Palladium‐Catalyzed Asymmetric [8+2] Dipolar Cycloadditions of Vinyl Carbamates and Photogenerated Ketenes

Higher‐order cycloadditions, particularly [8+2] cycloadditions, are a straightforward and efficient strategy for constructing significant medium‐sized architectures. Typically, configuration‐restrained conjugated systems are utilized as 8π‐components for higher‐order concerted cycloadditions. However, for this reason, 10‐membered monocyclic skeletons have never been constructed via catalytic asymmetric [8+2] cycloaddition with high peri‐ and stereoselectivity. Here, we accomplished an enantioselective [8+2] dipolar cycloaddition via the merger of visible‐light activation and asymmetric palladium catalysis. This protocol provides a new route to 10‐membered monocyclic architectures bearing chiral quaternary stereocenters with high chemo‐, peri‐, and enantioselectivity. The success of this strategy relied on the facile in situ generation of Pd‐containing 1,8‐dipoles and their enantioselective trapping by ketene dipolarophiles, which were formed in situ via a photo‐Wolff rearrangement.     

Catalytic Asymmetric Formal [3+3] Cycloaddition of an Azomethine Ylide with 3‐Indolylmethanol: Enantioselective Construction of a Six‐Membered Piperidine Framework

A catalytic asymmetric formal [3+3] cycloaddition of 3‐indolylmethanol and an in situ‐generated azomethine ylide has been established to construct a chiral six‐membered piperidine framework with two stereogenic centers. This approach not only represents the first enantioselective cycloaddition of isatin‐derived 3‐indolylmethanol, but also has realized an unusual enantioselective formal [3+3] cycloaddition of azomethine ylide rather than its common [3+2] cycloadditions. Besides, this protocol combines the merits of a multicomponent reaction and organocatalysis, which efficiently assembles a variety of isatin‐derived 3‐indolylmethanols, aldehydes, and amino esters into structurally diverse spiro[indoline‐3,4′‐pyridoindoles] with one all‐carbon quaternary stereogenic center in high yields and excellent enantioselectivities (up to 93 % yield, >99 % enantiomeric excess (ee)). Although the diastereoselectivity of the reaction is generally moderate, most of the diastereomers can be separated by using column chromatography followed by preparative TLC.     

Highly Enantioselective Catalytic Asymmetric [2+2] Cycloadditions of Cyclic α‐Alkylidene β‐Oxo Imides with Ynamides

Highly enantioselective catalytic asymmetric [2+2] cycloadditions of cyclic α‐alkylidene β‐oxo imides with ynamides are described. The high reactivity of the cyclic α‐alkylidene β‐oxo imide allows the [2+2] cycloadditions of a hindered substrate with unreactive ynamides at low temperature. The X‐ray crystallographic analysis of the product suggests that the enantioselectivity of the [2+2] cycloaddition can be well explained by the chelate model comprising the intramolecular hydrogen bond, wherein the cyclic α‐alkylidene β‐oxo imide coordinates with Cu^II through the two imide carbonyls. The imide group in the product can be transformed to amide, nitrile, and ester groups; moreover, it is removable.     

Catalytic Enantioselective and Regioselective [3+3] Cycloadditions Using 2‐Indolylmethanols as 3 C Building Blocks

The first catalytic asymmetric cycloaddition using 2‐indolylmethanols as 3C building blocks has been established by a chiral phosphoric acid‐catalyzed enantioselective and regioselective [3+3] cycloaddition of 2‐indolylmethanols with azomethine ylides, which constructed biologically important tetrahydro‐γ‐carboline frameworks in high yields and excellent enantioselectivities (up to 83 % yield, 99:1 e.r.). This reaction not only represents the first application of 2‐indolylmethanols as 3C building blocks in catalytic asymmetric cycloadditions, but also has established an abnormal regioselectivity in indolylmethanol‐involved transformations.     

Toward the development of a general chiral auxiliary. A total synthesis of (+)-tetronolide via a tandem ketene-trapping [4 + 2] cycloaddition strategy

A highly convergent, enantioselective total synthesis of the aglycone of the tetrocarcins, (+)-tetronolide, is described. The synthesis highlights the use of several new methods, including camphor auxiliary-directed asymmetric alkylation and the enantioselective preparation of acyclic mixed acetals bearing chirality at the acetal center, and the highly efficient connection of the two major precursors via a ketene-trapping/intramolecular [4 + 2] cycloaddition strategy.     

