Organocatalytic asymmetric synthesis of Si-stereogenic silacycles.

A strong and confined Brønsted acid catalyzed enantioselective cyclization of bis(methallyl)silanes provides enantioenriched Si-stereogenic silacycles. High enantioselectivities of up to 96.5:3.5 er were obtained for a range of bis(methallyl)silanes. NMR and ESI-MS studies reveal that the formation of a covalent adduct irreversibly inhibits turnover. Remarkably, we found that acetic acid as an additive promotes the collapse of this adduct, enabling full turnover. Experimental investigation and density functional theory (DFT) calculations were conducted to elucidate the origin of this phenomenon and the observed enantioselectivity.

Catalytic asymmetric cationic shifts of aliphatic hydrocarbons.

Asymmetric catalysis is an advanced area of chemical synthesis, but the handling of abundantly available, purely aliphatic hydrocarbons has proven to be challenging. Typically, heteroatoms or aromatic substructures are required in the substrates and reagents to facilitate an efficient interaction with the chiral catalyst. Confined acids have recently been introduced as tools for homogenous asymmetric catalysis, specifically to enable the processing of small unbiased substrates1. However, asymmetric reactions in which both substrate and product are purely aliphatic hydrocarbons have not previously been catalysed by such super strong and confined acids. We describe here an imidodiphosphorimidate-catalysed asymmetric Wagner-Meerwein shift of aliphatic alkenyl cycloalkanes to cycloalkenes with excellent regio- and enantioselectivity. Despite their long history and high relevance for chemical synthesis and biosynthesis, Wagner-Meerwein reactions utilizing purely aliphatic hydrocarbons, such as those originally reported by Wagner and Meerwein, had previously eluded asymmetric catalysis.

Acid-Catalyzed Oxy-aminomethylation of Styrenes.

We report a strong Brønsted acid-catalyzed three-component oxy-aminomethylation of styrenes with sym-trioxane and sulfonamides or carbamates. This transformation provides a variety of 1,3-oxazinanes in moderate to good yields under mild reaction conditions. The obtained heterocycles can be readily transformed into the corresponding 1,3-amino alcohols, which are useful building blocks for the synthesis of pharmaceutically relevant molecules. Mechanistic studies suggest the intermediacy of an in situ formed 1,3,5-dioxazinane and a subsequent reaction with the olefin.

Taming secondary benzylic cations in catalytic asymmetric SN1 reactions.

Benzylic stereogenic centers are ubiquitous in natural products and pharmaceuticals. A potentially general, though challenging, approach toward their selective creation would be asymmetric unimolecular nucleophilic substitution (SN1) reactions that proceed through highly reactive benzylic cations. We now report a broadly applicable solution to this problem by identifying chiral counteranions that pair with secondary benzylic cations to engage in catalytic asymmetric C-C, C-O, and C-N bond-forming reactions with excellent enantioselectivity. The critical cationic intermediate can be accessed from different precursors via Lewis- or Brønsted acid catalysis. Key to our strategy is the use of only weakly basic, confined counteranions that are posited to prolong the lifetime of the carbocation, thereby avoiding nonproductive deprotonation pathways to the corresponding styrene.

Asymmetric Catalytic Friedel-Crafts Reactions of Unactivated Arenes.

Since its discovery more than a century ago, the Friedel-Crafts reaction has manifested itself as a powerful method for the introduction of carbon substituents to arenes. Despite its potential generality, the scope of the reaction is intrinsically limited by the arene's nucleophilicity, which has previously restrained the applicability of asymmetric variants to activated substrates. To overcome this fundamental limitation, we report herein an asymmetric Friedel-Crafts reaction of unactivated, purely hydrocarbon arenes, alkoxybenzenes, and heteroarenes with N,O-acetals to give enantioenriched arylglycine esters. Highly regio- and stereoselective C-C bond formation was achieved using strong and confined Brønsted acid organocatalysts, enabling the first asymmetric catalytic Friedel-Crafts reaction of simple alkylbenzenes.

Direct Regioselective Dehydrogenation of α-Substituted Cyclic Ketones.

We disclose a highly regioselective, catalytic one-step dehydrogenation of α-substituted cyclic ketones in the presence of 2,3-dichlorobenzo-5,6-dicyano-1,4-benzoquinone (DDQ). The high regioselectivity originates from a phosphoric acid-catalyzed enolization, selectively affording the thermodynamically preferred enol, followed by the subsequent oxidation event. Our method provides reliable access to several α-aryl and α-alkyl substituted α,ß-unsaturated ketones.

Toward a Formyl-to-Phenyl Conversion: An Unexpected Photochemical Fulvene Rearrangement.

Toward a conversion of aldehydes into arenes, we designed a sequence involving the initial reaction of an aldehyde to give a fulvene, followed by photochemical and platinum-catalyzed rearrangements into a Dewar benzene derivative, which finally isomerizes into the targeted arene. While computational studies support the plausibility of this route, we found that fulvene irradiation resulted in an unexpected isomerization into a spiro[2.4]heptadiene. This unusual photorearrangement has been investigated mechanistically and provides access to a variety of spiro[2.4]heptadienes with different substituents.

