Dynamic and Persistent Cyclochirality in Hydrogen-Bonded Derivatives of Medium-Ring Triamines.

Cyclic triureas derived from 1,4,7-triazacyclononane (TACN) were synthesized; X-ray crystallography showed a chiral bowl-like conformation with each urea hydrogen-bonded to its neighbor with uniform directionality, forming a "cyclochiral" closed loop of hydrogen bonds. Variable-temperature 1H NMR, 1H-1H exchange spectroscopy, Eyring analysis, computational modeling, and studies in various solvents revealed that cyclochirality is dynamic (ΔG‡25°C = 63-71 kJ mol-1 in noncoordinating solvents), exchanging between enantiomers by two mechanisms: bowl inversion and directionality reversal, with the former subject to a slightly smaller enantiomerization barrier. The enantiomerization rate substantially increased in the presence of hydrogen-bonding solvents. Population of only one of the two cyclochiral hydrogen-bond directionalities could be induced by annulating one ethylene bridge with a trans-cyclohexane. Alternatively, enantiomerization could be inhibited by annulating one ethylene bridge with a cis-cyclohexane (preventing bowl inversion) and replacing one urea function with a formamide (preventing directionality reversal). Combining these structural modifications resulted in an enantiomerization barrier of ΔG‡25°C = 93 kJ mol-1, furnishing a planar-chiral, atropisomeric bowl-shaped structure whose stereochemical stability arises solely from its hydrogen-bonding network.

C(sp3)-Arylation by Conformationally Accelerated Intramolecular Nucleophilic Aromatic Substitution (SNAr).

The asymmetric synthesis of heavily substituted benzylic stereogenic centers, prevalent in natural products, therapeutics, agrochemicals, and catalysts, is an ongoing challenge. In this Account, we outline our contribution to this endeavor, describing our discovery of a series of new reactions that not only have synthetic applicability but also present significant mechanistic intrigue. The story originated from our longstanding interest in the stereochemistry and reactivity of functionalized organolithiums. While investigating the lithiation chemistry of ureas (a "Cinderella" sister of the more established amides and carbamates), we noted an unexpected Truce-Smiles (T-S) rearrangement involving the 1,4-N → C transposition of a urea N'-aryl group to the α-carbanion of an adjacent N-benzyl group. Despite this reaction formally constituting an SNAr substitution, we found it to be remarkably tolerant of the electronic properties of the migrating aryl substituent and the degree of substitution at the carbanion. Moreover, in contrast to classical SNAr reactions, the rearrangement was sufficiently rapid that it took place under conditions compatible with configurational stability in an organolithium intermediate, enabling enantiospecific arylation at benzylic stereogenic centers. Experimental and computational studies confirmed a low kinetic barrier to the aryl migration arising from the strong preference for a trans arrangement of the urea N'-aryl and carbonyl groups, populating a reactive conformer in which spatial proximity was enforced between the carbanion and N'-aryl group, hugely accelerating ipso-substitution.This discovery led us to uncover a whole series of conformationally accelerated intramolecular N → C aryl transfers using different anilide-based functional groups, including a diverse range of urea, carbamate, and thiocarbamate-substituted anions. Products included enantioenriched α-tertiary amines (including α-arylated N-heterocycles) and alcohols, as well as rare α-tertiary thiols. Synthetically challenging diarylated centers with differentiated aryl groups featured heavily in all product sets. The absolute enantiospecificity (retention versus inversion) of the reaction was dependent on the heteroatom α to the lithiation site: the origin of this stereodivergence was probed both experimentally and computationally. Asymmetric variants of the rearrangement were realized by enantioselective deprotonation, and connective strategies were developed in which an intermolecular C-C bond-forming event preceded the anionic rearrangement. Substrates where the N'-nucleofuge (at the aryl ipso position) was tethered to the migrating arene allowed us to use the rearrangement as a ring expansion method to generate 8- to 12-membered medium-ring N-heterocycles from very simple precursors. Stabilized carbon nucleophiles such as alkali metal enolates also readily promoted intramolecular N → C aryl transfer in N'-arylureas, opening up access to biologically relevant hydantoins, and enabling a "chiral memory" approach for the (hetero)arylation of chiral α-amino acids with programmable retention or inversion of configuration. Collectively, our studies of electronically versatile T-S rearrangements in anilide-based systems have culminated in a practical and general strategy for transition metal-free C(sp3)-arylation. More broadly, our results highlight the power of conformational activation to achieve unprecedented reactivity in the construction of challenging C-C bonds.

Synthesis and Atropisomeric Properties of Benzoazepine-Fused Isoindoles.

