Recent Progress in the Construction of Natural De-O-Sulfonated Sulfonium Sugars with Antidiabetic Activities

A group of sulfonium salts equipped with a polyhydroxylated side-chain structure have been isolated and identified as potent α-glycosidase inhibitors. Consequently, they have become an attractive target in diverse research disciplines, including organic synthesis, drug discovery, and chemical biology. To this end, the development of practical and effective synthetic strategies, especially for more bioactive de-O-sulfonated sulfonium salts, is a significant research area in organic synthesis. An ideal synthetic methodology should provide easily accessible intermediates with high chemical stability for the key coupling reaction to diastereoselectively construct the sulfonium cation center. This minireview summarizes recently developed strategies applied in the construction of natural de-O-sulfonated sulfonium sugars: 1) acid-catalyzed de-O-sulfonation of sulfonium sulfate inner salts, 2) a coupling reaction between side-chain fragments containing leaving groups and a thiosugar, 3) a coupling reaction between side-chain fragments containing epoxide structures and a thiosugar, and 4) a two-step sequential S_N2 nucleophilic substitution between side-chain fragments containing thiol groups and a diiodide derivative.     

PdII‐Catalyzed Domino Heterocyclization/Cross‐Coupling of α‐Allenols and α‐Allenic Esters: Efficient Preparation of Functionalized Buta‐1,3‐dienyl Dihydrofurans

A mild, palladium(II)‐catalyzed reaction of α‐allenols with α‐allenic esters in a heterocyclization/cross‐coupling sequence, applicable to a wide range of substitution patterns, has been developed for the preparation of 2,3,4‐trifunctionalized 2,5‐dihydrofurans. Our studies indicate high levels of chemo‐ and regiocontrol. The possibility of using optically active substrates as well as substrates of increased steric demand, such as tertiary α‐allenols, makes this novel sequence of heterocyclization/cross‐coupling an attractive method in organic synthesis. The current mechanistic hypothesis invokes a regiocontrolled palladium(II)‐mediated intramolecular oxypalladation of the free allenol component, that then undergoes a cross‐coupling reaction with the allenic ester partner, followed by a trans‐β‐deacyloxypalladation with concomitant regeneration of the Pd^II species.     

Copper‐catalyzed cross‐coupling of α‐seleno‐acylzirconocene chloride with haloalkynes: Synthesis of α‐seleno‐substituted vinyl alkynyl ketones

The copper‐catalyzed cross‐coupling reaction of α‐selenoacylzirconocene chloride 3 with haloalkynes in the presence of carbon monoxide gives α‐seleno‐substituted vinyl alkynyl ketones 5 in moderate yields. The reaction conditions are neutral and mild enough (room temperature, 1 atm carbon monoxide) that other functional groups in either coupling partner can be brought unaltered into the coupled product. The E geometry in the α‐alkylseleno vinylzirconocene reagent is maintained during the coupling reaction. © 2000 John Wiley & Sons, Inc. Heteroatom Chem 11:91–93, 2000     

Quadruple click reactions for the synthesis of cysteine‐terminated linear multiblock copolymers

Synthesis of cysteine‐terminated linear polystyrene (PS)‐b‐poly(ε‐caprolactone) (PCL)‐b‐poly(methyl methacrylate) (PMMA)/or poly(tert‐butyl acrylate)(PtBA)‐b‐poly(ethylene glycol) (PEG) copolymers was carried out using sequential quadruple click reactions including thiol‐ene, copper‐catalyzed azide–alkyne cycloaddition (CuAAC), Diels–Alder, and nitroxide radical coupling (NRC) reactions. N‐acetyl‐L ‐cysteine methyl ester was first clicked with α‐allyl‐ω‐azide‐terminated PS via thiol‐ene reaction to create α‐cysteine‐ω‐azide‐terminated PS. Subsequent CuAAC reaction with PCL, followed by the introduction of the PMMA/or PtBA and PEG blocks via Diels–Alder and NRC, respectively, yielded final cysteine‐terminated multiblock copolymers. By ¹H NMR spectroscopy, the DP_ns of the blocks in the final multiblock copolymers were found to be close to those of the related polymer precursors, indicating that highly efficient click reactions occurred for polymer–polymer coupling. Successful quadruple click reactions were also confirmed by gel permeation chromatography. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Direct Umpolung of Glycals and Related 2,3‐Unsaturated N‐Acetylneuraminic Acid Derivatives Using Samarium Diiodide

