Enantioselective α-heterofunctionalization reactions of catalytically generated C1-Lewis base enolates.

Chiral Lewis base (LB) organocatalysis has emerged as a powerful covalent catalysis concept which allows for highly selective asymmetric C-C and C-heteroatom bond formations. Considering significant recent progress in the development of strategies to access α-heterofunctionalized carboxylic acid derivatives under chiral LB catalysis, we wish to summarize the most significant concepts and advances in this field within this mini review now.

Enantioselective Syntheses of 3,4-Dihydropyrans Employing Isochalcogenourea-Catalyzed Formal (4+2)-Cycloadditions of Allenoates.

We herein successfully demonstrate the use of chiral isochalcogenoureas as Lewis Base catalysts for a variety of (4+2)-cycloaddition reactions of allenoates and different Michael acceptors. In all cases the same structural key-motive, a dihydropyran with a (Z)-configurated exocyclic double bond could be accessed as the major regio- and diastereoisomer in an enantioselective manner. Furthermore, these chiral dihydropyrans were successfully engaged in different follow-up transformations.

Asymmetric Organocatalyzed Transfer Hydroxymethylation of Isoindolinones Using Formaldehyde Surrogates.

The piperidine-based Takemoto catalyst has been successfully employed in a novel asymmetric transfer hydroxymethylation of activated isoindolinones, allowing us to prepare the enantioenriched hydroxymethylated adducts in good to excellent yields (48-96%) and enantiopurities (81:19-97:3 e.r.). To increase the reaction rate without compromising the selectivity, carefully optimized formaldehyde surrogates were employed, providing a convenient source of anhydrous formaldehyde with a base-triggered release. The substrate scope, including 34 entries, showed the considerable generality of the asymmetric transformation, and most entries exhibited complete conversions in 24-48 h. A scale-up experiment and multiple enantioselective downstream transformations were also carried out, suggesting the prospective synthetic utility of the products.

Chiral Isochalcogenourea-Catalysed Enantioselective (4+2) Cycloadditions of Allenoates.

Allenoates are versatile building blocks which are primarily activated and controlled using chiral tert. phosphine and tert. amine Lewis bases. We herein report the first example of allenoate activation by using chiral isochalcogenoureas (IChU) for formal (4+2) cycloaddition reactions. Compared to established phosphine and amine catalysis, the use of these easily available Lewis bases enables new stereoselective reaction pathways proceeding with high enantioselectivities, diastereoselectivities, and in good yields. In addition, the factors governing enantioselectivity and the origin of the observed differences compared to other commonly used Lewis bases are explained.

Chiral Isochalcogenourea-Catalysed Enantioselective (4+2) Cycloadditions of Allenoates.

Allenoates are versatile building blocks which are primarily activated and controlled using chiral tert. phosphine and tert. amine Lewis bases. We herein report the first example of allenoate activation by using chiral isochalcogenoureas (IChU) for formal (4+2) cycloaddition reactions. Compared to established phosphine and amine catalysis, the use of these easily available Lewis bases enables new stereoselective reaction pathways proceeding with high enantioselectivities, diastereoselectivities, and in good yields. In addition, the factors governing enantioselectivity and the origin of the observed differences compared to other commonly used Lewis bases are explained.

Correction: Monaco et al. Chiral Phase Transfer Catalysis in the Asymmetric Synthesis of a 3,3-Disubstituted Isoindolinone and Determination of Its Absolute Configuration by VCD Spectroscopy. Molecules 2020, 25, 2272.

In this note, we report a correction to the published article, Molecules2020, 25, 2272 [...].

Recent Developments and Trends in Asymmetric Organocatalysis.

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.

Photochemical Wolff Rearrangement Initiated Generation and Subsequent α-Chlorination of C1 Ammonium Enolates.

