Asymmetric synthesis of dialkyloxy-3-alkylammonium cationic lipids.
The cationic diether-linked cytofectin DOTMA (available commercially as a mixture, Lipofectin comprised of DOTMA:DOPE, 1:1) and analogues including DIMRIE and DORIE are frequently used for in vitro and in vivo transfections. Despite this wide usage direct synthetic routes to the optical isomers have received little attention to date. Here we describe strategies to synthesize enantiomers of DOTMA and analogues, including an extremely concise procedure to the trimethylammonium salts. One strategy utilized N-protection, as the imine, with concomitant ether formation and deprotection during the workup. Methylation of the 1-amino-2,3-dialkyloxypropane then generated the trimethylammonium cationic lipids directly. This methodology was extended to synthesize a novel headgroup functionalized lipid. A second route was also developed using an alternative chiral synthon.
Hurley
Christopher A
CA
Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, United Kingdom.
Wong
John B
JB
Hailes
Helen C
HC
Tabor
Alethea B
AB
D002412:Cations; D018014:Gene Transfer Techniques; D008055:Lipids / Q000138:chemical synthesis* / Q000737:chemistry; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
D002412:Cations; D008055:Lipids; D000644:Quaternary Ammonium Compounds; C054005:N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium