Addressing Reproducibility Challenges in High-Throughput Photochemistry.

Light-mediated reactions have emerged as an indispensable tool in organic synthesis and drug discovery, enabling novel transformations and providing access to previously unexplored chemical space. Despite their widespread application in both academic and industrial research, the utilization of light as an energy source still encounters challenges regarding reproducibility and data robustness. Herein we present a comprehensive head-to-head comparison of commercially available batch photoreactors, alongside the introduction of the use of batch and flow photoreactors in parallel synthesis.

Enabling Deoxygenative C(sp)-C(sp) Cross-Coupling for Parallel Medicinal Chemistry.

Herein we report the development of an automated deoxygenative C(sp)-C(sp) coupling of aryl bromide with alcohols to enable parallel medicinal chemistry. Alcohols are among the most diverse and abundant building blocks, but their usage as alkyl precursors has been limited. Although metallaphotoredox deoxygenative coupling is becoming a promising strategy to form C(sp)-C(sp) bond, the reaction setup limits its widespread application in library synthesis.

Accelerated Synthesis of Bicyclo[1.1.1]pentylamines: A High-Throughput Approach.

Strained bicyclic substructures such as bicyclo[1.1.1]pentylamines (BCPAs) are increasingly targeted in medicinal chemistry as arylamine bioisosteres.

Copper-Catalyzed Enantioselective Construction of Tertiary Propargylic Sulfones.

Tertiary propargylic sulfones are of significant importance in organic synthesis and medicinal chemistry, but to date no general asymmetric synthesis approach has been developed. We disclose a versatile copper-catalyzed sulfonylation of propargylic cyclic carbonates using sodium sulfinates that allows the construction of propargylic sulfones featuring elusive quaternary stereocenters. This method provides the first successful example of such an enantioselective propargylic sulfonylation, features high asymmetric induction, wide functional group tolerance, and scalability, and enables attractive product diversification.

Catalytic Transformations of Functionalized Cyclic Organic Carbonates.

Functionalized cyclic organic carbonates and related heterocycles have emerged as highly versatile heterocyclic substrates for ring-opening and decarboxylative catalytic transformations allowing for the development of new stereo- and enantioselective C-N, C-O, C-C, C-S and C-B bond formation reactions. Transition-metal-mediated conversions have only recently been rejuvenated as powerful approaches towards the preparation of more complex molecules. This minireview will highlight the potential of cyclic carbonates and structurally related heterocycles with a focus on their synthetic value and the mechanistic manifolds that are involved upon their conversion.

A Domino Process toward Functionally Dense Quaternary Carbons through Pd-Catalyzed Decarboxylative C(sp)-C(sp) Bond Formation.

An efficient protocol was developed to construct functionally dense quaternary carbons with concomitant formation of a new Csp-Csp bond via Pd-catalyzed decarboxylative transformation of vinyl cyclic carbonates. This redox-neutral catalytic system features stereocontrolled formation of multisubstituted allylic scaffolds with an aldehyde functionality generated in situ, and it typically can be performed at room temperature without any additives. DFT calculations provide a rationale toward the selective formation of these compounds and reveal a complex mechanism that with the help of microkinetic models is able to reproduce the nontrivial dependence of the identity of the product on the nature of the substituents in the substrate.

Copper-Mediated S2' Allyl-Alkyl and Allyl-Boryl Couplings of Vinyl Cyclic Carbonates.

A method for the copper-catalyzed borylmethylation and borylation of vinyl cyclic carbonates through an S2' mechanism is reported. These singular reactions involve selective S2' allylic substitutions with concomitant ring opening of the cyclic carbonate and with extrusion of CO and formation of a useful hydroxyl functionality in a single step. The stereoselectivity of the homoallylic borylation and allylic borylation processes can be controlled, and synthetically useful unsaturated (E)-pent-2-ene-1,5-diols and (E)-but-2-ene-1,4-diols are accessed.

Copper-Catalyzed Synthesis of γ-Amino Acids Featuring Quaternary Stereocenters.

The first general asymmetric synthesis of γ,γ-disubstituted γ-amino acids by copper-catalyzed ring opening of nonstrained lactones with amines is reported. This approach features ample scope, operational simplicity, and wide functional-group diversity. The catalytic process allows access to a series of highly functionalized enantioenriched γ-amino acids featuring quaternary stereocenters with excellent enantiomeric ratios of up to 98:2 and excellent yields of up to 98 %.

Metal-Free Synthesis of N-Aryl Amides using Organocatalytic Ring-Opening Aminolysis of Lactones.

Catalytic ring-opening of bio-sourced non-strained lactones with aromatic amines can offer a straightforward, 100 % atom-economical, and sustainable pathway towards relevant N-aryl amide scaffolds. Herein, the first general, metal-free, and highly efficient N-aryl amide formation is reported from poorly reactive aromatic amines and non-strained lactones under mild operating conditions using an organic bicyclic guanidine catalyst. This protocol has high application potential as exemplified by the formal syntheses of drug-relevant molecules.

Palladium-Catalyzed Stereoselective Formation of Substituted Allylic Thioethers and Sulfones.

A general method is reported for the stereoselective preparation of highly functionalized allylic thioethers. This protocol is based on a Pd-catalyzed thiolation of modular vinyl cyclic carbonate substrates and features high (Z)-selectivity, good yields, minimal waste, ample product scope, and operational simplicity. A one-pot strategy was used for the stereoselective formation of pharma-relevant allylic sulfones derived from their in situ prepared thioether precursors.