Catalytic Generation of Benzyl Anions from Aryl Ketones Utilizing [1,2]-Phospha-Brook Rearrangement and Their Application to Synthesis of Tertiary Benzylic Alcohols.

A synthetic method of tertiary alcohols was developed based on the formal umpolung addition of aryl ketones with electrophiles utilizing the [1,2]-phospha-Brook rearrangement under Brønsted base catalysis. The addition reaction of α-hydroxyphosphonates, derived from alkyl aryl- and diaryl ketones, with electrophiles such as phenyl vinyl sulfone, afforded phosphates having a tertiary alkyl group, which were readily convertible to the corresponding tertiary benzylic alcohols. This operationally simple protocol provides efficient complementary access to tertiary alcohols that are difficult to synthesize by conventional methods.

Development of a flow photochemical process for a π-Lewis acidic metal-catalyzed cyclization/radical addition sequence: in situ-generated 2-benzopyrylium as photoredox catalyst and reactive intermediate.

A flow photochemical reaction system for a π-Lewis acidic metal-catalyzed cyclization/radical addition sequence was developed, which utilizes in situ-generated 2-benzopyrylium intermediates as the photoredox catalyst and electrophilic substrates. The key 2-benzopyrylium intermediates were generated in the flow reaction system through the intramolecular cyclization of ortho-carbonyl alkynylbenzene derivatives by the π-Lewis acidic metal catalyst AgNTf2 and the subsequent proto-demetalation with trifluoroacetic acid. The 2-benzopyrylium intermediates underwent further photoreactions with benzyltrimethylsilane derivatives as the donor molecule in the flow photoreactor to provide 1H-isochromene derivatives in higher yields in most cases than the batch reaction system.

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.

Silver-Catalyzed para-Selective Sulfenyl Group Transfer Reactions of N-Sulfenylanilides.

Silver-catalyzed reactions of N-sulfenylanilides afforded the corresponding p-sulfenylanilides in good to high yields with good para selectivity. The transformation has a high compatibility of functional groups, such as ester, bromo, and iodo groups. Mechanistic studies indicate that the rearrangement reaction proceeds through intermolecular transfer of the sulfenyl group.

Synthesis of meta-Aminophenol Derivatives via Cu-Catalyzed [1,3]-Rearrangement-Oxa-Michael Addition Cascade Reactions.

Cu-catalyzed reactions of N-alkoxy-2-methylanilines and alcohols in the presence of catalytic amounts of IPrCuBr and AgSbF6 afforded the corresponding meta-aminophenol derivatives in good to high yields. These reactions proceed via a [1,3]-rearrangement, in which the alkoxy group migrates from the nitrogen atom to the methyl-substituted ortho position, followed by an oxa-Michael reaction of the resulting ortho-quinol imine intermediate.

Muscle synergies of multidirectional postural control in astronauts on Earth after a long-term stay in space.

Movements of the human biological system have adapted to the physical environment under the 1-g gravitational force on Earth. However, the effects of microgravity in space on the underlying functional neuromuscular control behaviors remain poorly understood. Here, we aimed to elucidate the effects of prolonged exposure to a microgravity environment on the functional coordination of multiple muscle activities. The activities of 16 lower limb muscles of 5 astronauts who stayed in space for at least 3 mo were recorded while they maintained multidirectional postural control during bipedal standing. The coordinated activation patterns of groups of muscles, i.e., muscle synergies, were estimated from the muscle activation datasets using a factorization algorithm. The experiments were repeated a total of five times for each astronaut, once before and four times after spaceflight. The compositions of muscle synergies were altered, with a constant number of synergies, after long-term exposure to microgravity, and the extent of the changes was correlated with the increased velocity of postural sway. Furthermore, the muscle synergies extracted 3 mo after the return were similar in their activation profile but not in their muscle composition compared with those extracted in the preflight condition. These results suggest that the modularity in the neuromuscular system became reorganized to adapt to the microgravity environment and then possibly reoptimized to the new sensorimotor environment after the astronauts were reexposed to a gravitational force. It is expected that muscle synergies can be used as physiological markers of the status of astronauts with gravity-dependent change.NEW & NOTEWORTHY The human neuromuscular system has adapted to the gravitational environment on Earth. Here, we demonstrated that prolonged exposure to a microgravity environment in space changes the functional coordination of multiple muscle activities regarding multidirectional standing postural control. Furthermore, the amount of change led to a greater regulatory balancing activity needed for postural control immediately after returning to Earth and differences in muscular coordination before space flight and 3 mo after the return to Earth.

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.

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.

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.

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.

Enantioconvergent Substitution Reactions of Racemic Electrophiles by Organocatalysis.

Over the past decades, the development of enantioselective catalysis using organocatalysts has evolved into an active research field and a number of enantioselective transformations have been established. However, despite their being a highly desirable process for the synthesis of organic molecules in an enantioenriched form, the enantioconvergent substitution reactions of racemic electrophiles using organocatalysts still present several challenges. Although intrinsic difficulties in the catalytic stereocontrol abound due to the initial chiral information of racemic electrophiles, in recent years, mechanistically diverse enantioconvergent processes have been intensively investigated in organocatalysis. This Minireview focuses on recent achievements in the development of enantioconvergent substitution reactions of racemic electrophiles using organocatalysts. The contents are classified on the basis of the mechanistic types of enantioconvergent processes.

