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.

Fe/Thiol Cooperative Hydrogen Atom Transfer Olefin Hydrogenation: Mechanistic Insights That Inform Enantioselective Catalysis.

Asymmetric hydrogenation of activated olefins using transition metal catalysis is a powerful tool for the synthesis of complex molecules, but traditional metal catalysts have difficulty with enantioselective reduction of electron-neutral, electron-rich, and minimally functionalized olefins. Hydrogenation based on radical, metal-catalyzed hydrogen atom transfer (mHAT) mechanisms offers an outstanding opportunity to overcome these difficulties, enabling the mild reduction of these challenging olefins with selectivity that is complementary to traditional hydrogenations with H2. Further, mHAT presents an opportunity for asymmetric induction through cooperative hydrogen atom transfer (cHAT) using chiral thiols. Here, we report insights from a mechanistic study of an iron-catalyzed achiral cHAT reaction and leverage these insights to deliver stereocontrol from chiral thiols. Kinetic analysis and variation of silane structure point to the transfer of hydride from silane to iron as the likely rate-limiting step. The data indicate that the selectivity-determining step is quenching of the alkyl radical by thiol, which becomes a more potent H atom donor when coordinated to iron(II). The resulting iron(III)-thiolate complex is in equilibrium with other iron species, including FeII(acac)2, which is shown to be the predominant off-cycle species. The enantiodetermining nature of the thiol trapping step enables enantioselective net hydrogenation of olefins through cHAT using a commercially available glucose-derived thiol catalyst with up to 80:20 enantiomeric ratio. To the best of our knowledge, this is the first demonstration of asymmetric hydrogenation via iron-catalyzed mHAT. These findings advance our understanding of cooperative radical catalysis and act as a proof of principle for the development of enantioselective iron-catalyzed mHAT reactions.

Scaffold-Oriented Asymmetric Catalysis: Conformational Modulation of Transition State Multivalency during a Catalyst-Controlled Assembly of a Pharmaceutically Relevant Atropisomer.

A new class of superbasic, bifunctional peptidyl guanidine catalysts is presented, which enables the organocatalytic, atroposelective synthesis of axially chiral quinazolinediones. Computational modeling unveiled the conformational modulation of the catalyst by a novel phenyl urea N-cap, that preorganizes the structure into the active, folded state. A previously unanticipated noncovalent interaction involving a difluoroacetamide acting as a hybrid mono- or bidentate hydrogen bond donor emerged as a decisive control element inducing atroposelectivity. These discoveries spurred from a scaffold-oriented project inspired from a fascinating investigational BTK inhibitor featuring two stable chiral axes and relies on a mechanistic framework that was foreign to the extant lexicon of asymmetric catalysis.

Chirality-matched catalyst-controlled macrocyclization reactions.

Macrocycles, formally defined as compounds that contain a ring with 12 or more atoms, continue to attract great interest due to their important applications in physical, pharmacological, and environmental sciences. In syntheses of macrocyclic compounds, promoting intramolecular over intermolecular reactions in the ring-closing step is often a key challenge. Furthermore, syntheses of macrocycles with stereogenic elements confer an additional challenge, while access to such macrocycles are of great interest. Herein, we report the remarkable effect peptide-based catalysts can have in promoting efficient macrocyclization reactions. We show that the chirality of the catalyst is essential for promoting favorable, matched transition-state relationships that favor macrocyclization of substrates with preexisting stereogenic elements; curiously, the chirality of the catalyst is essential for successful reactions, even though no new static (i.e., not "dynamic") stereogenic elements are created. Control experiments involving either achiral variants of the catalyst or the enantiomeric form of the catalyst fail to deliver the macrocycles in significant quantity in head-to-head comparisons. The generality of the phenomenon, demonstrated here with a number of substrates, stimulates analogies to enzymatic catalysts that produce naturally occurring macrocycles, presumably through related, catalyst-defined peripheral interactions with their acyclic substrates.

Aspartyl ß-Turn-Based Dirhodium(II) Metallopeptides for Benzylic C(sp3)-H Amination: Enantioselectivity and X-ray Structural Analysis.

