvinga pathway reasonable the of sulfa-Michael/retro-sulfa-Michael/sulfa-Michael/MichaelDKRreaction process. pathway of sulfa-Michael/retro-sulfa-Michael/sulfa-Michael/Michael reactions involving reactions the DKR involving process. the DKR process.

Scheme 17.17.Squaramide-catalyzed Squaramide-catalyzed asymmetric asymmetric cascade sulfa-Michael/Michaelcascade sulfa-Michael/Michael addition of thiosalicylatesaddition of Scheme 17. Squaramide-catalyzed asymmetric cascade sulfa-Michael/Michael addition of tothiosalicylates nitroalkene enoates.to nitroalkene enoates. thiosalicylates to nitroalkene enoates. 4. Conclusions Conclusions 4. Conclusions Asymmetric organocatalysis organocatalysis is is one one of of the the most most im importantportant research research areas areas in organic in organic synthesis synthesis and Asymmetric organocatalysis is one of the most important research areas in organic synthesis and andapplicable applicable in a inbroad a broad variety variety of reaction of reaction types, types, which which includes includes those thosereactions reactions involving involving the DKR the applicable in a broad variety of reaction types, which includes those reactions involving the DKR DKRprocess. process. In this In thisreview, review, we wehave have summarized summarized re recentcent significant significant developments developments on on the catalyticcatalytic process. In this review, we have summarized recent significant developments on the catalytic asymmetric reactions via the DKR process promoted by the (thio)urea (thio)urea and and squa squaramideramide organocatalysts. organocatalysts. asymmetric reactions via the DKR process promoted by the (thio)urea and squaramide organocatalysts. These reaction examples have confirmedconfirmed thatthat (thio)urea(thio)urea andand squaramidesquaramide organocatalystsorganocatalysts bearing These reaction examples have confirmed that (thio)urea and squaramide organocatalysts bearing hydrogen-bonding donors as catalysts have played an important role in achieving excellent results hydrogen-bonding donors as catalysts have played an important role in achieving excellent results from thethe transformationstransformations involving the DKRDKR process.process. In addition, further exciting and significantsignificant from the transformations involving the DKR process. In addition, further exciting and significant discoveries of (thio)urea and squaramide organocatalytic DKR process and developments with this discoveries of (thio)urea and squaramide organocatalytic DKR process and developments with this versatile type of bifunctionalbifunctional organocatalysis are to be expected in the near future with the advent of versatile type of bifunctional organocatalysis are to be expected in the near future with the advent of more systematic studies. more systematic studies. Acknowledgments: We thank the grant from Wuhan University (203273463, 203600400006), the support of the Acknowledgments: WeWe thank thank the the grant grant from from Wuhan Wuhan Univer Universitysity (203273463, (203273463, 203600400006), 203600400006), the support the support of the ofImportant the Important Sci-Tech Sci-Tech Innovative Innovative Project of Project Hubeiof Prov Hubeiince Province(2015ACA058), (2015ACA058), and “111” andProject “111” of the Project Ministry of the of MinistryEducationImportant of Sci-Techof Education China Innovativefor of financial China Project for support financial of Hubeiand support the Prov Nationince and al(2015ACA058), the Natural National Science Natural and Foundation “111” Science Project Foundationof Chinaof the Ministry(Grant of China No. of (Grant21372179,Education No. 21432007, of 21372179, China 21502145).for 21432007, financial 21502145). support and the National Natural Science Foundation of China (Grant No. Conflicts21372179, of21432007, Interest: 21502145).The authors declare no competing financial interest. Conflicts of Interest: The authors declare no competing financial interest. Conflicts of Interest: The authors declare no competing financial interest.

Molecules 2016, 21, 1327 10 of 14

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