Construction of 1,3-Nonadjacent Stereogenic Centers Through Enantioselective Addition of α-Thioacetamides to α-Substituted Vinyl Sulfones Catalyzed by Chiral Strong Brønsted Base.

An enantioselective addition reaction for the construction of 1,3-nonadjacent stereogenic centers is developed by means of a chiral strong Brønsted base catalyst. The chiral sodium ureate catalyst efficiently promoted the reaction of α-thioacetamides as less acidic pronucleophiles with vinyl sulfones having a variety of α-substituents including aryl, alkyl and halo groups, and α-phenylacrylates, accomplishing the construction of various 1,3-nonadjacent stereogenic centers in highly diastereo- and enantioselective manners. This is a rare example of the construction of 1,3-nonadjacent stereogenic centers with less acidic pronucleophiles. In addition, the application of Michael acceptors having various types of α-substituents in a single catalyst system is achieved for the first time, demonstrating the utility of the present catalyst system for the construction of 1,3-nonadjacent stereogenic centers.

Enantioselective direct Michael addition of cyanohydrin ether derivatives to enones catalyzed by chiral bis(guanidino)iminophosphorane organosuperbase.

The direct use of cyanohydrin ether derivatives as less acidic pronucleophiles was achieved for the first time in the catalytic enantioselective Michael addition reaction under transition metal free conditions. Chiral bis(guanidino)iminophosphoranes as the higher order organosuperbase facilitated the intended catalytic Michael addition to enones, giving rise to the corresponding products in high yields with moderate to high diastereo- and enantioselectivities in most cases. Further elaboration of the corresponding enantioenriched product was conducted by derivatization into a lactam derivative through hydrolysis followed by cyclo-condensation.

Synthesis of Polysubstituted Naphthofurans and Indenofurans Based on a Regiodivergent Intramolecular Carbometalation Strategy with 2-(2'-Alkynylaryl)-3-iodofurans.

Efficient methods for the synthesis of two types of furan-fused tricyclic compounds were developed based on a regiodivergent intramolecular carbometalation strategy using 2-(2'-alkynylaryl)-3-iodofurans as a common substrate. The iodine-magnesium exchange/copper-mediated 6-endo-anti intramolecular carbometalation sequence followed by nucleophilic substitution or palladium-catalyzed cross-coupling provided 2,3,4,5-tetrasubstituted naphtho[1,2-b]furans. On the other hand, the formal intramolecular 5-exo-anti carbopalladation/cross-coupling sequence afforded 2,3-disubstituted 4-alkylidene-4H-indeno[1,2-b]furans. The present methods provide new access to a wide range of well-organized polysubstituted naphtho[1,2-b]furans and indeno[1,2-b]furans in a positional selective manner that are otherwise difficult to access.

Formal Umpolung Addition of Phosphites to 2-Azaaryl Ketones under Chiral Brønsted Base Catalysis: Enantioselective Protonation Utilizing [1,2]-Phospha-Brook Rearrangement.

The formal enantioselective umpolung addition of dialkyl phosphites to 2-azaaryl ketones was developed under Brønsted base catalysis. The reaction involves the enantioselective protonation of the transient α-oxygenated (2-azaaryl)methyl anion generated through the 1,2-addition of the anion of dialkyl phosphite to the 2-azaaryl ketone and the subsequent [1,2]-phospha-Brook rearrangement. A chiral bis(guanidino)iminophosphorane organosuperbase efficiently catalyzed the reaction to provide enantio-enriched phosphates in high yields with good to high enantioselectivities. This is a rare example of the catalytic enantioselective protonation of transient carbanions other than enolates, constructing a trisubstituted stereogenic center α to 2-azaarenes.

Synthesis of 2,2-Disubstituted 2H-Chromenes through Carbon-Carbon Bond Formation Utilizing a [1,2]-Phospha-Brook Rearrangement under Brønsted Base Catalysis.

