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

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.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Doctoral -- first

Discipline thesis:degree_discipline

Chemistry

Grantor dc:publisher

Faculty of Graduate Studies and Research, University of Regina

Year dc:date.issued

2015

Author dc:creator

• Annadi, Krishna Reddy

Advisor dc:contributor.advisor

• Wee, Andrew G.

Committee members dc:contributor.committeemember

• Suh, Dae-Yeon
• East, Allan
• Stavrinides, John

Language dc:language.iso

en

DOI

https://doi.org/10.82465/4636

OAI identifier oai:identifier

oai:uregina.scholaris.ca:10294/6578