Asymmetric organocatalysis has experienced a long and spectacular way since the early reports over a century ago by von Liebig, Knoevenagel and Bredig, showing that small (chiral) organic molecules ...can catalyze (asymmetric) reactions. This was followed by impressive first highly enantioselective reports in the second half of the last century, until the hype initiated in 2000 by the milestone publications of MacMillan and List, which finally culminated in the 2021 Nobel Prize in Chemistry. This short Perspective aims at providing a brief introduction to the field by first looking on the historical development and the more classical methods and concepts, followed by discussing selected advanced recent examples that opened new directions and diversity within this still growing field.
Asymmetric organocatalysis has developed spectacularly over the last decades, and its general importance was recently highlighted by the 2021 Nobel Prize in Chemistry. This Perspective aims at providing a brief historical introduction to this field, as well as discussing selected advanced recent examples underscoring the diversity and potential of this still growing and vibrant field.
Non‐covalent molecular interactions on the basis of halogen and chalcogen bonding represent a promising, powerful catalytic activation mode. However, these “unusual” non‐covalent interactions are ...typically employed in the solid state and scarcely exploited in catalysis. In recent years, an increased interest in halogen and chalcogen bonding has been awaken, as they provide profound characteristics that make them an appealing alternative to the well‐explored hydrogen bonding. Being particularly relevant in the binding of “soft” substrates, the similar strength to hydrogen bonding interactions and its higher directionality allows for solution‐phase applications with halogen and chalcogen bonding as the key interaction. In this mini‐review, the special features, state‐of‐the‐art and key examples of these so‐called σ‐hole interactions in the field of organocatalysis are presented.
Organocatalysis: Organo‐halogen and chalcogen compounds present σ‐holes, electropositive regions, which make the X or the Ch atom adopt a Lewis acidic role and provide unique features for developing novel catalytic substrate activation modes. This Minireview provides an overview on the recent introduction and current applications of halogen and chalcogen bonding interactions in non‐covalent organocatalysis.
The asymmetric dearomatization of N‐heterocycles is an important synthetic method to gain bioactive and synthetically valuable chiral heterocycles. However, the catalytic enantio‐ and regioselective ...dearomatization of the simplest six‐membered‐ring N‐heteroarenes, the pyridines, is still very challenging. The first anion‐binding‐catalyzed, highly enantioselective nucleophilic dearomatization of pyridines with triazole‐based H‐bond donor catalysts is presented. Contrary to other more common NH‐based H‐bond donors, this type of organocatalyst shows a prominent higher C2‐regioselectivity and is able to promote high enantioinductions via formation of a close chiral anion‐pair complex with a preformed N‐acyl pyridinium ionic intermediate. This method offers a straightforward and useful synthetic approach to chiral N‐heterocycles from abundant and readily available pyridines.
Direct metal‐free access: For the asymmetric dearomatization of pyridines, only efficient metal‐catalyzed reactions have been available to date. The first organocatalytic approach with a triazole‐based H‐donor catalyst is now presented. The catalyst induces a high enantioselectivity by forming a chiral ion‐pair complex with the N‐acyl pyridinium intermediate (see picture).
Amino acids and peptides play an important role in nature, as well as in organic and pharmaceutical chemistry. Therefore, the easy, straightforward and versatile access of biogenic and unnatural ...derivatives is still highly demanding. This micro‐review intends to provide to the reader the current state of the art on site‐selective C–H bond functionalization technology applied on α‐amino acids and peptides, focusing on the different C–H positions that can successfully be addressed to date. It is structured in two main parts implying i) the α‐C–H functionalization at the peptide backbone and ii) the modification of the side‐chain. Herein, metal‐catalyzed C–H activation, oxidative C–H functionalization, as well as light mediated approaches, are discussed considering the challenges in reactivity and selectivity. The great potential of these transformations is also depicted with the derivatization and macrocyclization of complex peptides leading to products of pharmaceutical importance.
This review provides the current state of the art on site‐selective C–H bond functionalization applied on α‐amino acids and peptides, focusing on the different C–H positions that can successfully be addressed to date. Examples at the α‐C–H of the peptide backbone and C–H of the side‐chains, as well as late stage derivatization of complex peptides, are presented.