The enantioselective synthesis of α-chlorinated carboxylic acid esters with er up to 99:1 and yields up to 82% was achieved via a one-pot multistep protocol starting from α-diazoketones. This process proceeds via a photochemical Wolff rearrangement, trapping of the generated ketene with a chiral Lewis base catalyst, subsequent enantioselective α-chlorination, and a final nucleophilic displacement of the bound catalyst. The obtained products were successfully utilized for stereospecific nucleophilic displacement reactions with N- and S-nucleophiles.

Synthesis and Catalytic Activity of Bifunctional Phase-Transfer Organocatalysts Based on Camphor.

Ten novel bifunctional quaternary ammonium salt phase-transfer organocatalysts were synthesized in four steps from (+)-camphor-derived 1,3-diamines. These quaternary ammonium salts contained either (thio)urea or squaramide hydrogen bond donor groups in combination with either trifluoroacetate or iodide as the counteranion. Their organocatalytic activity was evaluated in electrophilic heterofunctionalizations of ß-keto esters and in the Michael addition of a glycine Schiff base with methyl acrylate. α-Fluorination and chlorination of ß-keto esters proceeded with full conversion and low enantioselectivities (up to 29% ee). Similarly, the Michael addition of a glycine Schiff base with methyl acrylate proceeded with full conversion and up to 11% ee. The new catalysts have been fully characterized; the stereochemistry at the C-2 chiral center was unambiguously determined.

(Thio)urea Containing Chiral Ammonium Salt Catalysts.

(Thio)-urea-containing bifunctional quaternary ammonium salts emerged as powerful non-covalently interacting organocatalysts over the course of the last decade. The most commonly employed catalysts in this field are either based on Cinchona alkaloids, α-amino acids, or trans-cyclohexane-1,2-diamine. Our group has been heavily engaged in the design and use of such catalysts, i. e. trans-cyclohexane-1,2-diamine-based ones for around 10 years now, and it is therefore the intention of this short personal account to provide an overview of the, at least in our opinion, most significant and pioneering achievements in this field by looking on catalyst design and asymmetric method development, with a special focus on our own contributions.

Isothiourea-Catalyzed Enantioselective Functionalisation of Glycine Schiff Base Aryl Esters via 1,6- and 1,4-Additions.

The enantioselective α-functionalisation of glycine Schiff base aryl esters through isothiourea catalysis is successfully demonstrated for 1,6-additions to para-quinone methides (21 examples, up to 95:5 dr and 96:4 er) and 1,4-additions to methylene substituted dicarbonyl or disulfonyl Michael acceptors (17 examples, up to 98:2 er). This nucleophilic organocatalysis approach gives access to a range of α-functionalised α-amino acid derivatives and further transformations of the activated aryl ester group provide a straightforward entry to advanced amino acid-based esters, amides or thioesters.

Cooperative Chiral Lewis Base/Palladium-Catalyzed Asymmetric Syntheses of Methylene-Containing δ-Lactams.

We herein report a two-step approach for the enantioselective synthesis of novel chiral δ-lactams. By using a cooperative chiral ITU/achiral Pd-catalyst system, this protocol proceeds via an asymmetric α-allylation of activated aryl esters first, followed by an acid-mediated lactam formation. A variety of differently substituted products could be obtained with usually high levels of enantioselectivities and in reasonable yields (16 examples, up to 98 : 2 er and 73 % yield over two steps). In addition, further utilizations of the products via transformations of the exocyclic double bond were successfully carried out as well.

Chiral Lewis Base-Catalysed Asymmetric Syntheses of Benzo-fused ϵ-Lactones.

We herein report a two-step protocol for the asymmetric synthesis of novel chiral benzofused ϵ-lactones starting from O-protected hydroxymethyl-para-quinone methides and activated aryl esters. By using chiral isothiourea Lewis base catalysts a broad variety of differently substituted products could be obtained in yields of around 50 % over both steps with high levels of enantioselectivities, albeit low diastereoselectivities only.

Enantioselective ß-Selective Addition of Isoxazolidin-5-ones to Allenoates Catalyzed by Quaternary Ammonium Salts.