Amination of C(sp3)-H bonds is a powerful tool to introduce nitrogen into complex organic frameworks in a direct manner. Despite significant advances in catalyst design, full site- and enantiocontrol in complex molecular regimes remain elusive using established catalyst systems. To address these challenges, we herein describe a new class of peptide-based dirhodium(II) complexes derived from aspartic acid-containing ß-turn-forming tetramers. This highly modular system can serve as a platform for the rapid generation of new chiral dirhodium(II) catalyst libraries, as illustrated by the facile synthesis of a series of 38 catalysts. Critically, we present the first crystal structure of a dirhodium(II) tetra-aspartate complex, which unveils retention of the ß-turn conformation of the peptidyl ligand; a well-defined hydrogen-bonding network is evident, along with a near-C4 symmetry that renders the rhodium centers inequivalent. The utility of this catalyst platform is illustrated by the enantioselective amination of benzylic C(sp3)-H bonds, in which state-of-the-art levels of enantioselectivity up to 95.5:4.5 er are obtained, even for substrates that present challenges with previously reported catalyst systems. Additionally, we found these complexes to be competent catalysts for the intermolecular amination of N-alkylamides via insertion into the C(sp3)-H bond α to the amide nitrogen, yielding differentially protected 1,1-diamines. Of note, this type of insertion was also observed to occur on the amide functionalities of the catalyst itself in the absence of the substrate but did not appear to be detrimental to reaction outcomes when the substrate was present.

An Asymmetric Aromatic Finkelstein Reaction: A Platform for Remote Diarylmethane Desymmetrization.

A first-of-its-kind enantioselective aromatic Finkelstein reaction is disclosed for the remote desymmetrization of diarylmethanes. The reaction operates through a copper-catalyzed C-I bond-forming event, and high levels of enantioselectivity are achieved through the deployment of a tailored guanidinylated peptide ligand. Strategic use of transition-metal-mediated reactions enables the chemoselective modification of the aryl iodide products; thus, the synthesis of a diverse set of otherwise difficult-to-access diarylmethanes with excellent levels of selectivity is realized from a common intermediate. A mixed experimental/computational analysis of steric parameters and substrate conformations identifies the importance of remote conformational effects as a key to achieving high enantioselectivity in this desymmetrization reaction.

Catalytic Asymmetric Hydrogen Atom Transfer: Enantioselective Hydroamination of Alkenes.

We report a highly enantioselective radical-based hydroamination of enol esters with sulfonamides jointly catalyzed by an Ir photocatalyst, Brønsted base, and tetrapeptide thiol. This method is demonstrated for the formation of 23 protected ß-amino-alcohol products, achieving selectivities up to 97:3 er. The stereochemistry of the product is set through selective hydrogen atom transfer from the chiral thiol catalyst to a prochiral C-centered radical. Structure-selectivity relationships derived from structural variation of both the peptide catalyst and olefin substrate provide key insights into the development of an optimal catalyst. Experimental and computational mechanistic studies indicate that hydrogen-bonding, π-π stacking, and London dispersion interactions are contributing factors for substrate recognition and enantioinduction. These findings further the development of radical-based asymmetric catalysis and contribute to the understanding of the noncovalent interactions relevant to such transformations.

Data Science-Enabled Palladium-Catalyzed Enantioselective Aryl-Carbonylation of Sulfonimidamides.

New methods for the general asymmetric synthesis of sulfonimidamides are of great interest due to their applications in medicinal chemistry, agrochemical discovery, and academic research. We report a palladium-catalyzed cross-coupling method for the enantioselective aryl-carbonylation of sulfonimidamides. Using data science techniques, a virtual library of calculated bisphosphine ligand descriptors was used to guide reaction optimization by effectively sampling the catalyst chemical space. The optimized conditions identified using this approach provided the desired product in excellent yield and enantioselectivity. As the next step, a data science-driven strategy was also used to explore a diverse set of aryl and heteroaryl iodides, providing key information about the scope and limitations of the method. Furthermore, we tested a range of racemic sulfonimidamides for compatibility of this coupling partner. The developed method offers a general and efficient strategy for accessing enantioenriched sulfonimidamides, which should facilitate their application in industrial and academic settings.

On the Ability of the N-O Bond to Support a Stable Stereogenic Axis: Peptide-Catalyzed Atroposelective N-Oxidation.

During studies of atroposelective, peptide-catalyzed N-oxidations of pyridines, we observed lower-than-expected barriers to atropisomerization for these stereodynamic processes under the reaction conditions. Mechanistic studies indicate a hydrogen bond-assisted racemization mechanism intrinsic to both the starting materials and products. We also identified a protonation-dependent barrier to rotation that operates for the starting materials alone. Nonetheless, several substrates were amenable to atroposelective N-oxidations via kinetic resolution, yielding krel values of up to 12.6 and the isolation of one N-oxide with >99:1 er after recrystallization.

Catalytic Asymmetric Synthesis of Atropisomeric N-Aryl 1,2,4-Triazoles.

The atroposelective synthesis of N-aryl 1,2,4-triazoles was developed. A cyclodehydration reaction was rendered asymmetric with the use of a chiral phosphoric acid catalyst to afford atropisomeric N-aryl 1,2,4-triazoles in up to 91:9 er. Recrystallization of the isolated heterocycle further enriched the atropisomeric ratio of several analogs to 99:1 er or greater. A divergent and substrate-dependent reaction pathway yielding a different heterocyclic product is also disclosed.

Asymmetric Photochemical [2 + 2]-Cycloaddition of Acyclic Vinylpyridines through Ternary Complex Formation and an Uncontrolled Sensitization Mechanism.

Stereochemical control of photochemical reactions that occur via triplet energy transfer remains a challenge. Suppressing off-catalyst stereorandom reactivity is difficult for highly reactive open-shell intermediates. Strategies for suppressing racemate-producing, off-catalyst pathways have long focused on formation of ground state, substrate-catalyst chiral complexes that are primed for triplet energy transfer via a photocatalyst in contrast to their off-catalyst counterparts. Herein, we describe a strategy where both a chiral catalyst-associated vinylpyridine and a nonassociated, free vinylpyridine substrate can be sensitized by an Ir(III) photocatalyst, yet high levels of diastereo- and enantioselectivity in a [2 + 2] photocycloaddition are achieved through a preferred, highly organized transition state. This mechanistic paradigm is distinct from, yet complementary to current approaches for achieving high levels of stereocontrol in photochemical transformations.

Chemoselective Acylation of Nucleosides.

Acylated nucleoside analogues play an important role in medicinal chemistry and are extremely useful precursors to various other nucleoside analogues. However, chemoselective acylation of nucleosides usually requires several protection and deprotection steps due to the competing nucleophilicity of hydroxy and amino groups. In contrast, direct protecting-group-free chemoselective acylation of nucleosides is a preferred strategy due to lower cost and fewer overall synthetic steps. Herein, a simple and efficient chemoselective acylation of nucleosides and nucleotides under mild reaction conditions, giving either O- or N-acylated products respectively with excellent chemoselectivity is reported.

Photocatalytic Reductive Olefin Hydrodifluoroalkylation Enabled by Tertiary Amine Reductants Compatible with Complex Systems.

Noncanonical amino acids (NCAAs) are imperative to many facets of chemistry and biology. Herein, we report a method for the reductive hydrodifluoroalkylation of olefins that utilizes triethylamine base as the terminal reductant. The alkene acceptors include a range of electronically diverse alkenes, chief among them, dehydroalanine in variously protected forms, which provides access to synthetically relevant NCAA scaffolds under mild and general reaction conditions. We have demonstrated that a chiral auxiliary may be incorporated to provide diastereocontrol for pro-stereogenic substrates. Mechanistically motivated experiments provide some insight into the reaction mechanism, which supports a terminal step involving proton transfer for electron-poor olefins, while H atom transfer assisted by a thiol cocatalyst may complete the catalytic cycle for electron-rich olefins. The protocol is found to be compatible with additions to complex molecules, including the natural product thiostrepton.

Asymmetric Catalysis Mediated by Synthetic Peptides, Version 2.0: Expansion of Scope and Mechanisms.

