Organocatalytic Enantioselective Conia‐Ene‐Type Carbocyclization of Ynamide Cyclohexanones: Regiodivergent Synthesis of Morphans and Normorphans

Described herein is an organocatalytic enantioselective desymmetrizing cycloisomerization of arylsulfonyl‐protected ynamide cyclohexanones, representing the first metal‐free asymmetric Conia‐ene‐type carbocyclization. This method allows the highly efficient and atom‐economical construction of a range of valuable morphans with wide substrate scope and excellent enantioselectivity (up to 97 % ee). In addition, such a cycloisomerization of alkylsulfonyl‐protected ynamide cyclohexanones can lead to the divergent synthesis of normorphans as the main products with high enantioselectivity (up to 90 % ee). Moreover, theoretical calculations are employed to elucidate the origins of regioselectivity and enantioselectivity.     

Palladium‐Catalyzed Oxidative Cycloisomerization of 2‐Cinnamyl‐1,3‐Dicarbonyls: Synthesis of Functionalized 2‐Benzyl Furans

A new palladium‐catalyzed intramolecular oxidative cycloisomerization of readily available starting materials, 2‐cinnamyl‐1,3‐dicarbonyls, has been demonstrated for the creation of structurally diverse 2‐benzyl furans. The cycloisomerization occurs by a regioselective 5‐exo‐trig pathway. The reaction shows a broad substrate scope with good to excellent yields. Furthermore, a one‐pot procedure has been executed by using readily available cinnamyl alcohols and 1,3‐diketones.     

Gold‐Catalyzed 6‐Exo‐Dig Cycloisomerization: A Versatile Approach to Functionalized Phenanthrenes

A novel gold‐catalyzed 6‐exo‐dig cycloisomerization of o‐propargylbiaryls has been developed that provides ready access to functionalized phenanthrenes in largely good to excellent yields. Notable features of this method are readily available starting materials, mild reaction conditions, and broad substrate scope.     

Phosphathiahelicenes: Synthesis and Uses in Enantioselective Gold Catalysis

Enantiomerically pure thiahelicenes displaying a terminal phosphole unit and a stereogenic phosphorus center have been prepared by oxidative photocyclization of a diaryl‐olefin precursor. Starting from one of these phosphathiahelicene oxides, the corresponding trivalent phosphine–Au^I complex is obtained with complete diastereoselectivity. It affords a new, excellent precatalyst for the enantioselective cycloisomerization of N‐tethered enynes (up to 96 % ee).     

Synthesis of Substituted 1,3‐Diene Synthetic Equivalents by a Ru‐Catalyzed Diyne Hydrative Cyclization

Catalyzed by [CpRu(CH₃CN)₃]PF₆, the hydrative cyclization of dipropargylic sulfone substrates provides an effective way to synthesize highly functionalized substituted 3‐sulfolenes. The amount of water is crucial for the reactivity of this cycloisomerization reaction. The scope and limitations of the Ru‐catalyzed cycloisomerization are discussed. A marked ketone‐directing effect was observed for the first time in ruthenium‐catalyzed cyclizations. A plausible mechanism for the ketone‐directed cycloisomerization is also rationalized. The utility of this method was demonstrated by both sulfur dioxide extrusion of the 3‐sulfolenes to afford 1,3‐dienes and subsequent inter‐ or intramolecular Diels–Alder reactions.     

Diversified Cycloisomerization/Diels–Alder Reactions of 1,6‐Enynes through Bimetallic Relay Asymmetric Catalysis

We report the combination of transition‐metal‐catalyzed diversified cycloisomerization of 1,6‐enynes with chiral Lewis acid promoted asymmetric Diels–Alder reaction to realize asymmetric cycloisomerization/Diels–Alder relay reactions of 1,6‐enynes with electron‐deficient alkenes. A broad spectrum of chiral [5,6]‐bicyclic products could be acquired in high yields (up to 99 %) with excellent diastereoselectivy (>19:1 dr) and enantioselectivity (up to 99 % ee).     

