Anodic Amide Research Articles

An Iodide-Mediated Anodic Amide Coupling.

Invited for the cover of this issue is the group of Till Opatz at the University of Mainz. The image depicts the electrochemical coupling of amines and carboxylic acids to form amides. Read the full text of the article at 10.1002/chem.202201768.

An Iodide-Mediated Anodic Amide Coupling.

The ubiquity of amide bonds, present in natural products and common pharmaceuticals renders this functional group one of the most prevalent in organic chemistry. Despite its importance and a wide variety of existing methods for its formation, the latter still can be a challenge for classical activating reagents such as chloridating agents or carbodiimides. As the spent reagents often cannot be recycled, the development of more sustainable methods is highly desirable. Herein, we report an operationally simple and mild indirect electrochemical protocol to effect the condensation of carboxylic acids with amines, forming a wide variety of carboxamides.

ChemInform Abstract: Conformationally Constrained Substance P Analogues: The Total Synthesis of a Constrained Peptidomimetic for the Phe7-Phe8 Region.

A lactam-based peptidomimetic for the Phe7-Phe8 region of substance P has been synthesized. The synthesis used an anodic amide oxidation to selectively functionalize the C5-position of a 3-phenylproline derivative. The resulting proline derivative was coupled to a Cbz-protected phenylalanine, and an intramolecular reductive amination strategy used to convert the coupled material into a bicyclic piperazinone ring skeleton. The net result was a dipeptide building block that imbedded one of two proposed receptor bound conformations for the Phe7-Phe8 region of substance P into a bicyclic ring skeleton. The building block was then converted into a constrained substance P analogue with the use of solid-phase peptide synthesis. A similar intramolecular reductive amination strategy was used to synthesize a substance P analogue having only Phe7 constrained, and the original 3-phenylproline was converted into a substance P analogue having only Phe8 constrained. All of the analogues were examined for their ability t...

Anodic Amide Oxidation/Olefin Metathesis Strategies: Developing a Unified Approach to the Synthesis of Bicyclic Lactam Peptidomimetics

In connection with efforts to build constrained peptidomimetics for the endocrine hormone TRH, a general strategy for the construction of bicyclic lactam peptide building blocks has been developed. This strategy used an anodic amide oxidation to selectively functionalize proline and then an olefin metathesis to build the desired lactam constraint. The route described provides a single approach for synthesizing both fully functionalized TRH analogs having seven- and eight-membered ring lactam constraints, as well as six- and seven-membered ring lactam analogs without the sidechain on the central amino acid.

Conformationally constrained substance P analogues: the total synthesis of a constrained peptidomimetic for the Phe7-Phe8 region.

A lactam-based peptidomimetic for the Phe7-Phe8 region of substance P has been synthesized. The synthesis used an anodic amide oxidation to selectively functionalize the C5-position of a 3-phenylproline derivative. The resulting proline derivative was coupled to a Cbz-protected phenylalanine, and an intramolecular reductive amination strategy used to convert the coupled material into a bicyclic piperazinone ring skeleton. The net result was a dipeptide building block that imbedded one of two proposed receptor bound conformations for the Phe7-Phe8 region of substance P into a bicyclic ring skeleton. The building block was then converted into a constrained substance P analogue with the use of solid-phase peptide synthesis. A similar intramolecular reductive amination strategy was used to synthesize a substance P analogue having only Phe7 constrained, and the original 3-phenylproline was converted into a substance P analogue having only Phe8 constrained. All of the analogues were examined for their ability to displace substance P from its NK-1 receptor.

Anodic electrochemistry and the use of a 6-volt lantern battery: A simple method for attempting electrochemically based synthetic transformations

A series of electrochemical transformations have been accomplished using a 6-volt lantern battery as a power supply. The reactions included both intramolecular anodic olefin coupling reactions and an anodic amide oxidation. In all cases, the reactions afforded preparatively useful amounts of product and demonstrated that electrochemical synthetic methods can be readily attempted without the need for specialized equipment.

New routes to conformationally restricted peptide building blocks: a convenient preparation of bicyclic piperazinone derivatives

A facile route for the synthesis of peptide building blocks that constrain the peptide backbone with a 1,4-diazabicyclo[4.3.0]nonane ring skeleton is reported. The synthesis employed an anodic amide oxidation based approach for generating a functionalized proline derivative, and then utilized the derivative as a general substrate for rapidly assembling the bicyclic ring system.

Electrochemical Cyclization of Dipeptides To Form Novel Bicyclic, Reverse-Turn Peptidomimetics. 2. Synthesis and Conformational Analysis of 6,5-Bicyclic Systems

