Asymmetric Synthesis of Methoxylated Ether Lipids: Total Synthesis of n-3 Polyunsaturated Docosahexaenoic Acid-Like Methoxylated Ether Lipid

Abstract

The first total synthesis of a docosahexaenoic acid (DHA)-like methoxylated ether lipid (MEL) is reported. This compound constitutes an all-cis methylene skipped hexaene framework identical to that present in DHA, the well-known omega-3 polyunsaturated fatty acid. The polyene C22 hydrocarbon chain, bearing a methoxyl group in the 2-position and Rconfiguration at the resulting chiral center, is attached by an ether linkage to the pro-S hydroxymethyl group (sn-1 position) of a glycerol backbone. The asymmetric synthesis is highly convergent and based on the polyacetylene approach involving iterative copper-promoted coupling reactions of propargyl bromides with terminal alkynes and semihydrogenation of the resulting hexayne. Starting from enantiopure R-solketal and racemic epichlorohydrin, the targeted MEL was accomplished in an 8.2% yield over eight steps (longest linear sequence) involving an enantio-and diastereopure glyceryl glycidyl ether key C6-building blocks from which the polyynes were constructed.

Asymmetric Synthesis of Methoxylated Ether Lipids: Total Synthesis of a Triene C18 : 3 Omega‐8 MEL Derivative

“…As has been previously described the over‐hydrogenation from the semi‐hydrogenation was easy to determine accurately by 1 H NMR analysis by comparison of the integration between the olefinic protons and the protons representing the glycerol backbone of the molecule [14] . It remained around 10 % in the crude product and had dropped to below detectable levels after the argentation chromatography treatment.…”

“…As based on the retrosynthetic approach demonstrated in Scheme 1 the synthesis of the MEL 6 starting from the diyne 8 is depicted in Scheme 2. The synthesis of diyne 8 has already been described in relation to our recently reported total synthesis of the n‐3 polyunsaturated DHA‐like MEL 5 [14] . The propargyl bromide 9 was prepared from commercially available dec‐2‐yn‐1‐ol in an Appel type reaction [19] which afforded the monoyne 9 in 91 % yield.…”

“…The triyne 10 was then submitted to the Lindlar catalyzed semi‐hydrogenation with quinoline in toluene, again under conditions identical to those used in our MEL 5 synthesis [14] . This afforded the crude triene 11 in 98 % yield after flash chromatography.…”

“…All six of the above mentioned MELs 1 , 2 , 3 and its saturated C18:0 MEL adduct, and MELs 4 and 5 were found present in the sample and their identity was confirmed by comparison studies between the MS/MS spectra of the MELs from the sample and the synthesized compounds to confirm their identity unequivocally [10] . These syntheses were based on the use of a glyceryl glycidol ether key building block that was recently introduced to our syntheses of the MELs 1 , 2 and 5 [13,14] …”

“…overall yield from the head piece 7 over four steps, [14] which in turn was made in 72 % yield from the chiral precursor Rsolketal. [13] This means 17 % overall yield for the synthesis of MEL 6 over eight steps as based on the R-solketal.…”