ChemDigest

Bulk up : A Pd‐catalyzed enantioselective β‐C(sp³)−H functionalization of thioamides has been developed using a chiral phosphoric acid (CPA) as the chiral auxiliary. Mass spectrometry studies and DFT analysis elucidate the role of the bulky CPA and the assistance of the thioamide ligand, which define a robust chiral cavity for achieving a high level of stereocontrol.

Abstract

A hybrid palladium catalyst assembled from a chiral phosphoric acid (CPA) and thioamide enables a highly efficient and enantioselective β‐C(sp³)−H functionalization of thioamides (up to 99 % yield, 97 % ee ). A kinetic resolution of unsymmetrical thioamides by intermolecular C(sp³)−H arylation can be achieved with high s‐factors. Mechanistic investigations have revealed that stereocontrol is achieved by embedding the substrate in a robust chiral cavity defined by the bulky CPA and a neutral thioamide ligand.

Peptide synthesis goes green : A water‐compatible 2,7‐disulfo‐9‐fluorenylmethoxycarbonyl (Smoc) protecting group has been developed that enables solid‐phase peptide synthesis under aqueous conditions as well as efficient postsynthetic purification of the peptides. This protecting group is fluorescent both when attached to an N_α atom and when cleaved and so also allows real‐time monitoring of building block coupling

Abstract

The growing interest in synthetic peptides has prompted the development of viable methods for their sustainable production. Currently, large amounts of toxic solvents are required for peptide assembly from protected building blocks, and switching to water as a reaction medium remains a major hurdle in peptide chemistry. We report an aqueous solid‐phase peptide synthesis strategy that is based on a water‐compatible 2,7‐disulfo‐9‐fluorenylmethoxycarbonyl (Smoc) protecting group. This approach enables peptide assembly under aqueous conditions, real‐time monitoring of building block coupling, and efficient postsynthetic purification. The procedure for the synthesis of all natural and several non‐natural Smoc‐protected amino acids is described, as well as the assembly of 22 peptide sequences and the fundamental issues of SPPS, including the protecting group strategy, coupling and cleavage efficiency, stability under aqueous conditions, and crucial side reactions.

Diethylsilane exhibits remarkable reactivity relative to typical hydrosilanes in the reduction of carbonyl compounds, imines, and amides catalyzed by Au nanoparticles.

Diethylsilane (Et₂SiH₂), a simple and readily available dihydrosilane, that exhibits superior reactivity, as compared to monohydrosilanes, in a series of reductive transformations catalyzed by recyclable and reusable Au nanoparticles (1 mol‐%) supported on TiO₂. It reduces aldehydes or ketones almost instantaneously at ambient conditions. It can be used in a one pot rapid reductive amination procedure, in which premixing of aldehyde and amine is required prior to the addition of the reducing agent and the catalyst, even in a protic solvent. An unprecedented method for the synthesis of N ‐arylisoindolines is also shown in the reductive amination between o ‐phthalaldehyde and anilines. In this transformation, it is proposed that the intermediate N ,2‐diphenylisoindolin‐1‐imines are reduced stepwise to the isoindolines. Finally, Et₂SiH₂ readily reduces amides into amines in excellent yields and shorter reaction times relative to previously known analogous nano Au⁽⁰⁾‐catalyzed protocols.

A variety of N‐methylated peptides were synthesized in high yield without severe racemization via the generation of acyl N‐methylimidazolium cations. Brønsted acids dramatically accelerated the reaction. The developed amidation reaction enabled the synthesis of a bulky peptide in higher yield and shorter reaction time in comparison with conventional amidation reactions. The first total synthesis of pterulamides I–IV was also achieved.

Abstract

The development of a robust amide‐bond formation remains a critical aspect of N‐methylated peptide synthesis. In this study, we synthesized a variety of dipeptides in high yields, without severe racemization, from equivalent amounts of amino acids. Highly reactive N‐methylimidazolium cation species were generated in situ to accelerate the amidation. The key to success was the addition of a strong Brønsted acid. The developed amidation enabled the synthesis of a bulky peptide with a higher yield in a shorter amount of time compared with the results of conventional amidation. In addition, the amidation can be performed by using either a microflow reactor or a conventional flask. The first total synthesis of naturally occurring bulky N‐methylated peptides, pterulamides I–IV, was achieved. Based on experimental results and theoretical calculations, we speculated that a Brønsted acid would accelerate the rate‐limiting generation of acyl imidazolium cations from mixed carbonic anhydrides.

Co‐Operation : An allied cooperation between cobalt catalysis and electrochemical synthesis enabled the mild catalytic carboxylation of allylic chlorides with atmospheric CO₂. The resulting products are useful as versatile synthons of γ‐arylbutyrolactones.

Abstract

The chemical use of CO₂ as an inexpensive, nontoxic C1 synthon is of utmost topical interest in the context of carbon capture and utilization (CCU). We present the merger of cobalt catalysis and electrochemical synthesis for mild catalytic carboxylations of allylic chlorides with CO₂. Styrylacetic acid derivatives were obtained with moderate to good yields and good functional group tolerance. The thus‐obtained products are useful as versatile synthons of γ‐arylbutyrolactones. Cyclic voltammetry and in operando kinetic analysis were performed to provide mechanistic insights into the electrocatalytic carboxylation with CO₂.

The first enantioselective S−H insertion reaction of α‐carbonyl sulfoxonium ylides was developed under thiourea catalysis. Up to 95 % ee and 97 % isolated yields were obtained in 31 examples.

Abstract

The first example of enantioselective S−H insertion reactions of sulfoxonium ylides is reported. Under the influence of thiourea catalysis, excellent levels of enantiocontrol (up to 95 % ee ) and yields (up to 97 %) are achieved for 31 examples in S−H insertion reactions of aryl thiols and α‐carbonyl sulfoxonium ylides.

Virtues we write in water : Cobalt‐catalyzed cycloisomerization occurs with efficiency in aqueous buffer at high dilution. A variety of putative metal hydride atom‐transfer (MHAT) reactions, including deallylation, proceed under these stringent conditions, even on DNA.

Abstract

Preparative reactions that occur efficiently under dilute, buffered, aqueous conditions in the presence of biomolecules find application in ligation, peptide synthesis, and polynucleotide synthesis and sequencing. However, the identification of functional groups or reagents that are mutually reactive with one another, but unreactive with biopolymers and water, is challenging. Shown here are cobalt catalysts that react with alkenes under dilute, aqueous, buffered conditions and promote efficient cycloisomerization and formal Friedel–Crafts reactions. The constraining conditions of bioorthogonal chemistry are beneficial for reaction efficiency as superior conversion at low catalyst concentration is obtained and competent rates in dilute conditions are maintained. Efficiency at high dilution in the presence of buffer and nucleobases suggests that these reaction conditions may find broad application.