Organocatalytic,Enantioselective Synthesis of Cyclohexadienone Containing Hindered Spirocyclic Ethers through an Oxidative Dearomatization/Oxa‐Michael Addition Sequence

An unprecedented enantioselective oxa‐Michael reaction of α‐tertiary alcohols using cinchona‐alkaloid‐based chiral bifunctional squaramide catalysts is reported. An oxidative dearomatization of phenol followed by an enantioselective oxa‐Michael addition sequence provided a broad array of chiral sterically hindered tetrahydrofurans and tetrahydropyrans attached to a cyclohexadienone moiety in spiro fashion. In general, good yields and excellent enantioselectivities (up to 99 %) were observed. The chiral oxo‐cycles obtained have easily been transformed into chromans without disturbing the enantioselectivity.     

Organocatalytic Domino Oxa‐Michael/1,6‐Addition Reactions: Asymmetric Synthesis of Chromans Bearing Oxindole Scaffolds

An asymmetric organocatalytic domino oxa‐Michael/1,6‐addition reaction of ortho‐hydroxyphenyl‐substituted para‐quinone methides and isatin‐derived enoates has been developed. In the presence of 5 mol % of a bifunctional thiourea organocatalyst, this scalable domino reaction affords 4‐phenyl‐substituted chromans bearing spiro‐connected oxindole scaffolds and three adjacent stereogenic centers in good to excellent yields (up to 98 %) and with very high stereoselectivities (up to >20:1 d.r., >99 % ee).     

Organocatalytic Asymmetric 1,6‐Addition/1,4‐Addition Sequence to 2,4‐Dienals for the Synthesis of Chiral Chromans

A novel asymmetric organocatalytic 1,6‐addition/1,4‐addition sequence to 2,4‐dienals is described. Based on a 1,6‐Friedel–Crafts/1,4‐oxa‐Michael cascade, the organocatalyst directs the reaction of hydroxyarenes with a vinylogous iminium‐ion intermediate to give only one out of four possible regioisomers, thus providing optically active chromans in high yields and 94–99 % ee. Furthermore, several transformations are presented, including the formation of an optically active macrocyclic lactam. Finally, the mechanism for the novel reaction is discussed based on computational studies.     

Enantioselective Organocatalytic Michael/Aldol Sequence: Anticancer Natural Product (+)‐trans‐Dihydrolycoricidine

A total synthesis of the anticancer natural product (+)‐trans‐dihydrolycoricidine is reported from α‐azidoacetone and cinnamaldehyde precursors. Key elements include an asymmetric organocatalytic sequence proceeding by a regiospecific secondary‐amine‐catalyzed syn Michael addition followed by an intramolecular aldol reaction. The sequence results in the formation of an advanced intermediate, containing three stereogenic centers, in one step which and was converted into the title compound in eight steps.     

Enantioselective Organocatalytic Conjugate Addition of Aldehydes to Vinyl Sulfones and Vinyl Phosphonates as Challenging Michael Acceptors

Chiral framework : Chiral amines with pyrrolidine frameworks catalyze the enantioselective conjugate addition of a wide range of aldehydes to various vinyl sulfones and vinyl phosphonates in high yields and with enantioselectivities up to >99 % ee (see scheme). The high versatility of the Michael adducts is exemplified by various functionalizations with conservation of the optical purity.

     

Asymmetric Synthesis of Fully Substituted Cyclopentane‐Oxindoles through an Organocatalytic Triple Michael Domino Reaction

An efficient, highly stereoselective asymmetric synthesis of fully functionalized cyclopentanes bearing an oxindole moiety and several other functional groups in one pot has been developed. Key step is an organocatalytic triple Michael domino reaction forming three C?C bonds and six stereocenters, including a quaternary one. Starting from equimolar amounts of simple substrates, a high molecular complexity can be reached after a Wittig olefination in one pot. The new protocol can easily be scaled up to gram amounts.     

Organocatalytic Enantioselective Synthesis of 1,4‐Dioxanes and Other Oxa‐Heterocycles by Oxetane Desymmetrization

A new asymmetric synthesis of chiral 1,4‐dioxanes and other oxa‐heterocycles has been developed by means of organocatalytic enantioselective desymmetrization of oxetanes. This mild process proceeds with exceedingly high efficiency and enantioselectivity to establish the quaternary stereocenters. This method complements the existing, yet limited, strategies for the synthesis of these oxa‐heterocycles.     

