Organocatalytic enantioselective domino reactions are an extremely attractive methodology, as their use enables the construction of complex chiral skeletons from readily available starting materials ...in two or more steps by a single operation under mild reaction conditions. Thus, these reactions can save both the quantity of chemicals and length of time typically required for the isolation and/or purification of synthetic intermediates. Additionally, no metal contamination of the products occurs, given that organocatalysts include no expensive or toxic metals. The aza-Morita–Baylis–Hillman (aza-MBH) reaction is an atom-economical carbon-carbon bond-forming reaction between α,β-unsaturated carbonyl compounds and imines mediated by Lewis base (LB) catalysts, such as nucleophilic phosphines and amines. aza-MBH products are functionalized chiral β-amino acid derivatives that are highly valuable as pharmaceutical raw materials. Although various enantioselective aza-MBH processes have been investigated, very few studies of aza-MBH-type domino reactions have been reported due to the complexity of the aza-MBH process, which involves a Michael/Mannich/H-transfer/β-elimination sequence. Accordingly, in this review article, our recent efforts in the development of enantioselective domino reactions initiated by MBH processes are described. In the domino reactions, chiral organocatalysts bearing Brønsted acid (BA) and/or LB units impart synergistic activation to substrates, leading to the easy synthesis of highly functionalized heterocycles (some of which have tetrasubstituted and/or quaternary carbon stereocenters) in high yield and enantioselectivity.
Conspectus Axially chiral compounds with rotationally constrained σ-bonds that exhibit atropisomerism are lucrative synthetic targets because of their ubiquity in functional materials and natural ...products. The metal complex-catalyzed enantioselective fabrication of axially chiral scaffolds has been widely investigated, and thus far, considerable progress has been made. Over the past two decades, we have developed a highly efficient strategy for constructing axially chiral biarenol derivatives using chiral mono- and dinuclear vanadium complexes. These complexes are readily prepared from vanadium(IV) salts and Schiff base ligands (generated from the condensation of (S)-tert-leucine and di- or monoformyl-(R)-1,1′-bi-2-naphthol (BINOL) derivatives) under O2 and act as highly active catalysts for highly stereoselective C–C bond formation. In particular, the vanadium complex-catalyzed enantioselective oxidative coupling of 2-naphthols 1 under oxygen or in air, which is a green oxidant, affords the desired axially chiral molecules in high yields and high stereoselectivity (up to quantitative yield and 97% ee), along with water as the sole coproduct. This coupling reaction tolerated various functional groups (such as halogens, alkoxys, and boryls) and avoided overoxidation of coupling products. The key feature of dinuclear vanadium(V) catalysts such as (R a,S,S)-5a is an outstanding mode of the homocoupling reaction, in which a single molecule of the catalyst activates two molecules of the starting material (e.g., 2-naphthols) simultaneously. With this “dual activation” mechanism, the oxidative coupling promoted by the dinuclear catalyst proceeds in an intramolecular manner. The homocoupling rate using 5 mol % of the dinuclear vanadium(V) complex (R a ,S,S)-5a was measured to be 111 times faster than that of the mononuclear vanadium(IV) complex (S)-4a bearing a half motif of the dinuclear vanadium complex. In the case of the heterocoupling reaction utilizing two different kinds of arenol derivatives, only a starting arenol having lower oxidation potential seems to be activated by the mononuclear vanadium complex. The reaction rate of the heterocoupling using either mono- or dinuclear vanadium complexes showed no difference to give the coupling product in high yields but with a different enantioselective manner; chiral mononuclear vanadium(V) complexes showed better enantioselectivites than that of the dinuclear vanadium(V) complexes. A competing heterocoupling study and a linear correlation between the ee of the mononucaler vanadium catalyst and ee of the heterocoupling suggested that the heterocoupling involves an intermolecular radical-anion coupling pathway. In this Account, we summarize the recent advances in vanadium-catalyzed coupling reactions that produced important chiral molecules, such as biresorcinols, polycyclic biphenols, oxa9helicenes, bihydroxycarbazoles, and C 1-symmetrical biarenols, and their coupling reaction mechanisms. By pursuing vanadium catalysis, we believe numerous additional transformations as well as a renewed interest in catalytic and chemo-, regio-, and enantioselective aryl–aryl bond constructions will be manifested.
An efficient and enantioselective synthesis of oxa9helicenes has been established via vanadium(V)-catalyzed oxidative coupling/intramolecular cyclization of polycyclic phenols. A newly developed ...vanadium complex cooperatively functions as both a redox and Lewis acid catalyst to promote the present sequential reaction and afford oxa9helicenes in good yields with up to 94% ee.