The enantioselective addition of isoxazolidin-5-ones to the ß-carbon of allenoates has been carried out by using a novel spirobiindane-based quaternary ammonium salt catalyst. This protocol, which proceeds under classical liquid-solid phase-transfer conditions, gives access to unprecedented highly functionalized ß2,2-amino acid derivatives with good enantioselectivities and in high yields, and further manipulations of these products have been carried out as well.

Scalable (Enantioselective) Syntheses of Novel 3-Methylated Analogs of Pazinaclone, (S)-PD172938 and Related Biologically Relevant Isoindolinones.

Herein, we report the application of an efficient and practical K2CO3 promoted cascade reaction of 2-acetylbenzonitrile in the synthesis of novel 3-methylated analogs of Pazinaclone and PD172938, belonging to isoindolinones heterocyclic class bearing a tetrasubstituted stereocenter. Organocatalytic asymmetric synthesis of the key intermediate and its transformation into highly enantioenriched 3-methylated analog of (S)-PD172938 was also developed. These achievements can be of particular interest also for medicinal chemistry, since the methyl group is a very useful structural modification in the rational design of new and more effective bioactive compounds.

Oxidative decarboxylative ammonium hypoiodite-catalysed dihydrobenzofuran synthesis.

The catalytic use of quaternary ammonium iodides under oxidative conditions allows for the direct conversion of readily available ß-ketolactones into dihydrobenzofurans via a decarboxylative oxidative cycloetherification sequence facilitated by an in situ formed ammonium hypoiodite species.

Enantioselective Catalytic Synthesis of α-Halogenated α-Aryl-ß2,2-amino Acid Derivatives.

The enantioselective synthesis of a broad variety of novel differently functionalized α-halogenated α-aryl-ß2,2-amino acid derivatives by means of an ammonium-salt-catalyzed asymmetric α-halogenation of isoxazolidin-5-ones was accomplished. Key to success to obtain high levels of enantioselectivities was the use of Maruoka's spirocyclic binaphthyl-based ammonium salts, and detailed accompanying mechanistic studies using density functional theory methods revealed the key features for the catalyst-substrate interactions.

Enantioselective organocatalytic syntheses of α-selenated α- and ß-amino acid derivatives.

Selenium-containing amino acids are valuable targets but methods for the stereoselective α-selenation of simple amino acid precursors are rare. We herein report the enantioselective electrophilic α-selenation of azlactones (masked α-amino acid derivatives) and isoxazolidin-5-ones (masked ß-amino acids) using Cinchona alkaloids as easily accessible organocatalysts. A variety of differently substituted derivatives was accessed with reasonable levels of enantioselectivities and further studies concerning the stability and suitability of these compounds for further manipulations have been carried out as well.

Stereoselective Syntheses of Masked ß-Amino Acid Containing Phthalides.

We herein report a protocol for the asymmetric aldol-initiated cascade addition of isoxazolidin-5-ones to ortho-cyanobenzaldehydes by using Takemoto's bifunctional organocatalyst. This approach allows for the synthesis of various novel ß2,2-amino acid-phthalide conjugates with good enantio- and diastereoselectivities in reasonable yields and the further ring-opening of these compounds to acyclic carboxylic acid derivatives was demonstrated too.

Enantioselective Synthesis of Acyclic Orthogonally Functionalized Compounds Bearing a Quaternary Stereocenter Using Chiral Ammonium Salt Catalysis.

We herein report an asymmetric protocol to access a series of orthogonally functionalized acyclic chiral target molecules containing a quaternary stereogenic center by carrying out the enantioselective α-alkylation of novel orthogonally functionalized dioxolane-containing cyanoacetates under chiral ammonium salt catalysis. By using just 1 mol % of Maruoka's spirocyclic ammonium salt catalysts enantioselectivities up to e.r.=97.5 : 2.5 could be achieved and further functional group manipulations of the products were carried out as well.