Electrophilic Reactivities of 1,2‐Diaza‐1,3‐dienes

The kinetics of the reactions of 1,2‐diaza‐1,3‐dienes 1 with acceptor‐substituted carbanions 2 have been studied at 20 °C. The reactions follow a second‐order rate law, and can be described by the linear free energy relationship log k(20 °C)=s(N+E) [Eq. (1)]. With Equation (1) and the known nucleophile‐specific parameters N and s for the carbanions, the electrophilicity parameters E of the 1,2‐diaza‐1,3‐dienes 1 were determined. With E parameters in the range of ?13.3 to ?15.4, the electrophilic reactivities of 1 a–d are comparable to those of benzylidenemalononitriles, 2‐benzylideneindan‐1,3‐diones, and benzylidenebarbituric acids. The experimental second‐order rate constants for the reactions of 1 a – d with amines 3 and triarylphosphines 4 agreed with those calculated from E, N, and s, indicating the applicability of the linear free energy relationship [Eq. (1)] for predicting potential nucleophilic reaction partners of 1,2‐diaza‐1,3‐dienes 1 . Enamines 5 react up to 10² to 10³ times faster with compounds 1 than predicted by Equation (1), indicating a change of mechanism, which becomes obvious in the reactions of 1 with enol ethers.     

Enzyme‐ and Ruthenium‐Catalyzed Enantioselective Transformation of α‐Allenic Alcohols into 2,3‐Dihydrofurans

An efficient one‐pot method for the enzyme‐ and ruthenium‐catalyzed enantioselective transformation of α‐allenic alcohols into 2,3‐dihydrofurans has been developed. The method involves an enzymatic kinetic resolution and a subsequent ruthenium‐catalyzed cycloisomerization, which provides 2,3‐dihydrofurans with excellent enantioselectivity (up to >99 % ee). A ruthenium carbene species was proposed as a key intermediate in the cycloisomerization.     

Dynamic Kinetic Asymmetric Transformation (DYKAT) by Combined Amine‐ and Transition‐Metal‐Catalyzed Enantioselective Cycloisomerization

The first examples of one‐pot highly chemo‐ and enantioselective dynamic kinetic asymmetric transformations (DYKATs) involving α,β‐unsaturated aldehydes and propargylated carbon acids are presented. These DYKATs, which proceed by a combination of catalytic iminium activation, enamine activation, and Pd⁰‐catalyzed enyne cycloisomerization, give access to functionalized cyclopentenes with up to 99 % ee and can be used for the generation of all‐carbon quaternary stereocenters.     

Rhodium(I)‐Catalyzed Cycloisomerization of Homopropargylallene‐Alkynes through C(sp3)−C(sp) Bond Activation

Upon exposure to a catalytic amount of [RhCl(CO)₂]₂ in 1,4‐dioxane, homopropargylallene‐alkynes underwent a novel cycloisomerization accompanied by the migration of the alkyne moiety of the homopropargyl functional group to produce six/five/five tricyclic compounds in good yields. A plausible mechanism was proposed on the basis of an experiment with ¹³C‐labeled substrate. The resulting tricyclic derivatives were further converted into the corresponding bicyclo[3.3.0] skeletons with vicinal cis dihydroxy groups.     

Copper(I)‐Catalyzed Asymmetric [3+2]‐Cycloaddition of α‐Substituted Iminoesters with α‐Trifluoromethyl α,β‐Unsaturated Esters

Reported herein is an example of highly regio‐, diastereo‐ and enantioselective Cu(I)‐catalyzed intermolecular [3+2] cycloaddition reaction of α‐substituted iminoesters with α‐trifluoromethyl α,β‐unsaturated esters. This novel strategy provided a facile access to pyrrolidines with two skipped (aza)quaternary stereocenters including a CF₃ all‐carbon quaternary stereocenter. A broad substrate scope was observed and high yields (up to 94%) with excellent diastereoselectivity (up to >20 : 1 d.r.) and enantioselectivity (up to 98% ee) were obtained.     

A Combined Experimental and Computational Study on the Cycloisomerization of 2‐Ethynylbiaryls Catalyzed by Dicationic Arene Ruthenium Complexes

Ruthenium‐catalyzed cycloisomerization of 2‐ethynylbiaryls was investigated to identify an optimal ruthenium catalyst system. A combination of [η⁶‐(p‐cymene)RuCl₂(PR₃)] and two equivalents of AgPF₆ effectively converted 2‐ethynylbiphenyls into phenanthrenes in chlorobenzene at 120 °C over 20 h. Moreover, 2‐ethynylheterobiaryls were found to be favorable substrates for this ruthenium catalysis, thus achieving the cycloisomerization of previously unused heterocyclic substrates. Moreover, several control experiments and DFT calculations of model complexes were performed to propose a plausible reaction mechanism.     

