Cysteine Borylation in Unprotected Peptides

Synthetic bioconjugation at cysteine (Cys) residues in peptides and proteins has emerged as a powerful tool in chemistry. Soft nucleophilicity of the sulfur in Cys renders an exquisite chemoselectivity with which various functional groups can be placed onto this residue under benign conditions. While a variety of reactions have been successful at producing Cys-based bioconjugates, the majority of these feature sulfur-carbon bonds. We report Cys-borylation, wherein a benchtop stable Pt(II)-based organometallic reagent can be used to transfer a boron-rich cluster onto a sulfur moiety in unprotected peptides forging a boron-sulfur bond. Discovered Cysborylation proceeds at room temperature and is tolerant to a variety of functional groups present in complex polypeptides. The resultant bioconjugates show no additional toxicity compared to their Cys aryl-based congeners. Finally, we demonstrate how the developed Cys-borylation can enhance the proteolytic stability of the produced peptide bioconjugates while maintaining the binding affinity to a protein target.

Cysteine Borylation in Unprotected Peptides

Synthetic bioconjugation at cysteine (Cys) residues in peptides and proteins has emerged as a powerful tool in chemistry. Soft nucleophilicity of the sulfur in Cys renders an exquisite chemoselectivity with which various functional groups can be placed onto this residue under benign conditions. While a variety of reactions have been successful at producing Cys-based bioconjugates, the majority of these feature sulfur-carbon bonds. We report Cys-borylation, wherein a benchtop stable Pt(II)-based organometallic reagent can be used to transfer a boron-rich cluster onto a sulfur moiety in unprotected peptides forging a boron-sulfur bond. Discovered Cysborylation proceeds at room temperature and is tolerant to a variety of functional groups present in complex polypeptides. The resultant bioconjugates show no additional toxicity compared to their Cys aryl-based congeners. Finally, we demonstrate how the developed Cys-borylation can enhance the proteolytic stability of the produced peptide bioconjugates while maintaining the binding affinity to a protein target.

Carbonyl umpolung as an organometallic reagent surrogate

Carbonyls can serve as surrogates for organometallic reagents via hydrazones.

Exploration of Mesyl Chloride in a One Pot Conversion of Carboxylic Acids to Ketones

Background: Due to the ubiquitous nature of the ketone functionality, it is considered an important functional group in organic chemistry. Hence, the synthesis of ketones from readily available starting materials is an important chemical transformation in organic synthesis. Consequently, several research efforts have been reported in the literature for the transformation of carboxylic acids to ketones in a one-pot synthesis. However, some of the procedures have limitations, such as long reaction times, harsh reaction conditions, and usage of expensive metal catalysts. Thus, a simple and convenient one-pot conversion of carboxylic acids to ketones remains desirable. Objective: We intended to develop a simple and convenient one-pot methodology for the synthesis of ketones from carboxylic acids. Our objective was to build up a carboxylic acid-based chemical template where various types of organometallic reagents can interact to produce the desired ketone. Methods: In this procedure, a carboxylic acid was converted to a mixed anhydride using mesyl chloride in the presence of a base. This mixed anhydride was then reacted with a suitable organometallic reagent at -20°C to obtain the desired ketone. The reaction was performed in a one-pot fashion. Results: Under the optimized reaction conditions, various aromatic and heteroaromatic carboxylic acids were converted to the corresponding ketones using organolithium and organomagnesium reagents with short reaction times. Moderate to good yields of the desired ketones were observed in many of these transformations. Conclusion: A simple and convenient one-pot method for the conversion of carboxylic acids to ketones has been reported. Specifically, various aromatic and `heteroaromatic carboxylic acids have been converted to the corresponding ketones in moderate to good yields. Organomagnesium and organolithium reagents were used as nucleophiles for this reaction.

One Pot Conversion of Carboxylic Acid to Ketone Using Trimethylsilyl Chloride

Background: Ketone is abundant in many natural products and in pharmaceuticals. It is believed to be one of the important functional groups in organic chemistry. Till date,several research approaches have been made to access ketone from a readily available starting materials. One such notable transformation consists of the conversion of carboxylic acid to the corresponding ketone in a one pot manner. Objective: We aimed to develop a simple one pot reaction for the conversion of carboxylic acid to ketone. This reaction could be useful to convert all types of carboxylic acid to ketone in a facile manner. Methods: In this procedure, a carboxylic acid has been converted to the corresponding trimethylsilyl ester using trimethylsilyl chloride in the presence of a base. A suitable organometallic reagent can interact with the ester formed at 20°C to produce the corresponding ketone. Results: Under the optimized reaction conditions, various aromatic, aliphatic and heteroaromatic carboxylic acids have been converted to the corresponding ketones using organolithium reagents, in a one pot manner. Moderate to good yields of the desired ketones were observed in most of the transformations. Conclusion: Conversion of carboxylic acid to ketone has been reported in a one pot fashion, where carboxylic acid has been transformed to its silyl ester. Organolithium reagents were used as nucleophile for our reaction purpose, whereas the organomagnesium reagents were not useful for this transformation. Aliphatic, aromatic and heteroaromatic carboxylic acids have been converted to the ketones following a simple process.

