DOI:10.1002/ajoc.201500486 Focus Review OrganocatalyticCascade Reactions Recent Developments in the Synthesis of Chiral Compounds with Quaternary Centers by Organocatalytic Cascade Reactions Li Tian, Yong-Chun Luo,Xiu-Qin Hu,and Peng-Fei Xu*[a] Asian J. Org. Chem. 2016, 5,580 –607 580 2016 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Focus Review Abstract: Quaternary carbon stereocenters are presentin tions, several efficient methods for the construction of opti- awide variety of organic compounds and drug molecules. cally pure compounds with quaternary carbon centers have Highly enantioselective construction of such quaternary been developed. This focusedreview highlightsthe asym- carbon stereocentershas received considerable attention metric synthesis of chiral compounds with quaternary cen- owing to the great challenges in their syntheses. With the ters through organocatalytic cascade reactions. development of asymmetricorganocatalytic cascade reac- 1. Introduction It is noteworthy that several terminologies have been uti- lized to describe multistep reactions that take place in one Opticallypurecompounds that play important roles in the pot, which include “cascade”, “domino”, and “tandem” reac- fields of chemistry,life sciences, and pharmacology are com- tions. For example, Tietze suggested the use of “domino” monly present in nature as avariety of natural products. rather than “cascade” or “tandem”, and defined adomino reac- Simple and convenient methods for the synthesis of chiral tion as aprocess involving two or more bond-formingtransfor- compounds have becomeaprolonged endeavor of chemists mations that take place under the same reactionconditions owing to their importance and broad applications.Asasym- without adding additional reagentsand catalysts, and in which metric catalysis has the advantages of high stereoselectivity, subsequentreactions result as aconsequence of the function- economical processing, environmental protection,and easy in- ality formed in the previousstep.[4] Denmark proposedkeeping dustrialization, it is currently the most effective methodfor the all-encompassing definition of “tandem”asreactions that asymmetricsynthesis. The field of asymmetriccatalysis was occur one after the other,and use of the modifiers “cascade” originally dominated by metal catalysis and biocatalysis for (or domino), “consecutive”,or“sequential” to specify how the along time. In 2000, List et al. first reported the proline-cata- two (or more) reactions will follow.[5] Fogg classified one-pot lyzed direct asymmetric intermolecularaldol reaction, and sug- processes as one-pot reactions, domino(cascade) catalysis, and gested that the mode of enamine catalysis could be used as tandemcatalysis, which werefurthersubdivided into orthogo- aversatile strategy.[1] Then, MacMillan et al. reported an asym- nal catalysis, auto-tandem catalysis, and assisted-tandem catal- metric Diels–Alder reaction catalyzed by their chiral imidazoli- ysis.[6] Hayashi utilized the term “one-pot synthesis” in his dinone catalyst and proposed the mode of imine catalysis.[2] review,which has amuch wider meaning than acascade, More importantly,they put forward the concept of organoca- domino, or tandem reaction, to encompass all such reaction talysis, whichhas been developed rapidly and become the types.[7] Nicolaou pointed out that the descriptors“domino”, third branch of asymmetric catalytic reactions since then. “cascade”,and “tandem”were often seeminglyinterchangea- Organocatalysis, the use of non-metallicsmall organic mole- ble from one another in the literature.[8] In this review,Nico- cules to catalyze organic transformations, has enjoyedphe- laou’s viewpoint has been employed and the term “cascade” is nomenal growth as these smallorganic molecule catalysts are mainly employed to encompass all of the above descriptors non-toxic, inexpensive, easy to prepare, stable in air and water just to be simple. and so on, compared with metal catalysts. So far,avariety of Quaternary carbon stereocenters, carbon centers with four organocatalytic modes have been developed. As an important different non-hydrogen substituents, are present in awide vari- field of asymmetric organocatalysis, organocatalytic cascade re- ety of naturalproducts and drug molecules. It used to be actions are characterizedbytheir high efficiencies and biomim- agreat challengetocreate quaternary carbon stereocenters etic syntheses of target molecules, which are similar to the bio- with high enantioselectivity in organicsynthesis, however,syn- synthesis of natural products.[3] Through organocatalytic one- thetic chemists were and still are very interested in this area.