Abstract Cheminformatics-based machine learning (ML) has been employed to determine optimal reaction conditions, including catalyst structures, in the field of synthetic chemistry. However, such ...ML-focused strategies have remained largely unexplored in the context of catalytic molecular transformations using Lewis-acidic main-group elements, probably due to the absence of a candidate library and effective guidelines (parameters) for the prediction of the activity of main-group elements. Here, the construction of a triarylborane library and its application to an ML-assisted approach for the catalytic reductive alkylation of aniline-derived amino acids and C-terminal-protected peptides with aldehydes and H 2 is reported. A combined theoretical and experimental approach identified the optimal borane, i.e., B(2,3,5,6-Cl 4 -C 6 H)(2,6-F 2 -3,5-(CF 3 ) 2 -C 6 H) 2 , which exhibits remarkable functional-group compatibility toward aniline derivatives in the presence of 4-methyltetrahydropyran. The present catalytic system generates H 2 O as the sole byproduct.
A highly atom-economical, chemoselective, and stereoselective Lewis base (LB)-catalyzed dual umpolung domino Michael reaction between cyclohexadienones and alkynyl esters has been developed. PPh3, as ...a LB catalyst, afforded either the hydroindole-2-carboxylates or hydrobenzofuran-2-carboxylates 3 as a single diastereomer in high yields (up to 89%). An obtained product could be easily transformed to a (S*,S*,R*)-octahydroindole-2-carboxylic acid ((S*,S*,R*)-Oic) analogue.
The Mills reaction and cyclization of readily available 2‐aminobenzyl alcohols and nitrosobenzenes using thionyl bromide provided 2H‐indazoles in up to 88 % yields. In the metal‐free process, acetic ...acid played a crucial role for the both Mills reaction and cyclization. A brominated 2H‐indazole could also be obtained through the one‐pot sequence.
Heterocycles: The Mills reaction and cyclization of readily available 2‐aminobenzyl alcohols and nitrosobenzenes using thionyl bromide provided 2H‐indazoles in up to 88 % yields (see scheme). In the metal‐free process, acetic acid played a crucial role for the both Mills reaction and cyclization. A brominated 2H‐indazole could also be obtained through the one‐pot sequence.
In recent years vanadium catalysis has been extended to a range of different and even complementary directions in asymmetric synthesis. Inspired by nature’s way to activate both substrate and reagent ...in many cases, the design of efficient bifunctional and dinuclear vanadium catalysts has been achieved. Furthermore, vanadium catalysis has been an early field in which “hybrid catalysts” have been studied in detail by incorporation of oxovanadium complexes into proteins, thus giving artificial enzymes. In addition, a high compatibility of vanadium with proteins enabled the use of vanadium chemocatalysts for combinations with enzyme catalysis in one‐pot, thus leading to dynamic kinetic resolutions. In this contribution, these three concepts of vanadium catalysis opening up new perspectives for asymmetric synthesis are reviewed.
Vanadium catalysis successfully extended: Inspired by nature's way to activate substrates and reagents, bifunctional and dinuclear vanadium catalysts for CC coupling have been designed. In addition, vanadium catalysis was “merged” with protein chemistry by developing “hybrid catalysts” through incorporation of vanadium into enzymes and by combining vanadium chemocatalysts with enzymes in the dynamic kinetic resolution of alcohols.
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Asymmetric oxidative coupling reactions of hydroxycarbazoles have been established using a chiral dinuclear vanadium complex. To demonstrate the utility of vanadium-catalyzed ...reactions, we have used them to synthesize (+)-bi-2-hydroxy-3-carbazole in three steps from cyclohexanone and commercially available aniline derivatives.
This study processes a facile and green approach for the Markovnikov-selective hydroamination of styrene with naphthylamine through irradiation with UV LED light (365 nm) via an electron ...donor-acceptor complexation between naphthylamines and oxygen in situ. This protocol showcases the synthetic potential for aerobic C-N bond formation without using a metal catalyst and photosensitizer. Three naphthylamines were examined and afforded desired C-N bond formation product in moderate yield.
Facile, selective, and organic: Acid–base organocatalyzed aza‐Morita–Baylis–Hillman/aza‐Michael domino reactions of α,β‐unsaturated carbonyl compounds 1 with N‐tosylimines 2 have been developed. The ...enantioselective process produces the highly functionalized isoindoline as a single diastereomer (Ts=4‐toluenesulfonyl).
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