Direct amino acid-catalyzed cascade biomimetic reductive alkylations: application to the asymmetric synthesis of Hajos-Parrish ketone analogues

A direct amino acid-catalyzed chemo- and enantioselective process for the double cascade synthesis of highly substituted 2-alkyl-cyclopentane-1,3-diones, 2-alkyl-3-methoxy-cyclopent-2-enones and Hajos-Parrish (H-P) ketone analogs is presented via reductive alkylation chemistry. For the first time, we have developed a single-step alkylation of cyclopentane-1,3-dione with aldehydes/ketones and a Hantzsch ester through an organocatalytic reductive alkylation strategy. A direct combination of amino acid-catalyzed cascade olefination-hydrogenation and cascade Robinson annulations of cyclopentane-1,3-dione, aldehydes/ketones, a Hantzsch ester and methyl vinyl ketone furnished the highly functionalized H-P ketone analogues in good to high yields and with excellent enantioselectivities. Many of the reductive alkylation products have shown direct applications in pharmaceutical chemistry.     

Total synthesis of (-)-nakadomarin A

A highly diastereoselective bifunctional organocatalyst controlled Michael addition, a nitro-Mannich/lactamization cascade, a furan N-acyliminium cyclisation, a sequential alkyne RCM/syn-reduction and an alkene RCM has allowed a 19 step, highly stereoselective synthesis of (-)-nakadomarin A.     

Highly stereoselective Michael reduction/intramolecular Michael reaction cascade to synthesize trans-stereodiad comprising an all-carbon quaternary stereogenic center

A highly stereoselective Michael reduction/intramolecular Michael reaction cascade is described. The cascade is initiated by the regioselective Michael reduction of an α-methylidene ester with L-Selectride. This is followed by the highly stereoselective intramolecular Michael reaction which efficiently constructs a six-membered carbocyclic ring with formation of the trans-stereodiad, composed of an all-carbon quaternary center and a tertiary stereogenic center. The stereoselectivity is perfectly controlled by the choice of alkene geometry in the Michael acceptor.     

Anion Relay Chemistry: Development of an Effective Diastereoselective [3+2] Annulation Tactic Exploiting an Aldol/Brook Rearrangement/Cyclization Cascade

An effective [3+2] annulation tactic for the construction of diverse bicyclic compounds possessing highly functionalized cyclopentane rings has been developed employing soft ketone enolates as the initial nucleophile for anion relay chemistry (ARC). The protocol entails a highly diastereoselective aldol/Brook rearrangement/cyclization cascade.     

Asymmetric Dearomatization of Indoles through a Michael/Friedel–Crafts‐Type Cascade To Construct Polycyclic Spiroindolines

A highly efficient asymmetric dearomatization of indoles was realized through a cascade reaction between 2‐isocyanoethylindole and alkylidene malonates catalyzed by a chiral N,N′‐dioxide/Mg^II catalyst. Fused polycyclic indolines containing three stereocenters were afforded in good yields with excellent diastereo‐ and enantioselectivities through a Michael/Friedel–Crafts/Mannich cascade. When 2‐substituted 2‐isocyanoethylindoles were used, spiroindoline derivatives were obtained through a Michael/Friedel–Crafts reaction.     

吗啉催化的串联反应合成多取代环己酮（英文稿）

本文以吗啉为催化剂,活泼亚甲基化合物与芳香醛发生串联反应,以最高90%的产率得到了系列多取代的环己酮。反应经历了Knoevenagel缩合、Michael加成、Aldol反应等系列过程。吗啉作为有机分子催化剂,在串联过程中通过亚胺离子活化及烯胺活化羰基化合物而发挥重要作用。合成的环己酮可通过已知方法进一步转化为2-环己烯酮。本方法具有简便、易操作和绿色的特点。     

Single‐Electron/Pericyclic Cascade for the Synthesis of Dienes

The highly efficient and diastereoselective synthesis of E dienes has been accomplished through radical cyclization of bromoallyl hydrazones. This methodology has been further extended to generate these products through a one‐pot condensation/radical cyclization/cycloreversion cascade from simple aldehyde starting materials in high yields (>75 %) and high diastereoselectivities (>95:5). Mechanistic investigations suggest that the cascade reaction proceeds through a cyclic diazene intermediate prior to the cycloreversion.     

Organocatalytic sequential one-pot double cascade asymmetric synthesis of Wieland-Miescher ketone analogues from a Knoevenagel/hydrogenation/Robinson annulation sequence: scope and applications of organocatalytic biomimetic reductions

A practical and novel organocatalytic chemo- and enantioselective process for the cascade synthesis of highly substituted 2-alkyl-cyclohexane-1,3-diones and Wieland-Miescher (W-M) ketone analogs is presented via reductive alkylation as a key step. First time, we developed the one-step alkylation of dimedone and 1,3-cyclohexanedione with aldehydes and Hantzsch ester through an organocatalytic reductive alkylation strategy. Direct combination of l-proline-catalyzed cascade Knoevenagel/hydrogenation and cascade Robinson annulation of CH acids (dimedone and 1,3-cyclohexanedione), aldehydes, Hantzsch ester, and methyl vinyl ketone furnished the highly functionalized W-M ketone analogues in good to high yields and with excellent enantioselectivities. Many of the reductive alkylation products show a direct application in pharmaceutical chemistry.     

Rapid construction of the unique BCD ring system of tricyclo[6.2.1.0] undecane in the C19-diterpenoid alkaloid aconitine

A model study leading to the preparation of the unique tricyclo [6.2.1.0] undecane BCD ring systems of aconitine is described. The synthesis features an unprecedented diastereoselective oxidative dearomatization/dimerization/retro-DA/IMDA cascade reaction and a highly efficient Wagner-Meerwein rearrangement.     