Palladium‐Catalyzed Asymmetric Aminohydroxylation of 1,3‐Dienes

A Pd^II‐catalyzed asymmetric aminohydroxylation of 1,3‐dienes with N‐tosyl‐2‐aminophenols was developed by making use of a chiral pyridinebis(oxazoline) ligand. The highly regioselective reaction provides direct and efficient access to chiral 3,4‐dihydro‐2H‐1,4‐benzoxazines in high yield and enantioselectivity (up to 96:4 e.r.). The reaction employs readily available N‐tosyl‐2‐aminophenols as a unique aminohydroxylation reagent and is complementary to known asymmetric aminohydroxylation methods.     

Gold(I)‐Catalyzed Generation of the Two Components of a Formal [4+2] Cycloaddition Reaction for the Synthesis of Tetracyclic Pyrano[2,3,4‐de]chromenes

Ortho‐Alkynylbenzaldehydes have been widely used to generate isochromenylium derivatives through gold‐catalyzed cycloisomerization. These isochromenylium derivatives have been exploited as formal diene derivatives for reactions with different dienophiles. Herein, we describe the behavior of ortho‐alkynylsalicylaldehydes, a particular case of ortho‐alkynylbenzaldehydes. The gold‐catalyzed cycloisomerization of ortho‐alkynylsalicylaldehydes delivers an unusual heterodiene derivative that reacts with electron‐rich alkenes through a formal [4+2] cycloaddition. In this reaction, both the diene and dienophile are generated in situ through gold‐catalyzed cycloisomerization of appropriate alkynamines or alkynols. This reaction was used to synthesize complex tetracyclic pyrano[2,3,4‐de]chromenes from two very simple starting materials (an ortho‐alkynylsalicylaldehyde and an alkynamine or alkynol) with complete atom economy and with selective formation of bonds, cycles, and stereocenters.     

An Enantioselective CpxRh(III)‐Catalyzed C−H Functionalization/Ring‐Opening Route to Chiral Cyclopentenylamines

A chiral Cp^xRh^III catalyst system in situ generated from a Cp^xRh^I(cod) precatalyst and bis(o‐toluoyl) peroxide as activating oxidant was developed for a C?H activation/ring‐opening sequence between aryl ketoxime ethers and 2,3‐diazabicyclo[2.2.1]hept‐5‐enes. This transformation provides access to densely functionalized chiral cyclopentenylamines in excellent yields and enantioselectivities of up to 97:3 er. The reported method is also well suitable for asymmetric alkenyl C?H functionalizations of α,β‐unsaturated oxime ethers, furnishing skipped dienes with high levels of enantiocontrol.     

α‐ZrP/Uracil/Cu2+ nanoparticles as an efficient catalyst in the Morita‐Baylis‐Hillman reaction

A facile synthesis of uracil‐Cu²⁺ nanoparticles immobilized on alpha‐zirconium hydrogen phosphate (α‐ZrP), abbreviated as α‐ZrP/Uracil/Cu²⁺, was presented. This compound was synthesized by the thermal method and used as a reusable catalyst for the Morita‐Baylis‐Hillman reaction without any additives. First, (3‐ iodopropyl) trimethoxysilane as a linker is reacted with α‐ZrP support to give the α‐ZrP/IPTMOS. Addition of uracil and then the addition of copper (II) acetate to α‐ZrP/IPTMOS results in the production of selected catalyst. The Morita‐Baylis‐Hillman reaction catalyzed by α‐ZrP/Uracil/Cu^{2 +} demonstrated high product yield, short reaction time and a straightforward work‐up. The catalyst with enough outside surface was easily recovered using centrifugation and reused five times without a significant reduction in its activity.     

