Novel Brønsted Acid Catalyzed C-C Bond Activation and α-Alkylation of Ketones.

A novel approach for the α-alkylation of ketones was developed using Brønsted acid-catalyzed C-C bond cleavage. Both aromatic and aliphatic ketones reacted smoothly with 2-substituted 1,3-diphenylpropane-1,3-diones to afford α-alkylation products with high yields and with excellent regioselectivity, in which the 1,3-dicarbonyl group acted as a leaving group in the presence of the catalyst TfOH. Mechanism experiments showed that the ß-C-C bond cleavage of diketone and the shift of the equilibrium towards the enol formation from ketone are driving forces that induce the desired products.

Olefination of Aromatic Carbonyls via Site-Specific Activation of Cycloalkanone Ketals.

Skeletal editing is an important strategy in organic synthesis as it modifies the carbon backbone to tailor molecular structures with precision, enabling access to compounds with specific desired properties. Skeletal editing empowers chemists to transform synthetic approaches of target compounds across diverse applications from drug discovery to materials science. Herein, we introduce a new skeletal editing method to convert readily available aromatic carbonyl compounds into valuable unsaturated carboxylic acids with extended carbon chains. Our reaction setup enables a cascade reaction of enolization-[2+2]cycloaddition-[2+2]cycloreversion between aromatic carbonyl compounds and ketals of cyclic ketones to generate unsaturated carboxylic acids as ring-opening products. Through a simple design, our substrates are specifically activated to react at predetermined positions to enhance selectivity and efficiency. This practical method offers convenient access to versatile organic building blocks as well as provides fresh insights into manipulating traditional reaction pathways for new synthetic applications.

Controlling Monoterpene Isomerization by Guiding Challenging Carbocation Rearrangement Reactions in Engineered Squalene-Hopene Cyclases.

The interconversion of monoterpenes is facilitated by a complex network of carbocation rearrangement pathways. Controlling these isomerization pathways is challenging when using common Brønsted and Lewis acid catalysts, which often produce product mixtures that are difficult to separate. In contrast, natural monoterpene cyclases exhibit high control over the carbocation rearrangement reactions but are reliant on phosphorylated substrates. In this study, we present engineered squalene-hopene cyclases from Alicyclobacillus acidocaldarius (AacSHC) that catalyze the challenging isomerization of monoterpenes with unprecedented precision. Starting from a promiscuous isomerization of (+)-ß-pinene, we first demonstrate noticeable shifts in the product distribution solely by introducing single point mutations. Furthermore, we showcase the tuneable cation steering by enhancing (+)-borneol selectivity from 1 % to >90 % (>99 % de) aided by iterative saturation mutagenesis. Our combined experimental and computational data suggest that the reorganization of key aromatic residues leads to the restructuring of the water network that facilitates the selective termination of the secondary isobornyl cation. This work expands our mechanistic understanding of carbocation rearrangements and sets the stage for target-oriented skeletal reorganization of broadly abundant terpenes.

Triflic Acid-Catalyzed Dehydrative Amination of 2-Arylethanols with Weak N-Nucleophiles in Hexafluoroisopropanol.

The catalytic deoxyamination of readily available 2-arylethanols offers an appealing, simple, and straightforward means of accessing ß-(hetero)arylethylamines of biological interest. Yet, it currently represents a great challenge to synthetic chemistry. In most cases, the alcohol has to be either pre-activated in situ or converted into a reactive carbonyl intermediate, limiting the substrate scope for some methods. Examples of direct dehydrative amination of 2-arylethanols are still scarce. Here, we describe a catalytic protocol based on the synergy of triflic acid and hexafluoroisopropanol, which enables the direct and stereospecific amination of a broad array of 2-arylethanols, and does not require any pre-activation of the alcohol. This approach yields high value-added products incorporating sulfonamide, amide, urea, and aniline functionalities. In addition, this approach was applied to the sulfidation of 2-arylethanols. Mechanistic experiments and DFT computations indicate the formation of phenonium ions as key intermediates in the reaction.

Catalytic Enantioselective [4+2] Cycloadditions of Salicylaldehyde Acetals with Enol Ethers.

A readily accessible conjugate-base-stabilized carboxylic acid (CBSCA) catalyst facilitates highly enantioselective [4+2] cycloaddition reactions of salicylaldehyde-derived acetals and cyclic enol ethers, resulting in the formation of polycyclic chromanes with oxygenation in the 2- and 4-positions. Stereochemically more complex products can be obtained from racemic enol ethers. Spirocyclic products are also accessible.

