Synlett

C–H activation of functionally rich molecules without the need for directing groups promises shorter organic syntheses and late-stage diversification of molecules for drug discovery. We highlight recent examples of palladium-catalyzed nondirected functionalization of C–H bonds in arenes as limiting substrates with a focus on the development of the concept of spatial anion control for direct C–H arylation.1 C–H Activation and the CMD Mechanism2 Nondirected C–H Functionalizations of Arenes as Limiting Substrates3 Nondirected C–H Arylation4 Spatial Anion Control for Direct C–H Arylation5 Coordination Chemistry with Spatial Anion Control6 Conclusion

C-Alkyl glycosides represent an attractive class of nonhydrolyzable carbohydrate mimetics which possess enormous potential as next-generation therapeutics. Methods for the direct stereoselective synthesis of C-alkyl glycosides with a broad substrate tolerance are limited, however. This is especially in the case of β-linked C-alkyl glycosides, where direct methods for synthesis from commonly available coupling partners remain limited. This Account describes the evolution of our laboratory’s studies on glycosyl sulfonate chemistry from a method for the construction of simple β-linked 2-deoxy-sugars to a technology for the direct synthesis of β-linked acyl and homoacyl glycosides that can be elaborated into more complex structures.1 Introduction2 Glycosyl Sulfonates3 Glycosyl Sulfonates in Oligosaccharide Synthesis4 Matching Donor and Sulfonate Reactivity5 β-Linked C-Acyl and Homoacyl Glycoside Synthesis6 Elaboration to other Products7 Conclusion

We report a simple protocol for (ethoxycarbonyl)difluoromethylthiolation of nucleophilic compounds using a difluoroalkyl sulfonium salt which can be prepared in situ via Tf2O-triggered electrophilic activation of a benzyl difluoroalkyl sulfoxide. With the protocol, difluoroalkylthiolated arenes, heteroarenes, α-difluoroalkylthiolated carbonyl compounds, etc. were obtained smoothly with good to excellent yields. Merits of the reaction include the readily available difluoroalkylthiolation reagent and substrates, mild conditions, and excellent regioselectivity.

A cascade reaction of 3-phenacylideneoxindoles with trimethylsilyl cyanide is described. This method provides an efficient route for the synthesis of furan-fused 1,3-benzodiazepin-2-one derivatives by simply refluxing a reaction mixture of various 3-phenacylideneoxindoles with trimethylsilyl cyanide in the presence of H2O and K2CO3.

A new general process for constructing ortho-tert-butyl phenols is presented within the context of other known methods. All are briefly evaluated with regards to regioselectivity, efficiency, and functional group tolerance. In addition, we present an assortment of tert-butyl substrates accessed through o-QM chemistry. Our conclusion is that the o-QM process provides greater yields, flexibility, and generality than most other known methods for delivering ortho-tert-buytlated phenols and their derivatives.1 Introduction2 Friedel–Crafts Alkylation3 Addition of t-Bu– or t-Bu• to Carbonyl Compounds4 ipso-SNAr Reactions of Aryl Methoxy and tert-Butylsulfoxide Moieties5 Metal-Mediated Coupling of Aryl Bromides6 Applications of o-Quinone Methides (o-QMs)7 Conclusion

Polyampholyte hydrogels have shown promise as functional biomaterial platforms with resistance to nonspecific protein adsorption (nonbiofouling). Yet there are few zwitterionic cross-linkers available to complement these materials and to provide an extended charge density throughout the 3D network. The recent development of peptide-based zwitterionic cross-linkers has shown merit. Indeed, the use of functionalizable amino acids permits the synthesis of a series of peptide-based zwitterionic methacrylate and methacrylamide cross-linkers. Methacrylate additions prior to peptide coupling provide an outside-in strategy when using natural l-serine or l-lysine as substrates to produce a series of methacrylate and methacrylamide combinations, expanding the library of peptide-based cross-linkers. Here, we describe the preparation of such dipeptide combinations as Ser-Lys, Lys-Ser, and Lys-Lys in zwitterionic bis(methacrylate/methacrylamide) cross-linkers. To highlight the utility of this method and its potential to increase the distance between zwitterionic components, syntheses of the tripeptide Lys-Gly-Lys dimethacrylamide and Ser-Gly-Ser dimethacrylate are reported.

Reductive radical cyclizations are ubiquitous in organic synthesis and have been applied to the synthesis of structurally complex molecules. N-Heterocyclic motifs can be prepared through the cyclization of α-haloamides; however, slow rotation around the amide C–N bond results in preferential formation of an acyclic hydrodehalogenated product. Here, we compare four different methods for preparing γ-, δ-, ε-, and ζ-lactams via radical cyclization. We found that a photoenzymatic method using flavin-dependent ‘ene’ reductases affords the highest level of product selectivity. We suggest that through selective binding of the cis-amide isomer, the enzyme preorganizes the substrate for cyclization, helping to avoid premature radical termination.

Spirocyclic 3,5-difluorocyclohexa-2,5-dienones possessing a triisopropylsiloxy-containing cyclic ether appendage were synthesized by oxidative dearomatization of the corresponding phenols. By group selectivity in the nucleophilic 1,4-addition/elimination reaction, highly stereoselective formation of the spiro center was successfully achieved. This reaction might provide access to total syntheses of (+)-bisdechlorogeodin and (+)-geodin with complete control of the formation of the spirocyclic structure.

The Thorpe–Ingold effect was applied to the design of a chiral ligand of π–copper(II) catalysts for the enantioselective α-fluorination of N-acyl-3,5-dimethylpyrazoles, and also for the enantioselective Mukaiyama–Michael, Diels–Alder, and 1,3-dipolar cycloaddition reactions of N-acryloyl-3,5-dimethylpyrazoles. The use of β,β-dimethyl-β-arylalanine-type ligand gave desired products with higher enantioselectivity compared to with previously reported β-arylalanine-type ligands.

A copper-catalyzed radical difluoroalkylation of arylacetylenes with bromodifluoroamides has been developed. The reaction exhibits good functional group tolerance and allows access to a variety of substituted α-alkynyl-α,α-difluoroacetamides in moderate to good yields. The potential for scale-up reaction and products derivatization also makes this method attractive for practical applications. Preliminary mechanistic studies suggest that a radical reaction pathway might be involved in the catalytic system.