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.
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.
Delgado
Oscar
O
Lehrstuhl für Organische Chemie I, Technische Universität München, D-85747 Garching, Germany.
Heckmann
Golo
G
Müller
H Martin
HM
Bach
Thorsten
T
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
D000605:Amino Alcohols; D000900:Anti-Bacterial Agents; D010456:Peptides, Cyclic; D013844:Thiazoles; C068122:GE 2270 A