Low molecular weight synthetic peptides have been demonstrated to be effective catalysts for an increasingly wide array of asymmetric transformations. In many cases, these peptide-based catalysts have enabled novel multifunctional substrate activation modes and unprecedented selectivity manifolds. These features, along with their ease of preparation, modular and tunable structures, and often biomimetic attributes make peptides well-suited as chiral catalysts and of broad interest. Many examples of peptide-catalyzed asymmetric reactions have appeared in the literature since the last survey of this broad field in Chemical Reviews (Chem. Rev. 2007, 107, 5759-5812). The overarching goal of this new Review is to provide a comprehensive account of the numerous advances in the field. As a corollary to this goal, we survey the many different types of catalytic reactions, ranging from acylation to C-C bond formation, in which peptides have been successfully employed. In so doing, we devote significant discussion to the structural and mechanistic aspects of these reactions that are perhaps specific to peptide-based catalysts and their interactions with substrates and/or reagents.

Catalytic Enantioselective Synthesis of Pyridyl Sulfoximines.

With unique chemical and biological activity, sulfoximines have attracted enormous attention in the past decades, whereas limited reports exist for their synthesis via asymmetric catalysis. We report the synthesis of chiral sulfoximines through the desymmetrizing N-oxidation of pyridyl sulfoximines using an aspartic acid-containing peptide catalyst. Various mono- and bis-pyridyl sulfoximine oxides are obtained with up to 99:1 er. The directing group introduced on the substrate highly enhances the enantioinduction and could be easily removed to give the free N-H sulfoximines. Additionally, peptides with methyl ester and the methyl amide C-terminal protecting group give the opposite enantiomers of the product. A binding model is proposed to explain this phenomenon.

Kinetic Analysis of a Cysteine-Derived Thiyl-Catalyzed Asymmetric Vinylcyclopropane Cycloaddition Reflects Numerous Attractive Noncovalent Interactions.

Kinetic studies of a vinylcyclopropane (VCP) cycloaddition, catalyzed by peptide-based thiyl radicals, are described. Reactions were analyzed by using reaction progress kinetic analysis, revealing that ring-opening of the VCP is both rate- and enantio-determining. These conclusions are further corroborated by studies involving racemic and enantiopure VCP starting material. Noncovalent interactions play key roles throughout: both the peptide catalyst and VCP exhibit unproductive self-aggregation, which appears to be disrupted by binding between the catalyst and VCP. This in turn explains the requirement for the key catalyst feature, a substituent at the 4-position of the proline residue, which is required for both turnover/rate and selectivity.

Tunable and Cooperative Catalysis for Enantioselective Pictet-Spengler Reaction with Varied Nitrogen-Containing Heterocyclic Carboxaldehydes.

Herein we report an organocatalytic enantioselective functionalization of heterocyclic carboxaldehydes via the Pictet-Spengler reaction. Through careful pairing of novel squaramide and Brønsted acid catalysts, our method tolerates a breadth of heterocycles, enabling preparation of a series of heterocycle conjugated ß-(tetrahydro)carbolines in good yield and enantioselectivity. Careful selection of carboxylic acid co-catalyst is essential for toleration of a variety of regioisomeric heterocycles. Utility is demonstrated via the three-step stereoselective preparation of pyridine-containing analogues of potent selective estrogen receptor downregulator and U.S. FDA approved drug Tadalafil.

Catalytic Dynamic Kinetic Resolutions in Tandem to Construct Two-Axis Terphenyl Atropisomers.

The defined structure of molecules bearing multiple stereogenic axes is of increasing relevance to materials science, pharmaceuticals, and catalysis. However, catalytic enantioselective approaches to control multiple stereogenic axes remain synthetically challenging. We report the catalytic synthesis of two-axis terphenyl atropisomers, with complementary strategies to both chlorinated and brominated variants, formed with high diastereo- and enantioselectivity. The chemistry proceeds through a sequence of two distinct dynamic kinetic resolutions: first, an atroposelective ring opening of Bringmann-type lactones produces a product with one established axis of chirality, and second, a stereoselective arene halogenation delivers the product with the second axis of chirality established. In order to achieve these results, a class of Brønsted basic guanidinylated peptides, which catalyze an efficient atroposelective chlorination, is reported for the first time. In addition, a complementary bromination is reported, which also establishes the second stereogenic axis. These bromo-terphenyls are accessible following the discovery that chiral anion phase transfer catalysis by C2-symmetric phosphoric acids allows catalyst control in the second stereochemistry-determining event. Accordingly, we established the fully catalyst-controlled stereodivergent synthesis of all possible chlorinated stereoisomers while also demonstrating diastereodivergence in the brominated variants, with significant levels of enantioselectivity in all cases.

