Iridium-Catalyzed Asymmetric Synthesis of Functionally Rich Molecules Enabled by (Phosphoramidite,Olefin) Ligands.

The catalytic, asymmetric synthesis of complex molecules has been a core focus of our research program for some time because developments in the area can have an immediate impact on the identification of novel strategies for the synthesis of value-added molecules. In concert with this central interest, we have emphasized the design of ligand scaffolds as a tactic to discover and develop novel chemistry and overcome well-recognized synthetic challenges. Based on our group's work on chiral pool-derived diolefin ligands, we designed and implemented a class of hybrid (phosphoramidite,olefin) ligands, which combines the properties of both phosphoramidite and olefin motifs to impact, fine-tune, and even override the inherent reactivity of the metal center. Specifically, we have utilized these unique modifying ligands to address several recognized limitations in the field of iridium-catalyzed, asymmetric allylic substitution. The methods we have documented typically employ branched, unprotected allylic alcohols as substrates and obviate the need for rigorous exclusion of air and moisture. Following Takeuchi's seminal report demonstrating the high aptitude of Ir(I)-phosphite catalysts for  branch-selective allylic substitution, concerted efforts from numerous research laboratories have led to a broadening of the synthetic utility of this reaction class. The first section of this Account outlines the process leading to our discovery of an unprecedented (phosphoramidite,olefin) ligand and its validation in the first iridium-catalyzed amination of branched, unprotected allylic alcohols. This section continues with our work involving heteroatom-based nucleophiles within inter- and intramolecular etherification, thioetherification and spiroketalization processes. The second section highlights the use of readily available carbon nucleophiles possessing sp, sp2, and sp3 hybridization in a series of enantioselective carbon-carbon bond-forming reactions. We describe how alkylzinc, allylsilane, and several classes of organotrifluoroborate nucleophiles can be coupled enantioselectively to enable construction of several key motifs including 1,5-dienes, 1,4-dienes, and 1,4-enynes. Since the unique electronic and steric properties of this class of ligands renders the (η3-allyl)-Ir(III) intermediate highly electrophilic, even weak nucleophiles such as alkyl olefins can be used. We also show that more nucleophilic alkene motifs such as enamines and in situ generated ketene acetals smoothly participate in substitution reactions with allylic alcohols to yield valuable piperidines and γ,δ-unsaturated esters, respectively. The concept of stereodivergent dual catalysis, which synergistically combines chiral amine catalysis with iridium catalysis to furnish α-allylated aldehydes containing two independently controllable stereocenters is then discussed. This process has enabled the independent, stereoselective synthesis of all four possible product stereoisomers from a single set of starting materials, and was highlighted in the stereodivergent synthesis of Δ9-tetrahydrocannabinol. This Account concludes with an overview of our organometallic mechanistic studies regarding relevant intermediates within the catalytic cycle of this class of allylic substitution. These studies have allowed us to better understand the origin of the unique characteristics exhibited by this catalyst in comparison to related systems.

Pyridinium Salts as Redox-Active Functional Group Transfer Reagents.

In this Review, we highlight recent advances in the understanding and design of N-functionalized pyridinium scaffolds as redox-active, single-electron, functional group transfer reagents. We provide a selection of representative methods that demonstrate reactivity and fundamental advances in this emerging field. The reactivity of these reagents can be divided into two divergent pathways: homolytic fragmentation to liberate the N-bound substituent as the corresponding radical or an alternative heterolytic fragmentation that liberates an N-centered pyridinium radical. A short description of the elementary steps involved in fragmentation induced by single-electron transfer is also critically discussed to guide readers towards fundamental processes thought to occur under these conditions.

Morpholine Ketene Aminal as Amide Enolate Surrogate in Iridium-Catalyzed Asymmetric Allylic Alkylation.

Morpholine ketene aminal is employed in iridium-catalyzed asymmetric allylic alkylation reactions as a surrogate for amide enolates to prepare γ,δ-unsaturated ß-substituted morpholine amides. Kinetic resolution or, alternatively, stereospecific substitution affords the corresponding products in high enantiomeric excess. The utility of the products generated by this method has been showcased by their further elaboration into amines, ketones, or acyl silanes. A putative catalytic intermediate (η3 -allyl)iridium(III) with achiral P,Olefin-ligand was synthetized and characterized for the first time.