Atropisomeric, bench-stable benzoazepine-fused isoindoles were synthesized via oxidation from isoindoline precursors. Using the isoindoles 5d-f as models, the stereochemistry and conformational folding of the systems were examined. Chiral UHPLC was used to analyze the rate of racemization and calculate the Gibbs free energy of enantiomerization (ΔG‡Enant). X-ray crystallography, 1H NMR spectroscopy, and DFT calculations were used to elucidate the three axes of chirality and clarify the structural factors contributing to ΔG‡Enant. Tandem rotation around the axes of chirality precludes the formation of diastereomers, with rotational restriction of the Caryl-Nsulfonamide bond determined as the moderator of atropisomeric stability in the system, affected primarily by steric hindrance as well as by π-stacking interactions facilitated by the folded conformation of the sulfonamide over the isoindole moiety.

Reversible Capture and Release of a Ligand Mediated by a Long-Range Relayed Polarity Switch in a Urea Oligomer.

Ethylene-bridged oligoureas characterized by a continuous, switchable chain of hydrogen bonds and carrying a binding site (an N,N'-disubstituted urea) for a hydrogen-bond-accepting ligand (a phosphine oxide) were synthesized. These oligomers show stronger ligand binding when the binding site is located at the hydrogen-bond-donating terminus than when the same binding site is at the hydrogen-bond-accepting terminus. An acidic group at the terminus remote from the binding site allows hydrogen bond polarity, and hence ligand binding ability, to be controlled remotely by a deprotonation/reprotonation cycle. Addition of base induces a remote conformational change that is relayed through up to five urea linkages, reducing the ability of the binding site to retain an intermolecular association to its ligand, which is consequently released into solution. Reprotonation returns the polarity of the oligomer to its original directionality, restoring the function of the remote binding site, which consequently recaptures the ligand. This is the first example of a synthetic molecular structure that relays intermolecular binding information, and these "dynamic foldamer" structures are prototypes of components for chemical systems capable of controlling chemical function from a distance.

N-Methyl Allylic Amines from Allylic Alcohols by Mitsunobu Substitution Using N-Boc Ethyl Oxamate.

We report the practical, scalable synthesis of a range of N-methyl allylic amines. Primary and secondary allylic alcohols underwent a regioselective Mitsunobu reaction with readily accessible N-Boc ethyl oxamate to deliver the corresponding N-Boc allylic amines, including in enantiopure form via stereospecific substitution. Subsequent N-methylation and Boc deprotection without chromatography yielded the amine products as hydrochloride salts. This method solves the problem of converting commercially available alcohols into often volatile N-methyl allylic amines, many of which have limited commercial availability.

Switchable Synthesis of Z-Homoallylic Boronates and E-Allylic Boronates by Enantioselective Copper-Catalyzed 1,6-Boration.

The enantioselective Cu-catalyzed 1,6-boration of (E,E)-α,ß,γ,δ-unsaturated ketones is described, which gives homoallylic boronates with high enantiomeric purity and unexpectedly high Z-selectivity. By changing the solvent, the outcome can be altered to give E-allylic boronates.

Diastereoselective Synthesis of Highly Substituted, Amino- and Pyrrolidino-Tetrahydrofurans as Lead-Like Molecular Scaffolds.

A series of highly substituted tetrahydrofurans (THFs), decorated with modifiable 2-aryl, 3-carboxy and 4-amino substituents, has been prepared for biological evaluation within the European Lead Factory. Diastereoselective reductive amination of pre-functionalised 4-oxofurans, readily prepared from cinnamate esters via oxa-Michael/Dieckmann annulation, provided the requisite THF cores on gram scale with three contiguous stereocentres, including full substitution at C-3. In a second series, a pyrrolidine ring was fused to the same oxofuran scaffold via an intramolecular reductive amination, inverting the configuration at C-4 relative to the other ring substituents. The resulting compounds, which displayed desirable physical properties as lead-like scaffolds, were derivatised into a small library of 24 compounds, demonstrating their ability to serve as starting points for drug discovery. Ultimately, this chemistry enabled the preparation of 1948 THF-containing compounds for inclusion in the Joint European Compound Library.

Pd-Catalyzed Dearomative [3 + 2] Cycloaddition of 3-Nitroindoles with 2-Vinylcyclopropane-1,1-dicarboxylates.

A trans-diastereoselective Pd-catalyzed dearomative [3 + 2] cycloaddition between vinylcyclopropane dicarboxylates and 3-nitroindoles has been developed. The reaction provides densely functionalized cyclopenta[b]indolines with versatile vinyl and nitro-groups. The addition of a halide additive was found to be critical for the diastereoselectivity of the reaction, which is proposed to be a result of a rapid π-σ-π interconversion between the intermediates allowing for Curtin-Hammett control. A switch in diastereoselectivity to afford products with the vinyl and nitro groups cis to each other is observed with a 4-substituted 3-nitroindole.