Enantioselective Formal [4+2] Cycloadditions to 3‐Nitroindoles by Trienamine Catalysis: Synthesis of Chiral Dihydrocarbazoles

The first enantioselective formal [4+2] cycloadditions of 3‐nitroindoles are presented. By using 3‐nitroindoles in combination with an organocatalyst, chiral dihydrocarbazole scaffolds are formed in moderate to good yields (up to 87 %) and enantioselectivities (up to 97 % ee). The reaction was extended to include enantioselective [4+2] cycloadditions of 3‐nitrobenzothiophene. The reaction proceeds through a [4+2] cycloaddition/elimination cascade under mild reaction conditions. Furthermore, a diastereoselective reduction of an enantioenriched cycloadduct is presented. The mechanism of the reaction is discussed based on experimental and computational studies.     

Dual catalysis in enantioselective oxidopyrylium-based [5 + 2] cycloadditions

A new method for effecting catalytic enantioselective intramolecular [5 + 2] cycloadditions based on oxidopyrylium intermediates is reported. The dual catalyst system consists of a chiral primary aminothiourea and a second achiral thiourea. Experimental evidence points to a new type of cooperative catalysis with each species being necessary to generate a reactive pyrylium ion pair that undergoes subsequent cycloaddition with high enantioselectivity.     

Development of catalytic asymmetric 1,4-addition and [3 + 2] cycloaddition reactions using chiral calcium complexes

Catalytic asymmetric 1,4-addition and [3 + 2] cycloaddition reactions using chiral calcium species prepared from calcium isopropoxide and chiral bisoxazoline ligands have been developed. Glycine Schiff bases reacted with acrylic esters to afford 1,4-addition products, glutamic acid derivatives, in high yields with high enantioselectivities. During the investigation of the 1,4-addition reactions, we unexpectedly found that a [3 + 2] cycloaddition occurred in the reactions with crotonate derivatives, affording substituted pyrrolidine derivatives in high yields with high enantioselectivities. On the basis of this finding, we investigated asymmetric [3 + 2] cycloadditions, and it was revealed that several kinds of optically active substituted pyrrolidine derivatives containing contiguous stereogenic tertiary and quaternary carbon centers were obtained with high diastereo- and enantioselectivities. In addition, optically active pyrrolidine cores of hepatitis C virus RNA-dependent polymerase inhibitors and potential effective antiviral agents have been synthesized using this [3 + 2] cycloaddition reaction. NMR spectroscopic analysis and observation of nonamplification of enantioselectivity in nonlinear effect experiments suggested that a monomeric calcium species with an anionic ligand was formed as an active catalyst. A stepwise mechanism of the [3 + 2] cycloaddition, consisting of 1,4-addition and successive intramolecular Mannich-type reaction was suggested. Furthermore, modification of the Schiff base structure resulted in a modification of the reaction course from a [3 + 2] cycloaddition to a 1,4-addition, affording 3-substituted glutamic acid derivatives with high diasterero- and enantioselectivities.     

Aromatic Amide‐Derived Non‐Biaryl Atropisomers as Highly Efficient Ligands in Silver‐Catalyzed Asymmetric Cycloaddition Reactions

The synthesis of a series of aromatic amide‐derived non‐biaryl atropisomers with a phosphine group and multiple stereogenic centers is reported. The novel phosphine ligands exhibit high diastereo‐ and enantioselectivities (up to >99:1 d.r., 95–99 % ee) as well as yields in the silver‐catalyzed asymmetric [3+2] cycloaddition of aldiminoesters with nitroalkenes, which provides a highly enantioselective strategy for the synthesis of optically pure nitro‐substituted pyrrolidines. In addition, the experimental results with regard to the carbon stereogenic center as well as the amide stereochemistry confirmed the potential of hemilabile atropisomers as chiral ligand in catalytic asymmetric [3+2] cycloaddition reaction.     

Cyclobutane and Cyclobutene Synthesis: Catalytic Enantioselective [2+2] Cycloadditions

Cyclobutanes and cyclobutenes are important structural motifs found in numerous biologically significant molecules, and they are useful intermediates for chemical synthesis. Consequently, [2+2] cycloadditions to access cyclobutanes and cyclobutenes have been established to be particularly useful transformations. Within the last 10 years, an increase in the frequency of publications for catalytic enantioselective [2+2] cycloadditions has occurred. These reactions provide access to a wide array of enantiomerically enriched chemical diversity that was not previously attainable. Described in this review are the advances made in catalytic enantioselective [2+2] cycloadditions to access cyclobutanes and cyclobutenes.     