Pyridyl Radical Cation for C-H Amination of Arenes.

Electron-transfer photocatalysis provides access to the elusive and unprecedented N-pyridyl radical cation from selected N-substituted pyridinium reagents. The resulting C(sp2 )-H functionalization of (hetero)arenes furnishes versatile intermediates for the development of valuable aminated aryl scaffolds. Mechanistic studies that include the first spectroscopic evidence of a spin-trapped N-pyridyl radical adduct implicate SET-triggered, pseudo-mesolytic cleavage of the N-X pyridinium reagents mediated by visible light.

Allenylic Carbonates in Enantioselective Iridium-Catalyzed Alkylations.

An enantioconvergent C(sp3)-C(sp3) coupling between racemic allenylic electrophiles and alkylzinc reagents has been developed. An Ir/(phosphoramidite,olefin) catalyst provides access to highly enantioenriched allenylic substitution products (93-99% ee) with complete regiocontrol (>50:1 rr in all cases) over the corresponding 1,3-diene isomers which are obtained predominantly when other metal catalysts are emplyed. The synthetic utility of the products obtained was highlighted in a variety of stereoselective transition metal-catalyzed difunctionalization reactions. Furthermore, a combination of experimental and theoretical studies provide support for a putative reaction mechanism wherein enantiodetermining C-C coupling occurs via nucleophilic attack on a highly planarized aryl butadienylium π-system that is coordinated to the Ir center in an η2-fashion.

Study of Intermediates in Iridium-(Phosphoramidite,Olefin)-Catalyzed Enantioselective Allylic Substitution.

Experimental mechanistic studies of iridium-catalyzed, enantioselective allylic substitution enabled by (phosphoramidite,olefin) ligands are reported. (η2-Allylic alcohol)iridium(I) and (η3-allyl)iridium(III) complexes were synthesized and characterized by NMR spectroscopy as well as X-ray crystallography. The substrate complexes are catalytically and kinetically competent to be intermediates in allylic substitutions of branched, racemic allylic alcohols with various nucleophiles. In addition, we have identified an off-cycle pathway involving reversible binding of molecular oxygen to iridium, which contributes to the air tolerance of the catalyst system.

Enantio- and Diastereoselective Spiroketalization Catalyzed by Chiral Iridium Complex.

Iridium-(P,olefin) complex-catalyzed enantio- and diastereoselective formation of substituted spiroketals from racemic, allylic carbonates is reported, which enables the installation of multiple stereogenic centers in a single operation. The protocol was effective for the preparation of a collection of spiroketals of various ring sizes and substituents, including heteroatoms with high enantio- and diastereoselectivity. Furthermore, cascade reactions that couple this enantio- and diastereoselective transformation to additional reversible processes have been achieved to exert concomitant stereocontrol over additional stereogenic centers.

Electrophile Scanning Reveals Reactivity Hotspots for the Design of Covalent Peptide Binders.

Protein-protein interactions (PPIs) are intriguing targets in drug discovery and development. Peptides are well suited to target PPIs, which typically present with large surface areas lacking distinct features and deep binding pockets. To improve binding interactions with these topologies and advance the development of PPI-focused therapeutics, potential ligands can be equipped with electrophilic groups to enable binding through covalent mechanisms of action. We report a strategy termed electrophile scanning to identify reactivity hotspots in a known peptide ligand and demonstrate its application in a model PPI. Cysteine mutants of a known ligand are used to install protein-reactive modifiers via a palladium oxidative addition complex (Pd-OAC). Reactivity hotspots are revealed by cross-linking reactions with the target protein under physiological conditions. In a model PPI with the 9-mer peptide antigen VL9 and major histocompatibility complex (MHC) class I protein HLA-E, we identify two reactivity hotspots that afford up to 87% conversion to the protein-peptide conjugate within 4 h. The reactions are specific to the target protein in vitro and dependent on the peptide sequence. Moreover, the cross-linked peptide successfully inhibits molecular recognition of HLA-E by CD94-NKG2A possibly due to structural changes enacted at the PPI interface. The results illustrate the potential application of electrophile scanning as a tool for rapid discovery and development of covalent peptide binders.

Abiotic peptides as carriers of information for the encoding of small-molecule library synthesis.

Encoding small-molecule information in DNA has been leveraged to accelerate the discovery of ligands for therapeutic targets such as proteins. However, oligonucleotide-based encoding is hampered by inherent limitations of information stability and density. In this study, we establish abiotic peptides for next-generation information storage and apply them for the encoding of diverse small-molecule synthesis. The chemical stability of the peptide-based tag allows the use of palladium-mediated reactions to efficiently synthesize peptide-encoded libraries (PELs) with broad chemical diversity and high purity. We demonstrate the successful de novo discovery of small-molecule protein ligands from PELs by affinity selection against carbonic anhydrase IX and the oncogenic protein targets BRD4(1) and MDM2. Collectively, this work establishes abiotic peptides as carriers of information for the encoding of small-molecule synthesis, leveraged herein for the discovery of protein ligands.

Enhanced Vaccine Immunogenicity Enabled by Targeted Cytosolic Delivery of Tumor Antigens into Dendritic Cells.

Molecular vaccines comprising antigen peptides and inflammatory cues make up a class of therapeutics that promote immunity against cancer and pathogenic diseases but often exhibit limited efficacy. Here, we engineered an antigen peptide delivery system to enhance vaccine efficacy by targeting dendritic cells and mediating cytosolic delivery. The delivery system consists of the nontoxic anthrax protein, protective antigen (PA), and a single-chain variable fragment (scFv) that recognizes the XCR1 receptor on dendritic cells (DCs). Combining these proteins enabled selective delivery of the N-terminus of lethal factor (LFN) into XCR1-positive cross-presenting DCs. Incorporating immunogenic epitope sequences into LFN showed selective protein translocation in vitro and enhanced the priming of antigen-specific T cells in vivo. Administering DC-targeted constructs with tumor antigens (Trp1/gp100) into mice bearing aggressive B16-F10 melanomas improved mouse outcomes when compared to free antigen, including suppressed tumor growth up to 58% at 16 days post tumor induction (P < 0.0001) and increased survival (P = 0.03). These studies demonstrate that harnessing DC-targeting anthrax proteins for cytosolic antigen delivery significantly enhances the immunogenicity and antitumor efficacy of cancer vaccines.

Total Synthesis and Stereochemical Assignment of (+)-Broussonetine H.

Herein, the first total synthesis and stereochemical assignment of (+)-broussonetine H are reported. The ambiguous stereocenters within different fragments were independently installed through asymmetric methods, namely a diastereo- and enantioselective, iridium-catalyzed spiroketalization and Brown allylation. Finally, convergent merging of the fragments enabled the synthesis of all potential diastereomers, allowing stereochemical assignment of (+)-broussonetine H.

Synthesis, Radiolabeling, and Biological Evaluation of 5-Hydroxy-2-[(18)F]fluoroalkyl-tryptophan Analogues as Potential PET Radiotracers for Tumor Imaging.

Aiming at developing mechanism-based amino acid (18)F-PET tracers for tumor imaging, we synthesized two (18)F-labeled analogues of 5-hydroxy-l-[ß-(11)C]tryptophan ([(11)C]5HTP) whose excellent in vivo performance in neuroendocrine tumors is mainly attributed to its decarboxylation by aromatic amino acid decarboxylase (AADC), an enzyme overexpressed in these malignancies. Reference compounds and precursors were synthesized following multistep synthetic approaches. Radiosynthesis of tracers was accomplished in good radiochemical yields (15-39%), high specific activities (45-95 GBq/µmol), and excellent radiochemical purities. In vitro cell uptake was sodium-independent and was inhibited ≥95% by 2-amino-2-norbornanecarboxylic acid (BCH) and ∼30% by arginine. PET imaging in mice revealed distinctly high tumor/background ratios for both tracers, outperforming the well-established O-(2-[(18)F]fluoroethyl)tyrosine ([(18)F]FET) tracer in a head-to-head comparison. Biological evaluation revealed that the in vivo performance is most probably independent of any interaction with AADC. Nevertheless, the excellent tumor visualization qualifies the new tracers as interesting probes for tumor imaging worthy for further investigation.