Current Challenges in Small Molecule Proximity-Inducing Compound Development for Targeted Protein Degradation Using the Ubiquitin Proteasomal System.

Bivalent proximity-inducing compounds represent a novel class of small molecule therapeutics with exciting potential and new challenges. The most prominent examples of such compounds are utilized in targeted protein degradation where E3 ligases are hijacked to recruit a substrate protein to the proteasome via ubiquitination. In this review we provide an overview of the current state of E3 ligases used in targeted protein degradation, their respective ligands as well as challenges and opportunities that present themselves with these compounds.

A Vicinal Diol Approach for the Total Synthesis of Molestin E, ent-Sinulacembranolide A and ent-Sinumaximol A.

In this work an approach for the synthesis of furanocembranoid natural products containing the C-7,8-diol moiety is disclosed. This culminated in the first total synthesis of the natural product molestin E, together with ent-sinulacembranolide A and ent-sinumaximol A as well as a thorough exploration of their chemistry. Late-stage ring-closure of the C-7,8-diols to the corresponding epoxides was also demonstrated.

Control of Absolute Stereochemistry in Transition-Metal-Catalysed Hydrogen-Borrowing Reactions.

Hydrogen-borrowing catalysis represents a powerful method for the alkylation of amine or enolate nucleophiles with non-activated alcohols. This approach relies upon a catalyst that can mediate a strategic series of redox events, enabling the formation of C-C and C-N bonds and producing water as the sole by-product. In the majority of cases these reactions have been employed to target achiral or racemic products.

Selective Inhibitors of Helicobacter pylori Methylthioadenosine Nucleosidase and Human Methylthioadenosine Phosphorylase.

Bacterial 5'-methylthioadenosine/ S-adenosylhomocysteine nucleosidase (MTAN) hydrolyzes adenine from its substrates to form S-methyl-5-thioribose and S-ribosyl-l-homocysteine. MTANs are involved in quorum sensing, menaquinone synthesis, and 5'-methylthioadenosine recycling to S-adenosylmethionine. Helicobacter pylori uses MTAN in its unusual menaquinone pathway, making H.

Photocatalytic reverse polarity Povarov reaction.

A visible light mediated iridium photocatalysed reverse polarity Povarov reaction of aryl imines and electron deficient alkenes is described. Operating a putative nucleophilic α-amino radical, generated by a proton coupled electron transfer process, addition to a range of conjugated electron deficient alkene substrates affords substituted tetrahydroquinoline products in high yields and with typically good to excellent diastereoselectivity in favor of the diastereoisomer. Sub-stoichiometric quantities of Hantzsch ester were found to be key to initiate the overall redox-neutral, free radical cyclization cascade.