Large-scale asymmetric synthesis of a cathepsin S inhibitor

The Journal of Organic Chemistry
Jon C LorenzChris H Senanayake

Abstract

A potent reversible inhibitor of the cysteine protease cathepsin-S was prepared on large scale using a convergent synthetic route, free of chromatography and cryogenics. Late-stage peptide coupling of a chiral urea acid fragment with a functionalized aminonitrile was employed to prepare the target, using 2-hydroxypyridine as a robust, nonexplosive replacement for HOBT. The two key intermediates were prepared using a modified Strecker reaction for the aminonitrile and a phosphonation-olefination-rhodium-catalyzed asymmetric hydrogenation sequence for the urea. A palladium-catalyzed vinyl transfer coupled with a Claisen reaction was used to produce the aldehyde required for the side chain. Key scale up issues, safety calorimetry, and optimization of all steps for multikilogram production are discussed.

References

Jan 1, 1971·Journal of the Chemical Society. Perkin Transactions 1·A S Dutta, J S Morley
Sep 21, 2002·Chemical Communications : Chem Comm·S H Bertz
Dec 3, 2002·Journal of Medicinal Chemistry·Yancey D WardMarc Giradot
Feb 14, 2003·Organic Letters·Carl A BusaccaEarl M Spinelli
Jun 10, 2004·Chemical Reviews·Ana M Martín Castro
Aug 4, 2004·The Journal of Organic Chemistry·Carl A BusaccaChiara Zavattaro
Dec 22, 2007·Organic Letters·Carl A BusaccaChris H Senanayake
Feb 14, 2008·Expert Opinion on Therapeutic Targets·Suman GuptaAbhijit Ray

❮ Previous
Next ❯

Citations

Feb 10, 2012·Chemical Society Reviews·David J AgerJohannes G de Vries
Jul 25, 2020·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·Caroline GrundkeTill Opatz
Mar 8, 2011·Chemistry : a European Journal·Axel Franzke, Andreas Pfaltz
Feb 23, 2013·Organic Letters·Carl A BusaccaChris H Senanayake

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.