The umpolung of glycals with samarium diiodide offers a simple route to novel carbohydrate‐derived nucleophilic reagents in a single step using a readily available reductant. The corresponding allyl samarium reagent that arises from the hexose series reacts with ketones at the C3 position with high stereoselectivity; carbon–carbon bond formation takes place only anti to the substituent at the C4 position of the dihydropyran ring. For the sialic acid series, the completely regio‐ and stereoselective coupling process of the samarium reagent occurs at the anomeric carbon atom and provides a new approach to the α‐C‐glycosides of N‐acetyl neuraminic acid.     

Hydrogen‐Bond‐Mediated Aglycone Delivery (HAD): A Highly Stereoselective Synthesis of 1,2‐cis α‐D‐Glucosides from Common Glycosyl Donors in the Presence of Bromine

Described herein is the expansion of the picoloyl protecting‐group assisted H‐bond mediated aglycone delivery (HAD) method recently introduced by our laboratory. At first it was noticed that high α‐stereoselectivity is only obtained with S‐ethyl glycosyl donors and only in the presence of dimethyl(methylthio)sulfonium trifluoromethanesulfonate (DMTST), in high dilution, and low temperature. Combining the mechanistic studies of the HAD reaction and bromine‐promoted glycosylations allowed a very effective method to be devised that allows for highly stereoselective α‐glycosidation of practically all common leaving groups (S‐phenyl, S‐tolyl, S/O‐imidates) at regular concentrations and ambient temperature.     

Thiol‐isocyanate‐acrylate ternary networks by selective thiol‐click chemistry

Thiol‐isocyanate‐acrylate ternary networks were formed by the combination of thiol‐isocyanate coupling, thiol‐acrylate Michael addition, and acrylate homopolymerization. This hybrid polymerization reaction sequence was preferentially controlled by using phosphine catalyst systems in combination with photolysis. The reaction kinetics of the phosphine/acrylate thiol‐isocyanate coupling reactions were systematically investigated by evaluating model, small molecule reactions. The thiol‐isocyanate reaction was completed within 1 min while the thiol‐acrylate Michael addition reaction required ～10 min. Both thiol‐isocyanate coupling and thiol‐acrylate Michael addition reactions involving two‐step anionic processes were found to be both quantitative and efficient. However, the thiol‐isocyanate coupling reaction was much more rapid than the thiol‐acrylate Michael addition, promoting initial selectivity of the thiol‐isocyanate reaction in a medium containing thiol, isocyanate, and acrylate functional groups. Films were prepared from thiol‐isocyanate‐acrylate ternary mixtures using 2‐acryloyloxyethylisocyanate and di‐, tri‐, and tetra‐functional thiols. The sequential thiol‐isocyanate, thiol‐acrylate, and acrylate homopolymerization reactions were monitored by infrared spectroscopy during film formation, whereas thermal and mechanical properties of the films were evaluated as a function of the chemical composition following polymerization. The results indicate that the network structures and material properties are tunable over a wide range of properties (T_g ～ 14–100 °C, FWHM ～ 8–46 °C), while maintaining nearly quantitative reactions, simply by controlling the component compositions. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 3255–3264, 2010     

Synthesis of α‐phosphonylated phosphonium and sulfonium ylides: Study of their thermal behavior

The additions of two equivalents of trialkylphosphites onto phosphonodithioformates produce stabilized α‐sulfanyl‐α‐phosphonyl phosphonium ylides. Their subsequent reaction with alkyl or benzyl halides gives stabilized sulfonium ylides. Thermal treatment of these phosphonium and sulfonium ylides leads to α‐sulfanyl methylene bis‐phosphonates through protonation–dealkylation intramolecular reactions. © 2009 Wiley Periodicals, Inc. Heteroatom Chem 20:164–171, 2009; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20530     

