1,3,5-Tri- and 1,3,4,5-tetra-substituted 1,4-diazepin-2-one solid-phase synthesis.
Solid-phase syntheses of 1,3,5-tri-substituted and 1,3,4,5-tetra-substituted 1,4-diazepin-2-ones 15-18 have been accomplished by employing inexpensive commercially available alpha- and beta-amino acids on Wang resin. Reductive amination of the imine formed by condensation of Wang aldehyde resin respectively with beta-alaninate 2 and beta-homophenylalaninate 3, followed by aminoacylation with a set of alpha-N-Boc amino acids (Phe epsilon-( Z)-Lys, and Leu) gave tertiary amide resins 7 and 8. Exposure of resins 7 and 8 to an excess of vinyl magnesium bromide in the presence of copper cyanide gave the corresponding gamma,delta-unsaturated ketone resins 9 and 10 by way of a cascade addition. Diazepinones were made by Boc deprotection and intramolecular reductive amination. To diversify the heterocycle, N-alkylation was performed using a series of alkyl halides. Alternatively, diazepinones 15e-g were obtained from treatment of methyl beta-alaninate resins 4 and 20 under similar copper-catalyzed cascade conditions to afford the gamma,delta-unsaturated ketone 21, which was acylated using alpha-N-Fmoc-amino acids (Phe, Trp, gamma-(t-Bu)-Glu). Formation of diazepinones 15 followed a similar protocol, after Fmoc removal with piperidine. Cleavage of the heterocycles with TFA/TES 95:5 gave the N1-p-hydroxybenzyl diazepinones 15-18 in overall isolated yields from 6 to 24% after purification in purities ranging from 81 to 100% according to LCMS analysis.
Iden
Hassan S
HS
Département de Chimie, Université de Montréal, C.P. 6128, Succursale Centre Ville, Montréal, Québec H3C3J7, Canada.
Lubell
William D
WD
D000447:Aldehydes / Q000737:chemistry; D000577:Amides / Q000737:chemistry; D000586:Amination; D000596:Amino Acids / Q000737:chemistry*; D049148:Aminoacylation; D001381:Azepines / Q000138:chemical synthesis*; D001965:Bromides / Q000737:chemistry; D002853:Chromatography, Liquid; D003300:Copper / Q000737:chemistry; D003486:Cyanides / Q000737:chemistry; D007097:Imines / Q000737:chemistry; D007659:Ketones / Q000737:chemistry; D013058:Mass Spectrometry; D008956:Models, Chemical; D012117:Resins, Synthetic / Q000737:chemistry*; D014753:Vinyl Compounds / Q000737:chemistry
D000447:Aldehydes; D000577:Amides; D000596:Amino Acids; D001381:Azepines; D001965:Bromides; D003486:Cyanides; D007097:Imines; D007659:Ketones; D012117:Resins, Synthetic; D014753:Vinyl Compounds; D003300:Copper