Phosphine-Catalyzed Stereospecific and Enantioselective Desymmetrizative [3+2] Cycloaddition of MBH Carbonates and N-(2-tert-Butylphenyl)maleimides.

Herein, we report an l-valine-derived amide phosphine-catalyzed [3+2] cyclization of MBH carbonates and N-(2-tert-butylphenyl)maleimides via asymmetric desymmetrization. Bicyclic N-aryl succinimide derivatives bearing three continuous chiral centers with a remote C-N atropisomeric chirality were constructed stereospecifically and enantioselectively. A wide variety of MBH carbonates could be employed in this process to deliver highly optically pure succinimide derivatives in moderate to excellent yields.

Rapid Construction of Tricyclic Furanobenzodihydropyrans by Asymmetric Tandem Reaction.

A process based on the organocatalyzed Mannich/cycloketalization/transesterification tandem reaction of 1-(2-hydroxyaryl)-1,3-diketones and ß,γ-alkynyl α-imino esters has been developed, delivering a variety of tricyclic furanobenzodihydropyrans with excellent results (up to 99% yield, 99% ee, and >19:1 dr).

Construction of Enantioenriched Quaternary C-Cl Oxindoles through Palladium-Catalyzed Asymmetric Allylic Substitution with Chloroenolates.

A palladium-catalyzed asymmetric chloroenolate allylation with vinyl benzoxazinanones under mild reaction conditions has been developed, affording a series of optically active 3,3-disubstituted oxindoles exhibiting a chloro-group and a linear aryl amino side chain in good yields with up to 96% ee. Versatile functional group tolerance on the benzene ring has been demonstrated, and the utility of this method was probed by a scale-up synthesis and highlighted by product derivatizations.

Palladium-Catalyzed Selective [2 + 2 + 2] Annulation of 2-(2-Enynyl)pyridines with Arynes.

The palladium-catalyzed chemo- and stereoselective [2 + 2 + 2] annulation reaction of 2-(2-enynyl)pyridines with arynes has been developed. A wide range of (E)- or (E/Z)-isomers of 2-(2-enynyl)pyridines and arynes was tolerated, providing a spectrum of (E)-phenanthrenylated 2-alkenylpyridines in good yield, together with the generation of a chiral axis between an alkene and a phenanthrene ring.

Divergent, Enantioselective Synthesis of Pyrroles, 3H-Pyrroles and Bicyclic Imidazolines by Ag- or P-Catalyzed [3+2] Cycloaddition of Allenoates with Activated Isocyanides.

The divergent, stereoselective formal [3+2] cycloadditions of allenoates with activated isocyanides catalyzed by silver or phosphine-based catalysts were investigated. Silver catalysis is capable of delivering a range of 3H-pyrroles in high stereoselectivities. These enantioenriched heterocycles can either undergo sequential cyclisation with isocyanoacetates to deliver unprecedented bicyclic imidazolines with excellent yields and stereoselectivity or undergo unusual aromatization pathways leading to polysubstituted pyrroles. On the other hand, a simple mix-and-go procedure using an amino acid-derived phosphine as the catalyst produces pyrroles bearing a benzylic stereocenter with good enantioselectivity.

Amino Acid-Derived Bifunctional Phosphines for Enantioselective Transformations.