A Catalytic Asymmetric Hydrolactonization.

Despite recent advancements in the development of catalytic asymmetric electrophile induced lactonization reactions of olefinic carboxylic acids, the archetypical hydrolactonization has long remained an unsolved and well-recognized challenge. Here, we report the realization of a catalytic asymmetric hydrolactonization using a confined imidodiphosphorimidate (IDPi) Brønsted acid catalyst. The method is operationally simple, scalable, and compatible with a wide variety of substrates. Its potential is showcased with concise syntheses of the sesquiterpenes (-)-boivinianin A and (+)-gossonorol. Through in-depth physicochemical and DFT analyses, we derive a nuanced picture of the mechanism and enantioselectivity of this reaction.

Catalytic asymmetric synthesis of cannabinoids and menthol from neral.

The selective conversion of natural or synthetic neral to (1R,6S)-trans-isopiperitenol would enable and expedite sustainable routes to menthol1,2 and cannabinoids3-5. However, this reaction has been considered impossible because its product is more reactive to the required acid catalysts than its starting material, resulting in several side products6-9. We now show that an unsymmetric, strong and confined chiral acid, a highly fluorinated imino-imidodiphosphate, catalyses this process with excellent efficiency and selectivity. Expanding the method to other α,ß-unsaturated aldehydes could enable access to new cannabinoids and menthol derivatives not readily accessible previously. Mechanistic studies suggest that the confined catalyst accomplishes this reaction by binding the product in an unreactive conformation, thereby preventing its decomposition. We also show how (1R,6S)-trans-isopiperitenol can be readily converted to pharmaceutically useful cannabinoids and menthol, each in the shortest and most atom-economic routes so far.

Organocatalytic DYKAT of Si-Stereogenic Silanes.

Chiral organosilanes do not exist in nature and are therefore absent from the "chiral pool". As a consequence, synthetic approaches toward enantiopure silanes, stereogenic at silicon, are rather limited. While catalytic asymmetric desymmetrization reactions of symmetric organosilicon compounds have been developed, the utilization of racemic silanes in a dynamic kinetic asymmetric transformation (DYKAT) or dynamic kinetic resolution (DKR) would significantly expand the breadth of accessible Si-stereogenic compounds. We now report a DYKAT of racemic allyl silanes enabled by strong and confined imidodiphosphorimidate (IDPi) catalysts, providing access to Si-stereogenic silyl ethers. The products of this reaction are easily converted into useful enantiopure monohydrosilanes. We propose a spectroscopically and experimentally supported mechanism involving the epimerization of a catalyst-bound intermediate.

Predicting Highly Enantioselective Catalysts Using Tunable Fragment Descriptors.

Catalyst optimization processes typically rely on inductive and qualitative assumptions of chemists based on screening data. While machine learning models using molecular properties or calculated 3D structures enable quantitative data evaluation, costly quantum chemical calculations are often required. In contrast, readily available binary fingerprint descriptors are time- and cost-efficient, but their predictive performance remains insufficient. Here, we describe a machine learning model based on fragment descriptors, which are fine-tuned for asymmetric catalysis and represent cyclic or polyaromatic hydrocarbons, enabling robust and efficient virtual screening. Using training data with only moderate selectivities, we designed theoretically and validated experimentally new catalysts showing higher selectivities in a challenging asymmetric tetrahydropyran synthesis.

Asymmetric counteranion-directed photoredox catalysis.

Photoredox catalysis enables distinctive and broadly applicable chemical reactions, but controlling their selectivity has proven to be difficult. The pursuit of enantioselectivity is a particularly daunting challenge, arguably because of the high energy of the activated radical (ion) intermediates, and previous approaches have invariably required pairing of the photoredox catalytic cycle with an additional activation mode for asymmetric induction. A potential solution for photoredox reactions proceeding via radical ions would be catalytic pairing with enantiopure counterions. However, although attempts toward this approach have been described, high selectivity has not yet been accomplished. Here we report a potentially general solution to radical cation-based asymmetric photoredox catalysis. We describe organic salts, featuring confined imidodiphosphorimidate counteranions that catalyze highly enantioselective [2+2]-cross cycloadditions of styrenes.

A Catalytic Asymmetric Pictet-Spengler Platform as a Biomimetic Diversification Strategy toward Naturally Occurring Alkaloids.

Tetrahydroisoquinoline (THIQ) alkaloids constitute a large and diverse class of bioactive natural products, with the parent compounds and related downstream biosynthetic secondary metabolites spanning thousands of isolated structures. Chemoenzymatic synthetic approaches toward the relevant THIQs rely on Pictet-Spenglerases such as norcoclaurine synthase (NCS), the scope of which is strictly limited to dopamine-related phenolic substrates. To overcome these limitations in the context of chemical synthesis, we herein report asymmetric Pictet-Spengler reactions of N-carbamoyl-ß-arylethylamines with diverse aldehydes toward enantioenriched THIQs. The obtained products proved to be competent intermediates in the synthesis of THIQ, aporphine, tetrahydroberberine, morphinan, and androcymbine natural products. Novel catalyst design with regard to the stabilization of cationic intermediates was crucial to accomplish high reactivity while simultaneously achieving unprecedented stereoselectivity for the reaction of biologically relevant substrates.

