Enantioselective Sulfonimidamide Acylation via a Cinchona Alkaloid-Catalyzed Desymmetrization: Scope, Data Science, and Mechanistic Investigation.

Methods to access chiral sulfur(VI) pharmacophores are of interest in medicinal and synthetic chemistry. We report the desymmetrization of unprotected sulfonimidamides via asymmetric acylation with a cinchona-phosphinate catalyst. The desired products are formed in excellent yield and enantioselectivity with no observed bis-acylation. A data-science-driven approach to substrate scope evaluation was coupled to high throughput experimentation (HTE) to facilitate statistical modeling in order to inform mechanistic studies. Reaction kinetics, catalyst structural studies, and density functional theory (DFT) transition state analysis elucidated the turnover-limiting step to be the collapse of the tetrahedral intermediate and provided key insights into the catalyst-substrate structure-activity relationships responsible for the origin of the enantioselectivity. This study offers a reliable method for accessing enantioenriched sulfonimidamides to propel their application as pharmacophores and serves as an example of the mechanistic insight that can be gleaned from integrating data science and traditional physical organic techniques.

Stereoconvergent and -divergent Synthesis of Tetrasubstituted Alkenes by Nickel-Catalyzed Cross-Couplings.

We report the development of a method to diastereoselectively access tetrasubstituted alkenes via nickel-catalyzed Suzuki-Miyaura cross-couplings of enol tosylates and boronic acid esters. Either diastereomeric product was selectively accessed from a mixture of enol tosylate starting material diastereomers in a convergent reaction by judicious choice of the ligand and reaction conditions. A similar protocol also enabled a divergent synthesis of each product isomer from diastereomerically pure enol tosylates. Notably, high-throughput optimization of the monophosphine ligands was guided by chemical space analysis of the kraken library to ensure a diverse selection of ligands was examined. Stereoelectronic analysis of the results provided insight into the requirements for reactive and selective ligands in this transformation. The synthetic utility of the optimized catalytic system was then probed in the stereoselective synthesis of various tetrasubstituted alkenes, with yields up to 94% and diastereomeric ratios up to 99:1 Z/E and 93:7 E/Z observed. Moreover, a detailed computational analysis and experimental mechanistic studies provided key insights into the nature of the underlying isomerization process impacting selectivity in the cross-coupling.

Hydrogen Bond Donor Catalyzed Cationic Polymerization of Vinyl Ethers.

The synthesis of high-molecular-weight poly(vinyl ethers) under mild conditions is a significant challenge, since cationic polymerization reactions are highly sensitive to chain-transfer and termination events. We identified a novel and highly effective hydrogen bond donor (HBD)-organic acid pair that can facilitate controlled cationic polymerization of vinyl ethers under ambient conditions with excellent monomer compatibility. Poly(vinyl ethers) of molar masses exceeding 50 kg mol-1 can be produced within 1 h without elaborate reagent purification. Modification of the HBD structure allowed tuning of the polymerization rate, while DFT calculations helped elucidate crucial intermolecular interactions between the HBD, organic acid, and polymer chain end.

Ring-opening carbonyl-olefin metathesis of norbornenes.

A computational and experimental study of the hydrazine-catalyzed ring-opening carbonyl-olefin metathesis of norbornenes is described. Detailed theoretical investigation of the energetic landscape for the full reaction pathway with six different hydrazines revealed several crucial aspects for the design of next-generation hydrazine catalysts. This study indicated that a [2.2.2]-bicyclic hydrazine should offer substantially increased reactivity versus the previously reported [2.2.1]-hydrazine due to a lowered activation barrier for the rate-determining cycloreversion step, a prediction which was verified experimentally. Optimized conditions for both cycloaddition and cycloreversion steps were identified, and a brief substrate scope study for each was conducted. A complication for catalysis was found to be the slow hydrolysis of the ring-opened hydrazonium intermediates, which were shown to suffer from a competitive and irreversible cycloaddition with a second equivalent of norbornene. This problem was overcome by the strategic incorporation of a bridgehead methyl group on the norbornene ring, leading to the first demonstrated catalytic carbonyl-olefin metathesis of norbornene rings.

Pseudophedrine-Derived Myers Enolates: Structures and Influence of Lithium Chloride on Reactivity and Mechanism.

