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Spirocycles play an important role in drug discovery and development. The direct, catalytic, and enantioselective synthesis of spirocycles from readily available starting materials and in an atom economic manner remains a highly sought-after task in organic synthesis. Herein, an enantioselective Pd-hydride-catalyzed cycloaddition method for the synthesis of spirocyclic compounds directly from two classes of commonly available starting materials, 1,3-enynes and cyclic carbon−hydrogen (C−H) bonds, is reported. The reactions employ a chiral Pd/WingPhos catalyst to both suppress the formation of bis-allenyl by-products and control the stereoselectivity. 1,3-Enynes are used as dielectrophilic four-carbon units in the cycloaddition reactions, which also enables an enyne substrate-directed enantioselectivity switch with good levels of stereocontrol. The present spirocycle synthesis tolerates a broad range of functional groups of 1,3-enyne substrates, including alcohols, esters, nitriles, halides, and olefins. A variety of diverse cyclic nucleophiles, including pharmaceutically important heterocycles and carbocycles, can be flexibly incorporated with spiro scaffolds., Spirocycles are traditionally difficult structures to synthesize due to the congested nature of the central atom. Here the authors show a method to synthesize quaternary carbon spirocycles in one step from 1,3-enynes and pyrazolidine-type heterocycles, both relatively unactivated structures, proceeding via palladium catalysis.

We demonstrate that α-aryl cyclic vinylogous esters are competent substrates in the direct intermolecular Pd-catalyzed asymmetric allylic alkylation, enabling a straightforward enantioselective synthesis of 6-allyl-6-aryl-3-ethoxycyclohex-2-en-1-ones, common motifs embedded in numerous structurally diverse natural products. As an initial demonstration of the utility of this protocol, the first catalytic enantioselective total synthesis of (+)-oxomaritidine and an improved five-step catalytic enantioselective synthesis of (-)-mesembrine have been completed divergently.

An unprecedented umpolung spirocyclopropanation reaction of p-quinone methides and α-keto carbonyls is described. Our umpolung strategy based on 1,6-conjugate addition and intramolecular nucleophilic substitution offers a new method for effective access to a series of highly functionalized spirocyclohexadienonyl cyclopropanes having two vicinal quaternary carbons in ≤98% yield and >20:1 dr. Significantly, cyclic and acyclic topological structures of α-keto carbonyls as 1,1-dipole one-carbon synthons have a distinct influence on the stereochemistry of products, showing a reversal of diastereoselectivity in this P(NMe2)3-mediated umpolung spirocyclopropanation.

A novel asymmetric catalytic (2+3) annulation of p-quinone methides with CN-substituted trimethylenemethane is described under palladium catalysis, providing an alternative approach for the enantio...

Chiral phosphoric acid-catalyzed biomimetic asymmetric [4 + 2] cycloaddition of ortho-alkenyl naphthols/phenols and ortho-quinone methides (o-QMs) has been demonstrated to afford various important 2,3,4-trisubstituted chromans in high yields with excellent enantio- and diastereoselectivities (up to 99% yield, 99% ee, >20:1 dr). Notably, this methodology not only enabled access to the trans-cis chiral trisubstituted chromans from 1-alkenyl 2-naphthols but also is compatible with 2-alkenyl 1-naphthols and phenols to deliver trans-trans chiral trisubstituted chromans.

A SPINOL-derived chiral phosphoric acid catalyzed asymmetric formal [2 + 3]-annulation of in situ generated alkynyl imines and 1,4-dithiane-2,5-diol has been developed to afford enantiopure α-alkynylated thiazolidones with up to 72% yield and 98.5 : 1.5 er. This tandem annulation involved a tandem S-addition of alkynyl imines/intramolecular acetalization, followed by PDC-mediated oxidation. The α-alkynylated thiazolidones could facilely afford the corresponding chiral α-alkynylated or α-alkenylated cyclic sulfoxides via further elaboration.