Even though seminal reports on phosphine catalysis appeared in the 1960s, in the last few decades of the past century trivalent phosphines were viewed primarily as useful ligands for transition-metal-mediated processes. The 1990s saw revived interest in using phosphines in organic catalysis, but the key advances in asymmetric phosphine catalysis have all come within the past decade. The uniqueness of phosphine catalysis can be attributed to the high nucleophilicity of the phosphorus atom. In typical phosphine-catalyzed reactions, nucleophilic attacks of the phosphorus atom on electron-deficient multiple bonds create different reactive ylide-type intermediates. When such structurally diverse zwitterionic species react with a variety of suitable substrates, new reaction patterns are often discovered and a diverse array of reactions can be developed. In recent years, substantial progress has been made in the field of asymmetric phosphine catalysis; many new reactions have been discovered, and numerous enantioselective processes have been reported. However, we felt that powerful and versatile phosphine catalysts that can work for a wide range of asymmetric reactions are still lacking. We therefore set our goal to develop a family of easily derived phosphine catalysts that are efficient in asymmetric induction for a broad range of phosphine-mediated transformations. This Account describes our efforts in the past few years on the development of amino acid-based bifunctional phosphines and their applications to enantioselective processes. Building upon our previous success in primary-amine-mediated enamine catalysis, we first established that bifunctional phosphines could be readily prepared from amino acids. In most of our studies, we chose threonine as the key backbone for catalyst development, and threonine-based monoamino acid or dipeptide bifunctional phosphines have displayed remarkable stereochemical control. We began our investigations by demonstrating the usefulness of our phosphine catalysts in aza-Morita-Baylis-Hillman (aza-MBH) and MBH reactions. We then showed the great power of amino acid/dipeptide phosphines in a wide range of [3 + 2] annulation processes, including [3 + 2] cycloaddition of allenoates to acrylates/acrylamides, [3 + 2] annulation of imines with allenoates, and [3 + 2] cyclization employing MBH carbonates and activated alkenes. By utilizing α-substituted allenoates and activated alkenes, we developed an enantioselective [4 + 2] annulation to access functionalized cyclohexenes. We also devised a novel enantioselective [4 + 2] annulation process by using α-substituted allenones for the construction of 3,4-dihydropyrans. With the use of ß'-acetate allenoate, a [4 + 1] annulation process has been designed to access chiral spiropyrazolones. Another array of reactions that make use of the basicity of zwitterionic phosphonium enolate intermediates have been successfully attained, including the first phosphine-catalyzed asymmetric Michael addition, enantioselective allylic substitution of MBH carbonates by phthalides, and enantioselective γ-additions of prochiral 3-substituted oxindoles, 5H-thiazol-4-ones, 5H-oxazol-4-ones, and oxazol-5-(4H)-ones to 2,3-butadienoates. Bifunctional modes of action in our reported reactions have been supported by experimental results and theoretical studies. With the establishment of the new families of powerful amino acid-derived bifunctional phosphines, the discovery of new modes of phosphine activation, unknown reactions, and more enantioselective processes are well-anticipated.

Enantioselective Phosphine-Catalyzed Formal [4+4] Annulation of α,ß-Unsaturated Imines and Allene Ketones: Construction of Eight-Membered Rings.

The first highly enantioselective phosphine-catalyzed formal [4+4] annulation has been developed. In the presence of amino-acid-derived phosphines, the unprecedented [4+4] annulations between benzofuran/indole-derived α,ß-unsaturated imines and allene ketones proceeded smoothly, thus affording azocines, bearing either a benzofuran or an indole moiety, in excellent yields and with nearly perfect enantioselectivities (≥98 % ee in most cases). This work marks the first efficient asymmetric construction of optically enriched eight-membered rings by phosphine catalysis.

Phosphine-mediated Highly Enantioselective Spirocyclization with Ketimines as Substrates.

Phosphine-catalyzed enantioselective annulation reactions involving ketimines are a daunting synthetic challenge owing to the intrinsic low reactivity of ketimine substrates. A highly enantioselective [3+2] cycloaddition reaction that makes use of isatin-derived ketimines as reaction partners was developed. Notably, both simple and γ-substituted allenoates could be utilized, and various 3,2'-pyrrolidinyl spirooxindoles with a tetrasubstituted stereocenter were obtained in excellent yields and with nearly perfect enantioselectivity (>98 % ee in all cases).

Enantioselective [3 + 2] annulation of α-substituted allenoates with ß,γ-unsaturated N-sulfonylimines catalyzed by a bifunctional dipeptide phosphine.

