Investigations in alycyclic chemistry : synthetic and stereochemical investigations in bicyclo (2.2.1) heptane and cyclopentane systems

Abstract

The thesis entitled "Investigations in Alicyclic Chemistry: Synthetic and Stereochemical Investigations in Bicyclo[2.2.1]heptane and Cyclopentane Systems" is divided into three Parts. Part I is divided into three Sections. In Section I is given a review of observations on magnetically non-equivalent methylene protons. The gradual unfolding of the understanding of the phenomenon of chemical shift nonequivalence of identical groups placed in diastereomeric positions is briefly traced. The conditions for observable nonequivalence and the origins of nonequivalence are detailed; a variety of examples of magnetically nonequivalent groups are included. Because of pertinence to the present investigation, special emphasis has been placed on the case of ethyl esters in asymmetric environments which exhibit AB-type nonequivalence of their O-methylene protons. The question of origin of this nonequivalence, whether interaction with a side chain is a necessary condition or the intrinsic rigidity of the ethyl ester group alone is sufficient, is discussed, pointing out the necessity for biasing of the "rigid" ester group about the R-CO?Et bond. The general observation has been made in these laboratories that tertiary ethyl esters with an ?-methyl group exhibit a much higher degree of O-methylene proton nonequivalence compared with their des-methyl analogues. It was conjectured that the ?-methyl group may have a direct and independent role in producing the higher degree of nonequivalence apart from that of effecting a significant conformational change (e.g., ring inversion) such that a highly anisotropic group is brought into the proximity of the ester group. Looking for evidence for this direct role, several substituted cyclopentane and bicyclo[2.2.1]heptane systems were synthesised bearing ethyl esters as substituents. Syntheses and attempted syntheses of such systems are described in Section II: failure of several sequences to yield diethyl cis-1,3-dimethylcyclopentane-1,3-dicarboxylate, success with the synthesis of diethyl anti-7-methylbicyclo[2.2.1]heptane-exo,syn-2,7-dicarboxylate after many failures and with that of ethyl 1,4-dimethyl-5,6-diphenylbicyclo[2.2.1]hept-5-en-7-one-endo-2-carboxylate, its ?-methyl analogue, and their products of hydrogenation are described. Section III discusses our observations regarding the presence or absence of observable O-methylene proton nonequivalence in substituted diethyl cis-cyclopentane-1,3-dicarboxylates, diethyl bicyclo[2.2.1]heptane-2,7-dicarboxylates and ethyl 1,4-dimethyl-5,6-diphenylbicyclo[2.2.1]hept-5-en-7-one-endo-2-carboxylate with and without an ?-methyl group. It concludes with a statement of reasons which have led us to believe that the main mode by which the ?-methyl group acts to increase observable nonequivalence is by creating biasing of the rotation of the "rigid" ethyl ester group about the R-CO?Et bond which is different from the des-methyl case. Other effects such as shifting the O-methylene protons into a region of higher anisotropic gradient are considered less significant. Part II, divided into four Sections, contains studies of the possibility of atropisomerism in endo,cis-2,3-diarylbicyclo[2.2.1]heptanes. A brief introduction relevant to the present study is given in Section I. In Section II, observations regarding the presence of atropisomerism in paracyclophanes have been reviewed in some detail since studies with molecular models of endo,cis-2,3-diarylbicyclo[2.2.1]heptanes indicated that these systems share some structural features with [3,4]paracyclophane (such as the inter-phenyl distances and the relative orientation of the phenyl groups). Distortion of the phenyl rings is thought not to occur in the latter, the abnormal ultraviolet absorption of which having been attributed to interstitial resonance effects. In Section III, after stating that interstitial resonance effects causing abnormal ultraviolet absorption and inter-annular interaction giving rise to chemical shift changes in the NMR spectra because of the proximity of the aryl groups in endo,cis-2,3-diarylbicyclo[2.2.1]heptan-7-ones, the possibility of molecular asymmetry arising from restricted rotation is looked into. The syntheses of systems relevant to this enquiry are then described. The results of our observations on the stereochemistry of the catalytic hydrogenation of the stilbene double bond in 2,3-diarylbicyclo[2.2.1]hept-2-enes are discussed in the last Section in the light of the abnormal ultraviolet spectra of the hydrogenated products which reveal the presence of interstitial effects as well as of their NMR spectra which indicate that biasing of rotation of the endo-oriented aryl groups does occur in these systems. This Section concludes with our failure to observe atropisomerism in 1,4-dimethyl-endo,cis-2,3-(m,m-dimethoxy)-diphenylbicyclo[2.2.1]heptan-7-one. This has been attributed to specific orientation of the m-anisole rings. An introduction to the previous work on the structure elucidation of Thiele’s ester comprises the first and second Sections of the Third Part. It is known that various methods of saturating the reactive bond in Thiele’s ester, such as catalytic hydrogenation, ylide addition, 1,5-dipolar addition and addition of dimethylamine and sodium methoxide lead to the endo-orientation of the C?-carbomethoxy group and to the (generally observed) downfield shift of the C?-vinylic proton signal. The latter could arise either because the C?-CO?Me polar bond is endo-oriented or because of the disappearance of C?–C? ?-circulation (other concomitant effects being taken to be minimal). This Part concludes with an attempt to analyse the various factors which may contribute to the observed deshielding.