Contiguous Quaternary Carbon Centers Research Articles

Silver‐Catalyzed Dearomative [2π+2σ] Cycloadditions of Indoles with Bicyclobutanes: Access to Indoline Fused Bicyclo[2.1.1]hexanes**

AbstractBicyclo[2.1.1]hexanes (BCHs) are becoming ever more important in drug design and development as bridged scaffolds that provide underexplored chemical space, but are difficult to access. Here a silver‐catalyzed dearomative [2π+2σ] cycloaddition strategy for the synthesis of indoline fused BCHs from N‐unprotected indoles and bicyclobutane precursors is described. The strain‐release dearomative cycloaddition operates under mild conditions, tolerating a wide range of functional groups. It is capable of forming BCHs with up to four contiguous quaternary carbon centers, achieving yields of up to 99 %. In addition, a scale‐up experiment and the synthetic transformations of the cycloadducts further highlighted the synthetic utility.

Silver-Catalyzed Dearomative [2π+2σ] Cycloadditions of Indoles with Bicyclobutanes: Access to Indoline Fused Bicyclo[2.1.1]hexanes.

Bicyclo[2.1.1]hexanes (BCHs) are becoming ever more important in drug design and development as bridged scaffolds that provide underexplored chemical space, but are difficult to access. Here a silver-catalyzed dearomative [2π+2σ] cycloaddition strategy for the synthesis of indoline fused BCHs from N-unprotected indoles and bicyclobutane precursors is described. The strain-release dearomative cycloaddition operates under mild conditions, tolerating a wide range of functional groups. It is capable of forming BCHs with up to four contiguous quaternary carbon centers, achieving yields of up to 99 %. In addition, a scale-up experiment and the synthetic transformations of the cycloadducts further highlighted the synthetic utility.

Intermolecular Formal Cycloaddition of Indoles with Bicyclo[1.1.0]butanes by Lewis Acid Catalysis.

Herein, we develop a new approach to directly access architecturally complex polycyclic indolines from readily available indoles and bicyclo[1.1.0]butanes (BCBs) through formal cycloaddition promoted by commercially available Lewis acids. The reaction proceeded through a stepwise pathway involving a nucleophilic addition of indoles to BCBs followed by an intramolecular Mannich reaction to form rigid indoline-fused polycyclic structures, which resemble polycyclic indole alkaloids. This new reaction tolerated a wide range of indoles and BCBs, thereby allowing the one-step construction of various rigid indoline polycycles containing up to four contiguous quaternary carbon centers.

Intermolecular Formal Cycloaddition of Indoles with Bicyclo[1.1.0]butanes by Lewis Acid Catalysis

AbstractHerein, we develop a new approach to directly access architecturally complex polycyclic indolines from readily available indoles and bicyclo[1.1.0]butanes (BCBs) through formal cycloaddition promoted by commercially available Lewis acids. The reaction proceeded through a stepwise pathway involving a nucleophilic addition of indoles to BCBs followed by an intramolecular Mannich reaction to form rigid indoline‐fused polycyclic structures, which resemble polycyclic indole alkaloids. This new reaction tolerated a wide range of indoles and BCBs, thereby allowing the one‐step construction of various rigid indoline polycycles containing up to four contiguous quaternary carbon centers.

Synthetic Studies Toward Daphnezomines A and B

AbstractSynthetic studies toward daphnezomines A and B, members of Daphniphyllum alkaloid group with a rare azaadamantane core structure, are reported. The tricyclic carbon skeleton with two contiguous quaternary carbon centers was synthesized in nine steps from (R)-piperitone. An intramolecular Tsuji–Trost reaction was used as a key reaction for the assembly of the skeleton.

Pd-catalyzed cascade cyclization of allenylethylene carbonates and indandiones: Synthesis of tetracyclic dihydrocyclopentaindenofuranone derivatives

A palladium-catalyzed cascade cyclization of allenylethylene carbonates with 1,3-indandiones was developed, providing biologically interesting tetracyclic dihydrocyclopentaindenofuranone derivatives having three contiguous quaternary carbon centers in moderate to high yields with excellent diastereoselectivities. In this reaction, the allene moiety was fully fused into the cyclopentene ring.