Recent Developments in Weinreb Synthesis and Their Applications

N-methoxy-N-methyl amides or Weinreb amides are worthy embranchment of amide group and their rich functional groups in organic synthesis become a strong else unfeasible conversion. Weinreb amides are produced as an intermediate product of the reaction of carboxylic acids, acid chloride or esters with organometallic reagents, which was first uncovered in 1981. The direct conversion of carboxylic acids or acid chlorides or esters to ketones or aldehydes using organometallic reagents do not lead in high yields, because the intermediate ketones are still highly reactive toward the organometallic reagent. However, after derivatization to the corresponding Weinreb Amide, reaction with organometallics does give the desired ketones, as the initial adduct is stabilized and doesn't undergo further reactions. A nucleophilic addition to the Weinreb amides results in a unique and stable five-membered cyclic tetrahedral intermediate which protects the over-addition, leading to a selective conversion.

A Comprehensive Review on C-3 Functionalization of β-Lactams

Background:A lot of advancement has been made in the area of β-lactams in recent times. Most of the research is targeted towards the synthesis of novel β-lactams, their functionalization and exploring their biological potential. The C-3 functionalization of β-lactams has continued to attract considerable interest of the scientific community due to their utility as versatile intermediates in organic synthesis and their therapeutic applications. This has led to the significant increase in efforts towards developing efficient and economic strategies for C-3 functionalized β-lactams.Objective:The present review aims to highlight recent advancement made in C-3 functionalization of β-lactams.Conclusion:To summarize, functionalization of β-lactams at C-3 is an essential aspect of β-lactam chemistry in order to improve/modify its synthetic utility as well as biological potential. The C-3 carbocation equivalent method has emerged as an important and convenient strategy for C-3 functionalization of β-lactam heterocycles which provides a wide range of β-lactams viz. 3-alkylated β-lactams, 3-aryl/heteroarylated β-lactams, 3- alkoxylated β-lactams. On the other hand, base mediated functionalization of β-lactams via carbanion intermediate is another useful approach but their scope is limited by the requirement of stringent reaction conditions. In addition to this, organometallic reagent mediated α-alkylation of 3-halo/3-keto-β-lactams also emerged as interesting methods for the synthesis of functionalized β-lactams having good yields and diastereoselectivities.

Rhodium(I)-Catalysed Aryl C–H Carboxylation of 2-Arylanilines with CO2

<b>An unprecedented amino-group assisted C–H carboxylation of 2-arylanilines with CO₂ under redox-neutral conditions using a Rhodium(I)-catalyst has been developed. This reaction was promoted by a phosphine ligand with <i>t</i>-BuOK as the base and did not require the use of an extra strong organometallic reagent. Notably, this protocol may involve an oxidative addition in the C–H bond cleavage step and is distinct from previous Rh(I) or Rh(II)-catalysed methods for C–H carboxylation with </b><b>CO₂ </b><b>mechanistically. It enabled an efficient direct conversion of a broad range of 2-(hetero)arylanilines including electron-deficient heteroarenes to various phenanthridinones, which could be further transformed to other synthetically useful compounds readily. Preliminary mechanistic studies were carried out and possible intermediates of the reaction were evaluated, which revealed that the Rh(I)-catalyst is essential for the C–H activation process, providing a promising general type of method for utilization of </b><b>CO₂</b><b> for C–C bond formation.</b><br>

Rhodium(I)-Catalysed Aryl C–H Carboxylation of 2-Arylanilines with CO2

<b>An unprecedented amino-group assisted C–H carboxylation of 2-arylanilines with CO₂ under redox-neutral conditions using a Rhodium(I)-catalyst has been developed. This reaction was promoted by a phosphine ligand with <i>t</i>-BuOK as the base and did not require the use of an extra strong organometallic reagent. Notably, this protocol may involve an oxidative addition in the C–H bond cleavage step and is distinct from previous Rh(I) or Rh(II)-catalysed methods for C–H carboxylation with </b><b>CO₂ </b><b>mechanistically. It enabled an efficient direct conversion of a broad range of 2-(hetero)arylanilines including electron-deficient heteroarenes to various phenanthridinones, which could be further transformed to other synthetically useful compounds readily. Preliminary mechanistic studies were carried out and possible intermediates of the reaction were evaluated, which revealed that the Rh(I)-catalyst is essential for the C–H activation process, providing a promising general type of method for utilization of </b><b>CO₂</b><b> for C–C bond formation.</b><br>