A DFT examination of the role of proximal boron functionalities in the S-alkylation of sulfenic acid anions

DFT modelling predicts proximal boron groups can accelerate sulfenate alkylation reactions, depending on boron substituents and boron distance from the reaction site.

Structural Basis for an Unprecedented Enzymatic Alkylation in Cylindrocyclophane Biosynthesis

The cyanobacterial enzyme CylK assembles the cylindrocyclophane natural products by performing two unusual alkylation reactions, forming new carbon-carbon bonds between aromatic rings and secondary alkyl halide substrates. This transformation is unprecedented in biology and the structure and mechanism of CylK are unknown. Here, we report x-ray crystal structures of CylK, revealing a distinctive fusion of a Ca2+ binding domain and a β-propeller fold. We use a mutagenic screening approach to locate CylK’s active site at its domain interface, identifying two residues, Arg105 and Tyr473, that are required for catalysis. Anomalous diffraction datasets collected with bound bromide ions, a product analog, suggest these residues interact with the alkyl halide electrophile. Additional mutagenesis and molecular dynamics simulations implicates Asp440 and Glu374 in activating the nucleophilic aromatic ring. Bioinformatic analysis of CylK homologs from other cyanobacteria establishes that they conserve these key catalytic amino acids but they are likely associated with divergent reactivity and altered secondary metabolism. By gaining a molecular understanding of this unusual biosynthetic transformation, this work fills a gap in our understanding of how alkyl halides are activated and used by enzymes as biosynthetic intermediates, informing enzyme engineering, catalyst design, and natural product discovery.

Asymmetric Rhodium-Catalyzed Allylic Substitution Reactions with Nitrile-Stabilized Carbanions

This Account summarizes our recent work on rhodium-catalyzed allylic alkylation reactions with nitrile-stabilized carbanions. Despite the challenges associated with employing nitrile stabilized nucleophiles in transition-metal-catalyzed reactions, we recently developed both enantiospecific and enantioselective allylic alkylation reactions. Notably, these novel reactions permit the expedient and selective access to an array of acyclic ternary and quaternary stereogenic centers that are present in important biologically active molecules. 1 Introduction 2 Enantiospecific Reactions of Nitrile-Stabilized Anions 3 Enantioselective Reactions of Nitrile-Stabilized Anions 4 Conclusion

Ir-Catalyzed Chemodivergent Allenylic Alkylation of Vinyl Az-ides: Highly Enantioselective Synthesis of α-Allenylic Amides and Ketones

Enantioselective allenylic alkylation reactions of unstabilized enolates have never been reported. We now present a unified fragment-coupling strategy for the first enantioselective synthesis of α-allenylic amides and ketones through allenyl-ic alkylation of vinyl azides. In these chemodivergent reactions, cooperatively catalyzed by Ir(I)/(phosphoramidite,olefin) complex and Sc(OTf)3, vinyl azides act as the surrogate for both amide enolates and ketone enolates. The desiccant (molecular sieves) plays a crucial role in controlling the chemodivergency of this enantioconvergent and regioselective reaction: Under otherwise identical reaction conditions, the presence of the desiccant led to α-allenylic amides while its absence resulted in α-allenylic ketones from the same substrate combinations. Utilizing race-mic allenylic alcohols as the alkylating agent, the overall process represents a dynamic kinetic asymmetric transformation (DyKAT), where both α-allenylic amides and ketones are formed with the same absolute configuration generally with outstanding enantioselectivity. To the best of our knowledge, this is the first example of the use of vinyl azide as the ketone enolate surrogate in an enantioselective transformation.

Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2H-pyrazolo[4,3-c]pyridines

A library of 2,4,6,7-tetrasubstituted-2H-pyrazolo[4,3-c]pyridines was prepared from easily accessible 1-phenyl-3-(2-phenylethynyl)-1H-pyrazole-4-carbaldehyde via an iodine-mediated electrophilic cyclization of intermediate 4-(azidomethyl)-1-phenyl-3-(phenylethynyl)-1H-pyrazoles to 7-iodo-2,6-diphenyl-2H-pyrazolo[4,3-c]pyridines followed by Suzuki cross-couplings with various boronic acids and alkylation reactions. The compounds were evaluated for their antiproliferative activity against K562, MV4-11, and MCF-7 cancer cell lines. The most potent compounds displayed low micromolar GI50 values. 4-(2,6-Diphenyl-2H-pyrazolo[4,3-c]pyridin-7-yl)phenol proved to be the most active, induced poly(ADP-ribose) polymerase 1 (PARP-1) cleavage, activated the initiator enzyme of apoptotic cascade caspase 9, induced a fragmentation of microtubule-associated protein 1-light chain 3 (LC3), and reduced the expression levels of proliferating cell nuclear antigen (PCNA). The obtained results suggest a complex action of 4-(2,6-diphenyl-2H-pyrazolo[4,3-c]pyridin-7-yl)phenol that combines antiproliferative effects with the induction of cell death. Moreover, investigations of the fluorescence properties of the final compounds revealed 7-(4-methoxyphenyl)-2,6-diphenyl-2H-pyrazolo[4,3-c]pyridine as the most potent pH indicator that enables both fluorescence intensity-based and ratiometric pH sensing.

Alkylation Reactions with Alkylsulfonium Salts

Application of alkylsulfonium salts as alkyl transfer reagents in organic synthesis has reemerged over the past years. Numerous heteroatom- and carbon-centered nucleophiles, alkenes, arenes, alkynes, organometallic reagents, and others were readily alkylated by alkylsulfonium salts under mild conditions. The reactions feature convenience, high efficiency, readily accessible and structurally diversified alkylation reagents, good functional group tolerance, and a wide range of substrate types, allowing for facile synthesis of various useful organic molecules from the commercially available building blocks. This review summarizes the alkylation reactions using either isolated or in situ formed alkylsulfonium salts via nucleophilic substitution, transition-metal-catalyzed reactions, and photoredox processes.

Structural Basis for the Friedel-Crafts Alkylation in Cylindrocyclophane Biosynthesis

The Lewis acid-catalyzed Friedel-Crafts alkylation of an aromatic ring with an alkyl halide is extensively used in organic synthesis. However, its biological counterpart was not reported until the elucidation of the cylindrocyclophane biosynthetic pathway in Cylindrospermum licheniforme ATCC 29412 by Balskus and co-workers. CylK is the key enzyme to catalyze the formation of the cylindrocyclophane scaffold through the Friedel-Crafts alkylation reactions with regioselectivity and stereospecificity. Further research demonstrates that CylK can accept other resorcinol rings and secondary alkyl halides as substrates. To date, the crystal structure of CylK has not been disclosed and the catalytic mechanism remains obscure. Herein we report the crystal structures of CylK in its apo form and its complexes with the analogues of its substrate and reaction intermediate. Combining the crystal structures, free energy simulations and the mutagenesis experiments, we proposed a concerted double-activation mechanism, which could explain the regioselectivity and stereospecificity. This work provides a foundation for engineering CylK as a biocatalyst to expand its substrate scope and applications in organic synthesis.