Practical syntheses of enantiomerically pure N-acetylbenzhydrylamines

• Published in: European Journal of Organic Chemistry
• Main Authors: Castagnolo, Daniele, Spinosa, Raffaella, GIORGI, GIANLUCA, CORELLI, FEDERICO, BOTTA, MAURIZIO
• Other Authors: Giorgi, Gianluca, Corelli, Federico, Botta, Maurizio
• Format: Article in Journal/Newspaper
• Language: English
• Published: 2007
• Subjects: Antarc*; Antarctica
• Online Access: http://hdl.handle.net/11365/27625; https://doi.org/10.1002/ejoc.200700193

Two practical routes for the synthesis of benzhydrylamine derivs. in enantiomerically pure form have been developed. Enzymic kinetic resoln. of racemic N-acetylpropargylamines RC6H4CH(NHAc)C≡CH with Candida antarctica Lipase B gave access to (R)-RC6H4CH(NHAc)C≡CH (1a-e; R = H, 4-F, 4-Cl, 3-F, 3-Me), which were subjected to alkyne-alkene cross-metathesis catalyzed by Grubbs' 2nd generation catalyst, yielding (R,E/Z)-RC6H4CH(NHAc)C(:CH2)CH:CHR1 (2a-j; same R, R1 = H, OEt, OAc, TMS, CN, 3-MeOC6H4). (E)-Isomers 2 undergo Diels-Alder cycloaddn., giving α-(1-cyclohexenyl)benzylamines (R)-RC6H4CH(NHAc)(1-C6H7-4-X-3-OEt) (3d-e; R = H, X = CHO, COMe), heterodienophiles (Et glyoxalate, DEAD) gave dihydropyran and tetrahydropyridazine derivs., 4-[PhCH(NHAc)]-2-(CO2Et)-6-EtOC5H5O (3g) and 4-[PhCH(NHAc)]-1,2-(CO2Et)2-6-EtOC4H4N2 (3f), resp. N-Acetylbenzhydrylamine 3e was converted in both enantiomers of the fungicide bifonazole in multi-step procedure, emphasizing the importance of these compds. as scaffolds for the synthesis of biol. active compds. in enantiopure form.