Stereoselective Radical Addition Research Articles

Synthesis of β-Tertiary Amino Acids Analogues via Cobalt-Catalyzed Stereoselective Radical Addition

Synthesis of β-Tertiary Amino Acids Analogues via Cobalt-Catalyzed Stereoselective Radical Addition

Nickel-Catalyzed Radical Mechanisms: Informing Cross-Coupling for Synthesizing Non-Canonical Biomolecules.

Nickel excels at facilitating selective radical chemistry, playing a pivotal role in metalloenzyme catalysis and modern cross-coupling reactions. Radicals, being nonpolar and neutral, exhibit orthogonal reactivity to nucleophilic and basic functional groups commonly present in biomolecules. Harnessing this compatibility, we delve into the application of nickel-catalyzed radical pathways in the synthesis of noncanonical peptides and carbohydrates, critical for chemical biology studies and drug discovery.We previously characterized a sequential reduction mechanism that accounts for chemoselectivity in cross-electrophile coupling reactions. This catalytic cycle begins with nickel(I)-mediated radical generation from alkyl halides, followed by carbon radical capture by nickel(II) complexes, and concludes with reductive elimination. These steps resonate with mechanistic proposals in nickel-catalyzed cross-coupling, photoredox, and electrocatalytic reactions. Herein, we present our insights into each step involving radicals, including initiation, propagation, termination, and the nuances of kinetics, origins of selectivity, and ligand effects.Radical generation from C(sp3) electrophiles via one-electron oxidative addition with low-valent nickel radical intermediates provides the basis for stereoconvergent and cross-electrophile couplings. Our electroanalytical studies elucidate a concerted halogen atom abstraction mechanism, where electron transfer is coupled with halide dissociation. Using this pathway, we have developed a nickel-catalyzed stereoselective radical addition to dehydroalanine, facilitating the synthesis of noncanonical peptides. In this application, chiral ligands modulate the stereochemical outcome through the asymmetric protonation of a nickel-enolate intermediate.The capture of the alkyl radical by nickel(II) expands the scope of cross-coupling, promotes reductive elimination through the formation of high-valent nickel(III) species, and governs chemo- and stereoselectivity. We discovered that nickel(II)-aryl efficiently traps radicals with a barrier ranging from 7 to 9 kcal/mol, followed by fast reductive elimination. In contrast, nickel(II)-alkyl captures radicals to form a nickel(III) species, which was characterized by EPR spectroscopy. However, the subsequent slow reductive elimination resulted in minimal product formation. The observed high diastereoselectivity of radical capture inspired investigations into C-aryl and C-acyl glycosylation reactions. We developed a redox auxiliary that readily couples with natural carbohydrates and produces glycosyl radicals upon photoredox activation. Nickel-catalyzed cross-coupling of the glycosyl radical with bromoarenes and carboxylic acids leads to diverse non-natural glycosides that can facilitate drug discovery.Stoichiometric studies on well-defined d8-nickel complexes have showcased means to promote reductive elimination, including ligand association, oxidation, and oxidative addition.In the final section, we address the influence of auxiliary ligands on the electronic structure and redox activity of organonickel intermediates. Synthesis of a series of low-valent nickel radical complexes and characterization of their electronic structures led us to a postulate that ligand redox activity correlates with coordination geometry. Our data reveal that a change in ligand redox activity can shift the redox potentials of reaction intermediates, potentially altering the mechanism of catalytic reactions. Moreover, coordinating additives and solvents may stabilize nickel radicals during catalysis by adjusting ligand redox activity, which is consistent with known catalytic conditions.

Late‐Stage Modification of Oligopeptides by Nickel‐Catalyzed Stereoselective Radical Addition to Dehydroalanine

AbstractRadical addition to dehydroalanine (Dha) represents an appealing, modular strategy to access non‐canonical peptide analogues for drug discovery. Prior studies on radical addition to the Dha residue of peptides and proteins have demonstrated outstanding functional group compatibility, but the lack of stereoselectivity has limited the synthetic utility of this approach. Herein, we address this challenge by employing chiral nickel catalysts to control the stereoselectivity of radical addition to Dha on oligopeptides. The conditions accommodate a variety of primary and secondary electrophiles to introduce polyethylene glycol, biotin, halo‐tag, and hydrophobic and hydrophilic side chains to the peptide. The reaction features catalyst control to largely override substrate‐based control of stereochemical outcome for modification of short peptides. We anticipate that the discovery of chiral nickel complexes that confer catalyst control will allow rapid, late‐stage modification of peptides featuring nonnatural sidechains.

Late-Stage Modification of Oligopeptides by Nickel-Catalyzed Stereoselective Radical Addition to Dehydroalanine.

