Streamlined Synthesis of Di-ω-(pyren-1-yl)alkanoylphosphatidylcholine Lipids from 5-(Pyren-1-yl)-1-pentene: Fluorescent Probes for Sensing Amphiphilic Membrane Lateral Pressure

Abstract 1,2-Di-ω-(pyren-1-yl)alkanoyl-sn-glycero-3-phosphocholines with C4, C6, C8, and C10 alkanoyl chain lengths, which are useful fluorescent probes for sensing changes in the physical properties of amphiphilic membranes such as fluidity or lateral pressure, were prepared in —two to three steps from 5-(pyren-1-yl)-1-pentene as a common precursor. This pyrenylpentene was generated from 1-bromopyrene by halogen–metal exchange (n-BuLi, TMEDA, THF, 0 °C) followed by alkylation of the aryllithium with 5-bromo-1-pentene (66% yield). The C4 lipid target was uniquely prepared by oxidative cleavage of the pyrenylpentene intermediate (cat. OsO4, Oxone, DMF, rt; 53% yield) followed by diacylation of sn-glycero-3-phosphocholine with the resulting 4-(pyren-1-yl)butanoic acid (CDI, CH2Cl2, rt; DBU, DMSO, 40 °C; 50% yield). The C6, C8, and C10 lipid targets were accessed by conversion of 5-(pyren-1-yl)-1-pentene to the appropriate chain-length ω-(pyren-1-yl)alkanoic acid (C6: 72% yield; C8: 72% yield; C10: 77% yield), by olefin cross-metathesis (with Grubbs 2 catalyst, CH2Cl2, 40 °C) with acrylic acid, 4-pentenoic acid, or 6-heptenoic acid, respectively, followed by hydrogenation (H2, Pd/C, EtOAc-EtOH); and then, diacylation of sn-glycero-3-phosphocholine with the pyrenyl alkanoic acid using the above CDI-based method (C6: 43% yield; C8: 39% yield; C10: 59% yield). In all cases, potentially useful 1-ω-(pyren-1-yl)alkanoyl-sn-glycero-3-phosphocholines were obtained as minor products from the esterification process (21–36% yield).