Asymmetric Synthesis of cis‐3,4‐Disubstituted Chromans and Dihydrocoumarins via an Organocatalytic Michael Addition/ Hemiacetalization Reaction

The organocatalytic domino Michael/hemiacetalization reaction between various aldehydes and ortho‐nitrovinylphenols has been developed. Under the catalysis of diphenyl prolinol trimethylsilyl ether, cis‐3,4‐disubstituted chromanols are obtained in high to excellent yields (81–98%) and stereoselectivities (dr: 86:14 to >99:1, ee 96 to >99%). The corresponding disubstituted chromans are available by dehydroxylation of the domino products in good to excellent yields (58–95%). Furthermore, oxidation of the domino products with pyridinium chlorochromate provided 3,4‐dihydrocoumarins in good yields (65–83%) without any epimerization.     

Chiral Squaramide‐Catalyzed Highly Enantioselective Michael Addition of 2‐Hydroxy‐1,4‐naphthoquinones to Nitroalkenes

A chiral squaramide‐organocatalyzed, highly enantioselective Michael addition of 2‐hydroxy‐1,4‐naphthoquinones to nitroalkenes has been developed. This reaction afforded the chiral naphthoquinones in excellent yields (up to 99%) and excellent enantioselectivity (up to 98% ee) under very low catalyst loading (0.25 mol%). This organocatalytic asymmetric Michael addition provides an efficient alternative route toward the synthesis of chiral functionalized naphthoquinones.     

Organocatalytic Asymmetric Michael Addition of Pyrazolin‐5‐ones to Nitroolefins with Bifunctional Thiourea: Stereocontrolled Construction of Contiguous Quaternary and Tertiary Stereocenters

The first organocatalytic diastereo‐ and enantioselective Michael addition reaction of 4‐substituted‐pyrazolin‐5‐ones to nitroolefins has been developed with a chiral bifunctional thiourea as organocatalyst. A wide variety of desired multi‐substituted pyrazolin‐5‐one derivatives with contiguous quaternary and tertiary stereocenters are smoothly obtained in very good yields (up to 98%) with excellent enantioselectivities (up to>99% ee) and acceptable diastereoselectivities (up to 80:20). This experimentally simple process facilitates the access to various enantioenriched, multiply substituted pyrazolin‐5‐one derivatives, potential biologically active molecules, starting from readily available starting materials.     

Asymmetric Synthesis of Dihydrocoumarins Containing Contiguous Quaternary and Tertiary Stereogenic Centers Catalyzed by a Cinchona‐Alkaloid‐Based Bifunctional Thiourea Derivative

A series of enantiomerically enriched 3,4‐dihydrocoumarins containing contiguous quaternary and tertiary stereogenic centers has been efficiently constructed via domino asymmetric Michael addition/transesterification reactions of azlactones with o‐hydroxychalcones using a quinine‐derived thiourea as bifunctional organocatalyst. Under mild reaction conditions, the optically active 3,4‐dihydrocoumarins were generally obtained in 63–96% yields with >20:1 dr and 81–96% ee.

     

Amino Acid‐Derived Phosphonium Salts‐Catalyzed Michael Addition of 3‐Substituted Oxindoles

A new type of phosphonium phase‐transfer catalyst prepared from easily available chiral amino acids was evaluated in a model reaction between oxindole and methyl vinyl ketone, and the catalyst derived from isoleucine was found to be the best. Michael additions of 3‐monosubstituted oxindoles to methyl vinyl ketone, acrolein or propargyl aldehyde proceeded smoothly to afford 3,3‐disubstituted oxindoles in good to excellent yields with moderate to excellent ees.

     

Enantioselective Synthesis of α‐Amino‐γ‐sulfonyl Phosphonates with a Tetrasubstituted Chiral α‐Carbon via Quinine‐Squaramide‐Catalyzed Michael Addition of Nitrophosphonates to Vinyl Sulfones

α‐Nitro‐γ‐sulfonyl phosphonates with a key tetrasubstituted chiral α‐carbon center have been synthesized for the first time in high yield and enantioselectivity through a quinine‐squaramide‐catalyzed conjugate addition of α‐nitro phosphonates to aryl vinyl sulfones. Representative examples presented here for the transformation of nitrosulfonyl phosphonates to aminosulfonyl phosphonates, alkylation at the α‐position of the sulfonyl group followed by desulfonation and scale‐up of the conjugate addition highlight the practical applications of the methodology.     

Stereocontrolled Construction of Quaternary Stereocenters by Inter‐ and Intramolecular Nitro‐Michael Additions Catalyzed by Bifunctional Thioureas

A highly diastereo‐ and enantioselective conjugate addition of β‐keto esters to nitroolefins, catalyzed by a chiral thiourea prepared from L ‐valine is described. The formation of two contiguous tertiary and quaternary stereocenters occurs in high yield and excellent diastereo‐ and enantioselection with only 2 mol% of catalyst loading. The reaction is general and different β‐keto esters and aryl‐ and alkylnitroolefins have been tested. The same catalyst has been used to promote the first intramolecular conjugate addition leading to the cyclic adduct in moderate diastereoselectivity and good enantioselectivity.     

Squaramide‐Catalyzed Enantioselective Cascade Approach to Bispirooxindoles with Multiple Stereocenters

A bifunctional squaramide‐catalyzed Michael/Michael cascade reaction for the construction of spirotetrahydrofuran bispirooxindoles was developed. The products were obtained in moderate to excellent yields with excellent diastereo‐ and enantioselectivities (up to >20:1 dr, >99% ee). This straightforward process serves as a powerful method for the enantioselective construction of potentially bioactive bispirooxindoles in which two of the four contiguous chiral centers are spiro all‐carbon quaternary centers on a single tetrahydrofuran ring. Meanwhile, the synthetic practicality of this methodology was illustrated by performing the reaction on a gram‐scale with the same efficiency and stereoselectivity.

     

Asymmetric Vinylogous Michael Addition/Cyclization Cascade Reaction for the Construction of Diversely Structured Spiro‐ Oxindole Skeletons

We present the first organocatalytic asymmetric vinylogous Michael/cyclization reaction of α,α‐dicyanoalkenes with 3‐alkylideneoxindoles. A series of diversely structured spiro‐oxindole skeletons was smoothly delivered with excellent yields and stereoselectivity control (94–99% yields, >20:1 dr and 91 to >99% ee).

     

Asymmetric Synthesis of Spiro β‐Lactams via a Squaramide‐ Catalyzed Sulfa‐Michael Addition/Desymmetrization Protocol

An efficient asymmetric synthesis of spirocyclohexenone β‐lactams bearing three contiguous stereocenters has been achieved in moderate to good yields and high stereoselectivities. The protocol involves the combination of a squaramide‐catalyzed sulfa‐Michael addition under desymmetrization via a dynamic kinetic resolution of racemic 2,5‐cyclohexadienones.

     

Organocatalytic Enantioselective Cascade Aza‐Michael/Michael Addition for the Synthesis of Highly Functionalized Tetrahydroquinolines and Tetrahydrochromanoquinolines

An efficient organocatalytic highly asymmetric cascade aza‐Michael/Michael addition reaction for the synthesis of tetrahydroquinolines and tetrahydrochromanoquinolines has been developed. This cascade reaction proceeds well at low catalyst loading with a broad substrate scope, furnishing the desired products in excellent yields with excellent diastereoselectivities and enantioselectivities (up to >99:1 dr, 99% ee) under mild conditions. Importantly, it is the first catalytic asymmetric method for tetrahydrochromanoquinolines. This protocol provides a straightforward entry to highly functionalized chiral tetrahydroquinoline and tetrahydrochromanoquinoline derivatives from simple starting materials.

     

A Chiral Functionalized Salt‐Catalyzed Asymmetric Michael Addition of Ketones to Nitroolefins

The chiral functionalized salt catalysis, which differs from the known enzyme‐ and transition metal‐based methods, has been successfully developed to carry out the Michael addition of ketones to nitroolefins. Chiral anion salt (type I ), chiral cation salt (type II ), or chiral anion‐chiral cation salt (type III ) could be expected to be remarkably effective catalysts and afford the corresponding chemically and optically pure Michael addition adducts. A primary amine group activating the ketone during salt catalysis was their obvious and common property. Based on preliminary experimental investigations and previous reports on primary amine catalysis, a reaction pathway via imine, enamine, iminium ion to imine was proposed.     

Asymmetric One‐Pot Synthesis of 1,4‐Dihydroquinolines via an Organocatalytic Aza‐Michael/Michael Cascade Strategy

A synthetic method for the construction of fully substituted enantioenriched 1,4‐dihydroquinolines using an organocatalytic aza‐Michael/Michael cascade reaction has been developed. The asymmetric reaction of 2‐(tosylamino)phenyl α,β‐unsaturated ketones with alkynyl aldehydes, promoted by diphenylprolinol O‐TMS ether as an organocatalyst, generated chiral 1,4‐dihydroquinolines in good to high yields with excellent enantioselectivities (up to 97 % ee).