Cooperative Friedel-Crafts Alkylation of Electron-Deficient Arenes via Catalyst Activation with Hexafluoroisopropanol.

A Friedel-Crafts alkylation of electron-deficient arenes with aldehydes through ''catalyst activation'' is presented. Through hydrogen bonding interactions, the solvent 1,1,1,3,3,3, -hexafluoroisopropanol (HFIP) interacted with the added Brønsted acid catalyst pTSA•H2 O, increasing its acidity. This activated catalyst enabled the Friedel-Crafts alkylation of electron-neutral as well as electron-deficient arenes. Strongly electron withdrawing arenes including arenes with multiple halogen atoms, NO2 , CHO, CO2 R, and CN, groups acted as efficient nucleophiles in this reaction. DFT studies reveal multiple roles of solvent HFIP viz; increasing the Brønsted acidity of the catalyst pTSA•H2 O, and stabilization of the transition states through a concerted pathway enabling the challenging reaction.

Brønsted-Acid-Catalyzed One-Pot Synthesis of ß,ß-Diaryl Esters: Direct Regioselective Approach to Diverse Arrays of 3-Aryl-1-indanone Cores.

A three-component, solvent-dependent, Brønsted-acid-catalyzed reaction of benzaldehydes, silyl enolates and arene nucleophiles has been developed for the synthesis of potential drug candidate 3-aryl-1-indanones. This reaction features the formation of three C-C bonds, high regioselectivity in a one-pot strategy, broad substrate generality, facile scalability (1.04g), high functional group tolerance and viable substrates. The ß-O-silyl ethers generated in-situ from the Mukaiyama aldol reaction were subjected to acid-catalyzed benzylic arylation with strong as well as weak nucleophiles, and the resultant ß,ß-diaryl esters can undergo a third C-C bond formation with excellent regioselectivity through intramolecular cyclization to afford the indanone products in the same pot. Detailed mechanistic insight leads to a feasible reaction pathway. This transformation opens up a practical and adaptable approach to producing a variety of synthetically valuable transformations and enable the synthesis of medicinally valuable (R)-tolterodine and (+)-indatraline.

Multifunctional Organocatalysts - Singly-Linked and Macrocyclic Bisphosphoric Acids for Asymmetric Phase-Transfer and Brønsted-Acid Catalysis.

The linking of phosphoric acids via covalent or mechanical bonds has proven to be a successful strategy for the design of novel organocatalysts. Here, we present the first systematic investigation of singly-linked and macrocyclic bisphosphoric acids, including their synthesis and their application in phase-transfer and Brønsted acid catalysis. We found that the novel bisphosphoric acids show dramatically increased enantioselectivities in comparison to their monophosphoric acid analogues. However, the nature, length and number of linkers has a profound influence on the enantioselectivities. In the asymmetric dearomative fluorination via phase-transfer catalysis, bisphosphoric acids with a single, rigid bisalkyne-linker give the best results with moderate to good enantiomeric excesses. In contrast, bisphosphoric acids with flexible linkers give excellent enantioselectivities in the transfer-hydrogenation of quinolines via cooperative Brønsted acid catalysis. In the latter case, sufficiently long linkers are needed for high stereoselectivities, as found experimentally and supported by DFT calculations.

Harnessing the Structure and Dynamics of the Squalene-Hopene Cyclase for (-)-Ambroxide Production.

Terpene cyclases offer enormous synthetic potential, given their unique ability to forge complex hydrocarbon scaffolds from achiral precursors within a single cationic rearrangement cascade. Harnessing their synthetic power, however, has proved to be challenging owing to their generally low catalytic performance. In this study, we unveiled the catalytic potential of the squalene-hopene cyclase (SHC) by harnessing its structure and dynamics. First, we synergistically tailored the active site and entrance tunnel of the enzyme to generate a 397-fold improved (-)-ambroxide synthase. Our computational investigations explain how the introduced mutations work in concert to improve substrate acquisition, flow, and chaperoning. Kinetics, however, showed terpene-induced inactivation of the membrane-bound SHC to be the major turnover limitation in vivo. Merging this insight with the improved and stereoselective catalysis of the enzyme, we applied a feeding strategy to exceed 105 total turnovers. We believe that our results may bridge the gap for broader application of SHCs in synthetic chemistry.