A convenient synthesis of α,α′‐ homo‐ and α,α′‐hetero‐bifunctionalized poly(ε‐caprolactone)s by ring opening polymerization: The potentially valuable precursors for miktoarm star copolymers

Two new ring opening polymerization (ROP) initiators, namely, (3‐allyl‐2‐(allyloxy)phenyl)methanol and (3‐allyl‐2‐(prop‐2‐yn‐1‐yloxy)phenyl)methanol each containing two reactive functionalities viz. allyl, allyloxy and allyl, propargyloxy, respectively, were synthesized from 3‐allylsalicyaldehyde as a starting material. Well defined α‐allyl, α′‐allyloxy and α‐allyl, α′‐propargyloxy bifunctionalized poly(ε‐caprolactone)s with molecular weights in the range 4200–9500 and 3600–10,900 g/mol and molecular weight distributions in the range 1.16–1.18 and 1.15–1.16, respectively, were synthesized by ROP of ε‐caprolactone employing these initiators. The presence of α‐allyl, α′‐allyloxy and α‐allyl, α′‐propargyloxy functionalities on poly(ε‐caprolactone)s was confirmed by FT‐IR, ¹H, ¹³C NMR spectroscopy, and MALDI‐TOF analysis. The kinetic study of ROP of ε‐caprolactone with both the initiators revealed the pseudo first order kinetics with respect to ε‐caprolactone consumption and controlled behavior of polymerization reactions. The usefulness of α‐allyl, α′‐allyloxy functionalities on poly(ε‐caprolactone) was demonstrated by performing the thiol‐ene reaction with poly(ethylene glycol) thiol to obtain (mPEG)₂‐PCL miktoarm star copolymer. α‐Allyl, α′‐propargyloxy functionalities on poly(ε‐caprolactone) were utilized in orthogonal reactions i.e copper catalyzed alkyne‐azide click (CuAAC) with azido functionalized poly(N‐isopropylacrylamide) followed by thiol‐ene reaction with poly(ethylene glycol) thiol to synthesize PCL‐PNIPAAm‐mPEG miktoarm star terpolymer. The preliminary characterization of A₂B and ABC miktoarm star copolymers was carried out by ¹H NMR spectroscopy and gel permeation chromatography (GPC). © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 844–860     

(Bromodimethyl)sulfonium Bromide Catalyzed Solvent‐Free Friedlander Synthesis of Substituted Quinolines

A simple and efficient (bromodimethyl)sulfonium bromide catalyzed synthesis of quinolines, by condensation of α‐amino carbonyl, that is, 2‐aminobenzophenone and 2‐aminoacetophenone with α‐methylene containing carbonyl like 1,3‐dicarbonyls has been developed. The reaction is versatile, solvent‐free protocol for generation of structurally diverse quinolines.     

A brief survey on the copper‐catalyzed allylation of alkylzinc and Grignard reagents under Barbier conditions

The same regioselectivity can be obtained in the CuI catalyzed allylic coupling of n‐butylzinc reagents prepared by either pre‐transmetallation or in situ transmetallation of Grignard reagents in the presence of allylic partner and catalyst. n‐Butylzinc bromide and di‐n‐butylzinc undergo γ‐selective allylation whereas tri‐n‐butylzincate gives preferential α‐selectivity. The regioselectivity obtained in the reaction of n‐butyl bromide and E‐crotyl chloride in the presence of Mg and CuCN is parallel to the coupling of preformed n‐butylmagnesium bromide. It is remarkable that the regiochemical outcome of copper catalyzed alkyl‐allyl coupling can be controlled by using Grignard reagents prepared under Barbier conditions and alkylzincs prepared by in situ transmetallation. Copyright © 2006 John Wiley & Sons, Ltd.     

A Highly Stereoselective Synthesis of Glycidic Amides Based on a New Class of Chiral Sulfonium Salts: Applications in Asymmetric Synthesis

A new type of chiral sulfonium salts that are characterized by a bicyclic system has been designed and synthesized from α‐amino acids. Their corresponding ylides, which were prepared by basic treatment of the sulfonium salts, reacted smoothly with a broad array of simple and chiral aldehydes to provide trans‐epoxy amides in reasonable to very good yields and excellent stereoselectivities (>98 %). The obtained epoxy amides were found to be useful as synthetic building blocks. Thus, they were reduced into their corresponding epoxy alcohols and subjected to oxirane‐ring‐opening reactions with different types of nucleophiles.     

