Editing Synthesis of Lipids (section)

== Synthesis of DOSPA ==

[[Image:DOTAP_synthesis1.png]]<br> 

[[Image:DOTAP_Synthesis2.png]]

DOSPA is a typical cytofectin and contains a cationic<br>head group attached by a linker to a hydrophobic moiety.<br>The synthesis of the hydrophobic part, 2, from 3-(dimeth-<br>ylamino)-1,2-propanediol (1) is depicted in Scheme 1,<br>and it is identical to the first step of the synthesis of<br>DOTMA. 15 Compound 3 was made by alkylation of 2<br>with N-(2-bromoethyl)phthalimide. The phthalimide<br>(Pht) group is readily removed by refluxing of 3 together<br>with hydrazine and methanol to give 4 with an 80% yield.<br>The free amine group of 4 is the site for linking of the<br>additional portion of the cationic head group.



The additional portion of the cationic head group,<br>tetra(tert-butoxycarbonyl)spermine-5-carboxylic<br>acid<br>(Boc 4 SperCOOH), was synthesized in three steps as<br>described previously by Remy et al., 1994 (Scheme 2). 16<br>Instead of using DMF as the solvent in the first step,<br>methanol was used to perform the addition of acrylonitrile<br>to L -ornithine tetramethylammonium salt. The substitu-<br>tion of methanol for DMF increased the yield to 85%.<br>After the hydrogenation and the protection of the amine<br>with a Boc group, the cationic head group precursor 8 has<br>only a free acid group, which can be coupled with the free<br>amine group of the hydrophobic part 4 under the standard<br>coupling condition.



As shown in Scheme 3, by using PyBOP, HOBt and DI-<br>PEA as standard coupling reagents, the hydrophobic part<br>4 and the protected cationic head group 8 can be linked to-<br>gether to give 9 with a yield of 70%. Treatment of 9 with<br>4 M HCl in dioxane led to the removal of the Boc group<br>of 9 to give the final product, DOSPA (10), 17 with a yield<br>of 65%.

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