The Synthesis of Phosphatidylinositol Bolalipids

Abstract

This thesis describes the attempted synthesis of phosphatidylinositol bolalipids to be used in the investigation of the mechanism of the phosphatidyl inositol transfer protein, Sec14, and the PI(4)-kinase, Pik1. The synthesis of two unique bolalipids was the goal of this thesis. The esterification of the sn1 position of a protected glycerol unit to stearic acid as well as esterification at the sn2 position to either the C20 or C36 diacid gave the framework of the desired bolalipid. Further success was seen in the coupling of benzyloxybis(diisopropylamino) phosphine to the sn3 position of the deprotected glycerol unit in the generation of a phosphoramidite. However, efforts in the final step of the synthetic method were unsuccessful and did not lead to the complete synthesis of the bola-PI. Though it was possible to couple the 2,3,4,5,6-benzyl protected myo- inositol to the phosphoramidite, the most significant issues in the synthesis of the bola-PI is the oxidation of the phosphite to the phosphonate. Despite multiple attempts with varying oxidizing agents, no oxidation was observed by TLC, P NMR or mass spectrometry data. Two phosphoramidites, precursors to the desired bola-PI molecules, have been synthesized to date. The two phosphoramidites were characterized by H NMR, C NMR, P NMR, mass spectrometry, and optical activity. They are both air and water sensitive and have been observed to decompose with storage, even when placed under nitrogen at -4 oC. Spectral and experimental data are provided for all new compounds.