Photoredox-Enabled Dearomatization of Protected Anilines: Access to Cyclohexadienone Imines with Contiguous Quaternary Centers

A photoredox-enabled alkylative dearomatization of protected anilines is reported. Under Ir catalysis and light irradiation, an N-carbamoyl-protected aniline and an α-bromocarbonyl compound could be simultaneously activated, and the two resulting radical species then recombine with each other to afford a dearomatized cyclohexadienone imine as the major product. A series of such imines with contiguous quaternary carbon centers were prepared, which can be further converted into cyclohexadienones, cyclohexadienols, and cyclohexyl amines.

Catalytic asymmetric construction of C2-symmetric contiguous quaternary carbon centers enabled a concise synthesis of (−)-chimonanthidine and (−)-folicanthine

Herein, we disclose a catalytic asymmetric conjugated addition of 3-substutited oxindoles to indol-2-one in situ generated from 3-bromooxindoles promoted by Ni(BF4)2·6H2O/chiral N,N′-chiral dioxide. This protocol enables forging C2-symmetric CQCCs in excellent enantioselectivities as single diastereoisomer via directly fusing two congested 3-substituted oxindoles. The asymmetric synthesis of (−)-chimonanthidine and (−)-folicanthine is concisely achieved respectively in four and five steps by taking advantage of this protocol.

A concise synthesis of herbertenolide.

A concise synthesis of (±)-herbertenolide has been accomplished herein. The strategy relies on a H2O2-mediated oxidative ring contraction of all-substituted cyclic α-formyl ketones for the stereospecific construction of contiguous quaternary carbon centers (CQCCs). Furthermore, a Sc(OTf)3/chiral N,N'-dioxide catalyzed asymmetric Michael addition of benzofuranone to MVK has been optimized for forging a chiral aromatic quaternary carbon center, which enables the formal synthesis of (+)-ent-herbertenolide.

Synthetic Studies on Bilobalide

We disclose our synthetic studies on bilobalide, which features a Diels–Alder reaction of a cyclic anhydride to form two contiguous quaternary carbon centers, desymmetrization of a symmetric diol, and construction of a cyclic acetal under acidic conditions with inversion of configuration at an allylic position.

Concise syntheses of (+)-austrodoral and (+)-austrodoric acid Based on H2O2 mediated oxidative ring contraction

Asymmetric synthesis of the marine nor-sesquiterpenoid (+)-austrodoric acid and (+)-austrodoral in seven and nine steps respectively from Wieland-Miescher ketone was described herein. The synthesis featured an oxidative ring contraction of α-formyl cyclic ketone mediated by H2O2 to forge the hydrindane scaffold together with the contiguous quaternary carbon centers simultaneously.

Synthesis of the ABCDG ring skeleton of communesin F based on carboborylation of 1,3-diene and Bi(OTf)3-catalyzed cyclizations.

Communesins, isolated from the mycelium of a strain of Penicillium sp., are cytotoxic heptacyclic indole alkaloids bearing a bis-aminal structure and two contiguous quaternary carbon centers. Toward a total synthesis of communesin F, we synthesized a pentacyclic ABCDG ring skeleton via carboborylation of 1,3-diene and a Friedel-Crafts-type cyclization, resulting in the formation of an azepine ring through a Bi(OTf)3-catalyzed SN2' reaction.

Phosphine-Catalyzed [3 + 2] Annulation of 2-Hydroxy-1,4-naphthaquinones and Allenoate: An Allene–Alkene [3 + 2] Annulation Mechanism Involving Consecutive γ-Addition–Aldol Reaction

A diastereoselective construction of biologically important tetrahydrocyclopenta[ b]naphthalene derivatives has been achieved via a phosphine-catalyzed [3 + 2] annulation of 2-hydroxy-1,4-naphthaquinone derivatives and allenoate. Various tetrahydrocyclopenta[ b]naphthalene derivatives containing contiguous quaternary carbon centers are obtained in good yields with excellent diastereoselectivities. The asymmetric version gave the chiral product in up to 57% ee under catalysis of Kwon chiral phosphine. The reaction undergoes a reaction mechanism involving consecutive γ-addition-aldol reaction.