Novel, highly constrained, 6,5-bicyclic dipeptides (1-aza-5-oxa-2-oxobicyclo[4.3.0]nonane ring skeletons, 2) have been synthesized by a one-step electrochemical cyclization from the dipeptides Boc-(S)-serine-(S)-proline-OMe (Boc-(S)-Ser-(S)-Pro-OMe, 3) and Boc-(R,S)-α-methylserine-(S)-proline-OMe (Boc-(R,S)-α-MeS-(S)-Pro-OMe, 12) in yields of 10−25% and 41%, respectively. The one-pot reaction uses selective anodic amide oxidation to generate an N-acyliminium cation which is trapped by an intramolecular hydroxyl group. The cyclization of Boc-(S)-Ser-(S)-Pro-OMe (3) to the 6,5-bicyclic skeleton 4 was highly diastereoselective, generating a new chiral center with an S configuration. This bicyclic compound was sufficiently stable to trifluoroacetic acid and anhydrous hydrofluoric acid for use in standard solid phase peptide synthesis methodologies. Oxidation of Boc-(R,S)-MeS-(S)-Pro-OMe (12) gave different results for each diastereoisomer. Cyclization only occurred for the S,S-diastereoisomer with very low stereoselectivity (6:4 ratio of diastereomers) at the newly-formed ring fusion. In terms of conformation, the 6,5-bicyclic system restricts two (ψ2 and φ3) of the four torsion angles that characterize a reverse turn. Conformational analyses of tetrapeptides containing the 6,5-bicyclic system were performed using Monte Carlo conformational searches and molecular dynamics simulations. All of the eight possible diastereomers arising from the three stereogenic centers (Ser Cα, Pro Cα, and newly formed bridgehead) were considered. These studies revealed that the 3S,7S,10S and 3R,7R,10R configurations are effective turn inducers although the torsion angles of the backbone do not exactly mimic those of classical β-turns. Other diastereomers were found to stabilize the peptide backbone in an extended conformation.

Conformationally Restricted TRH Analogs: The Compatibility of a 6,5-Bicyclic Lactam-Based Mimetic with Binding to TRH-R

A pair of conformationally restricted TRH analogs have been synthesized. Both analogs have the central histidine of TRH replaced by a cyclohexylalanine unit, and both analogs contain a 6,5-bicyclic lactam ring fusing the proline peptide bond into a trans conformation. The analogs differ at the bridgehead stereocenter. The synthesis of the analogs utilized an anodic amide oxidation reaction to selectively functionalize a proline derivative and a titanium tetrachloride-initiated cyclization−rearrangement sequence to assemble the desired bicyclic ring skeleton. The analogs were compared with the unrestricted cyclohexyalanine-containing TRH analog (cyclohexyl-Ala2-TRH) in order to determine how the added lactam ring affected the affinity and the potency of the analog for TRH-R. Both the affinity and potency of the restricted analogs were found to be critically dependent on the bridgehead stereochemistry of the bicyclic ring. The analog having R stereochemistry at the bridgehead was 478 times more potent than ...

ChemInform Abstract: Anodic Amide Oxidations: Conformationally Restricted Peptide Building Blocks from the Direct Oxidation of Dipeptides.

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.

Anodic amide oxidations: Conformationally restricted peptide building blocks from the direct oxidation of dipeptides

A pair of bicyclic lactam based conformationally restricted peptide mimetics have been synthesized in good yield by the direct anodic oxidation of dipeptides. This work highlights the simplicity of using electrochemistry to construct peptide mimetics and serves to further define the nature of the substituents that are compatible with an electrochemical procedure for annulating rings onto amino acid derivatives.

ChemInform Abstract: Anodic Amide Oxidations: The Synthesis of Two Spirocyclic L‐Pyroglutamide Building Blocks.

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.

Anodic amide oxidations: the synthesis of two spirocyclic L-pyroglutamide building blocks

Anodic amide oxidations: the synthesis of two spirocyclic L-pyroglutamide building blocks

Anodic amide oxidations: a novel synthesis of the angiotensin-converting enzyme inhibitor A58365A

An anodic amide oxidation based annulation procedure for fusing lactam rings onto amines has been used to construct the angiotensin-converting enzyme inhibitor A58365A.

Conformationally constrained thyroliberin analogs: a novel electrochemical route to a key rigid Pro-Phe building block

An anodic amide oxidation has been employed in the synthesis of a rigid Pro-Phe building block. The key electrochemical step allowed for the functionalization of a proline derivative and led to an annulation procedure for conveniently constructing the bicyclic ring system used to lock the dipeptide building block into a specific conformation.

ChemInform Abstract: Anodic Amide Oxidation in the Presence of Electron‐Rich Phenyl Rings: Evidence for an Intramolecular Electron‐Transfer Mechanism.

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.

Anodic amide oxidations in the presence of electron-rich phenyl rings: evidence for an intramolecular electron-transfer mechanism

The anodic oxidations of amides in the presence of mono-, di-, and trialkoxyphenyl rings were examined. For example, the anodic oxidations of ((3-methoxyphenyl)acetyl)pyrrolidine, ((2-methoxyphenyl)acetyl)pyrrolidine, ((3-methoxy-4-(pivaloyloxy)phenyl)acetyl)pyrrolidine, and ((3,5-dimethoxy-4-(pivaloyloxy)phenyl)acetyl)pyrrolidine all led to selective methoxylation of the pyrrolidine ring

Anodic amide oxidations: Fundamental studies concerning the annulation of six- and seven-membered rings onto amines

The compatibility of olefinic and acetylenic nucleophiles with an electrochemically based annulation procedure for fusing six- and seven-membered rings onto amines has been examined. Both monosubstituted olefins and acetylenes were found to be good nucleophiles for annulating seven-membered rings onto amines. Disubstituted olefins and acetylenes appear to be good nucleophiles for completing the annulation of six-membered rings onto amines. In addition, the compatibility of several proline derivatives with the annulation procedure was examined.