[9] pot multistep reactions, complicated chiral products can be Overman recently summarized some syntheticstrategies obtainedthrough organocatalytic cascade reactions from toward complex natural products with two or more contigu- simple and readily available substrates, under mild reaction ous quaternary carbon atoms in their intricate structures,with conditions, with simple operations without costly protection– emphasis on the methods to create quaternary carton stereo- deprotection processes, and also without the need to purify centers.[9d] Clearly, it is both significant and very useful to de- the intermediates. Several newly createdbonds and stereocen- velop efficient processes to construct quaternary carton stereo- ters can be established by these reactions with good stereose- centers in ahighly enantioselective manner. With the develop- lective control.Therefore, it is highly efficient to synthesize nat- ment of asymmetric organocatalytic cascade reactions,several ural products and bioactive molecules by asymmetric organo- new types of efficient methods for the construction of optically catalytic cascade reactions. pure compounds with quaternary carbon centers have been developed. Although many reviews about organocatalytic cas- [a] Dr.L.Tian, Dr.Y.-C. Luo, X.-Q. Hu, Prof. Dr.P.-F.Xu cade reactions have been reported,[3] it is still highly desirable State Key Laboratory of Applied OrganicChemistry to summarizethe asymmetric synthesisofchiral compounds College of Chemistryand Chemical Engineering Lanzhou University,Lanzhou 730000 (PR China) with quaternary centers through organocatalytic cascade reac- E-mail:[email protected] tions;thus, we will discuss these highly efficient methods for Asian J. Org. Chem. 2016, 5,580 –607 www.AsianJOC.org 581 2016 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Focus Review the highly enantioselective construction of quaternary carbon lished efficiently with a,b-unsaturated aldehydesand nitroole- stereocenters. fins. They have also proposed amechanism of quadruple imini- This review highlights the asymmetric synthesis of chiral um–enamine–iminium–enamine catalysis to explain this reac- compounds with quaternary centers through organocatalytic tion. As shown in Scheme 1, the intermediate 4 was generated cascade reactions, wherein aminocatalysis and hydrogen-bond- after the first cascade Michael–Michael reactionbetween 1 and ing catalysis are mainly described. At the end of this paper, one equivalent of the a,b-unsaturated aldehyde, then the ion-pairing catalysis is also briefly discussed. second Michael–aldol process occurred with the second equiv- 2. Asymmetric Aminocatalytic Cascade Reac- tions Li Tian receivedhis B.S. degreein2008 from LanzhouUniversity and then studied in Prof. Aminocatalysis, which includes iminium and enaminecatalysis, Xu’s group from 2009 to 2014.Hereceived his has maturedinthe 15 years since it was first reported in Ph.D.degree in 2014 with his research fo- 2000.[10] It is now awell-established andpowerful synthetic cusedonorganocatalytic cascade reactions. tool for the chemo- and enantioselective functionalization of carbonyl compounds. According to the differenttypes of cata- lysts, aminocatalysis has been classified into secondary andpri- mary amine catalysis. Certain chiralpentacyclicamines are mainly used as catalysts for secondary amine catalysis, in particularproline and its de- rivatives,[11] including diarylprolinol ethers and phenylalanine- derived imidazolidinones. They provide areliable synthetic Yong-Chun Luo received his Ph.D. degree platform forthe asymmetric functionalization of aldehydes at underthe supervisionofProfessor Xu from positions from a to e.Currently, the mostcommonly used pri- LanzhouUniversity in 2009 and then joined mary aminecatalysts are cinchona-based primary amines, such Prof. Xu’s group. In 2013,hewas appointed as 9-amino-9-deoxy-epi-cinchona alkaloids, which were devel- Associate Professor of Organic Chemistry.His researchfocuses on the researchofcatalytic oped independently and almostatthe same time by Chen organic reactions. et al.,[12] Melchiorre et al.,[13] and Connon et al.[14] in early 2007. Avariety of sterically hindered carbonyl compounds that cannotbefunctionalized by using secondary amines can be stereoselectively functionalized by using primary amines, which greatlyexpands the potentialapplication of chiral ami- nocatalysis. Asymmetric aminocatalyzed cascadereactions are divisible Xiu-Qin Hu received her B.S. degreein1988 into two classes;(1) iminium-initiated cascade reactions, (2) en- from Lanzhou University and then worked for amine-activated cascade reactions. Northwest Yongxin Chemical Co. Ltd. She re- ceivedher Master’s degree in 1998 and was appointed Associate Professor of Fine Chemi- 2.1. Iminium-initiated cascadereactions cal Engineering at Lanzhou Universityin 2003. Currently,her research focuses on the Cascade