Diastereoselective syntheses of new analogues of the farnesyltransferase inhibitor RPR 130401.
The access to several benzo[f]perhydroisoindolic analogues of farnesyltransferase inhibitors from a single dienic precursor is reported. An initial [4 + 2] cycloaddition between diphenylisobenzofuran6 and pyrrolines 11, 14, and 15 led to either the syn or the anti isomers, depending on the mode of activation of the cycloaddition. The syn diastereomers were isolated in 90% de under 12 kbar at room temperature, while their anti counterparts were obtained with the same selectivity by warming the reaction mixture to 110 degrees C in toluene at atmospheric pressure. Both syn and anti adducts were separately N-deprotected, and the resulting amines reacted with an activated ester derived from the acid (20) to afford the final targets (5). Two new analogues (5a and 5b) of the FT inhibitor RPR 130401 were thus synthesized in a mere three-step synthetic scheme with overall yields from 30 to 60%.
Pichon
Nicolas
N
Laboratoire des Fonctions Azotées et Oxygénées Complexes de l'IRCOF, UMR 6014 CNRS, INSA and Université de Rouen, 76821 Mont St Aignan, France.
Harrison-Marchand
Anne
A
Mailliet
Patrick
P
Maddaluno
Jacques
J
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism
D004791:Enzyme Inhibitors; D007211:Indoles; C400543:RPR 130401; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase