Synthetic Studies on Martinellines, Novel G-protein Linked Receptor Antagonist

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Martinelline and martinellic acid were isolated from tropical plant Martinella iquitosensis by Witherrup and coworkers. These alkaloids were the first naturally occurring nonpeptide bradykinin receptor antagonists and also the first naturally occurring pyrrolo[3,2-c]quinoline system. Interests on the unique structure of these as well as its biological activity led us to a total synthesis of martinelline and martinellic acid. The key step in our synthesis of these alkaloids is the asymmetric allylic substitution of aniline derivative by the combination of Pd (dba)_2 and 9-PBN. Basic experimental results showed that 2-vinyl-tetrahydroquinoline was provided with high enantioselectivity (92 %ee). For the synthesis of martinellines by this methodology, the precursor of cyclization product was prepared from hydroxyanthranilic acid by two methods. One was the ring closing metathesis reaction tethered with silicon atom and the other method was the regioselective crotylation reaction mediated with SnCl_4. Obtained tetrahydroquinoline was converted to the desired pyrroloquinoline ring with reductive amination reaction after introduction of cyanoethyl group at C-3. Vinyl group at C-2 was also converted to the desired cyanoethyl residue in general methods. And we also developed a new synthetic method for the preparation of hydroquinoline derivatives with Michael-Aldol reaction under the phase-transfer condition. This method is very useful method for not only the synthesis of martinellines but also biologically active quinoline derivatives. We achieved the synthesis of common intermediate of martinellines.