Synthesis of 4-membered ring alkaloid analogues via intramolecular [2+2] cycloaddition involving keteniminium salt intermediates

We have developed a very straightforward method for the synthesis of 4-membered ring alkaloid analogues via intramolecular [2+2] cycloadditions. This involves the cyclization of a keteniminium salt in which an alkene is linked by the nitrogen atom, and where, the resulting cyclobutane iminium is reduced in a diastereoselective manner. Competition reactions have been performed to fully understand the features of this sequence. Moreover, DFT calculations have verified that the [2+2] cycloaddition step is driven by kinetic and not thermodynamic factors confirming all the experimental observations.     

Co-Catalyzed Asymmetric Intramolecular [3+2] Cycloaddition of Yne-Alkylidenecyclopropanes and its Reaction Mechanism

Developing new transition metal-catalyzed asymmetric cycloadditions for the synthesis of five-membered carbocycles (FMCs) is a research frontier in reaction development due to the ubiquitous presence of chiral FMCs in various functional molecules. Reported here is our discovery of a highly enantioselective intramolecular [3+2] cycloaddition of yne-alkylidenecyclopropanes (yne-ACPs) to bicyclo[3.3.0]octadiene and bicyclo[4.3.0]nonadiene molecules using a cheap Co catalyst and commercially available chiral ligand (S)-Xyl-BINAP. This reaction avoids the use of precious Pd and Rh catalysts, which are usually the choices for [3+2] reactions with ACPs. The enantiomeric excess in the present reaction can be up to 92 %. Cationic cobalt(I) species was suggested by experiments as the catalytic species. DFT calculations showed that this [3+2] reaction starts with oxidative cyclometallation of alkyne and ACP, followed by ring opening of the cyclopropyl (CP) group and reductive elimination to form the cycloadduct. This mechanism is different from previous [3+2] reactions of ACPs, which usually start from CP cleavage, not from oxidative cyclization.     

Stereochemistry of the Diels–Alder reaction at high pressure: diastereo- and enantioselective [4+2]cycloaddition of buta-1,3-diene to glyoxylic acid derivatives catalysed by (salen) chromium(III) complexes

High-pressure [4+2]cycloadditions of buta-1,3-diene 1 to chiral 2a–c and achiral 7a–c glyoxylates, in the presence of (salen) chromium(III) complexes 5 and 6, were studied. The influence of such chiral Lewis acids on diastereoselectivity or enantioselectivity of the cycloaddition was investigated; a moderate asymmetric induction for both diastereo- and enantioselective variants of the cycloaddition was observed (up to 58% de and up to 71% ee, respectively).     

Utilizing Vinylcyclopropane Reactivity: Palladium-Catalyzed Asymmetric [5+2] Dipolar Cycloadditions

Vinylcyclopropanes (VCPs) are commonly used in transition-metal-catalyzed cycloadditions, and the utilization of their recently realized reactivities to construct new cyclic architectures is of great significance in modern synthetic chemistry. Herein, a palladium-catalyzed, visible-light-driven, asymmetric [5+2] cycloaddition of VCPs with α-diazoketones is accomplished by switching the reactivity of the Pd-containing dipolar intermediate from an all-carbon 1,3-dipole to an oxo-1,5-dipole. Enantioenriched seven-membered lactones were produced with good reaction efficiencies and selectivities (23 examples, 52–92 % yields with up to 99:1 er and 12.5:1 dr). In addition, computational investigations were performed to rationalize the observed high chemo- and periselectivities.     

Hydrogen‐Bonding Network Promoted [3+2] Cycloaddition: Asymmetric Catalytic Construction of Spiro‐pseudoindoxyl Derivatives

The enantioselective construction of a spirocyclic quaternary stereogenic carbon center at the C2 position of indole has long been an elusive problem in organic synthesis. Herein, by employing a rationally designed hydrogen‐bonding network activation strategy, for the first time, 2,2′‐pyrrolidinyl‐spirooxindole, which is a valuable and prevalent indole alkaloid scaffold, was directly obtained through a catalytic asymmetric [3+2] cycloaddition reaction with high yields and excellent stereoselectivities.     

