Synthetic approaches to the conformationally restricted serotonin analogs and vinylation of indole 3-position via palladium catalyzed cross-coupling reaction.
Committee ChairMartin, Arnold R.
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PublisherThe University of Arizona.
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AbstractAn adaptation of a malonic ester synthesis successfully yielded the tricyclic ketones 105 and 106 as key intermediates for the synthesis of conformationally restricted analogs, 12a-d and 13a-d. Investigation of alternative routes led to the development of a general, regiospecific method for the introduction of a vinyl group into the important indole 3-position utilizing the palladium-catalyzed cross-coupling reaction between 3-indole-boronic acids and vinyl triflates. The malonic ester route provided 105 in 14.8% overall yield. When the nitrogen atom of 105 was protected as the carbobenzyloxy (Cbz) derivative followed by the isomerization in a strong base, the stereochemistry of the product 106b was determined as cis-β by ¹H NMR spectroscopy using homodecoupling technique. N-deprotection of 106b under acidic conditions suggests that the apparent stereoselectivity of the PPA cyclization of 104 is due to partial equilibration of the tricyclic ketone 105 to the more stable trans-isomer 105a. Examination of molecular models of 106a and 106b reveals the existence of a severe 1,5-steric interaction between either of the carbamate oxygens and the benzylic carbon of the central ring in either 106a or the α-conformer of 106b. This steric interaction does not occur in the cis-β conformer of 106b. Molecular models of the β-conformer of 106b reveal steric congestion around the ketone carbonyl group, thus explaining the failure of attempts to successfully perform either the epoxidation or the Wittig reaction on 106b. From 1-substituted-3-piperidones, two kinds of triflates can be made with high regioselectivity depending on the substituents on the nitrogen. When the substituents are electron donating (methyl, benzyl), only the allylamine-type isomers (34a and 34b) could be detected by GC-MS and high field NMR. If the substituents are electron withdrawing (Cbz, Boc), the enamine-type isomer (35c and 35d) was exclusively obtained. For the synthesis of 3-indoleboronic acids, the mercuration-boronation route appears superior over halogen-metal exchange method.
Degree ProgramPharmaceutical Sciences