The first enantioselective [3 + 2] annulation of α-substituted allenoates with ß,γ-unsaturated N-sulfonylimines is described. In the presence of a dipeptide phosphine catalyst, a wide range of highly functionalized cyclopentenes bearing an all-carbon quaternary center were obtained in moderate to good yields and with good to excellent enantioselectivities.

Highly enantioselective synthesis of 3,4-dihydropyrans through a phosphine-catalyzed [4+2] annulation of allenones and ß,γ-unsaturated α-keto esters.

A phosphine-catalyzed novel [4+2] annulation process was devised employing allene ketones as C2 synthons and ß,γ-unsaturated α-keto esters as C4 synthons. In the presence of an L-threonine-derived bifunctional phosphine, 3,4-dihydropyrans were obtained in high yields and with virtually perfect enantioselectivities. The synthetic value of the dihydropyran motif was demonstrated by a concise preparation of an anti-hypercholesterolemic agent.

Phosphine-catalyzed enantioselective γ-addition of 3-substituted oxindoles to 2,3-butadienoates and 2-butynoates: use of prochiral nucleophiles.

The first phosphine-catalyzed enantioselective γ-addition with prochiral nucleophiles and 2,3-butadienoates as the reaction partners has been developed. Both 3-alkyl- and 3-aryl-substituted oxindoles could be employed in this process, which is catalyzed by a chiral phosphine that is derived from an amino acid, thus affording oxindoles that bear an all-carbon quaternary center at the 3-position in high yields and excellent enantioselectivity. The synthetic value of these γ-addition products was demonstrated by the formal total synthesis of two natural products and by the preparation of biologically relevant molecules and structural scaffolds.

Asymmetric synthesis of spiropyrazolones through phosphine-catalyzed [4+1] annulation.

An enantioselective synthesis of spiropyrazolones from allenoate-derived MBH acetates and pyrazolones through a phosphine-mediated [4+1] annulation process has been developed. Spiropyrazolones were readily prepared in good chemical yields and good to high enantioselectivities. This is the first asymmetric example in which α-substituted allenoates were utilized as a C4 synthon for phosphine-catalyzed [4+1] annulation.

Accessing ladder-shape azetidine-fused indoline pentacycles through intermolecular regiodivergent aza-Paternò-Büchi reactions.

Small molecules with conformationally rigid, three-dimensional geometry are highly desirable in drug development, toward which a direct, simple-to-complexity synthetic logic is still of considerable challenges. Here, we report intermolecular aza-[2 + 2] photocycloaddition (the aza-Paternò-Büchi reaction) of indole that facilely assembles planar building blocks into ladder-shape azetidine-fused indoline pentacycles with contiguous quaternary carbons, divergent head-to-head/head-to-tail regioselectivity, and absolute exo stereoselectivity. These products exhibit marked three-dimensionality, many of which possess 3D score values distributed in the highest 0.5% region with reference to structures from DrugBank database. Mechanistic studies elucidated the origin of the observed regio- and stereoselectivities, which arise from distortion-controlled C-N coupling scenarios. This study expands the synthetic repertoire of energy transfer catalysis for accessing structurally intriguing architectures with high molecular complexity and underexplored topological chemical space.

Electric charging effects on insulating surfaces in cryogenic liquids.

This paper presents a new technique to study the adsorption and desorption of ions and electrons on insulating surfaces in the presence of strong electric fields in cryoliquids. The experimental design consists of a compact cryostat coupled with a sensitive electro-optical Kerr device to monitor the stability of the electric fields. The behavior of nitrogen and helium ions on a poly(methyl methacrylate) (PMMA) surface was compared to a PMMA surface coated with a mixture of deuterated polystyrene and deuterated polybutadiene. Ion accumulation and removal on these surfaces were unambiguously observed. Within the precision of the data, both surfaces behave similarly for the physisorbed ions. The setup was also used to measure the (quasi-)static dielectric constant of PMMA at T ≈ 70 K. The impact of the ion adsorption on the search for a neutron permanent electric dipole moment in a cryogenic environment, such as the nEDM@SNS experiment, is discussed.

