Synthesis of enantiomerically pure 1,2-diamine derivatives of 7-azabicyclo[2.2.1]heptane. New leads as glycosidase inhibitors and rigid scaffolds for the preparation of peptide analogues.
Enantiomerically pure alcohols (-)- and (+)-7-tert-butoxycarbonyl-6-endo-p-toluenesulfonyl-7-azabicyclo[2.2.1]hept-2-en-5-endo-ol ((-)-11 and (+)-11) have been obtained from the Diels-Alder adduct of N-(tert-butoxycarbonyl)pyrroel and 2-bromo-1-p-toluenesulfonylacetylene, including a resolution method. These two alcohols were converted into (+)- and (-)-5-exo-amino-7-(tert-butoxycarbonyl)-2,3-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]heptane ((+)-18 and (-)-18) and (+)- and (-)-5-endo-amino-7-(tert-butoxycarbonyl)-2,3-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]heptane ((+)-19 and (-)-19) after adequate functionalization and desulfonylation steps. The corresponding conformationally constrained bicyclic 1,2-diamines (+)-4, (-)-4, (+/-)-5, (+/-)-6, (+)-7, and (-)-7 were obtained from the protected precursors 18 and 19 and evaluated as glycosidase inhibitors. Diamines (+)-4, (-)-4, (+)-6, and (-)-6 can be seen as new nonpeptide molecular scaffolds for the design of peptide analogues.
Moreno-Vargas
Antonio J
AJ
Institut de Chimie Moléculaire et Biologique de l'Ecole Polytechnique Fédérale de Lausanne, EPFL-BCH, CH-1015 Lausanne-Dorigny, Switzerland.
Schütz
Catherine
C
Scopelliti
Rosario
R
Vogel
Pierre
P
D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis*; D003959:Diamines / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D006536:Heptanes / Q000138:chemical synthesis; D020128:Inhibitory Concentration 50; D018716:Molecular Mimicry; D010455:Peptides; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D019086:Bridged Bicyclo Compounds, Heterocyclic; D003959:Diamines; D004791:Enzyme Inhibitors; D006536:Heptanes; D010455:Peptides; D006026:Glycoside Hydrolases