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Proteolysis‐targeting chimeras (PROTACs) have recently emerged as powerful molecules for targeted protein degradation. As such, synthetic methods for their modular synthesis are of prime importance in medicinal chemistry. We report the development of both batch and flow photoredox methodologies for Csp3−Csp2 cross‐electrophile couplings of alkyl bromides with E3 ligase‐binding aryl bromides (thalidomide and lenalidomide derivatives). Despite the challenging reaction system, containing several insoluble species, conditions were discovered to facilitate stable processing in an oscillatory flow photochemical reactor. The flow approach can enable processing of larger material quantities in a shorter time period. A range of saturated linker molecules, with various functional handles, were successfully combined with four ligand variants using the developed conditions. Finally, scalability in batch and use of an organic photocatalyst were explored. [ABSTRACT FROM AUTHOR]

Taking advantage of the C 2 -symmetry of the antitumor naturally occurring disorazole B 1 molecule, a symmetrical total synthesis was devised with a monomeric advanced intermediate as the key building block, whose three-step conversion to the natural product allowed for an expeditious entry to this family of compounds. Application of the developed synthetic strategies and methods provided a series of designed analogues of disorazole B 1 , whose biological evaluation led to the identification of a number of potent antitumor agents and the first structure-activity relationships (SARs) within this class of compounds. Specifically, the substitutions of the epoxide units and lactone moieties with cyclopropyl and lactam structural motifs, respectively, were found to be tolerable for biological activities and beneficial with regard to chemical stability.

Modular syntheses of disorazoles A 1 and B 1 analogues in which the epoxide moieties of the natural products were replaced with cyclopropyl units have been achieved. Targeted as part of a structure-activity relationships study, these syntheses were successfully extended to the thiazole counterparts of these analogues. The retrosynthetically defined fragments were assembled through Yamaguchi esterification, Cu/Pd-catalyzed cross-coupling, Yamaguchi macrolactonization, and Cu-catalyzed cross-coupling as the key reactions. Further synthetic and biological investigations of such analogues are expected to lead to the discovery and development of potential payloads for antibody-drug conjugates as targeted cancer therapies.

Here, we describe an efficient and diversity-oriented entry to both (-)-artemisinin (1) and its natural antipode (+)-artemisinin, starting from commercially and readily available S-(+)- and R-(-)-citronellene, respectively. Subsequently, we answered the still open question regarding the specificity of artemisinins action. By using a drug-sensitive Plasmodium falciparum NF54 strain, we showed that the antimalarial activity of artemisinin is not stereospecific. Our straightforward and biomimetic approach to this natural endoperoxide enables the synthesis of artemisinin derivatives that are not accessible through applying current methods and may help to address the problem of emerging resistance of Plasmodium falciparum towards artemisinin., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A straightforward synthesis of C-nor-D-homo steroids starting from (+)-Wieland-Miescher ketone is reported. This convergent synthetic strategy utilizes a scalable diastereoselective Nazarov cyclization of functionalized chiral aryl vinyl ketones, allowing for further functionalization. The ability to conduct this key transformation on a multi-gram scale paves the way for the synthesis of a variety of completely new C-nor-D-homo steroids, without the need of a classic steran steroid rearrangement or achiral linear reaction sequences., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)