Beyond the Rule of 5: Impact of PEGylation with Various Polymer Sizes on Pharmacokinetic Properties, Structure-Properties Relationships of mPEGylated Small Agonists of TGR5 Receptor.

PEGylation of therapeutic agents is known to improve the pharmacokinetic behavior of macromolecular drugs and nanoparticles. In this work, we performed the conjugation of polyethylene glycols (220-5000 Da) to a series of non-steroidal small agonists of the bile acids receptor TGR5. A suitable anchoring position on the agonist was identified to retain full agonistic potency with the conjugates.

Asymmetric Sulfur-Ylide-Mediated Formal [4+1]-Annulation Reaction: Scope and Mechanism.

A formal [4+1]-annulation strategy between sulfur ylides and 1,3-dienes was developed to afford functionalized cyclopentanoids. The process consists of a stereoselective cyclopropanation reaction followed, in situ, by a stereospecific MgI -catalyzed vinylcyclopropane-cyclopentene rearrangement. The use of chiral sulfur ylides provided cyclopentanoids with excellent enantiocontrol.

Rhodium-Catalyzed Alkene Difunctionalization with Nitrenes.

The Rh(II) -catalyzed oxyamination and diamination of alkenes generate 1,2-amino alcohols and 1,2-diamines, respectively, in good to excellent yields and with complete regiocontrol. In the case of diamination, the intramolecular reaction provides an efficient method for the preparation of pyrrolidines, and the intermolecular reaction produces vicinal amines with orthogonal protecting groups. These alkene difunctionalizations proceed by aziridination followed by nucleophilic ring opening induced by an Rh-bound nitrene generated in situ, details of which were uncovered by both experimental and theoretical studies.

Formal Asymmetric (4+1) Annulation Reaction between Sulfur Ylides and 1,3-Dienes.

A highly enantioselective synthesis of functionalized cyclopentanoids by a formal asymmetric (4+1) annulation strategy was developed. The methodology consists of a stereoselective cyclopropanation reaction between chiral sulfur ylides and 1,3-dienes followed by a, in situ, stereospecific MgI2 -catalyzed rearrangement of vinylcyclopropanes. This method is distinguished by a remarkable compatibility with functional groups and a high stereocontrol.

Nitrene chemistry in organic synthesis: still in its infancy?

The element nitrogen is essential to life. Considerable attention is thus paid to the development of synthetic methods for its introduction into molecules. Nitrenes, long regarded as highly reactive but poorly selective species, have recently emerged as useful tools for the formation of C-N bonds.