Catalytic Asymmetric (-)-Carbonyl-Ene Type Cyclizations.

The carbonyl-ene reaction between aldehydes and olefins constitutes a perfectly atom economic approach to homoallylic alcohols with concomitant C-C bond formation. However, the scope of catalytic asymmetric intermolecular versions is currently limited to activated substrates, while of the two intramolecular types only catalytic asymmetric (-)-carbonyl-ene type cyclizations can be considered mature. The corresponding (-)-cyclizations would arguably find equal utility in chemical synthesis but remain underdeveloped.

Catalytic Asymmetric Ionic Hydrogenation of α-Alkyl Styrenes.

Over the past two decades, chemists have made significant advances in the field of catalytic asymmetric transfer hydrogenation of various unsaturated compounds with biomimetic hydrogen donors. The reduction of carbon-carbon double bonds, however, has been limited to activated substrate classes, such as enals, enones, nitroolefins, or α-(2-hydroxyaryl) styrenes. Here we report a highly enantioselective Brønsted acid-catalyzed ionic hydrogenation of α-alkyl styrenes using a hydrosilane in combination with a protic additive.

The Overlooked Stereoisomers of the Ionizable Lipid ALC315.

Lipid nanoparticles (LNPs) are a powerful delivery platform for nucleic acid therapeutics such as mRNA vaccines and gene therapies. Central to their success are ionizable lipids, which facilitate the cellular uptake and endosomal escape of nucleic acids. However, achieving a high delivery efficiency often comes with the drawback of increased cytotoxicity.

Pericyclic Umpolung in a Catalytic Asymmetric Diels-Alder Reaction of Tropone with Enol Ethers.

One remarkable feature of catalysis in chemical synthesis is its capacity to override substrate-imposed reactivity and selectivity. The inversion of normal reaction patterns, commonly known as Umpolung, can be divided into (1) functional group Umpolung, where electrophilic groups are rendered nucleophilic (or vice versa), and (2) pericyclic Umpolung, in which the regioselectivity of pericyclic reactions is reversed relative to the predictions of frontier molecular orbital (FMO) theory. Although catalytic functional group Umpolung has been extensively investigated, the highly organized, concerted nature of pericyclic reactions makes inverting their conventional regioselectivity particularly challenging.

Organocatalytic Asymmetric Synthesis of Azabicyclo[2.1.1]hexanes.

The bioisosteric replacement of 2D aromatic scaffolds with sp-rich surrogates has become an important design element in modern medicinal chemistry. Within the sp-rich world, the azabicyclo[2.1.

From Reagent to Catalyst: Dispersion-Driven Design of a General Asymmetric Transfer Hydrogenation Catalyst.

Even though chemists have long underappreciated the role of London dispersion in catalysis, its importance in determining a reaction course is now well recognized. Dispersion interactions have been shown to stabilize transition states and govern the stereoselectivity. In this context, the transfer hydrogenation of α,β-unsaturated aldehydes reported by our group via asymmetric counteranion-directed catalysis (ACDC) was revisited mechanistically.

Bis-indole chiral architectures for asymmetric catalysis.

Chiral scaffolds are essential to the advancement of asymmetric synthesis, yet the development of privileged motifs that more effectively communicate asymmetry constitutes a grand challenge for chemists. Here we describe a method using a confined chiral Brønsted acid catalyst to combine two inexpensive and widely available materials-indole and acetone-into a class of C₂-symmetric, spirocyclic compounds called SPINDOLE. SPINDOLEs extend the versatility of established frameworks by offering greater flexibility and ease of synthesis.

Asymmetric Counteranion-Directed Halogen Bonding Catalysis.

Halogen bonding has been established as a promising tool in organocatalysis. Asymmetric processes are nevertheless scarce, and their applications are limited to a few studies applying chiral halogen bond donors. Herein, we combine halogen bonding with asymmetric counteranion-directed catalysis, providing the first highly enantioselective example of such an approach.

Bro̷nsted Acid-Catalyzed Reduction of Furans.

Bioderived furans play a pivotal role in advancing defossilized chemical pathways. The complete reduction of furans currently relies on impractical metal-catalyzed hydrogenations at high pressures and temperatures. In addition, the Birch reduction of unbiased furans to 2,5-dihydrofurans remains an unsolved synthetic challenge.

Catalytic Asymmetric Cycloaddition of Olefins with In Situ Generated -Boc-Formaldimine.

Chiral 1,3-amino alcohols are ubiquitous structural motifs in natural products and active pharmaceutical ingredients. We present a highly enantioselective, inverse-electron-demand hetero-Diels-Alder reaction of olefins with in situ generated -Boc-formaldimine catalyzed by strong and confined Bro̷nsted acids. This transformation provides direct access to valuable 1,3-amino alcohols from styrenes and 1,1-disubtituted alkenes.

Catalytic asymmetric fragmentation of cyclopropanes.

The stereoselective activation of alkanes constitutes a long-standing and grand challenge for chemistry. Although metal-containing enzymes oxidize alkanes with remarkable ease and selectivity, chemical approaches have largely been limited to transition metal-based catalytic carbon-hydrogen functionalizations. Alkanes can be protonated to form pentacoordinated carbonium ions and fragmented into smaller hydrocarbons in the presence of strong Brønsted acids.

Highly Acidic Electron-Rich Brønsted Acids Accelerate Asymmetric Pictet-Spengler Reactions by Virtue of Stabilizing Cation-π Interactions.

Electron-rich heteroaromatic imidodiphosphorimidates (IDPis) catalyze the asymmetric Pictet-Spengler reaction of -carbamoyl-β-arylethylamines with high stereochemical precision. This particular class of catalysts furthermore provides a vital rate enhancement compared to related Brønsted acids. Here we present experimental studies on the underlying reaction kinetics that shed light on the specific origins of rate acceleration.

A solid noncovalent organic double-helix framework catalyzes asymmetric [6 + 4] cycloaddition.

Whereas [4 + 2] cycloadditions are among the most powerful tools in the chemist's synthetic arsenal, controlling reactivity and selectivity of [6 + 4] cycloadditions has proven to be extremely challenging. Such transformations, especially if compatible with simple hydrocarbon-based substrates, could ultimately provide a general approach to highly valuable and otherwise difficult to access 10-membered rings. We report here that highly acidic and confined imidodiphosphorimidate catalysts do not catalyze this reaction under homogeneous conditions.

The catalytic asymmetric polyene cyclization of homofarnesol to ambrox.

Polyene cyclizations are among the most complex and challenging transformations in biology. In a single reaction step, multiple carbon-carbon bonds, ring systems and stereogenic centres are constituted from simple, acyclic precursors. Simultaneously achieving this kind of precise control over product distribution and stereochemistry poses a formidable task for chemists.

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.

Acid-Catalyzed Oxy-aminomethylation of Styrenes.

We report a strong Brønsted acid-catalyzed three-component oxy-aminomethylation of styrenes with -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.

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 substrates.

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 ,-acetals to give enantioenriched arylglycine esters.

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,β-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.

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.

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 menthol and cannabinoids. 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 products. We now show that an unsymmetric, strong and confined chiral acid, a highly fluorinated imino-imidodiphosphate, catalyses this process with excellent efficiency and selectivity.

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.