Doctor of Philosophy
Kumar, Naresh, Stereospecific synthesis of naphthoindolizidine and tetrahydrobenzisoquinoline derivatives, Doctor of Philosophy thesis, , University of Wollongong, 1983. http://ro.uow.edu.au/theses/2108
A new method has been developed for the stereospecific synthesis of optically active naphthoindolizidine and tetrahydrobenzisoquinoline derivatives. The synthesis was achieved by mild intramolecular Friedel- Crafts' acylation of aralkyl derivatives of alanine, proline and a-amino-n-butyric acid. The compounds synthesized represent simple analogues of phenanthroindolizidine alkaloids (possessing physiological activity). The simplification of the structure lies (i) in the deletion of either the "top" or the "bottom" benzene ring, (ii) in the opening of the fifth (fused pyrrolidine) ring, and (iii) in the retention of asymmetric centres with modified substitution patterns.
The new synthetic route required the successful development of the following five procedures:
(a) N-Alkylation of primary a-amino acid esters with naphthalenylmethyl chlorides in a way which allowed formation of only small amounts of dialkylated products; (b) N-Alkylation of proline itself (rather than that of proline esters) with naphthalenylmethyl chlorides in propan-2-ol; (c) Protection of the secondary nitrogen atom in the case of N-naphthalenylmethyl alanine, glycine and a-amino-n-butyric acid by the p-toluenesulphonyl group in order to achieve successfully their intramolecular acylation; (d) Stereospecific, Friedel-Crafts' type acylation of N-(naphthalenylmethyl) -N-tosylalanine, glycine and a-amino-n-butyric acid by using mild conditions, e.g. stannic chloride (or aluminium chloride in the case of proline derivatives) in benzene at low temperature; (e) Reduction of naphthoindolizidone with large excess of sodium borohydride and of N-tosyltetrahydrobenzisoquinolone derivatives with large excess of lithium aluminium hydride which, in case of the latter compounds, displaced simultaneously the N-tosyl group as well to yield a pair (unequal amounts) of two diastereoisomeric alcohols.