A new methodology for the synthesis of 2,2-disubstituted 2H-chromenes was developed by utilizing the [1,2]-phospha-Brook rearrangement under Brønsted base catalysis. Phosphazene P2-tBu efficiently catalyzed the addition reaction of 4H-chromen-4-ols containing a diethoxyphosphoryl group with α,ß-unsaturated ketones, which involved the catalytic generation of a carbanion through the [1,2]-phospha-Brook rearrangement and subsequent conjugate addition at the 2-position to afford adducts possessing an alkenylphosphate moiety in a highly diastereoselective manner. Further transformation of the adducts based on a nickel-catalyzed cross-coupling reaction with arylzinc reagents provided densely functionalized 2,2-disubstituted 2H-chromenes.

Brønsted base-catalyzed 1,2-addition/[1,2]-phospha-Brook rearrangement sequence providing functionalized phosphonates.

A new methodology for the introduction of functional groups into an organic molecule in which a keto or a formyl group is used as the connecting site was developed by utilizing the 1,2-addition/[1,2]-phospha-Brook rearrangement sequence under Brønsted base catalysis. The reaction of aromatic aldehydes and ketones with phosphinates having functional groups such as alkynyl, bromoalkyl, N-Boc amino, and boryl groups efficiently proceeded with the aid of phosphazene base P2-tBu as the catalyst, providing densely functionalized phosphonates in good yields.

Formal Fluorinative Ring Opening of 2-Benzoylpyrrolidines Utilizing [1,2]-Phospha-Brook Rearrangement for Synthesis of 2-Aryl-3-fluoropiperidines.

A ring expansion of 2-benzoylpyrrolidines, which involves the formal fluorinative ring opening utilizing the [1,2]-phospha-Brook rearrangement under Brønsted base catalysis and a subsequent intramolecular reductive amination, was developed. The operationally simple three-step protocol provides an efficient access to 2-aryl-3-fluoropiperidines. The methodology was further applied to the syntheses of azepanes and tetrahydroquinolines.

Brønsted Base-Catalyzed Formal Reductive [3+2] Annulation of 4,4,4-Trifluorocrotonate and α-Iminoketones.

A formal reductive [3+2] annulation of 4,4,4-trifluorocrotonate and α-iminoketones was developed under Brønsted base catalysis. A single phosphazene base efficiently catalyzes the one-pot tandem reaction involving two mechanistically different elementary processes, namely the chemoselective reduction of an imine moiety of α-iminoketones with thiols as the reductant and the subsequent intermolecular Michael addition of an enolate of α-aminoketones concomitant with lactam formation. This operationally simple method provides ß-trifluoromethyl-substituted γ-lactams with a tetrasubstituted carbon as a single diastereomer.

Enantioselective Protonation: Hydrophosphinylation of 1,1-Vinyl Azaheterocycle N-Oxides Catalyzed by Chiral Bis(guanidino)iminophosphorane Organosuperbase.

Enantioselective protonation by hydrophosphinylation of diarylphosphine oxides with 2-vinyl azaheterocycle N-oxide derivatives was demonstrated using chiral bis(guanidino)iminophosphorane as the higher-order organosuperbase catalyst. It was confirmed by several control experiments that a chiral weak conjugate acid of the chiral bis(guanidino)iminophosphorane, instead of achiral diarylphosphine oxides, directly functioned as the proton source to afford the corresponding product in a highly enantioselective manner in most cases. Enantioselective protonation by a weak conjugate acid generated from the higher-order organosuperbase would broaden the scope of enantioselective reaction systems because of utilization of a range of less acidic pronucleophiles. This method is highlighted by the valuable synthesis of a series of chiral P,N-ligands for chiral metal complexes through the reduction of phosphine oxide and N-oxide units of the corresponding product without loss of enantiomeric purity.

Synthesis of diarylalkanes through an intramolecular/intermolecular addition sequence by auto-tandem catalysis with strong Brønsted base.

An auto-tandem catalysis with a strong Brønsted base enabled the synthesis of diarylalkanes containing a benzofuran moiety. Potassium tert-butoxide efficiently catalyzed both the intramolecular cyclization of less acidic ortho-alkynylaryl benzyl ethers and the following intermolecular addition of diarylmethanes to styrenes, demonstrating the high potential of the catalysis in organic synthesis.

