Aminoalcohols are vital motifs in chemical synthesis; however, traditional synthetic technologies relying on polar disconnections have various limitations. Now, such motifs can be expediently accessed by leveraging a radical-based approach, enabling the stereoselective preparation of an array of valuable building blocks.

Visible-light photocatalysis has revolutionised synthetic chemistry by enabling the generation of reactive radical intermediates under mild conditions. Yet, the application of this strategy to the stereoselective synthesis of α-non-canonical amino acids (α-ncAAs) remains underdeveloped. This thesis explores photocatalysis as a general platform for constructing stereoenriched α-ncAAs by leveraging radical precursors derived from feedstock chemicals, radical activation modes, and coupling strategies.

Four complementary methodologies were developed to access α-amino acid derivatives from distinct starting materials. Deoxygenative C–O bond activation of oxalates derived from alcohols provides entry to alkyl radicals, while α-amino C–H functionalisation using both acridinium-based single-electron transfer and decatungstate-mediated hydrogen atom transfer delivered α-amino radicals and implemented these species into a C–C bond-forming transformation. A redox-neutral pathway was established for thioether activation, generating α-thioalkyl radicals directly from sulfides, and energy transfer catalysis was applied to oxime esters to forge quaternary α,α-disubstituted amino acids via radical–radical coupling.

Mechanistic studies, including quenching experiments, cyclic voltammetry, and computational investigations, elucidated the modes of radical generation and capture across these systems. Collectively, these findings demonstrate that the mechanisms accessible via visible-light photocatalysis, such as single-electron, proton-coupled electron transfer, and energy transfer, can be used as strategies for the synthesis of amino acids. The resulting methodologies not only expand the synthetic repertoire of radical chemistry but also establish new mechanistic paradigms for the stereocontrolled formation of α-ncAAs under photochemical conditions.

Fotokatalys med synligt ljus har revolutionerat den syntetiska kemin genom att möjliggöra genereringen av reaktiva radikalintermediärer under milda betingelser. Tillämpningen av denna strategi för stereoselektiv syntes av icke-kanoniska aminosyror är dock fortfarande begränsad, främst på grund av svårigheten att kontrollera intermediärer med oparade elektroner. Denna avhandling undersöker fotokatalys som en generell plattform för konstruktion av stereoanrikade icke-kanoniska aminosyror genom utvecklingen av nya radikalprekursorer, aktiveringsmoder och kopplingsstrategier.

Fyra kompletterande metoder har utvecklats för att erhålla α-aminosyraderivat från olika utgångsmaterial. Deoxygenerande C–O bindningsaktivering av oxalater härledda från alkoholer gav en modulär ingång till alkylradikaler, medan α-amino-C–H funktionalisering via akridiniumbaserad en-elektronöverföring eller volfram-medierad väteatomöverföring genererade α-aminoradikaler. En redox-neutral reaktionsväg etablerades för tioeteraktivering, vilket möjliggjorde bildning av α-tioalkylradikaler direkt från sulfider, och energiöverföringskatalys tillämpades på oximestrar för att framställa kvaternära α,α-disubstituerade aminosyror via radikal-radikalkoppling.

Mekanistiska studier, inklusive quenchningsförsök, cyklisk voltammetri och beräkningskemi, belyste mekanismerna för radikalbildning och efterföljande reaktioner i dessa system. Sammantaget visar resultaten att fotokatalys med synligt ljus kan förena en-elektronöverföring, proton-kopplad elektronöverföring och energiöverföringsprocesser i en sammanhängande strategi för syntes av aminosyror. De utvecklade metoderna utvidgar inte bara den syntetiska repertoaren inom radikalkemin, utan etablerar också nya mekanistiska paradigm för stereokontrollerad bildning av C–C bindningar under fotokemiska betingelser.

Herein, we present a prominent metal-free C–N cross-coupling platform that enables access to carbamoyl- and ketoazides from isocyanides or silyl enol ethers and trimethylsilyl azide (TMSN3) with an aid of iodine(III) promoter. This offers a rapid route to a diverse set of synthetically valuable azide decorated fragments with excellent substrate scope and good to excellent yields. The disclosed platform exemplifies the use of TMSN3 for incorporation of the azide fragment without the loss of N2.

Unnatural α-amino acids constitute a fundamental class of biologically relevant compounds. However, despite the interest in these motifs, synthetic strategies have traditionally employed polar retrosynthetic disconnections. These methods typically entail the use of stoichiometric amounts of toxic and highly sensitive reagents, thereby limiting the substrate scope and practicality for scale up. In this work, an efficient protocol for the asymmetric synthesis of unnatural α-amino acids is realized through photoredox-mediated C-O bond activation in oxalate esters of aliphatic alcohols as radical precursors. The developed system uses a chiral glyoxylate-derived N-sulfinyl imine as the radical acceptor and allows facile access to a range of functionalized unnatural α-amino acids through an atom-economical redox-neutral process with CO₂ as the only stoichiometric byproduct.

Herein, we report a silver-catalyzed protocol for decarboxylative cross-coupling between carboxylic acids and isocyanides, leading to linear amide products through a free-radical mechanism. The disclosed approach provides a general entry to a variety of decorated amides, accommodating a diverse array of radical precursors, including aryl, heteroaryl, alkynyl, alkenyl, and alkyl carboxylic acids. Notably, the protocol proved to be efficient for decarboxylative late-stage functionalization of several elaborate pharmaceuticals, demonstrating its potential applications.

Herein, a straightforward synthetic approach for the construction of phenanthridin-6(5H)-one skeletons is disclosed. The developed protocol relies on palladium catalysis, providing controlled access to a range of functionalized phenanthridin-6(5H)-ones in 59-88% yields. Furthermore, plausible reaction pathways are proposed based on mechanistic experiments.

Establishing chemodivergent synthetic strategies remains a daunting task in the realm of free-radical reaction manifolds. In the December issue of Chem, Glorius and co-workers resolve this challenge for selective difunctionalization of aliphatic alkenes. In the disclosed light-promoted radical relay process, switchable trifluoromethylation/alkylation or trifluoromethylation/sulfonylation of alkenes is achieved.

The Wittig reaction is a valuable and powerful tool in organic synthesis, providing a convenient route from aldehydes and ketones to alkenes. Herein, a novel copper-assisted Wittig-type olefination of aldehydes with p-toluenesulfonylmethyl isocyanide (TosMIC) is disclosed, providing a direct and operationally simple approach to (E)-vinyl sulfones under mild conditions, compatible with a multitude of common functional groups. Experimental and computational investigations imply that the reaction proceeds through an intriguing electronically-controlled (3 + 2)/retro-(3 + 2) cycloaddition pathway.

A protocol for silver-catalyzed controlled intermolecular cross-coupling of silyl enolates is disclosed. The protocol displays good functional group tolerance and allows efficient preparation of a series of synthetically useful 1,4-diketones. Preliminary mechanistic investigations suggest that the reaction proceeds through a one-electron process involving free radical species in which PhBr acts as the oxidant. 

A protocol for a tandem Pd/Cu-catalyzed intermolecular cross-coupling cascade between o-bromobenzoic acids and 2-(2-bromoaryl)-1H-benzo[d]imidazoles or the corresponding imidazoles is presented. The protocol provides conceptually novel and controlled access to synthetically useful N-fused (benzo)imidazophenanthridine scaffolds with high efficiency, a broad substrate scope, and excellent functional group compatibility.