Direct enantioselective Michael-type Friedel–Crafts arylations and heteroarylations of s-cis 1-azadienes were achieved by applying chiral bifunctional tertiary amine-urea catalysts when using 2-naphthols as the nucleophiles, and phosphoric acid catalysts when using indoles as the nucleophiles. These two catalytic protocols efficiently enabled access to a diverse variety of important benzofuran-containing hetero-triarylmethanes in up to 98% yield and with 99.5 : 0.5 er.

The strong binding ability of P-ylides with transition metals limits the utilization of stabilized P-ylide as nucleophiles in asymmetric organometallic catalysis. Herein we describe the first rhodium-catalyzed asymmetric ring-opening reaction of P-ylides utilizing oxabicyclic alkenes as the electrophilic partner. Various P-ylides including ester-, ketone- and amide-style P-ylides are all applicable. This asymmetric reaction occurs through the cleavage of two bridgehead C-O bonds and the formation of two C-C bonds, and oxabenzonorbornadienes are used as 1,4-biselectrophiles, thus providing access to benzonorcaradienes in good yields with high enantioselectivity and perfect diastereoselectivity. The present protocol also constitutes the first highly enantioselective direct catalytic asymmetric cyclopropanation of stabilized P-ylide nucleophiles.

The first Pd-catalyzed asymmetric allenylic [4+1] cycloaddition was successfully developed. Alternatively, tuning the Pd catalyst switched the reactivity toward an unprecedented [4+3] cycloaddition/cross-coupling. Ligands play a vital role in controlling the reaction pathway, allowing highly selective access to different products from identical substrates. Biological evaluation of the obtained compounds led to the discovery of new antitumor targets. A possible mechanism is proposed, suggesting two interesting catalytic cycles for the cycloaddition with palladium-butadienyls. This study also demonstrated the potential and utility of allenic esters as 1,4-biselectrophiles and C4 synthons for participating in cycloaddition reactions.

An unprecedented asymmetric catalytic (4 + 2) annulation reaction of aryl-substituted γ-methylidene-δ-valerolactones (GMDVs) with isatin-derived para-quinone methides (p-QMs) has been developed under the catalysis of palladium(0) and (S,S,S)-(-)-Xyl-SKP, offering a new approach for the diastereo- and enantioselective synthesis of chiral cyclohexadienone-fused cyclohexyl spirooxindoles. Significantly, three highly congested contiguous tetrasubstituted carbon atoms embedded in bispirocyclic skeleton, of which two are vicinal quaternary stereogenic centers, are forged in an effective and selective manner (up to 99% yield, up to 95% ee, >20/1 dr). The current reaction represents the first exploration of enantioselective catalytic (4 + 2) annulation forming the six-membered carbocycles in the chemistry of both GMDVs and p-QMs.

N-Tosylhydrazones have had widespread application in organic synthesis for more than a half century. In most of cases, N-tosylhydrazones, as masked diazo compounds, have been generally used in a series of important carbon–carbon and carbon–heteroatom bond-forming reactions. This review provides an update on progress in diverse coupling reactions of N-tosylhydrazones since 2012. The examples selected are mainly categorized by metal-catalyzed and metal-free systems, wherein four main types of transformations including insertion, olefination, alkynylation, and cyclization are discussed for each system.1 Introduction2 Transition-Metal-Catalyzed Coupling Reactions3 Metal-Free Coupling Reactions4 Conclusion and Outlook

The development of enantiodivergent catalysis for the preparation of both enantiomers of a chiral compound is of importance in pharmaceutical and bioorganic chemistry. With the design of a class of reactive and stereoselective organocatalysts, acyclic chiral secondary amines, a method for achieving the enantiodivergence is developed simply by changing the secondary N-i-Bu- to N-Me-group within the catalyst architecture while maintaining the same absolute configuration of the catalysts, which modulates the catalyst conformation. This catalyst-controlled enantiodivergent method not only enables challenging asymmetric transformations to occur in an enantiodivergent manner but also features a high level of stereocontrol and broad scope that is demonstrated in eight different reactions (90 examples), all delivering both enantiomers of a range of structurally diverse products including hitherto less accessible, yet important, compounds in good yields with high stereoselectivities., Enantiodivergent methods, which to access both enantiomers of the same compound, are of importance in drug synthesis. Here, the authors show that by simply changing a NiBu- to a NMe-group in readily available amine organocatalysts, high stereocontrol and broad scope are achieved in eight asymmetric reactions.

