Preparation of endothelin antagonist ABT-627

Organocatalytic Enantioselective Conjugate Addition of Nitromethane to Benzylidene-2-Benzoyl Acetate: Asymmetric Synthesis of ABT – 627, an Endothelin Receptor Antagonist

“…One of these classes of compounds is atrasentan (ABT 627), a potent selective antagonist of endothelin-A (ETA) receptor, inhibits angiogenesis and tumor cell proliferation by down regulating the endothelin-A (ETA) receptor signaling. Previously the total synthesis of ABT-627 had been achieved by employing chiral auxiliary mediated acylation (Winn et al, 1996), aldol reaction (Wittenberger and McLaughlin, 1999), and hetero Diels-Alder reaction (Buchholz and Reißig, 2003). Our journey for the catalytic enantioselective synthesis of ABT-627 began with the 1.0 mmol scale reaction of 3o with nitromethane under optimized condition.…”

Peptide Synthesis

“…Mixed anhydride formation with pivalic acid [263] as the activation reagent is sometimes recommended, especially for N a -acyl-protected asparagine. These unsymmetrical anhydrides are prepared analogously from N a -acyl amino acids and pivaloyl chloride, and react in high yields with amino nucleophiles.…”

Enantioselective Synthesis of the Pyrrolidine Core of Endothelin Antagonist ABT‐627 (Atrasentan) via 1,2‐Oxazines

“…The disadvantages of this method are poor diastereoselectivity and resolution of the enantiomers at a late stage, either by treatment of the carboxylic acid with a chiral oxazolidine and separation of the resulting diastereomers by chromatography, or by generation of a chiral salt and separation of the diastereomers by crystallisation. Wittenberger7 and Pfau8 have developed enantioselective syntheses with the use of a valine‐derived oxazolidinone or of methylbenzylamine as chiral auxiliaries. The pyrrolidine ring is formed either by a ring‐contraction of a 1,2‐oxazine, prepared by diastereoselective cyclization, or by a method similar to the original synthesis, but now with employment of an enantioselective Michael‐type reaction.…”