Radical addition to dehydroalanine (Dha) represents an appealing, modular strategy to access non-canonical peptide analogues for drug discovery. Prior studies on radical addition to the Dha residue of peptides and proteins have demonstrated outstanding functional group compatibility, but the lack of stereoselectivity has limited the synthetic utility of this approach. Herein, we address this challenge by employing chiral nickel catalysts to control the stereoselectivity of radical addition to Dha on oligopeptides. The conditions accommodate a variety of primary and secondary electrophiles to introduce polyethylene glycol, biotin, halo-tag, and hydrophobic and hydrophilic side chains to the peptide. The reaction features catalyst control to largely override substrate-based control of stereochemical outcome for modification of short peptides. We anticipate that the discovery of chiral nickel complexes that confer catalyst control will allow rapid, late-stage modification of peptides featuring nonnatural sidechains.

Odorless, One-Pot Regio- and Stereoselective Iodothiolation of Alkynes with Sodium Arenesulfinates under Metal-Free Conditions in Water.

A newly developed regio- and stereoselective radical addition of alkyne under metal-free conidtions has been disclosed. This chemistry, in which odorless sodium arenesulfinates in place of thiols are used as the sulfur reagent, provides an efficient, one-pot approach for the generation of β-iodoalkenyl sulfides, which can be easily further functionalized to derive various alkenes and alkynyl sulfides rendering this methodology attractive to both synthetic and medicinal chemistry.

ChemInform Abstract: Radical Additions of Arenethiols to Ynamides for the Selective Synthesis of N‐[(Z)‐2‐(Arylsulfanyl)‐1‐alkenyl]amides.

AbstractArenethiols undergo highly regio‐ and stereoselective radical addition to ynamides to furnish the title arylsulfanyl‐alkenylamides.

ChemInform Abstract: Stereoselective Radical Addition of an Acetal to Sterically Tuned Enantiomerically Pure N‐Sulfinyl Imines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Radical Additions of Arenethiols to Ynamides for the Selective Synthesis of N-[(Z)-2-(Arylsulfanyl)-1-alkenyl]amides

A variety of ynamides undergo highly regio- and stereoselective radical addition of arenethiols with the aid of trie-thylborane as a radical initiator. The products, N-[(Z)-2-arylsulfanyl-1-alkenyl]amides, can be reduced with triethylsilane in trifluoroacetic acid to yield N-[2-(arylsulfanyl)alkyl]amides.

Stereoselective Radical Addition of an Acetal to Sterically Tuned Enantiomerically Pure N-Sulfinyl Imines

Enantiomerically enriched sulfonamides were synthesized by the radical addition of an acetal to enantiomerically pure N-sulfinyl imines using dimethylzinc-air and boron trifluoride diethyl etherate. Higher levels of stereocontrol were observed by using a mesitylenesulfinyl group. Furthermore, an amine and an amino alcohol with high enantiomeric purity were obtainable from the sulfonamide product.

Toward Synthesis of the Isosteric Sulfonate Analogues of the AT-III Binding Domain of Heparin

D-glucuronate and l-iduronate containing disaccharides related to the antithrombin-binding pentasaccharide of heparin, in which one of the sulfate esters is systematically replaced by a sodium sulfonatomethyl moiety, were synthesized. The sulfonic acid group was introduced by stereoselective radical addition onto the exomethylene moiety of the appropriate glycoside derivatives, and the resulting sulfonatomethyl glucosides were used as acceptors.

ChemInform Abstract: Thieme Chemistry Journal Awardees — Where Are They Now? Regio‐ and Stereoselective Radical Additions of Thiols to Ynamides

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Thieme Chemistry Journal Awardees - Where are They Now? Regio- and Stereoselective Radical Additions of Thiols to Ynamides

Regioselective and stereoselective radical additions of arenethiols to various ynamides have been developed. Mixing yn­amides and arenethiols in the presence of a catalytic amount of triethylborane affords the corresponding adducts, (Z)-1-amino-2-thio-1-alkenes, in excellent yields with high selectivities. The products can be reduced by means of trifluoroacetic acid and triethylsilane to yield 1-amino-2-thioalkanes.

Sodium dithionite initiated regio- and stereoselective radical addition of polyfluoroalkyl iodide with norbornene analogs

Sodium dithionite initiated free-radical addition of polyfluoroalkyl iodides ( 2m– 2s) with norbornene 1a and its derivatives, such as norbornene-2-carboxylates 1b and 1c, and norbornene-2-carboxylic acids 1d and 1e was investigated. In all the cases, the addition of R F group was stereoselectively delivered at exo-position and the predominant configuration of products was trans. Under the similar condition, norbornene-2-carboxylic ethyl ester 1b reacted with 2p to give 6- exo-R F-5- endo-iodo adduct 3bp and 5- exo-R F-6- endo-iodo adduct 5bp in the ratio of 4:1. While 1c, which has a heavy crowded group in the 2- endo-position, gave 6- exo-R F-5- endo-iodo adduct 3cp and polyfluoroalkylated product 4cp retaining the trans-configuration and the exo-orientation of R F group. The fluoroalkylation–lactonization reaction occurred in the reaction of norbornene-2- endo-carboxylic acids 1d and 1e with polyfluoroalkyl iodides to afford the corresponding fluoroalkylated γ-lactone products ( 7dp– 7ds, and 7em– 7er). The configuration of the products was further confirmed by 2D NMR and X-ray diffraction analyses for the first time.

