Addition Cascade Research Articles

Visible Light Mediated Sulfenylation‐Annulation Cascade of Alkyne Tethered Cyclohexadienones

AbstractA mild and facile method to access sulfenylated dihydrochromenones via a visible light mediated thiol‐yne/conjugate addition cascade of alkyne‐tethered cyclohexadienones, using cheap and readily available organic photoredox catalyst (Eosin Y) is demonstrated. The utility and sustainability of the protocol were further justified by the high yields, excellent diastereoselectivities, broad substrate scope, gram scale synthesis, green chemistry metrics (atom economy and efficiency) and further synthetic transformations of the products.magnified image

Total Synthesis of (+)-Aspidospermidine.

A facile asymmetric total synthesis of (+)-aspidospermidine has been developed, which is accomplished in 11 steps in an overall yield of 9.6%. Key steps involve a palladium-catalyzed enantioselective decarboxylative allylation to install the quaternary carbon stereocenter and a highly efficient reductive amination-carbonyl reduction-dehydration-intramolecular conjugate addition cascade to build the cis D-ring.

Enantioselective, Organocatalytic, Dissymmetric 1,4- and 1,2-Addition of Malononitrile to a Keto-bisenone Followed by an Oxa-Michael Addition Cascade

An unprecedented enantioselective dissymmetric 1,4- and 1,2-addition of malononitrile to a keto-bisenone followed by an oxa-Michael addition cascade to trap the in situ generated unstable tertiary alcohol have been developed. The quinine-derived amino-squaramide bifunctional organocatalyst worked efficiently and provides the oxa-spiro-[4,4]-nonanes in good yields and excellent diastereo- and enantioselectivities (up to 99:1 dr and 99% ee). Notably, a complete chemoselective addition of a methylene unit to an aliphatic-tethered enone over the aromatic-tethered enone was observed.

Visible Light Driven Alkylation of C(sp3)–H Bonds Enabled by 1,6-Hydrogen Atom Transfer/Radical Relay Addition

A visible-light-driven sulfamate esters guided alkylation of unactivated C(sp3)-H bonds enabled by a 1,6-HAT/radical addition cascade is described. Not only structurally diverse Michael acceptors but also styrenes are amenable to this alkylation reaction. Notably, the N-H bonds activation radical relay refrained from prefunctionalization and using excess external oxidants.

Chiral Phosphoric Acid-Catalyzed Synthesis of Fluorinated 5,6-Dihydroindolo[1,2- c]quinazolines with Quaternary Stereocenters.

A chiral phosphoric acid-catalyzed enantioselective synthesis of fluorinated 5,6-dihydroindolo[1,2- c]quinazolines has been developed by a condensation/amine addition cascade from 2-(1 H-indolyl)anilines and fluorinated ketones, giving the fluorinated aminals with quaternary stereogenic centers with excellent yields and up to 97% ee. A series of the fluorinated aromatic, aliphatic ketones, and ethyl trifluoropyruvate are suitable.

Merging [2+2] Cycloaddition with 1,6‐/1,4‐Aza‐Binucleophilic Additions toward Unprecedented Indazole‐Containing Polycycles

AbstractThe first metal‐free [2+2] cycloaddition and 1,6‐/1,4‐aza‐binucleophilic addition cascade of yne‐allenone esters and cyclic aza‐binucleophiles was reported, leading to the atom‐economic protocol toward hitherto unreported indazole‐containing polycycles with one quaternary carbon‐amino functionality and good to excellent yields. The reaction pathway involves [2+2] cycloaddition, ring‐opening of fused cyclobutenes and 1,6‐/1,4‐aza‐binucleophilic addition sequence, resulting in continuous multiple bond‐forming events including C−C and C−N bonds to build up molecular complexitymagnified image

Synthesis of Benzofulvenes via Cp*Co(III)-Catalyzed C–H Activation and Carbocyclization of Aromatic Ketones with Internal Alkynes

A highly efficient and practical synthesis of benzofulvenes was developed via ketone-directed Cp*Co(III)-catalyzed sequential C-H activation, addition, cyclization, and dehydration cascade processes between simple aromatic ketones and alkynes. The reaction tolerates a variety of functional groups, and various benzofulvenes were efficiently synthesized in 42-92% yields.

Asymmetricsyn‐1,3‐Dioxane Construction via Kinetic Resolution of Secondary Alcohols Using Chiral Phosphoric Acid Catalysts

AbstractHerein, we present a novel enantioselective hemiacetalization/intramolecular oxy‐Michael addition cascade for the synthesis ofsyn‐1,3‐diol frameworks via kinetic resolution of chiral secondary alcohols using chiral phosphoric acid catalysts. By utilizing the recovered optically active starting material, both enantiomers of the corresponding protected 1,3‐diols could be obtained with high optical purities. In addition, the products with a carbonyl group were converted diastereoselectively to longer optically active 1,3‐polyols, which are representative motifs in polyketides. Moreover, the organocatalytic approach presented in this study facilitates a library construction of useful chiral building blocks for the asymmetric synthesis of bioactive compounds.

