The synthesis of disulfide-containing polypeptides represents a long-standing challenge in peptide chemistry, and broadly applicable methods for the construction of disulfides are in constant demand. Few strategies exist for on-resin formation of disulfides directly from their protected counterparts. We present herein a novel strategy for the on-resin construction of disulfides directly from Allocam-protected cysteines. Our palladium-mediated approach is mild and uses readily available reagents, requiring no special equipment. No reduced peptide intermediates or S-allylated products are observed, and no residual palladium can be detected in the final products. The utility of this method is demonstrated through the synthesis of the C-carboxy analog of oxytocin.

Rapid, selective detection of metals in complex samples remains an elusive goal that could provide critical analytical information for biological and environmental sciences and industrial waste management. Fast-scan cyclic voltammetry (FSCV) using carbon-fiber microelectrodes (CFMs) is an emerging technique for metal analysis with broad potential applicability because of its rapid response to changes in analyte concentration and minimal disturbance to the analysis medium. In this communication, we report the first effective application of covalently modified CFMs to achieve highly selective, subsecond Cu(II) measurements using FSCV. A two-part strategy is employed for maximum selectivity: Cu(II) binding is augmented by a covalently grafted ionophore, while binding of other metals is prevented by chemical blocking of nonselective surface adsorption sites. The resulting electrodes selectively detect Cu(II) in a complex medium comprising several interfering metals. Overall, this strategy represents a transformative innovation in real-time electrochemical detection of metal analytes.

Trace metal detection is of great importance in environmental and biological systems. It is crucial to develop a portable and sensitive device that can determine levels of trace metals in real time. Recently, we described a method for ultrafast and sensitive detection of Cu(II) and Pb(II) in aqueous environmental samples using fast scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes (CFMs). However, the application of this technique to more complex samples is limited by analytical selectivity. In this paper, we describe a scaffolding strategy for covalent modification of CFMs as a platform for creating selective adsorption sites. We create a monolayer of acetylene-terminated scaffolds on CFMs through the electrochemical reduction of alkynyl aryl diazonium salts bearing sterically differentiated silyl groups, which control the density of the scaffolds. Desilylation reveals the alkyne for further functionalization via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). As a proof of principle, we optimized the conditions for azidomethyl ferrocene to be grafted with the alkynes. All the surface variations of CFMs are electrochemically verified. This innovative strategy provides the groundwork for a broadly applicable method to generate analyte-selective CFMs. The generalized approach offers the potential to attach azide-appended recognition groups to different electrodes in a high throughput manner. This technology will ultimately allow real-time ultra-selective FSCV analysis of metals in complex ecological and biological systems.

A streamlined approach to the tertiary amine-containing core of the calyciphylline A and daphnicyclidin A-type Daphniphyllum alkaloids is presented. A known carvone derivative is converted into the core structure in only four synthetic operations, and it is well poised for further elaboration. The key enabling methodology is a radical cyclization cascade beginning with addition of a secondary, neutral aminyl radical to the β-position of an enone, followed by trapping with a pendant alkyne.

The synthesis of disulfide-containing polypeptides represents a long-standing challenge in peptide chemistry, and broadly applicable methods for the construction of disulfides are in constant demand. Few strategies exist for on-resin formation of disulfides directly from their protected counterparts. We present herein a novel strategy for the on-resin construction of disulfides directly from Allocam-protected cysteines. Our palladium-mediated approach is mild and uses readily available reagents, requiring no special equipment. No reduced peptide intermediates or S-allylated products are observed, and no residual palladium can be detected in the final products. The utility of this method is demonstrated through the synthesis of the C-carboxy analog of oxytocin.

Trace metal detection is of great importance in environmental and biological systems. It is crucial to develop a portable and sensitive device that can determine levels of trace metals in real time. Recently, we described a method for ultrafast and sensitive detection of Cu(II) and Pb(II) in aqueous environmental samples using fast scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes (CFMs). However, the application of this technique to more complex samples is limited by analytical selectivity. In this paper, we describe a scaffolding strategy for covalent modification of CFMs as a platform for creating selective adsorption sites. We create a monolayer of acetylene-terminated scaffolds on CFMs through the electrochemical reduction of alkynyl aryl diazonium salts bearing sterically differentiated silyl groups, which control the density of the scaffolds. Desilylation reveals the alkyne for further functionalization via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). As a proof of principle, we optimized the conditions for azidomethyl ferrocene to be grafted with the alkynes. All the surface variations of CFMs are electrochemically verified. This innovative strategy provides the groundwork for a broadly applicable method to generate analyte-selective CFMs. The generalized approach offers the potential to attach azide-appended recognition groups to different electrodes in a high throughput manner. This technology will ultimately allow real-time ultra-selective FSCV analysis of metals in complex ecological and biological systems.