Recent Advances in Catalytic Atroposelective Construction of Pentatomic Heterobiaryl Scaffolds
TL;DR: Recent advances of catalytic asymmetric construction of axially chiral pentatomic heterobiaryls through asymmetric catalysis are summarized in this review, involving their scope, mechanism, transformations, and applications.
Abstract: Pentatomic heterobiaryl performs as a key structural motif in various natural products and bioactive compounds. With the rapid growth of asymmetric catalysis, five‐membered heterobiaryl‐based catalysts and ligands have emerged as an efficient complementary toolbox for asymmetric catalysis. Therefore, the development of enantioselective construction of such pentatomic atropisomers has received significant attention in recent decade. Various catalytic asymmetric strategies have been established, including central to axial chirality conversion, direct generation of heteroaryl, direct assembly of aryl‐heteroaryls, functionalization of racemic or prochiral biaryls, and chirality transfer from atropisomeric alkenes. Hundreds of unprecedented pentatomic atropisomers have proliferated. Importantly, a few promising axially chiral catalysts and ligands have been obtained from the prepared heterobiaryls after simple transformations. Hence, recent advances of catalytic asymmetric construction of axially chiral pentatomic heterobiaryls through asymmetric catalysis are summarized in this review, involving their scope, mechanism, transformations, and applications.
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TL;DR: In this article , a new enantioselective synthesis strategy for axially chiral 3,3'-bisindoles was devised by the direct coupling of two indole rings.
Abstract: A new strategy for the enantioselective synthesis of axially chiral 3,3'-bisindoles was devised by the direct coupling of two indole rings. This strategy makes use of the C3-umpolung reactivity of 2-indolylmethanols, which enables the catalytic asymmetric addition reaction of 2-indolylmethanols with rationally designed 2-substituted indoles, thus constructing axially chiral 3,3'-bisindole scaffolds in overall excellent yields (up to 98%) with high enantioselectivities (up to 96 : 4 er). This approach not only has overcome the challenges in constructing axially chiral five-five-membered heterobiaryls, but also represents a new application of the C3-umpolung reactivity of 2-indolylmethanols in asymmetric catalysis. More importantly, this class of axially chiral 3,3'-bisindoles can undergo a variety of post-functionalizations to give axially chiral 3,3'-bisindole-based organocatalysts, which have found their preliminary applications in asymmetric catalysis. Appendix S1: Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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TL;DR: In this paper , the first atroposelective N-acylation reaction of quinazolinone type benzamides with cinnamic anhydrides was reported.
Abstract: Compared with the well-developed C-C and C-N axial chirality, the asymmetric synthesis of N-N axial chirality remains elusive and challenging. Herein we report the first atroposelective N-acylation reaction of quinazolinone type benzamides with cinnamic anhydrides for the direct catalytic synthesis of optically active atropisomeric quinazolinone derivatives. This reaction features mild conditions and a broad substrate scope and produces N-N axially chiral compounds with high yields and very good enantioselectivities. Besides, the synthetic utility of the protocol was proved by a large scale reaction, transformation of the product and the utilization of the product as an acylation kinetic resolution reagent. Moreover, DFT calculations provide convincing evidence for the interpretation of stereoselection.
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TL;DR: In this article , the superposition of axial and point chirality has been used to construct functional atropisomers with tunable electron and stereohindrance effects.
Abstract: ConspectusEnantiopure atropisomers have become increasingly important in asymmetric synthesis and catalysis, pharmaceutical science, and material science since the discovery of inherent features of axial chirality originating from rotational restriction. Despite the advances made in this field to date, it remains highly desirable to construct structurally diverse atropisomers with potentially useful functions. We propose superposition to match axial and point chirality as a potentially useful strategy to access structurally complex and diverse building blocks for organic synthesis and pharmaceutical science because merging atropisomeric backbones with one or more extra chiral elements can topologically broaden three-dimensional environments to create complex scaffolds with multiple tunable parameters. Over the past decade, we have successfully implemented a strategic design for the superposition of axial and point chirality to develop a series of enantiopure atropisomers and have utilized the synergistic functions of these molecules to enhance chirality transfer in various catalytic asymmetric transformations.In this Account, we present several novel atropisomers with superposed axial and point chirality developed in our laboratory. In our studies, this superposition strategy was used to design and synthesize both biaryl and non-biaryl atropisomers from commercially available chiral sources. Consequently, these atropisomers were used to demonstrate the importance of the synergetic functions of axial and point chirality in specific enantioselective reactions. For example, aromatic amide-derived atropisomers, simplified as Xing-Phos arrays, were broadly employed in Ag-catalyzed [3 + 2] cycloaddition by a series of reactions of aldiminoesters with activated alkenes and imines, as well as being used as chiral solvating agents for the discrimination of optically active mandelic acid derivatives. Considering the powerful potential of non-biaryl atropisomers for asymmetric catalysis, we also explored the transition-metal-catalyzed enantioselective construction of a novel backbone of non-biaryl atropisomers (Ar-alkene, Ar-N axis) bearing both axial and point chirality for the design and synthesis of chiral ligands and functional molecules.The studies presented herein are expected to stimulate further research efforts on the development of functional atropisomers by superposition of matching axial and point chirality. In addition to tunable electron and stereohindrance effects, the synergy between matching chiral elements of axial/point chirality and functional groups is proven to be a special function that cannot be ignored for promoting reactivity and chirality-transfer efficiency in enantioselective synthesis. Consequently, our novel types of scaffolds with superposed axial and point chirality that are capable of versatile coordination with various metal catalysts in asymmetric catalysis highlight the power of the superposition of matching axial and point chirality for the construction of synthetically useful atropisomers.