The structures and reactivities of pseudoephedrine-derived dianionic Myers enolates are examined. A combination of NMR and IR spectroscopic, crystallographic, and computational data reveal that the homoaggregated dianions form octalithiated tetramers displaying S4-symmetric Li8O8 cores and overall C2 symmetry. Computational and isotopic labeling studies reveal strong N-Li contacts in the carboxamide enolate moiety. The method of continuous variations proves deceptive, as octalithiated tetrameric homoaggregates afford hexalithiated trimeric heteroaggregates. A lithium diisopropylamide-lithium enolate mixed aggregate is found to be a C2-symmetric hexalithiated species incorporating two enolate dianions and two lithium diisopropylamide (LDA) subunits. Structural and rate studies show that lithium chloride has little effect on the dynamics of the enolate homoaggregates but forms adducts of unknown structure. Rate studies of alkylations indicate that the aging of the aggregates can have effects spanning orders of magnitude. The LiCl-enolate adduct dramatically accelerates the reaction but requires superstoichiometric quantities owing to putative autoinhibition. Efforts and progress toward eliminating the requisite large excess of LiCl are discussed.

Synthesis of 2H-Chromenes via Hydrazine-Catalyzed Ring-Closing Carbonyl-Olefin Metathesis.

The catalytic ring-closing carbonyl-olefin metathesis (RCCOM) of O-allyl salicylaldehydes to form 2H-chromenes is described. The method utilizes a [2.2.1]-bicyclic hydrazine catalyst and operates via a [3+2]/retro-[3+2] metathesis manifold. The nature of the allyl substitution pattern was found to be crucial, with sterically demanding groups such as adamantylidene or diethylidene offering optimal outcomes. A survey of substrate scope is shown along with a discussion of mechanism supported by DFT calculations. Steric pressure arising from syn-pentane minimization of the diethylidene moiety is proposed to facilitate cycloreversion.

The Hydrazine-O2 Redox Couple as a Platform for Organocatalytic Oxidation: Benzo[c]cinnoline-Catalyzed Oxidation of Alkyl Halides to Aldehydes.

An organocatalytic oxidation platform that capitalizes on the capacity of hydrazines to undergo rapid autoxidation to diazenes is described. Commercially available benzo[c]cinnoline is shown to catalyze the oxidation of alkyl halides to aldehydes in a novel mechanistic paradigm involving nucleophilic attack, prototropic shift, and hydrolysis. The hydrolysis and reoxidation events occur readily with only adventitious oxygen and water. A survey of the scope of viable substrates is shown along with mechanistic and computational studies that give insight into this mode of catalysis.

Lithium Amino Alkoxide-Evans Enolate Mixed Aggregates: Aldol Addition with Matched and Mismatched Stereocontrol.

Building on structural and mechanistic studies of lithiated enolates derived from acylated oxazolidinones (Evans enolates) and chiral lithiated amino alkoxides, we found that amino alkoxides amplify the enantioselectivity of aldol additions. The pairing of enantiomeric series affords matched and mismatched stereoselectivities. The structures of mixed tetramers showing 2:2 and 3:1 (alkoxide-rich) stoichiometries are determined spectroscopically. Rate and computational studies provide a viable mechanistic and stereochemical model based on the direct reaction of the 3:1 mixed tetramers, but they raise unanswered questions for the 2:2 mixed aggregates.

Structure-Reactivity Relationships in Lithiated Evans Enolates: Influence of Aggregation and Solvation on the Stereochemistry and Mechanism of Aldol Additions.

Aldol additions to isobutyraldehyde and cyclohexanone with lithium enolates derived from acylated oxazolidinones (Evans enolates) are described. Previously characterized trisolvated dimeric enolates undergo rapid addition to isobutyraldehyde to give a 12:1 syn:syn selectivity in high yield along with small amounts of one anti isomer. The efficacy of the addition depends critically on aging effects and the reaction quench. Unsolvated tetrameric enolates that form on warming the solutions are unreactive toward isobutyraldehyde and undergo retroaldol reaction under forcing conditions. Additions to cyclohexanone are relatively slow but form a single isomeric adduct in >80% yield. The ketone-derived aldolates are robust. All attempts to control stereoselectivity by controlling aggregation failed. Rate studies of addition to cyclohexanone trace the lack of aggregation-dependent selectivities to a monomer-based mechanism. The synthetic implications and possible utility of lithium enolates in Evans aldol additions are discussed.

Electrophilic C-H Borylation and Related Reactions of B-H Boron Cations.

Catalytic procedures are described for aminedirected borylation of aliphatic and aromatic tertiary amine boranes. Sequential double borylation is observed in cases where two or more C-H bonds are available that allow 5-center or 6-center intramolecular borylation. The HNTf2 catalyzed borylation of benzylamine boranes provides a practical means for the synthesis of ortho-substituted arylboronic acid derivatives, suitable for Suzuki-Miyaura cross-coupling applications.