A Practical Enantioselective Synthesis of a Novel Peptide Deformylase Inhibitor

Abstract

A practical synthesis of the peptide deformylase inhibitor LBM415,(2S)-N-(5-fluoro-1-oxido-2-pyridinyl)-1-[(2R)-2-[(formylhydroxyamino)methyl]-1-oxohexyl]-2-pyrrolidinecarboxamide, magnesium salt 11, is described. The key chiral intermediate, (2S)-N-(5-fluoro-2-pyridinyl)-1-[(2R)-2-[[formyl(phenylmethoxy)amino]methyl]-1-oxohexyl]-2-pyrrolidinecarboxamide 8, was made by coupling the corresponding amino acid 7 with the carboxamide 25 prepared from L-proline and 2-amino-5fluoropyridine. Following oxidation of the pyridine nitrogen, selective hydrogenolysis of the benzyl group afforded the free acid of the drug substance, which was converted to the magnesium salt in situ with magnesium chloride. The product was obtained in an overall yield of 16% with an ee > 99%.

Synthesis of Akt Inhibitor Ipatasertib. Part 2. Total Synthesis and First Kilogram Scale-up

“…The scale-up process to access β 2 -amino acid ( S )- 2 using Evans’s chiral auxiliary is illustrated in Scheme . For preparation of acyl oxazolidinone derivative ( R )- 17 , the carboxylic acid 15 was activated via the mixed anhydride method with pivaloyl chloride.…”

Preparation of perfluoroalkane-tagged chiral auxiliaries and their application to stereoselective synthesis of a β2-amino acid building block

“…6,7 A key aspect of this protocol was the application of FSPE purification techniques. As the fluorous tagged chiral auxiliaries 3d, 3e and 6 showed similar chromatographic behavior in several elution and separation experiments we choose 6 and ent-6 as auxiliaries in an asymmetric synthesis on larger scale due to the ease of synthesis.…”

“…[1][2][3] In this paper we report the short and efficient synthesis of perfluoroalkane tagged chiral DIOZ auxiliaries and their application to a novel synthesis of β 2 -phenylalanine. [4][5][6] …”

Synthesis and In Vitro Antibacterial Activity of (2S)‐N‐(Substitutedphenyl)‐1‐[(2R)‐2‐[(Formylhydroxyamino)Methyl]‐1‐Oxohexyl]‐2‐Pyrrolidinecarboxamides as Potential Peptide Deformylase Inhibitors

“…Finally, iodotrimethylsilane (TMSI) was selected for the deprotection of 1m and 1v (15,16). The intermediate (2 R )‐2‐[formyl(phenylmethoxy)amino]methylhexanoic acid dicyclohexylamine salt 3 , prepared following the published way (17,18), was activated with O ‐(7‐azabenzotriazol‐1‐yl)‐ N , N , N′ , N′ ‐tetramethyluronium hexafluorophosphate (HATU) and N , N ‐diisopropylethylamine (DIEA) (19), and then coupled with ( 2 S )‐ N ‐(substitutedphenyl)‐2‐pyrrolidinecarboxamide 2 to give (2 S )‐ N ‐(substitutedphenyl)‐1‐[(2 R )‐2‐[[formyl (phenylmethoxy)amino]methyl]‐1‐oxohexyl]‐2‐pyrrolidinecarboxamides 4 . Compound 4 was then subjected to debenzylation by palladium‐catalysed (Pd/C) hydrogenation affording compounds 5a – 5v (20).…”