title: Synthesis and configurational assignment of the amino alcohol in the eastern fragment of the GE2270 antibiotics by regio- and stereoselective addition of 2-metalated 4-bromothiazoles to alpha-chiral electrophiles.
abstract: A synthesis of the eastern fragment of the thiazole peptide GE2270 A (1) has been developed. The synthetic approach relies on the regioselective functionalization of 2,4-dibromothiazole (5) via metalation and nucleophilic addition (at C2) or palladium-mediated cross-coupling (at C2 or C4). The stereochemistry at the N-bearing stereocenter was established by coupling of 2-metalated 4-bromothiazoles (4) to enantiomerically pure mandelic acid derivatives. Both the erythro (2) and threo (3) configurated amino alcohols were prepared with high diastereoselectivities depending on the electrophile employed. More specifically, the threo-configurated (S,R)-4-bromothiazolyl beta-amino alcohol 6 was synthesized from O-TBS protected (R)-mandelonitrile in 62% yield. Its N-PMB protected (R,S)-enantiomer 20 was obtained from O-TBS protected (S)-mandelic aldehyde in 67% yield. The erythro-configurated (S,S)-4-bromothiazolyl beta-amino alcohol 29 was prepared from O-TBS protected (S)-ethyl mandelate in four steps and 33% overall yield. The bithiazole moiety in the desired products 2 and 3 was finally established by the regioselective Negishi coupling of 2,4-dibromothiazole (5) and the 4-zincated, N-Boc protected thiazole derivatives of the diastereomeric 4-bromothiazolyl beta-amino alcohols 6 and 29.
authors.affiliation: Lehrstuhl für Organische Chemie I, Technische Universität München, D-85747 Garching, Germany.
authors.forename: Oscar
authors.initials: O
authors.lastname: Delgado
authors.forename: Golo
authors.initials: G
authors.lastname: Heckmann
authors.forename: H Martin
authors.initials: HM
authors.lastname: Müller
authors.forename: Thorsten
authors.initials: T
authors.lastname: Bach
mesh_terms: D000605:Amino Alcohols / Q000138:chemical synthesis* / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000737:chemistry*; D013237:Stereoisomerism; D013844:Thiazoles / Q000737:chemistry
chemical_list: D000605:Amino Alcohols; D000900:Anti-Bacterial Agents; D010456:Peptides, Cyclic; D013844:Thiazoles; C068122:GE 2270 A