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.

The report describes the preparation and use of a double-C3 building block intended as a head group synthon in the synthesis of saturated, mono-, and polyunsaturated 1-O-alkyl-sn-glycerol type methoxylated ether lipids (MELs). The resulting head piece, an enantiopure isopropylidene-protected glyceryl glycidyl ether diastereomer, was accomplished in 49% yield (max 50%) from a 1:1 diastereomeric mixture obtained from R-solketal and racemic epichlorohydrin after treatment with the Jacobsen (S,S)-Co­(III)­salen catalyst for the hydrolytic kinetic resolution of terminal epoxides. The diol hydrolytic product obtained in 47% yield from the unwanted diastereomer was reconverted into epoxide with an inversion of configuration in a three-step operation involving a highly regioselective lipase. This enabled the recovery of a substantial amount of diastereopure material after a subsequent treatment with the Jacobsen catalyst to furnish the oxirane head piece in altogether 72% yield of higher than 99% diastereomeric purity. A modified synthesis of a monounsaturated 16:1 MEL confirmed the correct stereochemistry and excellent enantiopurity of the head piece and resulted in a dramatic improvement in yields, efficiency, and economy of the synthesis.

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The asymmetric synthesis of a triene C18 : 3 n‐8 methoxylated ether lipid (MEL) of the 1‐O‐alkyl‐sn‐glycerol type is described by two different routes. The C18 : 3 hydrocarbon chain is attached by an ether linkage to the pro‐S hydroxymethyl group of the glycerol backbone, and constitutes an all‐cis methylene skipped triene framework, along with a methoxyl group in the 2’‐position and R‐configuration at the resulting chiral centre. The initial synthesis was based on the polyacetylene approach involving a semi‐hydrogenation of the resulting triyne. A modified approach based on a combined polyacetylene‐Wittig strategy was also successfully executed and an attempt made to compare and evaluate these strategies. Both syntheses were started from our previously described enantio‐ and diastereomerically pure isopropylidene‐protected glyceryl glycidyl ether, a double‐C3 building block designed as a head group synthon for synthesis of various types of MELs which was shown to suit the Wittig‐based approach very well.