Umpolung Reactions of α‐Imino Esters: Useful Methods for the Preparation of α‐Amino Acid Frameworks

This paper summarizes our recent efforts toward the development of tandem reactions utilizing umpolung reactions of α‐imino esters. A highly diastereoselective tandem N‐alkylation–Mannich reaction of α‐imino esters was developed. A tandem N‐alkylation–addition reaction of α‐imino esters derived from ethyl glyoxylate with various aldehydes proceeded to give 1,2‐amino alcohols. The same reaction also proceeded efficiently using a novel flow system comprising two connected microreactors. Novel syntheses of α‐quaternary alkynyl amino esters and allenoates were developed through the use of umpolung N‐addition to β,γ‐alkynyl α‐imino esters, followed by regioselective acylation. In addition, a highly regioselective tandem N‐alkylation–vinylogous aldol reaction of β,γ‐alkenyl α‐imino esters was discovered. N‐Alkylation of α‐iminophosphonates followed by a Horner–Wadsworth–Emmons reaction with aldehydes occurred to afford enamines, which can be used in a four‐component coupling reaction with methyl vinyl ketone. α‐N‐Acyloxyimino esters served as highly efficient substrates for the N,N,C‐trialkylation reaction to introduce various nucleophiles at the imino nitrogen and carbon atoms.     

Enantioselective Construction of α‐Chiral Silanes by Nickel‐Catalyzed C(sp3)−C(sp3) Cross‐Coupling

An enantioselective C(sp³)?C(sp³) cross‐coupling of racemic α‐silylated alkyl iodides and alkylzinc reagents is reported. The reaction is catalyzed by NiCl₂/(S,S)‐Bn‐Pybox and yields α‐chiral silanes with high enantiocontrol. The catalyst system does not promote the cross‐coupling of the corresponding carbon analogue, corroborating the stabilizing effect of the silyl group on the alkyl radical intermediate (α‐silicon effect). Both coupling partners can be, but do not need to be, functionalized, and hence, even α‐chiral silanes with no functional group in direct proximity of the asymmetrically substituted carbon atom become accessible. This distinguishes the new method from established approaches for the synthesis of α‐chiral silanes.     

Transition‐Metal‐Free Cross‐Coupling of Benzothiophenes and Styrenes in a Stereoselective Synthesis of Substituted (E,Z)‐1,3‐Dienes

A transition metal‐free one‐pot stereoselective approach to substituted (E,Z)‐1,3‐dienes was developed by using an interrupted Pummerer reaction/ligand‐coupling strategy. Readily available benzothiophene S‐oxides, which can be conveniently prepared by oxidation of the parent benzothiophenes, undergo Pummerer coupling with styrenes. Reaction of the resultant sulfonium salts with alkyllithium/magnesium reagents generates underexploited hypervalent sulfurane intermediates that undergo selective ligand coupling, resulting in dismantling of the benzothiophene motif and the formation of decorated (E,Z)‐1,3‐dienes.     

Umpolung Strategy for α‐Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles

Nucleophile–nucleophile coupling is a challenging transformation in organic chemistry. Herein we present a novel umpolung strategy for α‐functionalization of aldehydes with nucleophiles. The strategy uses organocatalytic enamine activation and quinone‐promoted oxidation to access O‐bound quinol‐intermediates that undergo nucleophilic substitution reactions. These quinol‐intermediates react with different classes of nucleophiles. The focus is on an unprecedented organocatalytic oxidative α‐thiolation of aldehydes. The reaction scope is demonstrated for a broad range of thiols and extended to chemoselective bioconjugation, and applicable to a large variety of aldehydes. This strategy can also encompass organocatalytic enantioselective coupling of α‐branched aldehydes with thiols forming quaternary thioethers. Studies indicate a stereoselective formation of the intermediate followed by a stereospecific nucleophilic substitution reaction at a quaternary stereocenter, with inversion of configuration.     