Enantioselective hydrophosphinylation of 1-alkenylphosphine oxides catalyzed by chiral strong Brønsted base.

A catalytic enantioselective addition of diarylphosphine oxides to 1-alkenyl(diaryl)phosphine oxides was achieved by using a chiral ureate as a chiral strong Brønsted base catalyst. The reaction followed by the reduction of phosphine oxide moieties provided chiral 1,2-diphosphinoalkanes, which are a family of useful chiral ligands for asymmetric transition metal catalysis.

Brønsted Base-Catalyzed Transformation of α,ß-Epoxyketones Utilizing [1,2]-Phospha-Brook Rearrangement for the Synthesis of Allylic Alcohols Having a Tetrasubstituted Alkene Moiety.

A stereoselective transformation of α,ß-epoxyketones into alkenylphosphates having a hydroxymethyl group on the ß-carbon was established by utilizing the [1,2]-phospha-Brook rearrangement under Brønsted base catalysis. The reaction involves the catalytic generation of an α-oxygenated carbanion located at the α-position of an epoxide moiety through the [1,2]-phospha-Brook rearrangement and the following epoxide opening. Further transformation of the alkenylphosphates by the palladium-catalyzed cross-coupling reaction with Grignard reagents provided allylic alcohols having a stereodefined all-carbon tetrasubstituted alkene moiety.

Synthesis of Tetrasubstituted Furans through One-Pot Formal [3 + 2] Cycloaddition Utilizing [1,2]-Phospha-Brook Rearrangement.

An efficient method for the synthesis of tetrasubstituted furans was developed by utilizing the [1,2]-phospha-Brook rearrangement under Brønsted base catalysis. The two-step one-pot formal [3 + 2] cycloaddition involves the nucleophilic addition of a propargyl anion, which is catalytically generated through the [1,2]-phospha-Brook rearrangement, to an aldehyde and the subsequent intramolecular cyclization mediated by N-iodosuccinimide to provide 2,4,5-trisubstituted-3-iodofurans. The present method with readily available substrates provides new access to a wide range of well-organized tetrasubstituted furans.

Development of Chiral Organosuperbase Catalysts Consisting of Two Different Organobase Functionalities.

In the field of chiral Brønsted base catalysis, a new generation of chiral catalysts has been highly anticipated to overcome the intrinsic limitation of pronucleophiles that are applicable to the enantioselective reactions. Herein, we reveal conceptually new chiral Brønsted base catalysts consisting of two different organobase functionalities, one of which functions as an organosuperbase and the other as the substrate recognition site. Their prominent activity, which stems from the distinctive cooperative function by the two organobases in a single catalyst molecule, was demonstrated in the unprecedented enantioselective direct Mannich-type reaction of α-phenylthioacetate as a less acidic pronucleophile. The present achievement would provide a new guiding principle for the design and development of chiral Brønsted base catalysts and significantly broaden the utility of Brønsted base catalysis in asymmetric organic synthesis.

Development of Chiral Ureates as Chiral Strong Brønsted Base Catalysts.

Recently, chiral Brønsted bases having high basicity have emerged as a powerful tool in developing new catalytic enantioselective reactions. However, such chiral strong Brønsted base catalysts are still very scarce. Herein, we report the development of a chiral anionic Brønsted base having a N,N'-dialkyl ureate moiety as a basic site. Its prominent catalytic activity was demonstrated in the enantioselective addition reactions of α-thioacetamides as less acidic pronucleophiles with various electrophiles. Thus, the newly developed chiral catalyst with high accessibility and structural tunability would expand the scope of viable enantioselective transformations under Brønsted base catalysis.

Organocatalytic Nucleophilic Substitution Reaction of gem-Difluoroalkenes with Ketene Silyl Acetals.

An organocatalytic nucleophilic substitution reaction of gem-difluoroalkenes with ketene silyl acetals was developed. Phosphazene P4- tBu effectively catalyzed the reaction under mild conditions to provide monofluoroalkenes possessing an alkoxycarbonylmethyl group in high yields with high Z selectivities.