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.

Consecutive O-S/N-S Bond Cleavage in Gold-Catalyzed Rearrangement Reactions of Alkynyl N-Sulfinylimines.

Gold-catalyzed reactions of alkynyl N-sulfinylimines were used to produce the corresponding 2H-azirines possessing sulfenyl and acyl groups at the 3-position of the azirine ring in good to excellent yields. These reactions involved internal transfer of the sulfinyl oxygen atom to form a thiooxime intermediate tethered to an α-oxo gold carbene moiety. Subsequent insertion of the carbene into the N-S bond resulted in ring construction.

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.

Chiral Brønsted Acid Catalyzed Enantioconvergent Propargylic Substitution Reaction of Racemic Secondary Propargylic Alcohols with Thiols.

Despite the significant progress of the enantioselective reaction using chiral catalysts, the enantioselective nucleophilic substitution reaction at the chiral sp3 -hybridized carbon atom of a racemic electrophile has not been largely explored. Herein, we report the enantioconvergent propargylic substitution reaction of racemic propargylic alcohols with thiols using chiral bis-phosphoric acid as the chiral Brønsted acid catalyst. The substitution products were formed in high yields with high enantioselectivities in most cases. The cation-stabilizing effect of the sulfur functional group introduced at the alkynyl terminus is the key to achieving the efficient enantioconvergent process, in which chiral information originating from not only the racemic stereogenic center but also the formed contact ion pair is completely eliminated from the present system.

Exo-Cyclization: Intermolecular Methylene Transfer Sequence in Au-Catalyzed Reactions of O-Homopropargylic Oximes.

The Au-catalyzed reactions of O-homopropaylic oximes afforded the 3-alkenylated isoxazolines in good to high yields. The mechanistic studies suggest that the reaction proceeds through an exo-cyclization followed by intermolecular methylene group transfer. In addition, oligomeric species of the starting material were observed in the reaction mixture by mass spectra, supporting our proposed mechanism, which proceeds through a repeated intermolecular C-C bond forming process.

One-Pot Synthesis of Enantioenriched ß-Amino Secondary Amides via an Enantioselective [4+2] Cycloaddition Reaction of Vinyl Azides with N-Acyl Imines Catalyzed by a Chiral Brønsted Acid.

A catalytic enantioselective synthesis of ß-amino secondary amides was achieved using vinyl azides as the enamine-type nucleophile and chiral N-Tf phosphoramide as the chiral Brønsted acid catalyst through a five-step sequential transformation in one pot. The established sequential transformation involves an enantioselective [4+2] cycloaddition reaction of vinyl azides with N-acyl imines as the key stereo-determining step that is efficiently accelerated by a chiral N-Tf phosphoramide catalyst in a highly enantioselective manner in most cases. Further generation of the iminodiazonium ion intermediate through ring opening of the cycloaddition product and subsequent skeletal rearrangement involving Schmidt-type 1,2-aryl group migration followed by recyclization of the resulting nitrilium ion were also initiated by the same acid catalyst. Final acid hydrolysis of the recyclized products in the same pot gave rise to enantioenriched ß-amino amides through C-C bond formation at the α-position of the secondary amides.

Mechanism and Origin of Stereoselectivity in Chiral Phosphoric Acid-Catalyzed Aldol-Type Reactions of Azlactones with Vinyl Ethers.

The precise mechanism of the chiral phosphoric acid-catalyzed aldol-type reaction of azlactones with vinyl ethers was investigated. DFT calculations suggested that the reaction proceeds through a Conia-ene-type transition state consisting of the vinyl ether and the enol tautomer of the azlactone, in which the catalyst protonates the nitrogen atom of the azlactone to promote enol tautomerization. In addition, the phosphoryl oxygen of the catalyst interacts with the vinyl proton of the vinyl ether. The favorable transition structure features dicoordinating hydrogen bonds. However, these hydrogen bonds are not involved in the bond recombination sequence and hence the catalyst functions as a template for binding substrates. From the results of theoretical studies and experimental supports, the high enantioselectivity is induced by the steric repulsion between the azlactone substituent and the binaphthyl backbone of the catalyst under the catalyst template effect.

Chiral Phosphoric Acid-Catalyzed Enantioselective Phospha-Michael-Type Addition Reaction of Diarylphosphine Oxides with Alkenyl Benzimidazoles.

An enantioselective phospha-Michael-type addition reaction of diarylphosphine oxides with alkenyl benzimidazoles was demonstrated using a chiral phosphoric acid as the chiral Brønsted acid catalyst. Addition products having phosphorus and benzimidazole units were formed in high yields with excellent enantioselectivities in most cases. The reduction of the phosphine oxide unit in the addition product afforded the corresponding chiral phosphine, which is a potential benzimidazole-based chiral P,N-ligand, without loss of enantiomeric excess.

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.