title: Synthesis and functionalization of cyclic sulfonimidamides: a novel chiral heterocyclic carboxylic Acid bioisostere.
abstract: An efficient synthesis of aryl substituted cyclic sulfonimidamides designed as chiral nonplanar heterocyclic carboxylic acid bioisosteres is described. The cyclic sulfonimidamide ring system could be prepared in two steps from a trifluoroacetyl protected sulfinamide and methyl ester protected amino acids. By varying the amino acid, a range of different C-3 substituted sulfonimidamides could be prepared. The compounds could be further derivatized in the aryl ring using standard cross-coupling reactions to yield highly substituted cyclic sulfonimidamides in excellent yields. The physicochemical properties of the final compounds were examined and compared to those of the corresponding carboxylic acid and tetrazole derivatives. The unique nonplanar shape in combination with the relatively strong acidity (pK a 5-6) and the ease of modifying the chemical structure to fine-tune the physicochemical properties suggest that this heterocycle can be a valuable addition to the range of available carboxylic acid isosteres.
authors.affiliation: Medicinal Chemistry, AstraZeneca R&D , SE-431 83 Mölndal, Sweden.
authors.forename: Nils
authors.initials: N
authors.lastname: Pemberton
authors.affiliation: Medicinal Chemistry, AstraZeneca R&D , SE-431 83 Mölndal, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Graden
authors.affiliation: Medicinal Chemistry, AstraZeneca R&D , SE-431 83 Mölndal, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Evertsson
authors.affiliation: Medicinal Chemistry, AstraZeneca R&D , SE-431 83 Mölndal, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Bratt
authors.affiliation: Medicinal Chemistry, AstraZeneca R&D , SE-431 83 Mölndal, Sweden.
authors.forename: Matti
authors.initials: M
authors.lastname: Lepistö
authors.affiliation: Medicinal Chemistry, AstraZeneca R&D , SE-431 83 Mölndal, Sweden.
authors.forename: Petra
authors.initials: P
authors.lastname: Johannesson
authors.affiliation: AstraZeneca Pharm. Dev., AstraZeneca R&D , SE-151 85 Södertälje, Sweden ; Department of Applied Physical Chemistry, Royal Institute of Technology , SE-100 44 Stockholm, Sweden.
authors.forename: Per H
authors.initials: PH
authors.lastname: Svensson
keywords: Carboxylic acid bioisostere; acidic heterocycle; bioisostere; chiral heterocycle; sulfonimidamide