Investigations in stereochemistry and synthetic chemistry

Abstract

Part I

Cycloaddition of acrylates (methyl acrylate and methyl methacrylate) to an unsymmetrically substituted cyclopentadienone of type 1a yields the regioisomeric products 2 and 3; the disubstituted product 4 is obtained when the cyclopentadienone carries an -OMe group on each phenyl (1b). It has been shown that systems 2-4 exhibit temperature-dependent dynamic behaviour under normal NMR spectral determinations:

a) Products 2, 3, and 4 exhibit unequally populated two-site exchange in the solution phase in aprotic, nonpolar, or mildly polar solvents. The exchange process was attributed to the substituted phenyl (anisyl) group or groups adopting two different rotational attitudes. b) At the lowest temperature attained (220 K), the ratio of populations of stabilized conformers was 10:7 with systems 2 and 10:1 with systems 3 and 4. c) In view of the possibility that the o-anisyl group would experience considerable steric hindrance from the C-5 endo ester function when it is proximally situated at C-3 and endo rotated, structure 3 was assigned to the isomer exhibiting the greater disparity in stabilized conformer population at low temperature. This assignment has been independently confirmed by X-ray crystallography. Dynamic behaviour of systems 4 was closely similar to that of systems 2. d) A question remained as to which orientation of the anisyl group is the more stabilized in the case of systems 2. A technique that could determine relative stabilization in the solution phase was not readily available. Arguments advanced earlier, based on relative chemical-shift changes of the probe groups (-CMe, -OMe), assuming that such changes are largely induced by changes in the attitude of the highly anisotropic aryl groups influencing chemical shifts, had a large element of speculation. These matters are detailed in Chapter I. The attempt to assign stabilized attitudes was carried forward by calculating the enthalpy contents of the various rotational isomers through molecular mechanics, employing a commonly used and well-tested algorithm, MMP2. Results have shown that, while assignment in the case of system 3b as well as the disubstituted system 4b, both of which show the greater population disparity, would be unambiguous, that in the case of system 2b could still be open to further interpretation. These results are described and discussed in Chapter II.

An interesting speculation emerges when the effect of replacing the C-7 carbonyl group in systems 2, 3, or 4 by other groups or heteroatoms, which may alter the C-1-C-7-C-4 bond angle, is considered-whether such replacement would cause any observable change at all in the dynamic behaviour. The subject matter of Chapter III is a description of attempts to synthesize systems 5, 6, and 7 in which the C-7 carbonyl group in system 2 has been replaced, in order, by a phosphonate ester moiety, oxygen, or sulphur (a system with nitrogen at position 7 was expected to be difficult to prepare in view of anticipated reluctance of the appropriately substituted pyrrole to undergo Diels-Alder addition).

a) In the attempt to prepare phosphole oxide 8, methods were developed for preparing the required butadiene 9. The latter could not, however, be induced to undergo cycloaddition with phosphorus trichloride, presumably due to conformational constraints discussed fully in Section 2 of Chapter III. b) Two different approaches, both successful, were developed to obtain thiophenes 10. Thiophenes 10a and 10c, on reaction with methyl acrylate under conditions initially tried, did not yield any Diels-Alder product, the starting materials being recovered. Thiophene 10b did undergo the reaction, but the product was a desulphurized and aromatized material identified as the o-terphenyl 11. c) No difficulty was experienced in preparing substituted furans 12 by conventional methods, and conditions were established for obtaining Diels-Alder adducts, the oxabicyclo systems 13 and 14 (as mixtures of 5-exo and 5-endo esters). Necessary separation was effected in each case and ester configuration was assigned on the basis of NMR data. The endo isomer of the disubstituted system 14, interestingly and somewhat unexpectedly, did not exhibit dynamic changes in the range of temperature within which its C-7 carbonyl analogue 4 exhibited dynamic behaviour. Reasons are a matter for further investigation.

Part II Work described in Part II of the thesis is concerned with extending some earlier studies on the usefulness of the saturated and unsaturated ketoesters 15, 16, and 17 in synthesis, the main consideration being utilization of the ready geminal presence of a methyl and an ester function in these systems-a useful feature in the synthesis of terpene acids or in the construction of molecules with angular methyl groups. In one approach, it was found that the benzylic anion generated from the bromophenylacetonitrile 18 could be added to enone 19, used as a model of the substituted enone 17. Studies were carried out to effect cyclization of the resulting alkylated product 20 to hydrofluorene 21. Attempts at cyclization via the intermediacy of an aryne generated in situ did not succeed. Radical cyclization, tried next, employing tributyltin hydride and azobisisobutyronitrile, was partially successful in that the cyclized product 21 was obtained in rather low yield. It is thought necessary to carry out further studies to improve yields. The likely stereochemistry of AB ring junction in hydrofluorene 21 is discussed in Chapter I. In a second study, the debrominative cyclization of alkylated product 22, obtained on phenylethylation followed by dealkoxycarbonylation of ?-ketoester 18, was investigated. A series of model studies were carried out to see if an earlier claim that a reaction sequence, involving bromination of the precursor 22 with PTAB followed by treatment of product 23 with pyridine, results in cyclization to 24, could be substantiated. It was found that cyclization does not proceed as claimed. This last study has involved preparation of products 25 and 26 and establishment of structures obtained on application of the bromination/dehydrobromination sequence to them as well as investigation of other methods of their cyclization.