Asymmetric induction in 1,3-dipolar cycloaddition using chiral nitrones

Abstract

This thesis describes the development of methods for the preparation of chiral racemic substituted cyclic and a cyclic nitrones. This has been accomplished by the following points. In chapter 3, the diastereoselectivity in the cycloaddition reactions of several monoand disubstituted alkenes with a (-)norephedrine-derived methylenenitrone has been investigated. The stereochemical analysis of the addition products (i.e. isoxazolidines) has been carried out by X-ray, NMR and chemical conversions. The NMR spectra of the isoxazolidines at low temperatures indicated the presence of either a single or a predominant invertomer. The stereochemistry of the invertomers and nitrogen inversion barriers are determined using complete line-shape analysis and their dependence on solvent is discussed. In chapter 4, a study of the stereo- and face-selectivity of the cycloaddition reactions of several mono- and disubstituted alkenes with 4-hydroxymethyl-3,4,5,6-tetrahydropyridine 1-oxide has been carried out. The addition reactions have displayed a very high degree of face selectivity (13-48:1). Use of dimethyl methylenemalonate as a protective group in nitrone cycloaddition reactions has been demonstrated. The invertomeric analysis revealed that the bicyclic cycloadducts remain predominantly as the cis-fused isomer which leads to the formation of synthetically important secondgeneration cyclic aldonitrones via peracid oxidation. One interesting finding was that treatment of the cycloadducts with two equivalents of peracid afforded the cyclic N-hydroxy lactams, presumably via further oxidation of the aldonitrones. The piperidine ring has been elaborated by cycloaddition reaction of the second-generation nitrones with several alkenes, which in most cases gave the cycloadducts in a stereoselective manner. In chapter 5, the cycloaddition reactions of 4-(2-hydroxy-2-propyl)-3,4,5,6- tetrahydropyridine 1-oxide with mono- and di-substituted alkenes have been found to be highly stereo- as well as face-selective. In solution, the 6/5 fused bicyclic cycloadducts remain solely as the cis-fused invertomers in order to accommodate the bulky tertiary substituent 2-hydroxy-2-propyl in the equatorial orientation. The cycloadducts, upon peracid oxidation, leads to the exclusive formation of synthetically important secondgeneration cyclic aldonitrones. The stereo- and face-selectivity of the cycloaddition reactions of these second-generation nitrones bearing substituents at C(4) and C(6) have been briefly examined. In chapter 6, One interesting finding was that treatment of the first generation nitrone i.e., 4-hydroxymethyl-3,4,5,6-tetrahydropyridine 1-oxide or 4-(2-hydroxy-2-propyl)-3,4,5,6-tetrahydropyridine 1-oxide, with mercury(II) oxide afforded novel bicyclic nitrones, 1-oxa-5,6-dehydro-6-aza-bicyclo[3,2,1]heptane 6-oxides, whose cycloaddition reactions were briefly examined. In chapter 7, the cycloaddition reaction of 6-pentyl-3,4,5,6-tetrahydropyridine 1-oxide with butyl vinyl ether was used as a key step in the short stereoselcetive racemic synthesis of ladybird beetle alkaloid 2-epicalvine. The cycloadduct on quartenization with 2-bromoethanol followed by ring openinng and lactonization afforded the natural product in a single pot reaction.