Highly Diastereo-, α-Regioselective Catalyst-Free Construction of Adjacent Dispirobisoxindoles with Three Contiguous Quaternary Carbon Centers

A new methodology was developed for the highly diastereoselective construction of dispirobisoxindole scaffolds via a domino α-regioselective Michael/cyclization reaction sequence of 3-isothiocyanato oxindoles and isatylidene malononitriles under catalyst-free conditions. Complex polycyclic oxindoles featuring two side-by-side oxindole skeletons and three contiguous quaternary carbon centers were synthesized in up to 95% yield and >20:1 dr. This protocol could provide libraries of stereochemically rich small molecules that will help in the search for new bioactive molecules.

Lewis Base-Catalyzed One-Pot Cascade Sequences of O-Alkenyl-Substituted Cyanohydrins: Diastereoselective Synthesis of Multisubstituted Dihydrofurans.

The first example of the diastereoselective construction of polysubstituted 2,3-dihydrofurans incorporating contiguous quaternary and tertiary carbon centers via a Lewis base-catalyzed one-pot cascade sequence is described. The diversity and complexity of the final products can be efficiently constructed with high diastereoselectivities via this catalytic multistep process under mild reaction conditions.

New Strategy for Forging Contiguous Quaternary Carbon Centers via H2O2-Mediated Ring Contraction

Stereospecific construction of contiguous quaternary carbon centers constitutes a major challenge in natural product synthesis. A general protocol that enables stereospecific construction of all stereoisomers of such a moiety remains elusive. In this article, we will discuss the oxidative ring contraction of all-substituted cyclic α-formyl ketones mediated by H2O2, which provides a facile access to the stereospecific construction of contiguous quaternary carbon centers.

Brook Rearrangement as Trigger for Carbene Generation: Synthesis of Stereodefined and Fully Substituted Cyclobutenes.

Through a sequence that can be performed in a single vessel, involving regio- and diastereoselective copper-catalyzed carbomagnesiation of cyclopropenes, reaction with acylsilanes, and addition of THF as cosolvent, Brook rearrangement can be triggered to furnish a wide range of cyclobutenes with exceptional diastereoselectivity. Accordingly, stereodefined and highly substituted cyclobutenes with contiguous quaternary carbon centers can be synthesized easily and in high yield. The new strategy constitutes an unprecedented application of Brook rearrangement, one which involves the intermediacy of carbene species.

Transition-Metal-Free Cyclopropanation of 2-Aminoacrylates with N-Tosylhydrazones: A General Route to Cyclopropane α-Amino Acid with Contiguous Quaternary Carbon Centers.

Cyclopropanation of 2-aminoacrylates with N-tosylhydrazones could proceed smoothly under transition-metal-free conditions via a [3 + 2] cycloaddition process. This robust protocol exhibits excellent generality, delivering a wide spectrum of cyclopropane α-amino acid esters bearing contiguous quaternary carbon centers in high yields and diastereoselectivities. With these readily available products, the steric convergence of cyclopropane α-amino acids could be readily obtained.

Synthetic Studies towards Communesins: Diastereoselective Oxidative Rearrangement of Aurantioclavine Derivatives

AbstractCommunesins are a class of heptacyclic indole alkaloids that contain two aminal moieties and two contiguous quaternary carbon centers. We have investigated the construction of the pentacyclic skeleton of the communesins by employing the oxidative rearrangement of aurantioclavine derivatives, which are believed to be biosynthetic intermediates of the polycyclic communesin alkaloids. The quaternary C‐7 carbon center was constructed in a stereoselective manner, whereas the installation of the C‐11 stereocenter requires an epimerization process. The isolation of a 2‐ethoxyindolenine prior to the reduction of the nitro group and cyclization steps was critical to the success of this strategy.

Asymmetric tandem 1,5-hydride shift/ring closure for the synthesis of chiral spirooxindole tetrahydroquinolines.

The direct functionalization of sp(3) C-H bonds through a tandem 1,5-hydride shift/ring closure is described. Various optically active spirooxindole tetrahydroquinoline derivatives bearing contiguous quaternary or tertiary stereogenic carbon centers were readily synthesized. A chiral scandium complex of N,N'-dioxide promoted the reactions in good yields (up to 97%) with excellent diastereoselectivities (>20:1) and enantioselectivities (up to 94% ee). Kinetic isotope effect (KIE) experiments and internal redox reactions of chiral substrates were conducted, and the results provided intriguing information that helped clarify the mechanism of the reaction.