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TL;DR: In this paper , the first organocatalytic enantioselective synthesis of axially chiral N,N'-bisindoles via chiral phosphoric acid-catalyzed formal (3+2) cycloadditions of indole-based enaminones with 2,3-diketoesters was presented.
Abstract: This study establishes the first organocatalytic enantioselective synthesis of axially chiral N,N'-bisindoles via chiral phosphoric acid-catalyzed formal (3+2) cycloadditions of indole-based enaminones as novel platform molecules with 2,3-diketoesters, where de novo indole-ring formation is involved. Using this new strategy, various axially chiral N,N'-bisindoles were synthesized in good yields and with excellent enantioselectivities (up to 87% yield and 96% ee). More importantly, this class of axially chiral N,N'-bisindoles exhibited some degree of cytotoxicity toward cancer cells and was derived into axially chiral phosphine ligands with high catalytic activity. This study provides a new strategy for enantioselective synthesis of axially chiral N,N'-bisindoles using asymmetric organocatalysis and is the first to realize the applications of such scaffolds in medicinal chemistry and asymmetric catalysis.
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References
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TL;DR: The increasing demand to produce enantiomerically pure pharmaceuticals, agrochemicals, flavors, and other fine chemicals has advanced the field of asymmetric catalytic technologies, and asymmetric hydrogenation utilizing molecular hydrogen to reduce prochiral olefins, ketones, and imines has become one of the most efficient methods for constructing chiral compounds.
Abstract: The increasing demand to produce enantiomerically pure pharmaceuticals, agrochemicals, flavors, and other fine chemicals has advanced the field of asymmetric catalytic technologies.1,2 Among all asymmetric catalytic methods, asymmetric hydrogenation utilizing molecular hydrogen to reduce prochiral olefins, ketones, and imines, have become one of the most efficient methods for constructing chiral compounds.3 The development of homogeneous asymmetric hydrogenation was initiated by Knowles4a and Horner4b in the late 1960s, after the discovery of Wilkinson’s homogeneous hydrogenation catalyst [RhCl(PPh3)3]. By replacing triphenylphosphine of the Wilkinson’s catalystwithresolvedchiralmonophosphines,6Knowles and Horner reported the earliest examples of enantioselective hydrogenation, albeit with poor enantioselectivity. Further exploration by Knowles with an improved monophosphine CAMP provided 88% ee in hydrogenation of dehydroamino acids.7 Later, two breakthroughs were made in asymmetric hydrogenation by Kagan and Knowles, respectively. Kagan reported the first bisphosphine ligand, DIOP, for Rhcatalyzed asymmetric hydrogenation.8 The successful application of DIOP resulted in several significant directions for ligand design in asymmetric hydrogenation. Chelating bisphosphorus ligands could lead to superior enantioselectivity compared to monodentate phosphines. Additionally, P-chiral phosphorus ligands were not necessary for achieving high enantioselectivity, and ligands with backbone chirality could also provide excellent ee’s in asymmetric hydrogenation. Furthermore, C2 symmetry was an important structural feature for developing new efficient chiral ligands. Kagan’s seminal work immediately led to the rapid development of chiral bisphosphorus ligands. Knowles made his significant discovery of a C2-symmetric chelating bisphosphine ligand, DIPAMP.9 Due to its high catalytic efficiency in Rh-catalyzed asymmetric hydrogenation of dehydroamino acids, DIPAMP was quickly employed in the industrial production of L-DOPA.10 The success of practical synthesis of L-DOPA via asymmetric hydrogenation constituted a milestone work and for this work Knowles was awarded the Nobel Prize in 2001.3k This work has enlightened chemists to realize * Corresponding author. 3029 Chem. Rev. 2003, 103, 3029−3069
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TL;DR: P palladium-catalyzed synthesis can provide access to fine chemicals, agrochemical and pharmaceutical intermediates, and active ingredients in fewer steps and with less waste than classical.
Abstract: The substituted indole nucleus [indole is the acronym from indigo (the natural dye) and oleum (used for the isolation)] is a structural component of a vast number of biologically active natural and unnatural compounds. The synthesis and functionalization of indoles has been the object of research for over 100 years, and a variety of well-established classical methods are now available, to name a few of them, the Fisher indole synthesis, the Gassman synthesis of indoles from N-halo-anilines, the Madelung cyclization of N-acyl-o-toluidines, the Bischler indole synthesis, the Batcho-Leimgruber synthesis of indoles from o-nitrotoluenes and dimethylformamide acetals, and the reductive cyclization of o-nitrobenzyl ketones.1 In the last 40 years or so, however, palladiumcatalyzed reactions, generally tolerant of a wide range of functionalities and therefore applicable to complex molecules, have achieved an important place in the arsenal of the practicing organic chemist. Since the invention of an industrial process for the palladium-catalyzed production of acetaldehyde from ethylene in the presence of PdCl2 and CuCl2, an everincreasing number of organic transformations have been based on palladium catalysis. Almost every area of the organic synthesis has been deeply influenced by the profound potential of this versatile transition metal, modifying the way organic chemists design and realize synthetic processes.2,3 Because of its catalytic nature, palladium-catalyzed synthesis can provide access to fine chemicals, agrochemical and pharmaceutical intermediates, and active ingredients in fewer steps and with less waste than classical † In memory of Prof. Bianca Rosa Pietroni, a colleague and very close friend. * To whom correspondence should be addressed. Phone: + 39 (06) 4991-2785. Fax: + 30 (06) 4991-2780. E-mail: sandro.cacchi@ uniroma1.it. 2873 Chem. Rev. 2005, 105, 2873−2920
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