Highly efficient enantioselective three-component synthesis of 2-amino-4H-chromenes catalysed by chiral tertiary amine-thioureas

A three-component cascade reaction of salicylaldehyde, malononitrile/cyanoacetate and nitromethane catalysed by chiral tertiary amino-thioureas was developed, which leads to the production of highly functionalized 2-amino-4H-chromenes in good yields with good to excellent enantioselectivities.     

Paired electrolysis enabled annulation for the quinolyl-modification of bioactive molecules

A paired electrolysis enabled cascade annulation that enables the efficient synthesis of highly functionalized quinoline-substituted bioactive molecules from readily available starting materials is reported. Using this methodology, two goals, namely, the direct synthesis of quinolines and the introduction of quinoline moieties to bioactive molecules, can be simultaneously achieved in one simple operation. The use of electroreduction for the activation of isatin, together with the further anodic oxidation of KI to catalytically result in a cascade annulation, highlight the unique possibilities associated with electrochemical activation methods. This transformation can tolerate a wide range of functional groups and can also be used as a functionalization tactic in pharmaceutical research as well as other areas.

A paired electrolysis enabled cascade annulation that enables the efficient synthesis of highly functionalized quinoline-substituted bioactive molecules from readily available starting materials is reported.     

Enantioselective assembly of substituted dihydropyrones via organocatalytic reaction in water media

The diarylprolinol ether/HOAc-catalyzed cascade Michael addition and cyclization of aldehydes and alpha-keto-alpha,beta-unsaturated esters proceeds smoothly in water to afford cyclic hemiacetals, which are oxidized to furnish highly functionalized 3,4,5,6-tetrasubstituted dihydropyrones with excellent enantioselectivities.     

Total synthesis of (−)-nakadomarin A: alkyne ring-closing metathesis

A 13-step, highly stereoselective synthesis of (−)-nakadomarin A has been achieved using the combination of a bifunctional organocatalyst controlled Michael addition, a nitro-Mannich/lactamization cascade, an alkyne ring-closing metathesis/syn-reduction, and furan/iminium ion cyclization/reduction as key steps.     

Atom Transfer Oxidative Radical Cascade of Aryl Alkynoates towards 1,1‐Dichalcogenide Olefins

An oxidative trifunctionalization of aryl alkynoates has been devised via the chalcogenide radical triggered intramolecular 1,4‐aryl migration/decarboxylation cascade to prepare 1,1‐dichalcogenide tetrasubstituted alkenes in high yields (up to 98 %). This operationally simple reaction proceeds under metal‐free conditions, can be executed on gram scale, and highlights formal 1,1‐difunctionalization of alkynes. Synthetic potential of this protocol was demonstrated through a twofold cascade rearrangement to access highly conjugated tetra‐selenylated alkenes along with a cross‐dehydrogenative annulation to prepare fluorene derivative.     

Pd/Cu-catalyzed cascade Sonogashira coupling/cyclization reactions to highly substituted 3-formyl furans

An efficient palladium/copper-catalyzed approach to the synthesis of highly substituted 3-formyl furans from the reactions of readily available α-bromoenaminones with terminal alkynes has been developed. This methodology was realized by the cascade reactions of Sonogashira coupling and the subsequent intramolecular cyclization.     

Total Synthesis of (−)-Glaucocalyxin A

A practically useful method for the formation of the highly oxygenated bicyclo[3.2.1]octane ring system through Mn(OAc)₃-mediated radical cyclization of alkynyl ketones was developed, which opens up a new avenue for the total synthesis of a number of highly oxidized diterpenoids. Application of this method enabled the first total synthesis of (−)-glaucocalyxin A. Other salient features of the synthesis include a highly enantioselective conjugate addition/acylation cascade reaction, a Yamamoto aldol reaction, and an intramolecular Diels–Alder reaction to assemble the A/B ring system.     

Diastereoselective Pd/In bimetallic inter-intramolecular (class 2) cascade reactions of allenyl-imines and aryl iodides

A new diastereoselective Pd/In bimetallic inter-intramolecular cascade reaction employing allenyl-sulfinimines and aryl iodides is described. The tert-butanesulfinyl chiral auxiliary affords chiral, highly substituted cis-pyrrolidines and piperidines.     

Utilizing an o‐Quinone Methide in Asymmetric Transfer Hydrogenation: Enantioselective Synthesis of Brosimine A,Brosimine B,and Brosimacutin L

A concise and highly enantioselective synthesis of the flavonoids brosimine A, brosimine B, and brosimacutin L is reported for the first time. The key transformation is a single‐step conversion of a flavanone into a flavan by means of an asymmetric transfer hydrogenation/deoxygenation cascade.     

A highly convergent cascade cyclization to cis-hydrindanes with all-carbon quaternary centers and its application in the synthesis of the aglycon of dendronobiloside A

An efficient and versatile ZnBr(2)-catalyzed Diels-Alder/carbocyclization cascade reaction has been developed for construction of highly functionalized cis-hydrindanes (70-96% yields with high diastereoselectivity), and it has been successfully utilized in the synthesis of the aglycon of dendronobiloside A.     

Five-Step Enantioselective Synthesis of Islatravir via Asymmetric Ketone Alkynylation and an Ozonolysis Cascade

A 5-step enantioselective synthesis of the potent anti-HIV nucleoside islatravir is reported. The highly efficient route was enabled by a novel enantioselective alkynylation of an α,β-unsaturated ketone, a unique ozonolysis-dealkylation cascade in water, and an enzymatic aldol-glycosylation cascade.