Synthesis of oxa-bridged analogues of farnesyltransferase inhibitor RPR 115135.
Two synthetic routes to new oxygen-bridged analogues of farnesyltransferase inhibitors are described that follow either a [3 + 2]/[4 + 2] or a [4 + 2]/[3 + 2] sequence of reactions. The first approach has been achieved by reacting the in situ generated phenylisobenzofuran (PIBF) 4 with pyrroline 5a and has led stereoselectively to racemic 18, which was transformed in a few steps into the target molecule 2. The second pathway relies on a key intermediate 6, obtained either by condensation of PIBF with methyl acrylate, followed by a deprotonation/selenation and an oxidation/elimination sequence, or by cycloaddition between PIBF and alpha-phenylselenoacrylate 11, followed by the same oxidation/elimination sequence. The reaction of 6 with amino dipole 7 gives diastereoselective access to pyrrolidine 25, a precursor of the second target 3, an epimer of 2.
Martin
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Laboratoire des Fonctions Azotées et Oxygénées Complexes de l'IRCOF, UMR 6014 CNRS, Université de Rouen, 76821 Mont St Aignan, France.
Mailliet
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P
Maddaluno
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J
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D003500:Cyclization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D007202:Indicators and Reagents; D007211:Indoles; D009682:Magnetic Resonance Spectroscopy; D014961:X-Ray Diffraction
D001952:Bridged-Ring Compounds; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D007211:Indoles; C426728:RPR115135; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase