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.

     

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.     

Catalytic Asymmetric β‐Peroxidation of Nitroalkenes

The first example of an asymmetric β‐peroxidation of nitroalkenes is disclosed. The reaction is promoted by catalytic loadings of a commercially available diaryl‐2‐pyrrolidinemethanol derivative and tert‐butyl hydroperoxide as the oxidant. A synthetically useful class of peroxides is obtained in good yield and enantioselectivity (up to 84% ee).     

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.     

Catalytic Enantioselective Addition of Pyrazol‐5‐ones to Trisubstituted Nitroalkenes with an N‐Sulfinylurea Organocatalyst

The first example of enantioselective nitronate protonation following Michael addition of a carbon nucleophile to an α,β,β‐trisubstituted nitroalkene is reported. An N‐sulfinylurea catalyst was employed to catalyze the addition of a variety of 3‐substituted pyrazol‐5‐one nucleophiles to trisubstituted nitroalkenes incorporating an oxetane or azetidine ring at the β‐position. The nitroalkane‐pyrazolone adducts were obtained with good yield and enantioselectivity. Furthermore, the Michael addition products can be reduced to the corresponding enantioenriched amines with minimal loss of enantiomeric purity.

     

A Polystyrene‐Supported,Highly Recyclable Squaramide Organocatalyst for the Enantioselective Michael Addition of 1,3‐Dicarbonyl Compounds to β‐Nitrostyrenes

A chiral squaramide has been supported onto a polystyrene (PS) resin through a copper‐catalyzed azide–alkyne cycloaddition (CuAAC) reaction and used as a very active, easily recoverable and highly reusable organocatalyst for the asymmetric Michael addition of 1,3‐dicarbonyl compounds to β‐nitrostyrenes. The PS‐supported squaramide could be recycled up to 10 times.     

Highly Efficient Ion‐Tagged Catalyst for the Enantioselective Michael Addition of Aldehydes to Nitroalkenes

The ion‐tagged diphenylprolinol silyl ether 6 very efficiently catalyzes the asymmetric Michael addition of aliphatic aldehydes to nitroalkenes with ee of up to>99.5% at low catalyst loadings (0.25–5 mol%) and using only a slight excess of aldehydes (1.2–2 equiv.). This new organocatalyst can be used with the same outstanding efficiency in a wide variety of solvents and 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.     

Direct and Enantioselective Vinylogous Michael Addition of α‐Alkylidenepyrazolinones to Nitroolefins Catalyzed by Dual Cinchona Alkaloid Thioureas

While several protocols exist for the asymmetric functionalization of pyrazolinones at the α‐position relying on nucleophilic addition or annulation procedures, use of α‐alkylidene electron‐rich analogues in asymmetric vinylogous coupling to carbon electrophiles is substantially an uncharted domain. We now report, for the first time, that alkylidenepyrazolinones carrying an enolizable carbon at the γ‐position efficiently participate in direct and asymmetric, catalytic vinylogous Michael‐type additions to nitroolefins providing the expected adducts in high yields, with complete γ‐site selectivity and with extraordinary levels of enantio‐, diastereo‐, and geometrical selectivities. Both enantiomeric adducts were equally accessed by employing a quasi‐enantiomeric quinine‐ or quinidine‐based thiourea catalyst pair.

     

A Bifunctional Cinchona Alkaloid‐Squaramide Catalyst for the Highly Enantioselective Conjugate Addition of Thiols to trans‐Chalcones

A chiral squaramide catalysts‐promoted asymmetric sulfa‐Michael conjugated addition of thiols to trans‐chalcones is presented. Moderate to excellent yields and high enantioselectivities (up to 99% ee) were achieved under mild conditions.     

Palladium‐Catalyzed Asymmetric 1,4‐Addition of Diarylphosphines to Nitroalkenes for the Synthesis of Chiral P,N‐Compounds

A highly stereoselective asymmetric 1,4‐addition of diarylphosphines to nitroalkenes catalyzed by a bis(phosphine) pincer‐palladium complex has been developed for the synthesis of chiral P,N compounds with good to excellent enantioselectivities (up to 94% ee) under mild conditions.     

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.

     

Deoxycholic Acid‐Derived Biaryl Phosphites as Versatile and Enantioselective Ligands in the Rhodium‐Catalyzed Conjugate Addition of Arylboronic Acids to Nitroalkenes

A highly enantioselective conjugate addition of arylboronic acids to cyclic as well as acyclic aromatic and aliphatic nitroalkenes is presented. The rhodium complexes obtained from deoxycholic acid‐derived binaphthyl and flexible biphenyl phosphites showed good activity as well as very high enantioselectivity (ee up to 99%) in the conjugated addition even in the presence of challenging substrates such as 1‐nitrocyclohexene or aliphatic acyclic nitroalkenes.

