Synthesis of a series of new racemic [2,3-bis(acyloxy)propyl]phosphonocholines

Abstract

Dedicated to Prof. Paweł Kafarski in honor of his scientific achievements within his career AbstractAn efficient synthesis of [2,3-bis(acyloxy)propyl]phosphonocholines is described. The reaction pathway for the synthesis involves the Michaelis-Arbuzov reaction of allyl bromide with triethyl phosphite and epoxidation of the resulting diethyl (prop-2-en-1-yl)phosphonate (1) with m-CPBA to afford the phosphonated diol (3). The acylation of diol (3) with carboxylic acids gave a series of diacyloxypropylphosphonates (4). The introduction of choline to a pyridinium salt of [2,3-bis(acyloxy)propyl]phosphonic acid (5) was the most intensively studied reaction. The total yield of a six-step sequence synthesis of a series of phosphonolipids was in the range of 30-40%.

Comparative Studies on the Susceptibility of (R)-2,3-Dipalmitoyloxypropylphosphonocholine (DPPnC) and Its Phospholipid Analogues to the Hydrolysis or Ethanolysis Catalyzed by Selected Lipases and Phospholipases

“…Yield 94% (576 mg), white powder, R f = 0.35 (hexane: ethyl acetate, 2:1, v/v), HPLC: R t = 9.90 min, [α] 20 D = −0.58 (c = 0.5, hexane), ee 87%, spectroscopic data were in accordance with literature report [16].…”

“…silica gel, CHCl 3 :MeOH:H 2 O, 65:25:3, v/v/v) to give pure DPPnC (4) with the following physical data: Yield 51% (293 mg), white powder, R f = 0.41 (CHCl 3 :MeOH:H 2 O, 65:25:2), HPLC: R t = 11.16 min, [α]20 D = + 8.1 (c = 0.4, CHCl 3 ), ee 87%, spectroscopic data were in accordance with literature report[16].…”

“…The total yield of synthesis of 4 from (R)-phosphonate 1 was 51%. The described synthetic pathway, established earlier for racemic 2,3-diacyloxypropylphosphonocholines [16], ensured the retention of R configuration for final phosphonolipid 4.…”

“…Synthesis of (R)-2,3-Dipalmitoyloxypropylphosphonocholine (DPPnC, 4) Synthesis of (R)-DPPnC (4) is shown in Scheme 1. The key step of this procedure was regioand enantioselective hydrolysis of racemic diethyl 2,3-dipalmitoyloxypropylphosphonate (1), which was obtained as described in our previous paper [16]. The reaction was catalyzed by phospholipase A 2 from porcine pancreas in isooctane/Tris-HCl system (pH = 8.5) in the presence of AOT and Ca 2+ ions.…”

“…A few years ago, we also reported the synthesis of a series of phosphonolipids with C-P bond on a glycerol side. They contained different fatty acid residues and choline in their structure [16]. We have been planning to compare their biological activity, mainly cytotoxic, with the activity of corresponding phosphatydylcholines.…”