Divergent NHC-catalyzed oxidative transformations of 3-bromoenal: selective synthesis of 2H-pyran-2-ones and chiral dihydropyranones.

A selective synthesis of either 2H-pyran-2-ones (4) or chiral dihydropyranones (6) from the same substrates of 3-bromoenals and 1,3-dicarbonyl compounds upon oxidative N-heterocyclic carbene catalysis is presented. It is shown that the oxidative transformation of 3-bromoenals under NHC catalyst can be well controlled to proceed through two pathways, i.e., elimination of reducible ß-bromide or by an external oxidant 3, allowing the selective generation two sorts of unsaturated acyl azoliums, respectively.

Visible-Light-Induced Radical gem-Iodoallylation of 2,2,2-Trifluorodiazoethane.

A visible-light-induced radical gem-iodoallylation of CF3CHN2 was developed under mild conditions, delivering a variety of α-CF3-substituted homoallylic iodide compounds in moderate to excellent yields. The transformation features broad substrate scope, good functional group compatibility, and operational simplicity. The described protocol provides a convenient and attractive tool to apply CF3CHN2 as CF3-introduction reagent in radical synthetic chemistry.

Phosphine-catalyzed Rauhut-Currier reaction of γ-alkyl allenoate and subsequent trapping using the Diels-Alder reaction.

We have disclosed a Rauhut-Currier reaction of γ-alkyl-substituted allenoate, catalyzed by L-valine-derived amide phosphine, to form trisubstitued allenoate, which was trapped by maleimide or DMAD via the Diels-Alder reaction. Exo-bicyclic succinimide derivatives including three continuous stereocenters with an exo-carbon-carbon double bound were constructed in up to quantitative yields with high stereospecificity.

Synthesis of Fluorinated Pyrrolo[2,1-a]isoquinolines through Decarboxylative/Dehydrofluorinative [3 + 2] Cycloaddition Aromatization of Isoquinolinium N-Ylides with Difluoroenoxysilanes.

A decarboxylative/dehydrofluorinative formal [3 + 2] cycloaddition aromatization of isoquinolinium N-ylides with difluoroenoxysilanes has been developed. This methodology provides a facile and straightforward synthetic pathway to afford highly functionalized fluorinated pyrrolo[2,1-a]isoquinolines in good to excellent yields under mild conditions. Moreover, gram-scale and synthetic derivatization experiments for the late-stage functionalization of drug molecules have also been demonstrated.

Asymmetric Synthesis of Multicyclic Spirooxindole Derivatives Bearing Stereogenic Quaternary Carbon Atoms.

An organocatalyzed stereoselective domino reaction as a facile approach to multicyclic spirooxindole derivatives bearing two stereogenic quaternary carbon atoms is reported. The alkyl-substituted chiral thiourea catalyst was efficient for the reaction to tolerate a wide range of substrates, furnishing a new class of spirooxindole derivatives bearing an O,O-acetal-fused tricyclic skeleton or tetrahydroxanthone moiety in moderate to good yields with good to excellent selectivities. The products generated from this method have promising anticancer activities.

Enantioselective Construction of C4-Quaternary Quinolinones via Copper(II)-Catalyzed Asymmetric [1,3] O-to-C Rearrangement.

An efficient asymmetric [1,3] O-to-C rearrangement of quinolin-2(1H)-ones enabled by a chiral bisoxazoline/copper complex has been developed. This strategy tolerated a wide range of substrates to provide a series of 1,4-dihydroquinoline-2,3-diones containing a quaternary stereocenter. A further cyclization of the [1,3] O-to-C rearrangement products was also realized, which led to various optically active 3,4-dihydroquinolin-2-ones with broad substrate scope.