Brønsted Base-Catalyzed Reductive Cyclization of Alkynyl α-Iminoesters through Auto-Tandem Catalysis.

A novel reductive cyclization of alkynyl α-iminoesters was developed through auto-tandem catalysis with a Brønsted base as the catalyst. The reaction system involves two mechanistically different elementary processes, both of which are efficiently catalyzed by an organosuperbase P2- tBu: the unprecedented reduction of α-iminoesters with 1-dodecanethiol as the reductant to provide α-aminoesters and the following intramolecular addition of ester enolates to an alkyne. The operationally simple reaction under mild conditions provides new efficient access to N-H indoline derivatives, demonstrating the high potential of auto-tandem catalysis with a Brønsted base as a methodology for organic synthesis.

Enantioselective Intramolecular Nicholas Reaction Catalyzed by Chiral Phosphoric Acid: Enantioconvergent Synthesis of Seven-Membered Cyclic Ethers from Racemic Diols.

An enantioconvergent intramolecular Nicholas reaction of racemic diols was developed using BINOL- and SPINOL-derived phosphoric acids as the chiral Brønsted acid catalyst. The developed reaction features an efficient approach to the synthesis of seven-membered cyclic ethers in a highly enantioselective manner. Further derivatization of the enantioenriched cyclic ethers, initiated by the de-complexation of the dicobalt species, afforded densely functionalized cyclic ethers having an unsaturated diester moiety without loss of enantiomeric excess.

Chiral Brønsted acid-catalyzed intramolecular SN2' reaction for enantioselective construction of a quaternary stereogenic center.

An enantioselective intramolecular anti-SN2' cyclization reaction for the construction of a quaternary stereogenic center was accomplished through the activation of the leaving group using a binaphthol-derived phosphoramide as the chiral Brønsted acid catalyst. The present allylic substitution reaction is beneficial not only for the regioselective nucleophilic substitution at the multi-substituted site of the double bond but also for controlling the stereochemical outcome because of using a geometrically defined double bond. Indeed, the reaction afforded synthetically useful amino alcohol derivatives having a tetra-substituted carbon center in a highly enantioselective manner in most cases, in which the modification of the sulfonamide unit of the phosphoramide catalyst was demonstrated to improve the enantioselectivity. Experimental and theoretical elucidation of the reaction mechanism suggested that the reaction proceeds through a synchronous anti-SN2' pathway, although NMR monitoring of the reaction indicated the formation of the phosphorimidate ester via the SN2 reaction of the catalyst with the substrate, which results in catalyst deactivation. Further theoretical studies of the origin of the stereochemical outcome at the generated quaternary stereogenic center were performed. Structural analysis of the transition states at the enantio-determining step revealed that the distinct discrimination of the substituents attached to the geometrically defined double bond is achieved by the anthryl and sulfonamide substituents of the catalyst through the three-point hydrogen bonding interactions and the T-shaped C-H···π interactions.

Efficient Synthesis of Polysubstituted Pyrroles Based on [3+2] Cycloaddition Strategy Utilizing [1,2]-Phospha-Brook Rearrangement under Brønsted Base Catalysis.

An efficient method for the synthesis of polysubstituted pyrroles was established based on the [3+2] cycloaddition strategy utilizing the [1,2]-phospha-Brook rearrangement under Brønsted base catalysis. The less-explored approach of the [3+2] cycloaddition, that is, the reaction of a C3 subunit with imines, was successfully achieved by making use of newly designed C3 subunits containing the requisite umpolung. The two-step formal [3+2] cycloaddition involves the catalytic generation of an α-oxygenated propargyl anion through the [1,2]-phospha-Brook rearrangement followed by γ-addition to the imine under Brønsted base catalysis and the subsequent intramolecular cyclization mediated by Au catalyst or a halogenation reagent to afford polysubstituted pyrroles having a variety of substituents in a positional selective manner. The pyrroles thus synthesized were amenable to further transformations, such as palladium-catalyzed cross-coupling reactions. The operationally very simple method with readily available substrates provides new access to a diverse array of well-organized polysubstituted pyrroles.