Bimetallic Catalytic Asymmetric Tandem Reaction of β‐Alkynyl Ketones to Synthesize 6,6‐Spiroketals

The enantioselective tandem reaction of β,γ‐unsaturated α‐ketoesters with β‐alkynyl ketones was realized by a bimetallic catalytic system of achiral Au^ΙΙΙ salt and chiral N,N′‐dioxide‐Mg^ΙΙ complex. The cycloisomerization of β‐alkynyl ketone and asymmetric intermolecular [4+2] cycloaddition with β,γ‐unsaturated α‐ketoesters subsequently occurred, providing an efficient and straightforward access to chiral multifunctional 6,6‐spiroketals in up to 97 % yield, 94 % ee and >19/1 d.r. Besides, a catalytic cycle was proposed based on the results of control experiments.     

Intermolecular 1,4‐Carboamination of Conjugated Dienes Enabled by Cp*RhIII‐Catalyzed C−H Activation

A protocol for the three‐component 1,4‐carboamination of dienes is described. Synthetically versatile Weinreb amides were coupled with 1,3‐dienes and readily available dioxazolones as the nitrogen source using [Cp*RhCl₂]₂‐catalyzed C?H activation to deliver the 1,4‐carboaminated products. This transformation proceeds under mild reaction conditions and affords the products with high levels of regio‐ and E‐selectivity. Mechanistic investigations suggest an intermediate Rh^III–allyl species is trapped by an electrophilic amidation reagent in a redox‐neutral fashion.     

Substrate Range of the Titanium TADDOLate Catalyzed Asymmetric Fluorination of Activated Carbonyl Compounds

The substrate range of the [TiCl₂(TADDOLate)] (TADDOL=α,α,α′,α′‐tetraaryl‐1,3‐dioxolane‐4,5‐dimethanol)‐catalyzed asymmetric α‐fluorination of activated β‐carbonyl compounds has been investigated. Optimal conditions for catalysis are characterized by using 5 mol‐% of TiCl₂(naphthalen‐1‐yl)‐TADDOLate) as catalyst in a saturated (0.14 mol/l) MeCN solution of F‐TEDA (1‐(chloromethyl)‐4‐fluoro‐1,4‐diazoniabicyclo[2.2.2]octane bis‐[tetrafluoroborate]) at room temperature. A series of α‐methylated β‐keto esters (3‐oxobutanoates, 3‐oxopentanoates) with bulky benzyl ester groups (60–90% ee) or phenyl ester (67–88% ee) have been fluorinated readily, whereas α‐acyl lactones were also readily fluorinated, but gave lower inductions (13–46% ee). Double stereochemical differentiation in β‐keto esters with chiral ester groups raised the stereoselectivity to a diastereomeric ratio (dr) of up to 96.5 : 3.5. For the first time, β‐keto S‐thioesters were asymmetrically fluorinated (62–91.5% ee) and chlorinated (83% ee). Lower inductions were observed in fluorinations of 1,3‐diketones (up to 40% ee) and β‐keto amides (up to 59% ee). General strategies for preparing activated β‐carbonyl compounds as important model substrates for asymmetric catalytic α‐functionalizations are presented (>60 examples).     

Tuned C?H Functionalization to Construct Aza‐Podophyllotoxin/Aza‐Conidendrin Derivatives by Means of Domino Cyclization

An efficient domino cyclization method for the construction of aza‐podophyllotoxin/aza‐conidendrin derivatives has been established. Reactions of different dienes with aryl halides in the presence of a palladium catalytic system produced different kinds of podophyllotoxin derivatives through a highly regioselective C? H functionalization. Treatment of dienes with aryl halides that have electron‐withdrawing substituents on the phenyl ring created aza‐podophyllotoxin derivatives by means of the functionalization of the C? H bonds ortho to the C? halide bonds of the incoming aryl halides. The reaction of dienes with 1‐iodobenzene or aryl halides that incorporate electron‐donating groups produced aza‐conidendrin derivatives by means of the functionalization of both sp³ C? H and sp² C? H bonds. The regioselective C? H functionalization for the formation of different pseudo‐podophyllotoxin/‐conidendrin derivatives is proven by analyses of the ¹H NMR spectra of the products and selective X‐ray analyses of the structures of the products. Thus, the palladium‐catalyzed domino cyclization of 1,6‐dienes for the preparation of aza‐podophyllotoxin/aza‐conidendrin derivatives can be controlled by selectively controlling the C? H functionalization.