Route exploration and synthesis of the reported pyridone-based PDI inhibitor STK076545

Abstract

The enzyme protein disulfide isomerase (PDI) is essential for the correct folding of proteins and the activation of certain cell surface receptors, and is a promising target for the treatment...

A Mild and Highly Diastereoselective Preparation of N-Alkenyl-2-Pyridones via 2-Halopyridinium Salts and Aldehydes

“…The major Z stereoisomer was assigned on the basis of 1 H NMR spectroscopy and by analogy to previously reported compounds. 9 Specifically, the vinylic hydrogen H a appears significantly downfield (∼7.9 ppm) in the Z isomer (shown) compared to the E diastereomer (H a ∼ 7.0 ppm). This structural assignment was later confirmed through X-ray crystallography ( vide infra ).…”

“…4 , 5 , 8 − 27 While a straightforward means of obtaining N -alkyl-2-pyridones is through direct N -alkylation of 2-hydroxypyridine (2-pyridone), this method often suffers from competitive O -alkylation. 9 , 28 − 32 Methods to isomerize 2-alkoxypyridines to N -alkyl-2-pyridones ( O - to N - alkyl migration) using transition metal catalysts or Brønsted/Lewis acid promoters have also been described. 14 , 17 , 19 − 23 , 25 − 27 …”

“… 35 Aldol-type condensations between preformed N -alkylpyridones and aldehydes is of potentially wide scope and delivers more complex olefin substitution patterns ( Scheme 1 d). 4 , 5 , 9 However, this tactic requires the use of strong base and preparation of the N -alkylpyridone reactants often suffer from competitive O -alkylations to provide product mixtures that require careful purification. 9 , 28 , 29 We envisioned a new strategy to access N -alkenyl-2-pyridones that relies on aldol like condensations between N -alkyl-2-halopyridinium salts and aldehydes in order to circumvent shortcomings of the aforementioned methods ( Scheme 1 e).…”

“…4 , 5 , 9 However, this tactic requires the use of strong base and preparation of the N -alkylpyridone reactants often suffer from competitive O -alkylations to provide product mixtures that require careful purification. 9 , 28 , 29 We envisioned a new strategy to access N -alkenyl-2-pyridones that relies on aldol like condensations between N -alkyl-2-halopyridinium salts and aldehydes in order to circumvent shortcomings of the aforementioned methods ( Scheme 1 e). Specifically, using 2-halopyridinium salts as precursors to 2-pyridones obviates issues related to N - versus O -pyridone alkylation while simultaneously activating the 2-halo substituent toward substitution with an O nucleophile ( vide infra ).…”

Pd-Catalyzed Regio- and Enantioselective Aminoarylation of Allenols with Aryl Iodides and 2-Pyridones

“…C hiral N-substituted 2-pyridones have emerged as useful motifs in many natural products and medicinally relevant agents, as exemplified by aspernigrin B 1 isolated from Axinella damicornis and Aspergillus welwitschiae CUGBMF180262, respectively, human rhinovirus 3C protease inhibitors, 2 GDC-0994 as an extracellular-signal-regulated kinase inhibitor 3 (Figure 1), and many others. 4 In this context, the development of synthetic approaches to chiral N-substituted 2-pyridone derivatives became an important goal in pharmaceutical research and drug discovery. In general, they are prepared via stereoselective nucleophilic substitution of 2-pyridones to chiral electrophiles, or by the reaction of 2H-pyran-2-ones with chiral amines.…”