Organocatalyzed Cascade Aza‐Michael/Michael Addition for the Asymmetric Construction of Highly Functionalized Spiropyrazolone Tetrahydroquinolines

An organocatalyzed diastereo‐ and enantioselective cascade aza‐Michael/Michael addition of 2‐tosylaminoenones to unsaturated pyrazolones has been developed to afford novel chiral spiropyrazolone tetrahydroquinolines containing three contiguous stereocenters. This cascade reaction proceeded well with 2 mol % chiral bifunctional tertiary amine squaramide catalyst to give the desired products in excellent yields (up to 99 %) with excellent diastereoselectivity (up to >25:1 diastereomeric ratio) and high enantioselectivity (up to 91 % enantiomeric excess).     

有机催化蒽酮与β-硝基烯烃的不对称Michael加成反应

将金鸡纳生物碱衍生物用于催化蒽酮和β-硝基芳基乙烯的不对称Michael加成反应。 考察了溶剂、温度及催化剂用量对反应催化性能的影响。 结果表明,最佳条件为5%(摩尔分数)催化剂1b、甲苯为溶剂、0 ℃反应,得到了91%~99%的化学产率和最高达95%ee的对映体选择性。     

Highly Efficient Enantioselective Construction of Bispirooxindoles Containing Three Stereocenters through an Organocatalytic Cascade Michael–Cyclization Reaction

Bispirooxindole derivatives containing three stereocenters, including two spiro quaternary centers, were synthesized in a high‐yielding, atypically rapid, and stereocontrolled cascade Michael–cyclization reaction between methyleneindolinones and isothiocyanato oxindoles catalyzed by a bi‐ or multifunctional organocatalyst. Mild conditions were used to construct bispirooxindoles with excellent enantio‐ and diastereomeric purities within less than 1 min. Catalyst reconfiguration offered access to the opposite enantiomer. This exceptionally highly efficient procedure will allow diversity‐oriented syntheses of this intriguing class of compounds with potential biological activities.     

Diastereo‐ and Enantioselective Construction of a Bispirooxindole Scaffold Containing a Tetrahydro‐β‐carboline Moiety through an Organocatalytic Asymmetric Cascade Reaction

The first catalytic asymmetric construction of a new class of bispirooxindole scaffold‐containing tetrahydro‐β‐carboline moiety has been established through chiral phosphoric acid‐catalyzed three‐component cascade Michael/Pictet–Spengler reactions of isatin‐derived 3‐indolylmethanols, isatins, and amino‐ester, which afforded structurally complex and diverse bispirooxindoles with one quaternary and one tetrasubstituted stereogenic centers in excellent stereoselectivities (all >95:5 diastereomeric ratio (d.r.), up to 98:2 enantiomeric ratio (e.r.)). This intriguing class of chiral bispirooxindoles integrated the two important structures of tetrahydro‐β‐carboline and bispirooxindole, both of them possessing significant bioactivities. This approach also combined the merits of asymmetric organocatalysis and multicomponent tandem reaction, which provided a unique strategy for the preparation of structurally rigid bispiro‐architectures with concomitant creation of multiple quaternary stereogenic centers.     

Polymer‐Supported Enantioselective Bifunctional Catalysts for Nitro‐Michael Addition of Ketones and Aldehydes

Introduction of an L ‐amino acid as a spacer and a urea‐forming moiety in a polymer‐supported bifunctional urea–primary amine catalyst, based on (1R, 2R)‐(+)‐1,2‐diphenylethylenediamine, significantly improves the catalyst’s activity and stereoselectivity in the asymmetric addition of ketones and aldehydes to nitroolefins. Yields and enantioselectivities, unprecedented for immobilized catalysts, were obtained with such challenging donors as acetone, cyclopentanone, and α,α‐disubstituted aldehydes, which usually perform inadequately in this reaction (particularly when a secondary‐amine‐based catalyst is used). Remarkably, though in the examined catalysts the D ‐amino acids as spacers were significantly inferior to the L isomers, for the chosen configuration of the diamine (match–mismatch pairs) the size of the side chain of the amino acid hardly influenced the enantioselectivity of the catalyst. These results, combined with the reactivity profile of the catalysts with substrates bearing two electron‐withdrawing groups and the behavior of the catalysts’ analogues based on tertiary (rather than primary) amine, suggest an enamine‐involving addition mechanism and a particular ordered C? C bond‐forming transition state as being responsible for the catalytic reactions with high enantioselectivity.