Enantioselective Synthesis of Cyclohexadienone Containing Spiroketals via DyKat Ketalization/oxa-Michael Addition Cascade.

An oxidative dearomatization of phenol followed by a dynamic kinetic (DyKat) ketalization/oxa-Michael addition cascade using cinchona alkaloid-based chiral bifunctional amino-squaramide catalysts is reported. A broad array of sterically hindered [5,5]-spiroketals attached to a cyclohexadienone moiety in spiro-fashion is synthesized in an enantiopure form. Further, the methodology was optimized and extended to the corresponding benzannulated [5,5]-spiroketals attached to a cyclohexadienone moiety in spiro-fashion. In general, good yields and excellent diastereoselectivies and enantioselectivities (up to 20:1 dr and up to 99% ee) were obtained.

Organocatalyzed Asymmetric Dearomative Aza-Michael/Michael Addition Cascade of 2-Nitrobenzofurans and 2-Nitrobenzothiophenes with 2-Aminochalcones.

An organocatalyzed dearomative aza-Michael/Michael addition cascade of 2-nitrobenzofurans and 2-nitrobenzothiophenes with 2-aminochalcones has been developed, opening a new channel to access a series of optically active tetrahydrobenzofuro[3,2- b]quinolines and tetrahydrobenzo[4,5]thieno[3,2- b]quinolines bearing three contiguous stereocenters with excellent diastereo- and enantioselectivities (all cases >20:1 dr, up to 99% ee). This study features the first asymmetric dearomative cascade reaction of 2-nitrobenzofurans and 2-nitrobenzothiophenes beginning with aza-Michael addition. The potential applications of the methodology were demonstrated by the preparative-scale experiment and the versatile transformations of the products.

Generation of 1,3-Dimethylene-Substituted Isobenzofurans via Pd(II)-Catalyzed Selective Oxo-cyclization/SO2 Insertion Cascade of β-Alkynyl Ketones.

A new palladium(II)-catalyzed cyclization-radical addition cascade enables the direct construction of 1,3-dimethylene-substituted isobenzofuran derivatives containing a vinyl aryl sulfone unit in good yields by treating with β-alkynyl ketones, aryl diazonium salts, and DABCO·(SO2)2. The oxidant-free multicomponent reaction features good substrate scope and functional group tolerance, which proceeds through a sequence of Heck coupling, oxo-cyclization, and SO2 insertion.

Gold(i)-catalyzed stereoselective cyclization of 1,3-enyne aldehydes by a 1,3-acyloxy migration/Nazarov cyclization/aldol addition cascade

Stereoselective synthesis of bicyclo[3.3.0]octenones from chiral 1,3-enyne aldehydes bearing propargylic acetates is described. The method is based on a Au(i)-catalyzed domino sequence with concomitant transfer of chirality involving 1,3-acyloxy migration followed by Nazarov cyclization and an unprecedented aldol addition. The method furnishes densely functionalized bicyclic structures in high yields, with up to 97% ee and good diastereoselectivity.

Hydroalkynylative cyclization of 1,6-enynes with terminal alkynes.

A rhodium-catalyzed highly regio- and enantioselective hydroalkynylation, generating cis-hydrobenzofuranone-tethered enynes has been developed. The reaction proceeds with a selective head-to-head insertion and symmetry breaking Michael addition cascade. One product was produced from tens of possible isomers through precise control of chemo-, regio-, and stereoselectivities using a single rhodium catalyst. Notable features of this method include 100% atom-economy, mild reaction conditions and a very broad substrate scope.

Biomimetic Approach Toward Enterocin and Deoxyenterocin.

Enterocin (vulgamycin) is a structurally remarkable natural product with significant antibiotic activity. The synthesis of a linear polyketide resembling a biosynthetic precursor was achieved using an unusual acyloin reaction. A diazo group was introduced as a protecting group for an enolizable ketone. We were unable to bring about the envisioned biomimetic aldol addition cascade and gained insights into the feasibility of this process by DFT calculations. As an alternative approach to enterocin, we developed a Cu-catalyzed intramolecular cyclopropanation followed by a MgI2-induced fragmentation to install the 2-oxabicyclo[3.3.1]nonane core of the natural product.

Fe(III)-Catalyzed Bicyclization of Yne-Allenones With Indoles for the Atom-Economic Synthesis of 3-Indolyl Cyclobutarenes.

