Enantioselective Copper-Catalysed Propargylic Substitution: Synthetic Scope Study and Application in Formal Total Syntheses of (+)-Anisomycin and (−)-Cytoxazone

• Published in: Chemistry : a European journal Vol. 17; no. 21; pp. 5921 - 5930
• Main Authors: Detz, Remko J., Abiri, Zohar, le Griel, Remi, Hiemstra, Henk, van Maarseveen, Jan H.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 16.05.2011; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Subjects: Alkenes - chemistry; Amines; Amines - chemistry; Anisomycin - chemical synthesis; Anisomycin - chemistry; Antibiotics; asymmetric catalysis; Carbon; Catalysis; Chemistry; Chemistry, Multidisciplinary; copper; Copper - chemistry; Cytokines; Esters; homogeneous catalysis; Ligands; Modulators; Molecular Structure; Nucleophiles; Oxazoles - chemical synthesis; Oxazoles - chemistry; Physical Sciences; propargylic substitution; Pyridines - chemistry; Science & Technology; Stereoisomerism; synthetic methods; ASYMMETRIC-SYNTHESIS; STEREOSPECIFIC SYNTHESIS; asymmetric catalysis; (-)-ANISOMYCIN; ANISOMYCIN; ALCOHOLS; homogeneous catalysis; ABSOLUTE-CONFIGURATION; propargylic substitution; BIOLOGICAL EVALUATION; copper; CYTOKINE MODULATOR; STEREOSELECTIVE-SYNTHESIS; INHIBITORS; synthetic methods
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201003727

A copper catalyst with a chiral pyridine‐2,6‐bisoxazoline (pybox) ligand was used to convert a variety of propargylic esters with different side chains (R=Ar, Bn, alkyl) into their amine counterparts in very high yields and with good enantioselectivities (up to 90 % enantiomeric excess (ee)). Different amine nucleophiles were applied in the reactions and the highest enantioselectivities were obtained for aniline and its analogues. Interestingly, some carbon nucleophiles could also be used and with indoles excellent ee values were obtained (up to 98 % ee). The versatility of the propargylic amines obtained was demonstrated by their further elaboration to formal total syntheses of the antibiotic (+)‐anisomycin and the cytokine modulator (−)‐cytoxazone. Acetylenes with chiral neighbours: CuI‐catalysed enantioselective propargylic substitution starting from propargylic acetates and a variety of N‐ and C‐centred nucleophiles gives facile access to chiral propargylic compounds (see scheme). The synthetic scope of the methodology is discussed together with formal total syntheses of (+)‐anisomycin and (−)‐cytoxazone.