Document Type



Doctor of Philosophy


Chemistry, Organic

Date of Defense


Graduate Advisor

Christopher D. Spilling, Ph.D.


John Chibnall, Ph.D.

Prof. Keith J. Stine

Dr. Janet Braddock-Wilking


A number of important classes of natural product (eg. amphidinolide C, (-)-centrolobine, etc) contain common structural features of tetrahydrofurans and tetrahydropyrans. This study involved the development of stereoselective mothods for the synthesis of tetrahydrofurans and tetrahydropyrans including the application of allylic hydroxy phosphonates and their derivatives as chiral, non racemic building blocks for the synthesis of biological active molecules. The enantiomeric excess of non racemic α-hydroxy phosphonates and carbonate derivatives prepared via the asymmetric Pudovik reaction can be improved by kinetic resolution. Both chemical and enzyme catalysts were utilized in the kinetic resolution of phosphonates. Enantioselective acylation of a variety of racemic α-hydroxy phosphonates using Birman catalysts (generation 0, I, II and III) was studied. Birman?s generation II catalyst acylated a representative non racemic benzylic α-hydroxy phosphonate with moderate 70 % e.e. and resulted in enhanced enantiomeric excess (97 % e.e.) in preparative scale. The enzyme catalyzed resolution via the asymmetric hydrolysis of phosphono allylic carbonate using different lipases was explored. Among a variety of lipases (14 kinds) screened, CALB showed adequate selectivity (E = 3.3) at 40oC and was chosen for the hydrolysis of the phosphono allylic carbonate. By virtue of encapsulation, CALB can be reused up to 5 times and still provide satisfactory enantioselectivities. These two methods were found to be quite effective in producing enantiomerically enriched allylic phosphonates in high e.e. and reasonable yield. The methodology was also successfully applied to the formal synthesis of natural product (+)-centrolobine.

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