Kinetic Resolution of Azaarylethynyl Tertiary Alcohols by Chiral Brønsted Acid Catalysed Phosphine-Mediated Deoxygenation.

A chiral Brønsted acid catalysed phosphine-mediated deoxygenation protocol is reported. This metal-free method provides a precise kinetic resolution platform for azaarylethynyl tertiary alcohols, which are a broad category of biologically and synthetically important azaarene derivatives. In addition to providing an efficient method for the first asymmetric preparation of these tertiary alcohols, the strategy facilitates the construction of azaaryl-functionalized allenes with good to excellent enantioselectivities. The high selectivity factors (s up to 235), broad substrate scope, and ability to convert azaaryl compounds into both chiral tertiary alcohols and allenes robustly underscore the efficiency and promising utility of this method. The practicability is further validated by the successful synthesis of deuterated allenes with high ee values and substantial incorporation of deuterium using inexpensive D2 O as the deuterium source.

Identification of Crucial Intermediates in the Formation of Humins from Cellulose-Derived Platform Chemicals Under Brønsted Acid Catalyzed Reaction Conditions.

Humins are one of the undesirable products formed during the dehydration of sugars as well as the conversion of 5-hydroxymethylfurfural (HMF) to value-added products. Thus, reducing the formation of humins is an important strategy for improving the yield of the aforementioned reactions. Even after a plethora of studies, the mechanism of formation and the structure of humins are still elusive. In this regard, we have employed density functional theory-based mechanistic studies and microkinetic analysis to identify crucial intermediates formed from glucose, fructose, and HMF that can initiate the polymerization reactions resulting in humins under Brønsted acid-catalyzed reaction conditions. This study brings light into crucial elementary reaction steps that can be targeted for controlling humins formation. Moreover, this work provides a rationale for the experimentally observed aliphatic chains and HMF condensation products in the humins structure. Different possible polymerization routes that could contribute to the structure of humins are also suggested based on the results. Importantly, the findings of this work indicate that increasing the rate of isomerization of glucose to fructose and reducing the rate of reaction between HMF molecules could be an efficient strategy for reducing humins formation.

Annulation of Perimidines with 5-Alkynylpyrimidines en Route to 7-Formyl-1,3-Diazopyrenes.

Unusual rearrangements were shown to accompany Brønsted acid-assisted peri-annulations of 1H-perimidines with 5-alkynylpyrimidines. These transformations take different routes depending on the nature of acetylene precursor, and lead to the formation of 7-formyl-1,3-diazopyrenes.

One-Pot Synthesis of (E)-2-(3-Oxoindolin-2-ylidene)-2-arylacetonitriles.

A highly efficient and expeditious one-pot approach towards 2-(3-oxoindolin-2-yl)acetonitriles was designed, which involves a base-assisted aldol reaction of ortho-nitroacetophenones, followed by hydrocyanation, triggering an unusual reductive cyclization reaction.

Improved Method for Preparation of 3-(1H-Indol-3-yl)benzofuran-2(3H)-ones.

3-(1H-Indol-3-yl)benzofuran-2(3H)-ones were efficiently accessed via polyphosphoric acid-mediated condensation of 3-(2-nitrovinyl)-1H-indoles with phenols.

Hydrogen Bonding Networks Enable Brønsted Acid-Catalyzed Carbonyl-Olefin Metathesis.

Synthetic chemists have learned to mimic nature in using hydrogen bonds and other weak interactions to dictate the spatial arrangement of reaction substrates and to stabilize transition states to enable highly efficient and selective reactions. The activation of a catalyst molecule itself by hydrogen-bonding networks, in order to enhance its catalytic activity to achieve a desired reaction outcome, is less explored in organic synthesis, despite being a commonly found phenomenon in nature. Herein, we show our investigation into this underexplored area by studying the promotion of carbonyl-olefin metathesis reactions by hydrogen-bonding-assisted Brønsted acid catalysis, using hexafluoroisopropanol (HFIP) solvent in combination with para-toluenesulfonic acid (pTSA). Our experimental and computational mechanistic studies reveal not only an interesting role of HFIP solvent in assisting pTSA Brønsted acid catalyst, but also insightful knowledge about the current limitations of the carbonyl-olefin metathesis reaction.

