Samarium(II) folding cascades involving hydrogen atom transfer for the synthesis of complex polycycles

The expedient assembly of complex, natural product-like small molecules can deliver new chemical entities with the potential to interact with biological systems and inspire the development of new drugs and probes for biology. Diversity-oriented synthesis is a particularly attractive strategy for the delivery of complex molecules in which the 3-dimensional architecture varies across the collection. Here we describe a folding cascade approach to complex polycyclic systems bearing multiple stereocentres mediated by reductive single electron transfer (SET) from SmI2. Simple, linear substrates undergo three different folding pathways triggered by reductive SET. Two of the radical cascade pathways involve the activation and functionalization of otherwise inert secondary alkyl and benzylic groups by 1,5-hydrogen atom transfer (HAT). Combination of SmI2, a privileged reagent for cascade reactions, and 1,5-HAT can lead to complexity-generating radical sequences that unlock access to diverse structures not readily accessible by other means

SmCp^R ₂-mediated cross-coupling of allyl and propargyl ethers with ketoesters and a telescoped approach to complex cycloheptanols

A selective coupling of allyl/propargyl ethers and δ-ketoesters, mediated by SmCpR2, delivers δ-lactones, or complex cycloheptanols via a telescoped approach.</p

Samarium(II) folding cascades involving hydrogen atom transfer for the synthesis of complex polycycles

Diversity-oriented synthesis is a valuable strategy to construct complex molecules of medicinal interest. Here, the authors show a folding cascade strategy to convert linear substrates into polycyclic compounds with multiple stereocentres by combining the reductive chemistry of SmI2 with 1,5-hydrogen atom transfer

CCDC 1531051: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

CCDC 1543525: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

GEMSTONE

Experimental data for GEMSTONE and GEMSTONE-NOE NMR pulse sequences applied to estradiol, synthetic carbocycles, and a mixture of cinchona alkaloids. Supporting information for DOIs: 10.1002/anie.202011642 and 10.1002/ange.202011642

Rapid PROTAC discovery platform: nanomole scale array synthesis and direct screening of reaction mixtures to facilitate the expedited discovery and follow-up of PROTAC hits.

Precise linker length, shape and linker attachment point are all integral components to designing efficacious PROTACs. Due to the increased synthetic complexity of these heterobifunctional degraders and the difficulty of computational modelling to aid PROTAC design, the exploration of structure-activity-relationship (SAR) remains mostly empirical, which requires a significant time and resource investment. To facilitate rapid hit finding we developed capabilities for PROTAC parallel synthesis and purification by harnessing an array of pre-formed E3-ligand linker intermediates. In the next iteration of this approach, we developed a rapid, nanomole-scale PROTAC synthesis methodology using amide coupling that enables direct screening of non-purified reaction mixtures in cell-based degradation assays, as well as logD and EPSA measurements. This approach greatly expands and accelerates PROTAC SAR exploration (5 days instead of several weeks) while using nanomole amounts of reagents. Lastly, it avoids laborious and solvent-demanding purification of the reaction mixtures, thus making it an economical and more sustainable methodology for PROTAC hit finding