Organocatalytic Asymmetric Synthesis of Si-Stereogenic Silyl Ethers.

Functionalized enantiopure organosilanes are important building blocks with applications in various fields of chemistry; nevertheless, asymmetric synthetic methods for their preparation are rare. Here we report the first organocatalytic enantioselective synthesis of tertiary silyl ethers possessing "central chirality" on silicon. The reaction proceeds via a desymmetrizing carbon-carbon bond forming silicon-hydrogen exchange reaction of symmetrical bis(methallyl)silanes with phenols using newly developed imidodiphosphorimidate (IDPi) catalysts. A variety of enantiopure silyl ethers was obtained in high yields with good chemo- and enantioselectivities and could be readily derivatized to several useful chiral silicon compounds, leveraging the olefin functionality and the leaving group nature of the phenoxy substituent.

Organocatalytic stereoselective cyanosilylation of small ketones.

Enzymatic stereoselectivity has typically been unrivalled by most chemical catalysts, especially in the conversion of small substrates. According to the 'lock-and-key theory'1,2, enzymes have confined active sites to accommodate their specific reacting substrates, a feature that is typically absent from chemical catalysts. An interesting case in this context is the formation of cyanohydrins from ketones and HCN, as this reaction can be catalysed by various classes of catalysts, including biological, inorganic and organic ones3-7. We now report the development of broadly applicable confined organocatalysts for the highly enantioselective cyanosilylation of aromatic and aliphatic ketones, including the challenging 2-butanone. The selectivity (98:2 enantiomeric ratio (e.r.)) obtained towards its pharmaceutically relevant product is unmatched by any other catalyst class, including engineered biocatalysts. Our results indicate that confined chemical catalysts can be designed that are as selective as enzymes in converting small, unbiased substrates, while still providing a broad scope.

Design of an Organocatalytic Asymmetric (4 + 3) Cycloaddition of 2-Indolylalcohols with Dienolsilanes.

Here we present the design of a highly enantioselective, catalytic (4 + 3) cycloaddition of gem-dialkyl 2-indolyl alcohols and dienolsilanes, enabled by strong and confined IDPi Lewis acids. The method furnishes novel bicyclo[3.2.2]cyclohepta[b]indoles with up to three stereogenic centers, one of which is quaternary. A broad substrate scope is accompanied by versatile downstream chemical modifications. Density functional theory-supported mechanistic studies shed light on the importance of the in situ generated silylium species in an overall concerted yet asynchronous cycloaddition.

Catalytic Asymmetric Spirocyclizing Diels-Alder Reactions of Enones: Stereoselective Total and Formal Syntheses of α-Chamigrene, ß-Chamigrene, Laurencenone C, Colletoic Acid, and Omphalic Acid.

We disclose a general catalytic enantioselective Diels-Alder reaction of exo-enones with dienes to give spirocyclanes. The obtained products feature highly congested quaternary stereogenic spirocenters and are used in concise total and formal syntheses of several sesquiterpenes, including of α-chamigrene, ß-chamigrene, laurencenone C, colletoic acid, and omphalic acid. The stereo- and regioselectivities of our spirocyclizing cycloaddition are effectively controlled by strongly acidic and confined imidodiphosphorimidate catalysts. Computational studies shed light on the origin of reactivity and selectivity.

Direct and Catalytic C-Glycosylation of Arenes: Expeditious Synthesis of the Remdesivir Nucleoside.

Since early 2020, scientists have strived to find an effective solution to fight SARS-CoV-2, in particular by developing reliable vaccines that inhibit the spread of the disease and repurposing drugs for combatting its effects on the human body. The antiviral prodrug Remdesivir is still the most widely used therapeutic during the early stages of the infection. However, the current synthetic routes rely on the use of protecting groups, air-sensitive reagents, and cryogenic conditions, thus impeding a cost-efficient supply to patients. We have, therefore, focused on the development of a straightforward, direct addition of (hetero)arenes to unprotected sugars. Here we report a silylium-catalyzed and completely stereoselective C-glycosylation that initially yields the open-chain polyols, which can be selectively cyclized to provide either the kinetic α-furanose or the thermodynamically favored ß-anomer. The method significantly expedites the synthesis of Remdesivir precursor GS-441524 after a subsequent Mn-catalyzed C-H oxidation and deoxycyanation.

Chiral Phosphoric Acid Catalyzed Conversion of Epoxides into Thiiranes: Mechanism, Stereochemical Model, and New Catalyst Design.

Computations and experiments leading to new chiral phosphoric acids (CPAs) for epoxide thionations are reported. Density functional theory calculations reveal the mechanism and origin of the enantioselectivity of such CPA-catalyzed epoxide thionations. The calculated mechanistic information was used to design new efficient CPAs that were tested experimentally and found to be highly effective. Bulky ortho-substituents on the 3,3'-aryl groups of the CPA are important to restrict the position of the epoxide in the key transition states for the enantioselectivity-determining step. Larger para-substituents significantly improve the enantioselectivity of the reaction.