Facile and Efficient Synthesis of Bolaamphiphilic Tetraether Phosphocholines

Abstract

A facile synthesis of ether-linked bolaform phospholipids in good yields has been developed. Triflic acid catalyzed oxirane ring opening of benzyl-protected rac-glycidyl with long-chain 1,ω-alkanediols (n = 16, 20) produced 1,1‘-diglycerol diethers in 80−90% yield. Double alkylation of the secondary hydroxy groups with 1-bromooctane or 1-bromodecane gave the corresponding benzyl-protected tetraethers in 66% yield. Hydrogenolysis of the benzyl groups in the presence of Pd/C (55−66% yield) followed by phosphorylation with 2 equiv of 2-chloro-2-oxo-1,3,2-dioxaphospholane and amination with excess trimethylamine produced the tetraether bolaform bisphosphocholines as white powders in ∼75% yield. This approach provides a reliable and efficient method for preparing a wide variety of symmetrical bolaform phospholipids on a multigram scale