Enantiopure Trans-4,5-Disubstituted 2-Imidazolidinones via Copper(I)-Catalyzed Ring Opening of 1,1'-DiBoc-2,2'-Biaziridine with Grignard Reagents.

The copper-catalyzed ring opening of chiral-pool-derived 1,1'-diBoc-2,2'-biaziridine with Grignard reagents affords enantiopure 2-imidazolidinones in a desymmetrizing, cascade process involving the Boc protecting group. This divergent strategy provides reaction-ready, N-differentiated products and allows two C-C bond constructions concurrent to imidazolidinone formation. A variety of alkyl, cyclic, and aryl Grignard reagents are tolerated in reasonable to good yields.

Cyclic Phosphine Oxides and Phosphinamides from Di-Grignard Reagents and Phosphonic Dichlorides: Modular Access to Annulated Phospholanes.

The reaction between 1,4-di-Grignard reagents and phosphonous(III) dichlorides is a classical method for the direct synthesis of phospholanes. Reported here is an extension of this approach to the preparation of value-added, annulated phospholane oxides, achieved through the combination of carbocyclic-fused di-Grignard reagents and readily available phosphonic(V) dichlorides. The procedure is amenable to (benz)annulation at both the 2,3- and 3,4-positions of the phospholane ring, and a variety of aliphatic, cyclic and aryl P-electrophiles are tolerated in reasonable to excellent yields.

Binaphthyl-1,2,3-triazole peptidomimetics with activity against Clostridium difficile and other pathogenic bacteria.

Clostridium difficile (C. difficile) is a problematic Gram positive bacterial pathogen causing moderate to severe gastrointestinal infections. Based on a lead binaphthyl-tripeptide dicationic antimicrobial, novel mono-, di- and tri-peptidomimetic analogues targeting C. difficile were designed and synthesized incorporating one, two or three d-configured cationic amino acid residues, with a common 1,2,3-triazole ester isostere at the C-terminus. Copper- and ruthenium-click chemistry facilitated the generation of a 46 compound library for in vitro bioactivity assays, with structure-activity trends over the largest compound subset revealing a clear advantage to triazole-substitution with a linear or branched hydrophobic group. The most active compounds were dicationic-dipeptides where the triazole was substituted with a 4- or 5-cyclohexylmethyl or 4,5-diphenyl moiety, providing MICs of 4 µg mL(-1) against three human isolates of C. difficile. Further biological screening revealed significant antimicrobial activity for several compounds against other common bacterial pathogens, both Gram positive and negative, including S. aureus (MICs ≥2 µg mL(-1)), S. pneumoniae (MICs ≥1 µg mL(-1)), E. coli (MICs ≥4 µg mL(-1)), A. baumannii (MICs ≥4 µg mL(-1)) and vancomycin-resistant E. faecalis (MICs ≥4 µg mL(-1)).

Synthesis and antimicrobial activity of binaphthyl-based, functionalized oxazole and thiazole peptidomimetics.

Thirty two new binaphthyl-based, functionalized oxazole and thiazole peptidomimetics and over thirty five novel leucine-containing intermediate oxazoles and thiazoles were prepared in this study. This includes the first examples of the direct C-5 arylation of an amino acid dipeptide-derived oxazole. Moderate to excellent antibacterial activity was observed for all new compounds across Gram positive isolates with MICs ranging from 1-16 µg mL(-1). Results for Gram negative E. coli and A. baumannii were more variable, but MICs as low as 4 µg mL(-1) were returned for two examples. Significantly, the in vitro results with a fluoromethyl-oxazole derivative collectively represent the best obtained to date for a member of our binaphthyl peptide antimicrobials.

A molecular communication channel consisting of a single reversible chain of hydrogen bonds in a conformationally flexible oligomer.

Communication of information through the global switching of conformation in synthetic molecules has hitherto entailed the inversion of chirality. Here, we report a class of oligomer through which information may be communicated through a global reversal of polarity. Ethylene-bridged oligoureas are constitutionally symmetrical, conformationally flexible molecules organized by a single chain of hydrogen bonds running the full length of the oligomer. NMR reveals that this hydrogen-bonded chain may undergo a coherent reversal of directionality. The directional uniformity of the hydrogen-bond chain allows it to act as a channel for the spatial communication of information on a molecular scale. A binding site at the terminus of an oligomer detects local information about changes in pH or anion concentration and transmits that information-in the form of a directionality switch in the hydrogen-bond chain-to a remote polarity-sensitive fluorophore. This propagation of polarity-encoded information provides a new mechanism for molecular communication.

Benzoazepine-Fused Isoindolines via Intramolecular (3 + 2)-Cycloadditions of Azomethine Ylides with Dinitroarenes.