The first oxoammonium salt mediated formation of C–C bonds from benzylic C(sp3)–H bonds adjacent to an oxygen or nitrogen atom by dehydrogenative coupling with enolizable carbonyls has been ...developed. The use of these oxidants in combination with catalytic amounts of Fe(OTf)2 as Lewis acid allows the reaction to be carried out under mild conditions, leading to the corresponding coupling products in moderate to good yields.
The dehydrogenative cross‐coupling reactions of C(sp3)–H bonds α to a heteroatom with enolizable nucleophiles by using easy‐to‐handle and nontoxic TEMPO salts is presented. These soft oxidants in combination with a Fe catalyst were efficiently employed to selectively generate the desired C–C coupling products under mild reaction conditions.
Over the last decade, a variety of methodologies for the direct functionalization of C-H bonds have been developed. Among others, visible light photoredox reactions have recently emerged as one of ...the most efficient and highly selective processes for the direct introduction of a functionality into organic molecules. Easy reaction setups, as well as mild reaction conditions, make this approach superior to other methodologies applying transition metals or strong oxidants, in terms of both costs and substrate and functional group tolerance. In this review, the recent developments in organophotocatalyzed C-H bond functionalization reactions are presented.
This review provides a current overview of the recent developments in the visible light mediated organophotocatalyzed C-H bond functionalization methodologies.
A newly designed class of acridinium‐based organophotocatalysts bearing an imide group at the C9‐position is presented. To achieve these unprecedented structures, a synthetic strategy based on a ...novel straightforward oxidative Ugi‐type reaction at the benzylic position of C9‐unsubstituted acridanes was developed. The introduction of the imide‐unit affords a notable photocatalytic activity enhancement, allowing efficient transformations in different oxidative and reductive visible‐light catalytic reactions.
Sweet′n′salty: The first, mild, modular, oxidative Ugi reaction on benzylic substrates, such acridanes, allows the development of an unprecedented family of imide‐acridinium visible‐light photocatalysts with boosted reactivities in both oxidative and reductive processes.
Easily accessible and tunable chiral triazoles have been introduced as a novel class of C−H bond‐based H‐donors for anion‐binding organocatalysis. They have proven to be effective catalysts for the ...dearomatization reaction of different N‐heteroarenes. Although this dearomatization approach represents a powerful strategy to build chiral heterocycles, to date only a few catalytic methods to this end exist. In this work, the organocatalyzed enantioselective Reissert‐type dearomatization of isoquinoline derivatives employing a number of structurally diverse chiral triazoles as anion‐binding catalysts was realized. The here presented method was employed to synthesize a number of chiral 1,2‐dihydroisoquinoline substrates with an enantioselectivity up to 86:14 e.r. Moreover, a thorough study of the determining parameters affecting the activity of this type of anion‐ binding catalysts was carried out.
Against the elements: A family of chiral triazoles has been introduced as innovative C−H bond‐based hydrogen donors for anion‐binding catalysis. Contrary to the believed inefficiency of the low polarized C−H bonds for promoting organocatalysis, these structures proved to be competitive with respect to the more established N−H‐type hydrogen donors in enantioselective Reissert‐type reactions.
Given its ready availability, low price and environmentally friendly character, iron is an attractive and often advantageous alternative to other transition metals in the field of catalysis. This ...tutorial review summarises recent progress in the development of novel and practical iron-catalysed reactions with a particular focus on those which provide access to new carbon-heteroatom and heteroatom-heteroatom linkages. It shall be of interest for both the academic as well as the industrial community.
Mukaiyama aldol, Mannich, and Michael reactions are arguably amongst the most important C–C bond formation processes and enable access to highly relevant building blocks of various natural products. ...Their vinylogous extensions display equally high potential in the formation of important key intermediates featuring even higher functionalization possibilities through an additional conjugated C–C double bond. Hence, it is much desired to develop highly selective vinylogous methods in order to enable unconventional, more efficient asymmetric syntheses of biologically active compounds. In this regard, silyl-dienolates were discovered to display high regioselectivities due to their tendency toward γ-additions. The control of the enantio- and diastereoinduction of these processes have been for a long time dominated by transition metal catalysis, but it received serious competition by the application of organocatalytic approaches since the beginning of this century. In this review, the organocatalytic applications of silyl-dienolates in asymmetric vinylogous C–C bond formations are summarized, focusing on their scope, characteristics, and limitations.
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