Source: Dissertation Abstracts International, Volume: 77-12(E), Section: B.

Adviser: Jonathan A. Ellman.

Piperidines and pyridines are prevalent structural motifs in pharmaceutical agents and biologically active natural products, and comprise the two most frequently occurring nitrogen heterocycles in FDA-approved small-molecule drugs.1 Despite the importance of piperidines and pyridines, the preparation of multiply substituted derivatives continue to pose regio- and stereochemical challenges. This thesis will discuss a series of new methods developed for the synthesis of densely substituted piperidines and pyridines with high levels of regio- and stereochemical control.

Chapter 1 describes the development of regio- and stereoselective methods for the synthesis of multisubstituted tetrahydropyridines from 1,2-dihydropyridines accessed via Rh(I)-catalyzed C---H functionalization from a,(3-unsaturated imines and internal alkynes. Computational investigation of the relative stability of the four possible protonated iminium ion structures is discussed. A regio- and stereodivergent protocol is developed where by tuning the acidity of the proton source as well as varying the length of the equilibration time, the 1,2-dihydropyridines are selectively protonated at either the kinetically favored C3 position or the thermodynamically favored C5 position to give two distinct iminium ion isomers. X-ray crystal data of the two iminium ion isomers show excellent agreement with the computed structures. Facile hydride and carbon nucleophile additions to these iminium ions provide tetrahydropyridine products with high diastereoselectivity.

Chapter 2 describes the development of a regio- and diastereoselective method of preparing multisubstituted tetrahydropyridines from 1,2-dihydropyridines by way of an alkylation/nucleophilic addition sequence. This study constitutes the first literature example of C-alkylation of 1,2-dihydropyridines to introduce tetrasubstituted carbon centers in a highly regio- and stereoselective manner. Hydride and carbon nucleophile additions to the resultant iminium ions proceed with high overall diastereoselectivity to yield tetrahydropyridines with adjacent tetrasubstituted ring carbon atoms. X-ray crystallographic analysis of the relative stereochemistry of the tetrahydropyridine products indicate that while the diastereoselectivity of the alkylation step is primarily controlled by the C6 substituent, the diastereoselectivity of the nucleophilic addition step is primarily controlled by the sterics of the newly established C3 stereocenter, and in particular by the size of the newly added carbon electrophile in the alkylation step relative to the existing C3 substituent.

Chapter 3 describes the development of regio- and diastereoselective methods of accessing oxygenated piperidines via epoxidation of two classes of tetrahydropyridines with distinct stereochemical displays of functionalities. A new and practical in situ prepared epoxidation reagent was developed for the diastereoselective epoxidation of one class of especially sterically hindered tetrahydropyridines. The novel epoxidation agent, 2-carboperoxy-3,4,5,6-tetrafluorobenzoic acid, was designed to incorporate a highly reactive peracid and a pendant carboxylic acid, which through hydrogen bonding to the amine successfully overrides steric effects and directs epoxidation to occur at the more hindered face of the tetrahydropyridine. Nucleophilic ring-opening of the epoxypiperidines with water, alcohols and HF proceeded with high regioselectivity, affording hydroxypiperidine products with adjacent tetrasubstituted carbons.

Chapter 4 describes the development of methods for the synthesis of multisubstituted tropanes with high regio- and stereoselectivity. The tropanes were accessed from TMS-substituted 1,2-dihydropyridines by C-alkylation and subsequent desilylation of the resultant iminium ions to generate unstabilized azomethine ylides, which were then subjected to [3 + 2] cycloadditions with dipolarophiles. An intermolecular alkylation/desilylation/cycloaddition sequence incorporates a range of asymmetric and symmetric alkyne, alkene and carbonyl dipolarophiles to afford densely substituted tropanes and bridged oxazolidines in good yields and with high regio- and stereoselectivity. An intramolecular alkylation/desilylation/cycloaddition sequence provides convenient and rapid entry into bridged tricyclic tropane skeletons, allowing for five carbon stereocenters to be set in a single experimental operation and under mild conditions.

Chapter 5 describes the development of a Rh(III)-catalyzed C--H functionalization approach for the preparation of multisubstituted 3-fluoropyridines from alpha-fluoro-alpha,beta-unsaturated oximes and alkynes. Ketoximes substituted with aryl, heteroaryl, and alkyl beta-substituents were effective coupling partners, as were symmetrical and unsymmetrical alkynes with aryl and alkyl substituents. The first examples of coupling alpha,beta-unsaturated oximes with terminal alkynes were also demonstrated and proceeded with uniformly high regioselectivity to provide single 3-fluoropyridine regioisomers. In addition, reactions were conveniently set up in air on the benchtop.

Reference [1] Vitaku, E.; Smith, T. S.; Njardarson, J. T. J. Med. Chem. 2014, 57, 10257-10274.