ABSTRACT
We demonstrate the application of ligand-to-metal charge transfer (LMCT) excitation to the direct catalytic generation of energetically challenging alkoxy radicals from alcohols through a coordination-LMCT-homolysis process with an abundant and inexpensive cerium salt as the catalyst. This catalytic manifold provides a simple and efficient way to utilize the characteristic reactivity and selectivity of transient alkoxy radicals for δ-selective C-H bond functionalization. Under mild redox-neutral conditions without the need for prefunctionalization, this method provides a versatile platform to access molecular complexity from simple and abundant alcohols.
ABSTRACT
Synthetic modification of cyclosporin A at P3-P4 positions led to the discovery of NIM258, a next generation cyclophilin inhibitor with excellent anti-hepatitis C virus potency, with decreased transporter inhibition, and pharmacokinetics suitable for coadministration with other drugs. Herein is disclosed the evolution of the synthetic strategy to from the original medicinal chemistry route, designed for late diversification, to a convergent and robust development synthesis. The chiral centers in the P4 fragment were constructed by an asymmetric chelated Claisen rearrangement in the presence of quinidine as the chiral ligand. Identification of advanced crystalline intermediates enabled practical supply of key intermediates. Finally, macrocyclization was carried out at 10% weight concentration by a general and unconventional "slow release" concept.
Subject(s)
Antiviral Agents/chemistry , Cyclosporine/chemistry , Hepacivirus/physiology , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Cyclization , Cyclosporine/chemical synthesis , Cyclosporine/pharmacology , Dipeptides/chemical synthesis , Dipeptides/chemistry , Drug Design , Quinidine/chemistry , Stereoisomerism , Virus Replication/drug effectsABSTRACT
Myxomas are the most common type of primary cardiac tumors. We report our use of totally thoracoscopic surgery in resecting cardiac myxomas in 12 cases with 10 in the left atria and 2 in the right atria. Totally thoracoscopic surgical resection of myxoma was successfully performed in all cases through three minimal incisions, with the largest incision less than 3 cm. The cardiopulmonary bypass time was 96 to 126 minutes, and the aortic cross-clamp time was 46 to 63 minutes. Postoperative ventilation assistance was 3 to 11 hours. We show that the method is safe and achieves complete tumor resection.