Aminobenzaldehydes bearing a pendant 3,5-dinitrophenyl group react thermally with N-substituted α-amino acids to form unprecedented benzoazepine-fused isoindolines. The reaction proceeds via a dearomatization/rearomatization sequence involving an intramolecular (3 + 2)-cycloaddition between the in situ formed azomethine ylide and the dinitroarene. Various glycine derivatives are tolerated as well as branched substrates based on cyclic, α-mono-, and α,α-disubstituted amino acids, giving single diastereomers in many cases. The method is scalable and gives products with a nitro group ready for further manipulation.

Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles: synthesis, antibacterial evaluation and preliminary mechanism of action studies.

Synthetic small molecular antimicrobial peptidomimetics represent a promising new class of potential antibiotics due to their membrane-disrupting ability and their decreased propensity for bacterial resistance. A library of 43 mono- and di-cationic biaryl 1,2,3-triazolyl peptidomimetics was designed and synthesized based upon previously established lead biarylpeptidomimetics and a known pharmacophore. A reliable, facile and modular synthetic pathway allowed for the efficient synthesis of multiple unique scaffolds which were subjected to divergent derivatization to furnish the amphiphilic compounds. In vitro testing revealed enhanced antibacterial efficacy against a range of pathogenic bacteria, including bacterial isolates with methicillin, vancomycin, daptomycin, or multi-drug resistance. Preliminary time-kill kinetics and membrane-disruption assays revealed a likely membrane-active mechanism for the tested peptidomimetics. An optimal balance between hydrophobicity and cationic charge was found to be essential for reduced cytotoxicity/haemolysis (i.e. membrane selectivity) and enhanced Gram-negative activity. The cationic biaryl amphiphile 81 was identified as a potent, broad-spectrum peptidomimetic with activity against Gram-positive (methicillin-resistant Staphylococcus aureus - MIC = 2 µg/mL) and Gram-negative (Escherichia coli - MIC = 4 µg/mL) pathogenic bacteria.

Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles targeting Clostridioides (Clostridium) difficile: Synthesis, antibacterial evaluation and an in vivo C. difficile infection model.

Clostridioides (formerly Clostridium) difficile is a Gram-positive anaerobic bacterial pathogen that causes severe gastrointestinal infection in humans. The current chemotherapeutic options are vastly inadequate, expensive and limited; this results in an exorbitant medical and financial burden. New, inexpensive chemotherapeutic treatments for C. difficile infection with improved efficacy are urgently needed. A streamlined synthetic pathway was developed to allow access to 38 novel mono- and di-cationic biaryl 1,2,3-triazolyl peptidomimetics with increased synthetic efficiency, aqueous solubility and enhanced antibacterial efficacy. The monocationic arginine derivative 28 was identified as a potent, Gram-positive selective antibacterial with MIC values of 4 µg/mL against methicillin-resistant Staphylococcus aureus and 8 µg/mL against C. difficile. Furthermore, the dicationic bis-triazole analogue 50 was found to exhibit broad-spectrum activity with substantial Gram-negative efficacy against Acinetobacter baumannii (8 µg/mL), Pseudomonas aeruginosa (8 µg/mL) and Klebsiella pneumoniae (16 µg/mL); additionally, compound 50 displayed reduced haemolytic activity (<13%) in an in vitro haemolysis assay. Membrane-disruption assays were conducted on selected derivatives to confirm the membrane-active mechanism of action inherent to the synthesized amphiphilic compounds. A comparative solubility assay was developed and utilized to optimize the aqueous solubility of the compounds for in vivo studies. The biaryl peptidomimetics 28 and 67 were found to exhibit significant efficacy in an in vivo murine model of C. difficile infection by reducing the severity and slowing the onset of disease.

Ring-opening and -expansion of 2,2'-biaziridine: access to diverse enantiopure linear and bicyclic vicinal diamines.

The chiral pool-derived 1,1'-ditosyl-2,2'-biaziridine has been established as a valuable building block for the divergent synthesis of enantiopure vicinal diamines. Efficient procedures for the regioselective ring opening of the biaziridine with oxygen, sulfur, nitrogen, and carbon nucleophiles are described. The strategic use of nucleophiles bearing pendant functionality allows further elaboration of the acyclic products to a variety of 2,2'-bicyclic-embedded diamines. Desymmetrization of the biaziridine has also been accomplished via the selective monoaddition of organocuprates.

Asymmetric synthesis of indole homo-Michael adducts via dynamic kinetic Friedel-Crafts alkylation with cyclopropanes.

An enantioconvergent Friedel-Crafts alkylation of indoles with donor-acceptor cyclopropanes is described. The reaction is catalyzed by pybox•MgI2 and proceeds via a type I dynamic kinetic asymmetric transformation (DyKAT).

The first syntheses of enantiopure 2,2'-biindoline.

The first two syntheses of chiral 2,2'-biindoline are reported either in five steps from 2,2'-bioxirane, or three steps from 2,2'-biaziridine, both with exceptional enantiopurity.