Synthesis and X‐ray Crystal Structures of Zinc Complexes Supported by Chelating Ligands: Various Reactions of α‐Iminopyridines with ZnEt2

α‐Iminopyridine (α‐IP) is an important redox‐noninnocent ligand. The substituents on the imino function of α‐IPs have important impact on the reaction selectivity with diethylzinc. For the α‐IPs with a hydrogen substituent on the imino carbon, reduction occurred for the non‐bulky N‐substituents phenyl and 2‐methylphenyl groups, whereas alkyl addition and coupling reactions can be selectively achieved for the sterically bulky N‐substituents 2,6‐dimethylphenyl or 2,4,6‐trimethylphenyl group. However, for the α‐IPs with a CH₃ substituent on the imino carbon, the deprotonation reaction happened regardless of the N‐substituents of 2‐methylphenyl or 2,6‐dimethylphenyl group. All the products were isolated and characterized by single‐crystal X‐ray diffraction. The possible mechanisms of these reactions were also discussed.     

Photochemistry and photocuring properties of thiol‐substituted α‐aminoalkylphenone as radical photoinitiator

Thiol‐substituted α‐aminoalkylphenone was newly developed as a radical photoinitiator. Introduction of the thiol group drastically improved photosensitivity in an alkaline developable resist formulation composed of a prepolymer and a multifunctional acrylate monomer. The improvement in the photocuring speed was explained by a mechanism based on chain transfer reaction of the thiol group. Time‐resolved electron spin resonance (ESR) spectroscopy indicated that the thiol group attached to the chromophore does not influence the photochemical process to generate primary radicals. The photoinitiation of α‐aminoalkylphenone can be spectrally sensitized by 2,4‐diethylthioxanthone (DETX). However, thiol‐substituted α‐aminoalkylphenone showed smaller spectral sensitization than the corresponding compound without a thiol group. Time resolved laser flash photolysis indicated that the rate constant of the quenching of the triplet state of DETX by thiol‐substituted α‐aminoalkylphenone is twice as large as that by the corresponding one without a thiol group. This suggests that, besides energy transfer from DETX in the excited triplet state to the α‐aminoalkylphenone, the thiol group quenches the excited triplet state of DETX via charge transfer and/or hydrogen transfer, as supported by the ESR analysis using a spin trapping technique, and lowers the efficiency of the spectral sensitization effect. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 1684–1695, 2005     

Synthesis of Bacterial Metabolites of Polycyclic Aromatic Hydrocarbons: Benzochromenones,o‐Carboxyvinylnaphthoates,and o‐Substituted Aryl‐α‐Oxobutenoates

Bacterial metabolites of phenanthrene and anthracene include benzochromenones, o‐carboxyvinylnaphthoates, and o‐substituted aryl α‐oxobutenoates, which were synthesized with the Wittig reaction, the Heck reaction, and coupling of aromatic aldehyde with pyruvate.     

Functionalization of Carbon Nanotubes with Well‐Defined Functional Polymers via Thiol‐Coupling Reaction

Summary: Thiol‐reactive‐functionality decorated multi‐walled carbon nanotubes (MWNTs) have been obtained. Trithiocarbonate‐ended poly(N‐(2‐hydroxypropyl)methacrylamide) (PHPMA) is prepared by reversible addition‐fragmentation chain transfer (RAFT) polymerization of N‐(2‐hydroxypropyl)methacrylamide (HPMA) using S‐1‐dodecyl‐S′‐(α,α′‐dimethyl‐α″‐acetic acid)trithiocarbonate as chain transfer agent, subsequently, thiol‐terminated PHPMA (PHPMA‐SH) is obtained by treating trithiocarbonate‐ended PHPMA with hexylamine. The PHPMA‐S‐S‐MWNT conjugate is formed by simply stirring the mixture of thiol‐reactive‐functionality decorated MWNTs with PHPMA‐SH in phosphate buffered saline by a thiol‐coupling reaction. FT‐IR, HRTEM, ¹H NMR, and TGA results show that this thiol‐coupling reaction is effective to produce aqueous soluble polymer–MWNT conjugates under mild conditions.

Thiol‐reactive‐functionality decorated multi‐walled carbon nanotubes are modified with thiol end‐capped polymers by a thiol‐coupling reaction.