RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.

Over the last several years, radical‐mediated decarboxylative cross‐coupling reactions employing alkyl carboxylic acids have emerged as a powerful tool for the regiospecific construction of carbon−carbon bonds. Under thermal or photocatalytic conditions, a wide variety of C(sp3)‐carboxylic acids and their redox‐active esters undergo decarboxylative C−C bond formation with suitable reactant partners, leading to complex chemical scaffolds with wide‐ranging applications. This synthetic strategy has several advantages over the more conventional organometallic reagents, including abundant starting material availability and high functional group tolerance associated with the mild reaction conditions. This review article highlights recent developments in the functionalization of α‐heteroatom‐substituted carboxylic acids as well as the more challenging unactivated acids, with representative examples discussed against the backdrop of insightful comments on reaction mechanisms. In addition, examples of the synthesis of natural products, drug molecules, and the late‐stage modification of bioactive molecules employing this non‐traditional C−C bond formation strategy are included. This review has been categorized into three main sections that are organized around the type of C−C bond being forged: C(sp3)−C(sp2), C(sp3)−C(sp3), and C(sp3)−C(sp). Further, the reactions of carboxylic acids and their redox‐active esters have been organized separately in each section.

No abstract

In the presence of allyl tri-n-butyltin--AIBN, cyclopropylmethyl bromides/xanthates undergo ring-opening reaction with concomitant formation of geminal diallyl derivatives in good yields. The ring closing metathesis reactions on geminal diallyl derivatives with Grubbs' catalyst provided spirocyclopentenyl products. Combination of these two methodologies has been applied to the synthesis of mono-, bis-cyclopentyl-carbohydrates as well as spirocyclopentylproline derivatives.

No abstract

A versatile approach to construct gem-diallyl functionality has been described.

An enantioselective synthesis of (S)-7-amino-5H, 7H-dibenzo[b,d]azepin-6-one (S-1) is described. The key step in the sequence involved crystallization-induced dynamic resolution (CIDR) of compound 7 using Boc-D-phenylalanine as a chiral resolving agent and 3,5-dichlorosalicylaldehyde as a racemization catalyst to afford S-1 in 81% overall yield with 98.5% enantiomeric excess.

No abstract