The asymmetric synthesis of tetrahydroisoquinoline alkaloids using an amino acid-derived oxazoline as a chiral mediator
Date of Award
Doctor of Philosophy (Ph.D.)
First Committee Member
R. E. Gawley - Committee Chair
The isoquinoline alkaloids form a unique class of compounds, exhibiting biological properties almost as varied as the structures themselves. Over the past decade, there has been a concerted effort within the scientific community, to breach the stereochemical barrier and thereby offer novel syntheses of these naturally occurring pharmacological giants. The research presented in this dissertation, represents one such effort through which the formation of an enantiomerically enriched isoquinoline alkaloid can be achieved. The framework of this synthetic sequence is based upon the use of a chiral auxiliary, an oxazoline. This moiety, when coupled to the isoquinoline skeleton, exerts a stereofacial bias over the protons on the C-1 position of the isoquinoline ring system. Therefore, deprotonation of the activated isoquinoline at a low temperature (eg. $-$78$\sp\circ$C) using a suitable organometallic base (such as tert-butyllithium), followed by alkylation with the appropriate electrophile produces the key intermediate, the precursor to the naturally occurring alkaloid, with the correct stereochemistry at the newly formed chiral center. The 1-alkylated isoquinoline products were obtained in high yields (80-90%) with a significant degree of asymmetric induction (30:1) observed for the reaction process. Removal of the chiral auxiliary, coupled with some functional group manipulations, ultimately afforded the natural alkaloids in high enantiomeric excess.
Smith, Gregory Anthony, "The asymmetric synthesis of tetrahydroisoquinoline alkaloids using an amino acid-derived oxazoline as a chiral mediator" (1989). Dissertations from ProQuest. 2769.