Stereoselective Synthesis of Atropisomeric Acridinium Salts by the Catalyst-Controlled Cyclization of ortho-Quinone Methide Iminiums.

Quinone methides are fundamental intermediates for a wide range of reactions in which catalyst stereocontrol is often achieved by hydrogen bonding. Herein, we describe the feasibility of an intramolecular Friedel-Crafts 6π electrocyclization through ortho-quinone methide iminiums stereocontrolled by a contact ion pair. A disulfonimide catalyst activates racemic trichloroacetimidate substrates and imparts stereocontrol in the cyclization step, providing a new avenue for selective ortho-quinone methide iminium functionalization. A highly stereospecific oxidation readily transforms the enantioenriched acridanes into rotationally restricted acridiniums. Upon ion exchange, the method selectively affords atropisomeric acridinium tetrafluoroborate salts in high yields and an enantioenrichment of up to 93 : 7 e.r. We envision that ion-pairing catalysis over ortho-quinone methide iminiums enables the selective synthesis of a diversity of heterocycles and aniline derivatives with distinct stereogenic units.

Direct Synthesis of Unsymmetrical Dithioacetals.

Dithioacetals are a frequently used motif in synthetic organic chemistry and have recently seen increasing attention as structural motif in promising antiviral agents against plant pathogens. Most existing reports, however, only discuss symmetrical dithioacetals. Examples of mixed dithioacetals are scarce and no general method for the selective synthesis of these compounds exists. Herein, a synthetically simple general one-step protocol was developed for the synthesis of a broad range of unsymmetrical dithioacetals consisting of one aromatic and one aliphatic thiol moiety from the corresponding aldehyde/thiol mixture. The mixed S,S-acetals were obtained in high yields, and a great variety of functional groups was tolerated. Kinetic control enabled an excellent selectivity in regard to the unsymmetrical dithioacetal.

Stereoselective Directed Cationic Cascades Enabled by Molecular Anchoring in Terpene Cyclases.

Cascade reactions appeared as a cutting-edge strategy to streamline the assembly of complex structural scaffolds from naturally available precursors in an atom-, as well as time, labor- and cost-efficient way. We herein report a strategy to control cationic cyclization cascades by exploiting the ability of anchoring dynamic substrates in the active site of terpene cyclases via designed hydrogen bonding. Thereby, it is possible to induce "directed" cyclizations in contrast to established "non-stop" cyclizations (99:1) and predestinate cascade termination at otherwise catalytically barely accessible intermediates. As a result, we are able to provide efficient access to naturally widely occurring apocarotenoids, value-added flavors and fragrances in gram-scale by replacing multi-stage synthetic routes to a single step with unprecedented selectivity (>99.5 % ee) and high yields (up to 89 %).

Mild Intermolecular Synthesis of a Cyclopropane-Containing Tricyclic Skeleton: Unusual Reactivity of Isobenzopyryliums.

Cyclopropanes embedded in a polycyclic bridged architecture are a versatile structural motif, but such complex frameworks often impose substantial synthetic challenges. Herein we introduce a new approach for the expedient access to such spring-loaded strained systems via an exceptionally mild intermolecular convergent process between the readily available isobenzopyryliums and vinyl boronic acids. Different from the typical conventional approaches, our protocol does not involve the highly active carbenoid intermediates or strong conditions in order to overcome the disfavored kinetic and thermodynamic problems. Instead, the key cyclopropane ring was formed between the well-positioned nucleophile and electrophile in the adduct from the regioselective [4+2] cycloaddition. Thus, this unusual process also represents a new reactivity of the versatile isobenzopyryliums. The choice of a Brønsted acid catalyst with proper acidity is crucial to the high efficiency and selectivity for this multiple bond-forming process. The strained products are precursors to other useful synthetic building blocks.

Catalytic Enantioselective Desymmetrizing Fischer Indolization through Dynamic Kinetic Resolution.

The first catalytic enantioselective Fischer indolization of prochiral diketones containing enantiotopic carbonyl groups is developed and shown to proceed through dynamic kinetic resolution (DKR). Catalyzed by the combination of a spirocyclic chiral phosphoric acid and ZnCl2 (Lewis acid assisted Brønsted acid), this direct approach combines 2,2-disubstituted cyclopentane-1,3-diones with N-protected phenylhydrazines to furnish cyclopenta[b]indole derivatives containing an all-carbon quaternary stereocenter with good to excellent enantioselectivities.