Fused tetracycles with a benzene or cyclohexadiene core: [2 + 2 + 2] cycloadditions on macrocyclic systems

A series of fused tetracycles with a benzene or cyclohexadiene core (2a-h) is satisfactorily prepared by intramolecular [2 + 2 + 2] cycloadditions of triynic and enediynic macrocycles (1a-h) under RhCl(PPh3)3 catalysis; the enantioselective cycloaddition of macrocycles 1b and 1e and gives chiral tetracycles with moderate enantiomeric excess.     

Asymmetric Brønsted Base Catalyzed and Directed [3+2] Cycloaddition of 2‐Acyl Cycloheptatrienes with Azomethine Ylides

Conjugated cyclic trienes have the potential for different types of cycloaddition reactions. In the present work, we will, in a novel asymmetric cycloaddition reaction, demonstrate that the organocatalytic reaction of 2‐acyl cycloheptatrienes with azomethine ylides proceeds as a [3+2] cycloaddition, which is in contrast to the Lewis acid‐catalyzed reaction, in which a [3+6] cycloaddition takes place. In the presence of a chiral organosuperbase, 2‐acyl cycloheptatrienes react in a highly enantioselective manner in the [3+2] cycloaddition with azomethine ylides, providing the 1,3‐dipolar cycloaddition product in high yields and up to 99 % ee. It is also shown that the diene formed by the reaction can undergo stereoselective dihydroxylation, bromination, and cycloaddition reactions. Finally, based on experimental observations, some mechanistic considerations are discussed.     

Rhodium N-heterocyclic carbene-catalyzed [4 + 2] and [5 + 2] cycloaddition reactions

[reactions: see text] A rhodium complex of N-heterocyclic carbene (NHC) has been developed for intra- and intermolecular [4 + 2] and intramolecular [5 + 2] cycloaddition reactions. This is the first use of a transition-metal NHC complex in a Diels-Alder-type reaction. For the intramolecular [4 + 2] cycloaddition reactions, all the dienynes studied were converted to their corresponding cycloadducts in 91-99% yields within 10 min. Moreover, up to 1900 turnovers have been obtained for the intramolecular [4 + 2] cycloaddition at 15-20 degrees C. For the intermolecular [4 + 2] cycloadditions, high yields (71-99%) of the corresponding cycloaddition products were obtained. The reaction time and yield were highly dependent upon the diene and the dienophile. For the intramolecular [5 + 2] cycloaddition reactions, all the alkyne vinylcyclopropanes studied were converted to their corresponding cycloadducts in 91-98% yields within 10 min. However, the catalytic system was not effective for an intermolecular [5 + 2] cycloaddition reaction.     

Cycloaddition reactions of 2H-benzo[b]thiete and conjugated cyclic dienes

2H-Benzo[b]thiete 1 reacts with cyclopentadiene 3 in consecutive [8π + 2π]cycloadditions yielding the condensed heterocycles 6–8 . Tetracyclone 9 on the other hand gives only the monoadduct 10 . An [8π + 8π]cycloaddition can be observed for 1 and diphenylisobenzofuran 11 . The related π system 13 shows again consecutive [477π + 27π]processes ( 1 + 13 ← 14, 15 ).     

Asymmetric Rh(I)-catalyzed intramolecular [3 + 2] cycloaddition of 1-yne-vinylcyclopropanes for bicyclo[3.3.0] compounds with a chiral quaternary carbon stereocenter and density functional theory study of the origins of enantioselectivity

A highly enantioselective Rh(I)-catalyzed intramolecular [3 + 2] cycloaddition of 1-yne-VCPs to bicyclo[3.3.0] compounds with an all-carbon chiral quaternary stereocenter at the bridgehead carbon was developed. DFT calculations of the energy surface of the catalytic cycle (complexation, cyclopropane cleavage, alkyne insertion, and reductive elimination) of the asymmetric [3 + 2] cycloaddition reaction indicated that the rate- and stereo-determining step is the alkyne-insertion step. Analysis of the alkyne-insertion transition states revealed that the serious steric repulsion between the substituents in the alkyne moiety of the substrates and the rigid H(8)-BINAP backbone is responsible for not generating the disfavored [3 + 2] cycloadducts.