A new Fe(III)-catalyzed bicyclization reaction of yne-allenones with indoles has been established, enabling the direct construction of cyclobuta[a]naphthalen-4-ols with an all-carbon quaternary center in good to excellent yields. This reaction was performed by using low-cost FeCl3 as the catalyst and EtOH as the environmentally benign solvent, providing a green protocol for constructing the cyclobutarene framework with a high degree of atom economy and functional group compatibility. The reaction mechanism was proposed to proceed through a [2 + 2] cycloaddition/1,6-conjugate addition cascade.

Transition Metal Free Cycloamination of Prenyl Carbamates and Ureas Promoted by Aryldiazonium Salts

AbstractUpon treatment with aryldiazonium salts, prenyl carbamates and ureas undergo redox‐neutral azocycloamination. In general, N‐aryl O‐prenyl carbamates cyclize in a photocatalytic reaction with visible light and an organic dye. With electron‐deficient diazonium salts, electronic matching with an electron‐rich N‐aryl substituent results in a reaction proceeding in the ground state, without either light or photocatalyst. Cyclic voltammetry suggests that this radical reaction is initiated by hydrogen‐atom abstraction mediated by an aryl radical, followed by a radical addition cascade and proton‐coupled hole propagation. The reaction proceeds at room temperature in short reaction times, and a range of functional groups is tolerated.

Transition Metal Free Cycloamination of Prenyl Carbamates and Ureas Promoted by Aryldiazonium Salts.

Upon treatment with aryldiazonium salts, prenyl carbamates and ureas undergo redox-neutral azocycloamination. In general, N-aryl O-prenyl carbamates cyclize in a photocatalytic reaction with visible light and an organic dye. With electron-deficient diazonium salts, electronic matching with an electron-rich N-aryl substituent results in a reaction proceeding in the ground state, without either light or photocatalyst. Cyclic voltammetry suggests that this radical reaction is initiated by hydrogen-atom abstraction mediated by an aryl radical, followed by a radical addition cascade and proton-coupled hole propagation. The reaction proceeds at room temperature in short reaction times, and a range of functional groups is tolerated.

Expediently Scalable Synthesis and Antifungal Exploration of (+)-Yahazunol and Related Meroterpenoids.

The efficient synthesis and antifungal exploration of (+)-yahazunol and related natural products are described. Central to this strategy is the Barton decarboxylative coupling, comprising a one-pot radical decarboxylation and quinone addition cascade. The scalable synthesis of (+)-yahazunol was accomplished in five longest linear sequences (LLS) starting from commercially available and inexpensive (-)-sclareol. The divergent translational potential of (+)-yahazunol was demonstrated by the expedient preparation of (-)-zonarone, (-)-isozonarone, (-)-zonarol, (-)-isozonarol, (+)-chromazonarol, and (+)-yahazunone. This approach also enables the formal synthesis of puupehenol, puupehedione, and hongoquercin A. Antifungal evaluation was performed, and this represents the first biological profiles for (+)-yahazunone, (+)-8- O-acetylyahazunone, and (+)-8- O-acetylyahazunol. (+)-Chromazonarol and (+)-yahazunone are promising candidates against Sclerotinia scleotiorum, with EC50 values of 24.1 and 28.7 μM, respectively, demonstrating advantages over the original model (DM) and synthesized heterocyclic mimic (3a) of meroterpenoids. This will favor the establishment of a chemical repertoire in the management of different plant diseases.

Organocatalytic, Chemoselective Hydrophosphenylation/oxa-Michael Addition Cascade toward Diastereo- and Enantioenriched 1,3-Dihydroisobenzofuryl Phosphonates.

An efficient method for the construction of chiral C-P bond via an enantioselective 1,2-hydrophosphenylation followed by an oxa-Michael addition cascade of ortho-formyl chalcones has been developed. This provides the diastereoenriched ( cis)-1,3-dihydroisobenzofuryl phosphonates with excellent enantioselectivities (up to >99%). The origin of enantio- and diastereoselectivity is induced by using a chiral bifunctional organocatalyst. Further, functionalization to highly enantioselective 3-substituted phthalides has also been demonstrated.

Modular One‐Step Three‐Component Synthesis of Tetrahydroisoquinolines Using a Catellani Strategy

Reported is a modular one-step three-component synthesis of tetrahydroisoquinolines using a Catellani strategy. This process exploits aziridines as the alkylating reagents, through palladium/norbornene cooperative catalysis, to enable a Catellani/Heck/aza-Michael addition cascade. This mild, chemoselective, and scalable protocol has broad substrate scope (43 examples, up to 90 % yield). The most striking feature of this protocol is the excellent regioselectivity and diastereoselectivity observed for 2-alkyl- and 2-aryl-substituted aziridines to access 1,3-cis-substituted and 1,4-cis-substituted tetrahydroisoquinolines, respectively. Moreover, this is a versatile process with high step and atom economy.