Asymmetric Catalysis upon Helically Chiral Loratadine Analogues Unveils Enantiomer-Dependent Antihistamine Activity.

Analogues of the conformationally dynamic Claritin (loratadine) and Clarinex (desloratadine) scaffolds have been enantio- and chemoselectively N-oxidized using an aspartic acid containing peptide catalyst to afford stable, helically chiral products in up to >99:1 er. The conformational dynamics and enantiomeric stability of the N-oxide products have been investigated experimentally and computationally with the aid of crystallographic data. Furthermore, biological assays show that rigidifying the core structure of loratadine and related analogues through N-oxidation affects antihistamine activity in an enantiomer-dependent fashion. Computational docking studies illustrate the observed activity differences.

Peptide-Based Catalysts Reach the Outer Sphere through Remote Desymmetrization and Atroposelectivity.

Nature's catalytic machinery has provided endless inspiration for chemists. While the enzymatic ideal has yet to be fully realized, the field has made tremendous strides toward synthetic, small-molecule catalysts for a wide array of transformations, often drawing upon biological concepts in their design. One strategy that has been particularly influenced by enzymology is peptide catalysis, wherein oligopeptides are implemented as chiral catalysts in synthetically relevant reactions. The fundamental goal has been to mimic enzymatic active sites by taking advantage of secondary structures that allow for multifunctional activation of substrates within a framework of significantly reduced molecular complexity. Our group has now been studying peptide-based catalysis for over two decades. At the outset, there were many reasons to be concerned that general contributions might not be possible. Precedents existed, including the Juliá-Colonna epoxidations mediated by helical oligopeptides, among others. However, we sought to explore whether peptide catalysts could find broad applications in organic synthesis despite what was expected to be their principal liability: conformational flexibility. Over time, we have been able to identify peptidic catalysts for a variety of site- and enantioselective transformations ranging from hydroxyl group and arene functionalizations to redox and C-C bond forming reactions. The peptides often exhibited excellent catalytic activities, in many cases enabling never-before-seen patterns of selectivity. Recent studies even suggest that, in certain situations, the conformational flexibility of these catalysts may be advantageous for asymmetric induction. In the course of our studies, opportunities to employ peptide-based catalysis to solve long-standing and stereochemically intriguing problems in asymmetric synthesis presented themselves. For example, we have found that peptides provide exceptional enantiotopic group differentiation in catalytic desymmetrization reactions. Early results with symmetrical polyol substrates, such as myo-inositols and glycerols, eventually spurred the development of remote desymmetrizations of diarylmethanes, in which the enantiotopic groups are separated from the prochiral center by ∼6 Å and from one another by nearly 1 nm. Various hydroxyl group functionalizations and electrophilic brominations, as well as C-C, C-O, and C-N cross-coupling reactions using peptidic ligands on copper(I) have now been developed within this reaction archetype. Additionally, the preponderance of axially chiral, atropisomeric compounds as ligands, organocatalysts, and pharmacophores encouraged us to employ peptides as atroposelective catalysts. We have developed peptide-catalyzed brominations of pharmaceutically relevant biaryl, non-biaryl, and hetero-biaryl atropisomers that take advantage of dynamic kinetic resolution schemes. These projects have vastly expanded the reach of our original hypotheses and raised new questions about peptide-based catalysts and the extent to which they might mimic enzymes. Herein, we recount the development and optimization of these stereochemically complex reactions, with a particular focus on structural and mechanistic aspects of the peptide-based catalysts that make them well-suited for their respective functions. The ability of these peptides to address important yet fundamentally challenging issues in asymmetric catalysis, combined with their modularity and ease-of-synthesis, make them primed for future use in organic synthesis.