     

Highly Enantioselective Michael Addition Reactions of 3‐Substituted Benzofuran‐2(3H)‐ones to Chalcones Catalyzed by a Chiral Alkyl‐Substituted Thiourea

A highly enantioselective Michael addition of 3‐substituted benzofuran‐2(3H)‐ones to chalcones catalyzed by a chiral bifunctional thiourea was developed. Several chiral 3,3′‐substituted benzofuran‐2(3H)‐ones derivatives, bearing adjacent quaternary‐tertiary stereocenters, were efficiently synthesized with excellent enantioselectivities.     

Facile Construction of Vicinal Quaternary and Tertiary Stereocenters via Regio‐ and Stereoselective Organocatalytic Michael Addition to Nitrodienes

A highly regio‐ and stereoselective protocol for the synthesis of vicinal quaternary and tertiary stereocenters has been developed. The 6′‐OH Cinchona alkaloids ( BnCPN or BnCPD ) at low catalyst loading (0.5–5 mol%) catalyze the Michael addition of trisubstituted carbon nucleophiles to nitrodienes in good to excellent yield (up to >99), high enantioselectivity (up to 99% ee) and high diastereoselectivity (up to >99:1 dr) under mild reaction conditions.     

Quinine‐Catalyzed Enantioselective Michael Addition of Diphenyl Phosphite to Nitroolefins: Synthesis of Chiral Precursors of α‐Substituted β‐Aminophosphonates

A quinine‐promoted, enantioselective Michael addition reaction of diphenyl phosphite with nitroalkenes has been developed. This methodology affords a facile access to enantiomerically enriched β‐nitrophosphates, precursors for the preparation of synthetically and biologically useful β‐aminophosphonates.     

Asymmetric Synthesis of 3,4‐Dihydrocoumarins Bearing an α,α‐Disubstituted Amino Acid Moiety

An organocatalytic approach for the stereoselective synthesis of 3,4‐dihydrocoumarins with an α,α‐disubstituted amino acid moiety incorporated is presented. The developed methodology is based on the cascade reaction between α‐substituted azlactones and 2‐hydroxychalcones. It is initiated by a chiral Brønsted base‐catalyzed enantio‐ and diastereoselective Michael reaction followed by the azlactone ring opening to construct a 3,4‐dihydrocoumarin framework. Products bearing two adjacent stereogenic centers, one being quaternary, were formed with high enantioselectivities and excellent diastereoselectivities. Furthermore, the complete regioselectivity of the new cascade reactivity is worthy of notice.

     

Stereoselective thia‐Michael 1,4‐Addition to Acyclic 2,4‐Dienones and 2‐En‐4‐ynones

Organocatalyzed highly stereoselective 1,4‐thia‐Michael addition of mercaptans to linear 2,4‐dienones and 2‐en‐4‐ynones was developed using Cinchona alkaloid‐based squaramides. Application of only 0.5–1 mol % loading afforded products in up to 98:2 e.r. and above 99:1 after a single recrystallization. The adducts of allyl mercaptan can be conveniently further transformed to new chiral 2‐substituted 2,5‐dihydrothiophenes by ring‐closing metathesis.

     

A Rhodium‐Catalyzed Tandem Alkyne Dimerization/ 1,4‐Addition Reaction

A convenient three‐component coupling reaction for the construction of conjugated enynes using rhodium catalysis is reported. Dimerization of a monosubstituted alkyne followed by trapping of the vinyl metal intermediate with an electron‐deficient alkene, such as methyl vinyl ketone, provided moderate to good yields of these enynes. The use of the hindered electron‐rich tris(ortho‐tolyl)phosphine as a ligand for the rhodium catalyst provided the best conversions to these complex products.

     

Prolylprolinol‐Catalyzed Asymmetric Michael Addition of Aliphatic Aldehydes to Nitroalkenes

Several novel prolylprolinol catalysts have been designed and synthesized. This type of compound showed high catalytic efficiency on promoting the direct addition of unmodified aldehydes to nitroalkenes. Among the catalysts surveyed, the least bulky member ( 8d ) exhibited the best performance on both efficiency and stereoselectivity, providing the products with up to 97% ee value with 1.5–5 mol% catalyst loading. Additionally, computational studies of the transition state have been conducted to explain the high diastereo‐ and enantioselectivity.