Mn-Mediated Coupling of Alkyl Iodides and Chiral N-Acylhydrazones: Optimization, Scope, and Evidence for a Radical Mechanism

Stereoselective radical additions have excellent potential as mild, nonbasic carbon-carbon bond constructions for direct asymmetric amine synthesis. Efficient intermolecular radical addition to C=N bonds with acyclic stereocontrol has previously been limited mainly to secondary and tertiary radicals, a serious limitation from the perspective of synthetic applications. Here, we provide full details of the use of photolysis with manganese carbonyl to mediate stereoselective intermolecular radical addition to N-acylhydrazones. Photolysis (300 nm) of alkyl halides and hydrazones in the presence of Mn2(CO)10 and InCl(3) as a Lewis acid led to reductive radical addition; diastereomer ratios ranged from 93:7 to 98:2 at ca. 35 degrees C. The reaction tolerates additional functionality in either reactant, enabling subsequent transformations as shown in an efficient asymmetric synthesis of coniine. A series of hydrazones bearing different substituents on the oxazolidinone auxiliary were compared; consistently high diastereocontrol revealed that the identity of the substituent had little practical effect on the diastereoselectivity. Further mechanistic control experiments confirmed the intermediacy of radicals and showed that independently prepared alkyl- or acylmanganese pentacarbonyl compounds do not undergo efficient addition to the N-acylhydrazones under thermal or photolytic (300 nm) conditions. These Mn-mediated conditions avoid toxic tin reagents and enable stereoselective intermolecular radical additions to C=N bonds with the broadest range of alkyl halides yet reported, including previously ineffective primary alkyl halides.

Synthesis and some stereoselective radical additions of bis[(phenyldimethylsilyl)methyl]tin dihydride

The synthesis of the new bis[(phenyldimethylsilyl)methyl]tin dihydride (6) starting from chloromethyldimethylsilicon chloride is reported. A study on the radical additions of 6 to various monoand disubstituted alkynes shows that these reactions take place with high and in some cases with complete stereoselectivity. Full H-, C-, and Sn-NMR data of the new organtins are given.

Highly Regioselective and Stereoselective Radical Addition of p‐TsBr to α‐Allenic Alcohols and Their Elimination Reaction: Synthesis of β‐p‐Tosyl‐Substituted α,β‐Unsaturated Ketones.

Regio- and stereoselective radical addition of α-allenic alcohols with p-TsBr in the presence of a catalytic amount of AIBN afforded (E)-γ-bromo-β-sulfonyl allylic alcohols in moderate yields. The base-promoted 1,4-elimination followed by isomerization to give β-sulfonyl-α,β-unsaturated ketones is described.

HIGHLY REGIOSELECTIVE AND STEREOSELECTIVE RADICAL ADDITION OF p-TsBr TO α-ALLENIC ALCOHOLS AND THEIR ELIMINATION REACTION: SYNTHESIS OF β-p-TOSYL-SUBSTITUTED α,β-UNSATURATED KETONES

ABSTRACT Regio- and stereoselective radical addition of α-allenic alcohols with p-TsBr in the presence of a catalytic amount of AIBN afforded (E)-γ-bromo-β-sulfonyl allylic alcohols in moderate yields. The base-promoted 1,4-elimination followed by isomerization to give β-sulfonyl-α,β-unsaturated ketones is described.

ChemInform Abstract: Highly Regioselective and Stereoselective Radical Addition of p‐TsBr to Substituted Terminal Allenes and Their Nucleophilic Substitutions: Synthesis of α,β‐Unsaturated Sulfones.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Highly Efficient and Stereoselective Radical Addition of Tertiary Amines to Electron‐Deficient Alkenes — Application to the Enantioselective Synthesis of Necine Bases.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Highly Regioselective and Stereoselective Radical Addition of p-TsBr to Substituted Terminal Allenes and Their Nucleophilic Substitutions: Synthesis of α,β-Unsaturated Sulfones

Highly Regioselective and Stereoselective Radical Addition of p-TsBr to Substituted Terminal Allenes and Their Nucleophilic Substitutions: Synthesis of α,β-Unsaturated Sulfones