Studies on Syntheses of 1-Azaspirocycles, 2,6-Disubstituted 3-Piperidinols and cls-Decahydroquinolines

Annadi, Krishna Reddy
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Faculty of Graduate Studies and Research, University of Regina
Pyrrolidines and piperidines bearing a nitrogen-substituted quaternary stereocenter are commonly encountered structural motifs in many naturally occurring alkaloids, and therefore development of methods for their synthesis are important. The Rh(II)-catalyzed intramolecular tertiary C-H insertion reaction of 5-(-diazoacetoxy)piperidin-2-ones and 3-(-diazoacetoxy)pyrrolidines carrying C6 and C2 alkyl substituents, respectively, was investigated for the formation of bicyclic lactones bearing a nitrogen-substituted quaternary stereocenter. Both Rh(II)-carboxylate and Rh(II)-carboxamidate catalysts with varying electronic and steric properties were examined; however, these reactions usually resulted in the formation of complex mixture of products and the desired tertiary CH insertion products were not formed. The steric interactions encountered by the Rh(II)-carbenoid with the tertiary CH insertion site might have impeded the desired CH insertion reaction pathway. Alkylidenecarbene generation-1,5-CH insertion reaction of 5-(3-oxobutyl)pyrrolidin-2-ones and 6-(3-oxobutyl)piperidin-2-ones was next investigated for the formation of 7-methyl-2-azaspiro[4,4]non-6-ene-3-ones and 2-methyl-6-azaspiro[4,5]dec-1-ene-7-ones, respectively. The precursors 5-(3-oxobutyl)pyrrolidin-2-ones and 6-(3-oxobutyl)piperidin-2-ones required for this study were obtained from Wacker oxidation of 5-(but-2-enyl)pyrrolidin-2-ones and 6-(but-2-enyl)piperidin-2-ones, respectively with excellent regioselectivity (11:1). Further studies on Wacker oxidation have suggested that the lactam ring has a strong influence on the observed regioselectivity. Optimization studies for alkylidenecarbene generation-CH insertion reaction indicated that the efficiency of the CH insertion reaction is sensitive to the reaction temperature and the amount of lithio(trimethylsilyl)diazomethane employed. Under the optimized reaction conditions, 7-methyl-2-azaspiro[4,4]non-6-ene-3-ones and 2-methyl-6-azaspiro[4,5]dec-1-ene-7-ones were obtained in very good yields. The application of the developed method was successfully demonstrated in the total synthesis of both racemic- and ()-adalinine. The utility of a chiral non-racemic bicyclic lactam lactone (BLL) as a chiral building block was shown by developing approaches for the synthesis of two structural classes of alkaloids, the 2,6-disubstituted-3-piperidinols and cis-decahydroquinolines (cis-DHQs). The BLL was efficiently converted to (5S,6S)-5-hydroxymethyl-6-hydroxypiperidin-2-one and (5S,6S)-5-hydroxy-6-methylpiperidin-2-one, and the former intermediate was successfully used in the synthesis of (+)-2-epi-deoxoprosopinine and ()-deoxoprosophylline. For the synthesis of cis-DHQ alkaloids, (4aR,5S,8aS)- and (4aR,5R,8aS)-5-[(phenylsulfonyl)methyl]octahydroquinolin-2-ones were prepared by employing a 6-exo-trig free-radical cyclization reaction as the key step. The stereoselectivity observed in the free-radical cyclization step was found to be governed by allylic 1,2-strain arising from the interaction of the N-(p-methoxybenzyl) group and the C6 substituent in the lactam ring of the free-radical intermediate. The (4aR,5S,8aS)- and (4aR,5R,8aS)-5-[(phenylsulfonyl)methyl]octahydroquinolin-2-ones were successfully converted to (+)-cis-195A and 2,5-diepi-cis-195A, respectively. Further, a competitive oxidation pathway was uncovered in the cerium(IV) ammonium nitrate oxidation of N-PMB -lactams, which resulted in the unprecedented formation of N-(hydroxymethyl) -lactam along with the desired unprotected lactam. A mechanistic rationalization for this unexpected outcome was proposed.
A Thesis Submitted to the Faculty of Graduate Studies and Research In Partial Fulfillment of the Requirements For the Degree of Doctor of Philosophy in Chemistry. University of Regina. xxvi, 347 p.