Bioconjugation technologies have revolutionized the practice of biology and medicine by allowing access to novel biomolecular scaffolds. New methods for residue-selective bioconjugation are highly ...sought to expand the toolbox for a variety of bioconjugation applications. Herein we report a site-selective methionine bioconjugation protocol that uses photoexcited lumiflavin to generate open-shell intermediates. This reduction-potential-gated strategy enables access to residues unavailable with traditional nucleophilicity-based conjugation methods. To demonstrate the versatility and robustness of this new protocol, we have modified various proteins and further utilized this functional handle to append diverse biological payloads.
A concise and highly enantioselective total synthesis of the akuammiline alkaloid (-)-vincorine has been accomplished. A key element of the synthesis is a stereoselective organocatalytic Diels-Alder, ...iminium cyclization cascade sequence, which serves to construct the tetracyclic alkaloid core architecture in one step from simple achiral precursors. The challenging seven-membered azepanyl ring system is installed by way of a single electron-mediated cyclization event initiated from an acyl telluride precursor. The total synthesis of (-)-vincorine is achieved in nine steps and 9% overall yield from commercially available starting materials.
The direct decarboxylative arylation of α‐oxo acids has been achieved by synergistic visible‐light‐mediated photoredox and nickel catalysis. This method offers rapid entry to aryl and alkyl ketone ...architectures from simple α‐oxo acid precursors via an acyl radical intermediate. Significant substrate scope is observed with respect to both the oxo acid and arene coupling partners. This mild decarboxylative arylation can also be utilized to efficiently access medicinal agents, as demonstrated by the rapid synthesis of fenofibrate.
The direct decarboxylative arylation of α‐oxo acids has been achieved by synergistic visible‐light‐mediated photoredox and nickel catalysis. This method offers rapid entry to aryl and alkyl ketone architectures from simple α‐oxo acid precursors via an acyl radical intermediate. Significant substrate scope is observed with respect to both the oxo acid and arene coupling partners.
Herein, we report a convenient and broadly applicable strategy for the difluoromethylation of aryl bromides by metallaphotoredox catalysis. Bromodifluoromethane, a simple and commercially available ...alkyl halide, is harnessed as an effective source of difluoromethyl radical by silyl‐radical‐mediated halogen ion. The merger of this fluoroalkyl electrophile activation pathway with a dual nickel/photoredox catalytic platform enables the difluoromethylation of a diverse array of aryl and heteroaryl bromides under mild conditions. The utility of this procedure is showcased in the late‐stage functionalization of several drug analogues.
Bromodifluoromethane, a commercial alkyl halide, was harnessed as an effective source of difluoromethyl radical by silyl‐radical‐mediated halogen ion. The merger of this fluoroalkyl electrophile activation pathway with a dual nickel/photoredox catalytic platform enables the difluoromethylation of a diverse array of (hetero)aryl bromides under mild conditions.
Multicomponent reactions are relied on in both academic and industrial synthetic organic chemistry owing to their step- and atom-economy advantages over traditional synthetic sequences
. Recently, ...bicyclo1.1.1pentane (BCP) motifs have become valuable as pharmaceutical bioisosteres of benzene rings, and in particular 1,3-disubstituted BCP moieties have become widely adopted in medicinal chemistry as para-phenyl ring replacements
. These structures are often generated from 1.1.1propellane via opening of the internal C-C bond through the addition of either radicals or metal-based nucleophiles
. The resulting propellane-addition adducts are then transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. Although this approach has been effective so far, a multicomponent reaction that enables single-step access to complex and diverse polysubstituted drug-like BCP products would be more time efficient compared to current stepwise approaches. Here we report a one-step three-component radical coupling of 1.1.1propellane to afford diverse functionalized bicyclopentanes using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. This copper-mediated reaction operates on short timescales (five minutes to one hour) across multiple (more than ten) nucleophile classes and can accommodate a diverse array of radical precursors, including those that generate alkyl, α-acyl, trifluoromethyl and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which is substantially more metabolically stable than its commercial progenitor.
Herein we report a highly efficient method for nickel‐catalyzed C−N bond formation between sulfonamides and aryl electrophiles. This technology provides generic access to a broad range of N‐aryl and ...N‐heteroaryl sulfonamide motifs, which are widely represented in drug discovery. Initial mechanistic studies suggest an energy‐transfer mechanism wherein C−N bond reductive elimination occurs from a triplet excited NiII complex. Late‐stage sulfonamidation in the synthesis of a pharmacologically relevant structure is also demonstrated.
A method for C−N bond formation between sulfonamides and aryl electrophiles is reported. This method provides generic access to a broad range of N‐aryl and N‐heteroaryl sulfonamide motifs, which are widely represented in drug discovery. Initial mechanistic studies suggest an energy‐transfer mechanism wherein C−N bond reductive elimination occurs from a triplet excited NiII complex.
Serendipity has long been a welcome yet elusive phenomenon in the advancement of chemistry. We sought to exploit serendipity as a means of rapidly identifying unanticipated chemical transformations. ...By using a high-throughput, automated workflow and evaluating a large number of random reactions, we have discovered a photoredox-catalyzed C-H arylation reaction for the construction of benzylic amines, an important structural motif within pharmaceutical compounds that is not readily accessed via simple substrates. The mechanism directly couples tertiary amines with cyanoaromatics by using mild and operationally trivial conditions.
The use of small organic molecules as catalysts has been known for more than a century. But only in the past decade has organocatalysis become a thriving area of general concepts and widely ...applicable asymmetric reactions. Here I present my opinion on why the field of organocatalysis has blossomed so dramatically over the past decade.
Decarboxylative Hydroalkylation of Alkynes Till, Nicholas A; Smith, Russell T; MacMillan, David W C
Journal of the American Chemical Society,
05/2018, Letnik:
140, Številka:
17
Journal Article
Recenzirano
Odprti dostop
The merger of open- and closed-shell elementary organometallic steps has enabled the selective intermolecular addition of nucleophilic radicals to unactivated alkynes. A range of carboxylic acids can ...be subjected to a CO
extrusion, nickel capture, migratory insertion sequence with terminal and internal alkynes to generate stereodefined functionalized olefins. This platform has been further extended, via hydrogen atom transfer, to the direct vinylation of unactivated C-H bonds. Preliminary studies indicate that a Ni-alkyl migratory insertion is operative.
Direct β-alkylation of saturated aldehydes has been accomplished by synergistically combining photoredox catalysis and organocatalysis. Photon-induced enamine oxidation provides an activated ...β-enaminyl radical intermediate, which readily combines with a wide range of Michael acceptors to produce β-alkyl aldehydes in a highly efficient manner. Furthermore, this redox-neutral, atom-economical C–H functionalization protocol can be achieved both inter- and intramolecularly. Mechanistic studies by various spectroscopic methods suggest that a reductive quenching pathway is operable.
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