     

Asymmetric Synthesis of 2,3,4‐Trisubstituted Functionalised Tetrahydrofurans via an Organocatalytic Michael Addition as Key Step

The organocatalytic Michael addition of various aldehydes to (2E,4E)‐ethyl 5‐nitropenta‐2,4‐dienoate has been achieved under the catalysis of diphenylprolinol trimethylsilyl ether furnishing the products in good to excellent yields (61–94%) and high stereoselectivities (dr up to >98:2, ee=97 to >99%). Starting from these Michael adducts, 2,3,4‐trisubstituted functionalized tetrahydrofurans are available in two steps by reduction of the aldehyde followed by an intramolecular oxa‐Michael addition in good yields (54–76%) and stereoselectivities (dr up to >95:5, ee=97 to >99%).     

Iridium‐Catalyzed Enantioselective Hydrogenation of β,β‐Disubstituted Nitroalkenes

A highly efficient, iridium‐catalyzed, enantioselective hydrogenation of β,β‐disubstituted nitroalkenes has been developed. Using a complex consisting of iridium and (S,S)‐f‐spiroPhos as the catalyst, a variety of β,β‐disubstituted nitroalkenes were successfully hydrogenated to the corresponding chiral nitroalkanes with excellent enantioselectivities (up to 98% ee) and high turnover numbers (TON=1000).

     

Direct Regio‐, Diastereo‐, and Enantioselective Vinylogous Michael Addition of Prochiral 3‐Alkylideneoxindoles to Nitroolefins

3‐Alkylidene‐2‐oxindoles represent a simple, yet enabling subfamily of indole alkaloids, and their ability to react as electron‐poor acceptors has largely been investigated. In contrast, their utility as pronucleophilic synthons remains elusive. In this context, the present article describes the successful execution of the direct, organocatalytic asymmetric Michael addition of prochiral 3‐alkylideneoxindoles to nitroolefins. A variety of γ‐substituted alkylideneoxindoles carrying two stereocenters at both the γ‐ and δ‐carbon sites was assembled with excellent stereoselectivity and without olefin isomerization or stereochemical ablation.     

Enantioselective Addition of Malonates and β‐Keto Esters to Nitroalkenes over an Organonickel‐Functionalized Periodic Mesoporous Organosilica

A periodic mesoporous organosilica (PMO) with chiral cyclohexyldiamine‐based nickel(II) complexes incorporated within the silica framework was prepared through a co‐condensation of (1R,2R)‐cyclohexyldiamine‐derived silane and Ph‐bridged silane followed by complexation of nickel(II) bromide in the presence of (1R,2R)‐N,N′‐dibenzylcyclohexyldiamine. Structural analyses by X‐ray powder diffraction, nitrogen sorption and transmission electron microscopy disclosed its orderly mesostructure while characterization by solid‐state NMR and X‐ray photoelectron spectroscopy demonstrated the well‐defined single‐site chiral bis(cyclohexyldiamine)‐based nickel(II) active centers incorporated within the PMO material. In particular, as a heterogeneous chiral catalyst, this periodic mesoporous organosilica showed high catalytic activity and excellent enantioselectivity in asymmetric Michael addition of 1,3‐dicarbonyl compounds to nitroalkenes (more than 92% conversions and up to 99% ee values). More importantly, this heterogeneous catalyst could be recovered easily and reused repeatedly nine times without obviously affecting its ee value, showing good potential for industrial applications.     

Enantioselective Organocatalytic Michael Addition of Cyclobutanones to Nitroalkenes

Synthetic applications of cyclobutanones other than ring expansion and fragmentation reactions are rare. Herein, highly efficient diastereo‐ and enantioselective organocatalytic Michael additions of 2‐substituted cyclobutanone derivatives to nitroalkenes are reported allowing the stereocontrolled creation of ‘all‐carbon’ quaternary centers. The approach relies on both the use of Brønsted base/hydrogen‐bond donor bifunctional organocatalysts, and importantly, the specific stabilization and activation of cyclobutanone with a secondary amide moiety. The reaction was found to nicely accommodate a broad scope of substrates, allowing the control of up to three contiguous stereogenic centers. This work has opened new synthetic opportunities.