Catalytic asymmetric and divergent assembly of tricyclic and tetracyclic 3,3′-pyrrolidonyl spirooxindoles was developed, involving a one-pot chiral Bronsted base catalyzed asymmetric propargylation for the synthesis of oxindole 1,6-enynes and a subsequent switchable site-selective and highly diastereoselective electrophilic iodocyclization of 1,6-enynes. In addition, antitumor properties of the newly synthesized compounds were evaluated.

The first highly stereoselective intermolecular catalytic asymmetric dearomatization (CADA) of α-naphthols through C–C formation and the first asymmetric allylic dearomatization of naphthols by chiral organocatalysis have been achieved. These new and complete atom-economic reactions provide enantioriched α- and β-naphthalenones bearing an all-carbon quaternary center.

A novel strategy for the asymmetric construction of functionalized 4-aryl-3,4-dihydrocoumarins and 4-aryl-3,4-dihydroquinolin-2-ones via an intramolecular vinylogous Rauhut-Currier reaction of para-quinone methides (p-QMs) under the bifunctional catalysis of chiral amine-phosphine is described. This intramolecular mode for the catalytic enantioselective 1,6-conjugate addition of p-QMs has been explored for the first time, delivering two types of synthetically important heterocycles in high yields and enantioselectivites.

A novel Au-catalyzed [2 + 3] annulation reaction of enamides with propargyl esters has been developed, providing a new method for expeditious assembly of synthetically useful functionalized 1-azaspiro[4.4]nonane building blocks. Based on this key annulation, strategic installation of the pivotal azaspirocyclic core, followed by constructing the benzazepine unit via Witkop cyclization, led to the divergent total syntheses of cephalotaxine and cephalezomine H.

Lycopodium alkaloids with structural diversity and biological significance have been stimulating an increasing interest in the synthetic and medicinal communities, in which inspiration and exploration of their related biogenetic relationship generally constitute one of the major concerns. Driven by the plausible biogenetic entry to lycojaponicumin D as the first member of Lycopodium alkaloids having a structurally unusual C3-C13-linked scaffold, a new connection with lycodoline has been proposed and discovered on the basis of the design of an unprecedented bioinspired tandem fragmentation/Mannich reaction. Initiated by expeditious assembly of bridgehead heterofunctionalization in the [3.3.1] bicyclic system of lycodoline, a novel tandem palladium-mediated oxidative dehydrogenation/hetero-Michael reaction has been developed for the strain-driven formation of the C-heteroatom bond, leading to a new approach to conformationally rigid bridgehead heteroquaternary carbons. The present unified strategy provides a scenario for the divergent total syntheses of nine natural Lycopodium alkaloids and four unnatural C12 epimers, wherein (±)-lycojaponicumin D and six lycodoline-type alkaloids have been synthetically achieved for the first time.

A novel enantioselective [4 + 2] annulation of the allenoates having a unique positive ortho-effect with in situ generated ortho-quinone methides has been developed under the catalysis of Cinchona alkaloid. This chiral amine-catalyzed reaction provides an alternative route to asymmetric catalytic construction of synthetically interesting, highly functionalized chiral chromans in good to excellent enantioselectivities (up to 97% ee).

A novel base-mediated tandem spirocyclopropanation/rearrangement reaction of vinyl p-quinone methides (p-VQMs) with sulfonium salts is described. The unprecedented reactivity of p-VQMs was explored for the first time in the spiroannulation cascade, providing a stereoselective approach to the construction of synthetically interesting, densely functionalized spirocyclopentenyl p-dienones.

