Synthesis of N-(Hydroxy)amide- and N-(Hydroxy)thioamide-containing peptides.
Methods developed with N-(benzoyloxy)amines and hydroxamic acids were used in the synthesis of N-(hydroxy)amide-containing pseudopeptides. Acylation of N-(benzoyloxy)phenethylamine with the acid chloride of N(alpha)-Fmoc-L-leucine provided a N(alpha)-Fmoc-N-(benzoyloxy)-L-leucinamide in 90% yield. Deprotection of the benzoyl group (using 10 vol % NH(4)OH/MeOH) provided the N(alpha)-Fmoc-N-(hydroxy)-L-leucinamide in 87% yield. In general, the appended Fmoc group allowed for further elaboration of the N-hydroxy-N-(alkyl)amides using classic peptide-coupling methods. A practical synthetic strategy was developed, and racemization issues were addressed using diastereomeric Val-Leu derivatives. In addition, N-(hydroxy)thioamides were generated from the corresponding N-(benzoyloxy)thioamides. N-(Benzoyloxy)thioamides were obtained in moderate yields (53-76%) from the reaction of the corresponding N-(benzoyloxy)amides with Lawesson's reagent (i.e., 2, 4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disu lfide). In summary, this new technology allows for the introduction of either N-hydroxyamide or N-(hydroxy)thioamide linkages into pseudopeptide chains without racemization.
Wang
L
L
Department of Chemistry, Center for the Discovery of Drugs and Diagnostics, University of Central Florida, Orlando, Florida 32816-2366, USA.
Phanstiel
O
O
D000215:Acylation; D000577:Amides / Q000737:chemistry* / Q000378:metabolism; D000588:Amines / Q000378:metabolism; D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D005449:Fluorenes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D006877:Hydroxamic Acids / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism
D000577:Amides; D000588:Amines; D000596:Amino Acids; D005449:Fluorenes; D006877:Hydroxamic Acids; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D010455:Peptides