A novel strategy based on phase transfer catalysis for the diastereoselective and enantioselective direct assembly of unsymmetric β,β-diaryl-α-amino acid esters via 1,6-conjugate addition of para-quinone methides and glycine derivatives is described. This protocol also provides an alternative route to the synthetically interesting functionalized chiral tetrahydroisoquinoline and its analogues.

A novel DBU-mediated stereoselective spirocyclopropanation of para-quinone methides with sulfonium salts has been developed on the basis of the mode involving a 1,6-conjugate addition/intramolecular dearomatizing cyclization cascade. This reaction provides a mild and effective method for the assembly of synthetically and structurally interesting spirocyclopropanyl para-dienones. The feasibility for the enantioselective access to such functionalized para-dienones has also been explored by using the axially chiral sulfonium salt. Importantly, the regioselective ring openings of the related spirocyclopropanyl para-dienones have been achieved divergently.

The asymmetric catalytic 1,6-addition of p-QMs with racemic oxindoles under the bifunctional catalysis of C2-symmetric dimeric Cinchona-derived squaramide is described. This tertiary amine-squaramide catalyzed reaction provides a diastereoselective and enantioselective approach to the effective assembly of diverse diarylmethine-substituted oxindoles having vicinal tertiary and quaternary stereocenters.

A novel strategy based on phase transfer catalysis for the diastereoselective and enantioselective direct assembly of unsymmetric β,β-diaryl-α-amino acid esters via 1,6-conjugate addition of para-quinone methides and glycine derivatives is described. This protocol also provides an alternative route to the synthetically interesting functionalized chiral tetrahydroisoquinoline and its analogues.

The asymmetric catalytic 1,6-addition of p-QMs with racemic oxindoles under the bifunctional catalysis of C2-symmetric dimeric Cinchona-derived squaramide is described. This tertiary amine-squaramide catalyzed reaction provides a diastereoselective and enantioselective approach to the effective assembly of diverse diarylmethine-substituted oxindoles having vicinal tertiary and quaternary stereocenters.

A novel DBU-mediated stereoselective spirocyclopropanation of para-quinone methides with sulfonium salts has been developed on the basis of the mode involving a 1,6-conjugate addition/intramolecular dearomatizing cyclization cascade. This reaction provides a mild and effective method for the assembly of synthetically and structurally interesting spirocyclopropanyl para-dienones. The feasibility for the enantioselective access to such functionalized para-dienones has also been explored by using the axially chiral sulfonium salt. Importantly, the regioselective ring openings of the related spirocyclopropanyl para-dienones have been achieved divergently.

For the first time, cross-aldol reactions between acetaldehyde and activated acyclic ketones are achieved in the presence of chiral primary amine catalysts giving optically active tertiary alcohols with high enantioselectivities.

Highly enantioselective cross-aldol reactions between acetaldehyde and activated acyclic ketones are reported for the first time. Various acyclic ketones, such as saturated and unsaturated keto esters, reacted with acetaldehyde in the presence of a chiral primary amine and a Bronsted acid to afford optically enriched tertiary alcohols in good yields and with excellent enantioselectivities. Trifluoromethyl ketones were tolerable under the reaction conditions, thereby affording the trifluoromethyl carbinol in good-to-excellent yields and enantioselectivities. Structural modification of the chiral amines from the same chiral source switched the stereoselectivity of the products. The utility of aldol chemistry was demonstrated in the brief synthesis of functionally enriched δ-lactones. Theoretical calculations on the transition-state structure indicated that the protonated tertiary amine could effectively activate the carbonyl group of a keto ester to promote the addition process through hydrogen-bonding interaction and, simultaneously, provide an appropriate attacking pattern for the approach of the keto ester to the enamine, which is formed from acetaldehyde and the chiral catalyst, on a particular face, resulting in high enantioselectivity.