Method of synthesising plasmalogen compounds

Abstract

A use of a compound of formula Y: (Y) to form a protected nucleophile, wherein a single substituent selected from R1-R4 is -CH2-LG or -CH2-OH, wherein LG is a leaving group; at least one substituent s

Description

BACKGROUND Functionalisation of the triol glycerol:

[0001] Plasmalogen synthesis requires selective functionalisation of the triol glycerol. Each functionalisation poses its own synthetic complications: • the sn-1 Z-vinyl ether is thermodynamically unfavourable relative to the E isomer and labile under oxidative and acidic conditions (E. Taskinen, Thermodynamics of vinyl ethers II. Configurational assignment of the geometric isomers of 3-methoxy-4-methyl-2-pentene by means of thermodynamic data of isomerization, J. Chern. Thermodynamics, 1974, 6, 271 -280; O. H. Morand, R. A. Zoeller, C. R. Raetz, Disappearance of plasmalogens from membranes of animal cells subjected to photosensitized oxidation, J. Biol. Chern., 1988, 23, 11597 - 11606; V. C. Anderson and D. H. Thompson, Triggered release of hydrophilic agents from plasmalogen liposomes using visible light or acid, Biochimica et Biophysica Acta., 1992, 1109, 33-42); • the sn-2 acyl group is susceptible to acyl migration and / or cleavage under acidic or basic conditions (D. R. Kodali, A. Tercyak, D. A. Fahey, D. M. Small, Acyl migration in 1,2-dipalmitoyl-sn-glycerol, Chern. Phys. Lipids, 1990, 52, 163- 170); • the zwitterionic sn-3 phosphate head group containing the charged group -NH3+ or-NMe3+ restricts solubility in certain organic solvents and is a potential leaving group.

[0002] Additionally, to selectively functionalise glycerol is challenging as there is no simple chemical distinction between its two prochiral 1° alcohols, and minimal distinction between the 1° and 2° alcohols. Therefore, masked glycerol derivatives are commonly used to overcome this selectivity issue. The three most common derivatives are solketal, glycidol, and 4-(hydroxymethyl)-1,3-dioxolan-2-one: solketal glycidol 4-(hydroxymethyl)- 1,3-dioxolan-2-one OH" Selective functionalisation of three glycerol derivatives at the 1° alcohol and the subsequent conditions needed to liberate glycerol hydroxyl groups.

[0003] For plasmalogen synthesis, all three derivatives are restricted to sn-1 functionalisation initially as only one 1° alcohol is accessible. However, adding the sn-3 phosphate early in the synthesis is not viable due to its potential lability, as well as undesirable effects on solubility and chromatographic properties. Therefore, the Z-vinyl ether, or a precursor that later affords it, is preferably installed early in the synthesis. Solketal requires an acidic catalyst to cleave the isopropylidene ketal and afford a diol, conditions which are incompatible with a Z-vinyl ether already present. Glycidol requires epoxide ring-opening via an oxygen nucleophile (e.g. phosphate salt) to afford the glycerol backbone. This route requires neutralisation of the phosphate moiety with an acid to liberate the free phosphoric acid (V. G. Noskov, S. V. Shishkov, Y. L. Kruglyak, M. V. Kiseleveskii, V. S. Dobryanskii, N. N. Makisimtseva, M. A. Sokal’skii, SYNTHESIS AND ANTIHYPERTENSIVE ACTIVITY OF SOME 1-O-ALKYLGLYCERO-3-PHOSPHOCHOLINE DERIVATIVES, Pharm. Chern. J., 1996, 30, 607 - 610). Even under slightly acidic conditions the free secondary hydroxyl will react with the vinyl ether to give a cyclic acetal which makes this option unattractive: o NaO NMe3 MeOH Epoxide ring-opening via phosphate salt, and subsequent unwanted reaction of alcohol and vinyl ether under acidic conditions.

[0004] The third option, 4-(hydroxymethyl)-1,3-dioxolan-2-one, requires basic hydrolysis to cleave the carbonate and afford the diol, conditions which are compatible with vinyl ethers but selectivity between the resulting 1 ° and 2° alcohol is still a significant synthetic challenge. To overcome all the above issues, it is essential that hydroxyl protecting groups (PG) are incorporated into the synthetic route in a manner that enables all three glycerol hydroxyl groups to be distinguished.

[0005] Benzyl (Bn) ethers are a common hydroxyl PG that are stable to a wide range of acidic and basic conditions, as well as most metal hydride reducing agents and many oxidising agents. Cleavage of the benzyl protecting group is achieved by hydrogenolysis, dissolving metal reduction, or exposure to a strong acid (protic or Lewis) (T. W. Greene, in Greene’s Protective Groups in Organic Synthesis, John Wiley &Sons, Inc., New Jersey, 4th edn, 2007, ch. 2, pp. 102-130). p-Methoxybenzyl (PMB) and 3,4-dimethoxybenzyl (DMB) are more electron rich derivatives of Bn. They are less stable to acids than Bn and are especially susceptible to oxidative cleavage under neutral conditions [using 2,3-dichloro-5,6-dicyanoquinone (DDQ) or ceric ammonium nitrate (CAN)] (P. J. Kocienski, in Protecting Groups, ed. D. Enders, R. Noyori, B. M. Trost, Georg Thieme Verlag, Stuttgart, 1st edn, 1994, ch. 2, pp. 46-54). In principle, PMB or DMB could be employed in plasmalogen synthesis and removed under neutral oxidative conditions that do not catalyse acyl migration. However, previous work by the Golding group and others found that PMB is incompatible with polyunsaturated functionality when oxidatively cleaved with DDQ (A. B. Maude, New Synthetic Approaches to Chiral C3 Compounds, PhD thesis, Newcastle University, 1992): Golding Experiments highlighting the incompatibility of PMB with polyunsaturation and Z-vinyl ethers.

[0006] Bittman was able to cleave PMB via Birch reduction without perturbation of the vinyl ether but not without considerable synthetic challenge. The reduction was found to be incompatible with other protecting groups (e.g. p-methoxyphenyl, PMP) and, if lithium was used in place of sodium, the vinyl ether was rapidly isomerised to the E-isomer. This led to Bittman’s 13-step overall synthesis, which included 8-steps solely dedicated to the installation or removal of various protecting groups. While the Birch reduction is excellent for small-scale syntheses, the combination of pyrophoric sodium and liquid ammonia, which is volatile and potentially flammable, makes this reduction challenging for scale-up. Hence, there is a need for an alternative protecting group that can be installed and removed in the presence of all plasmalogen functionality, without the need for Birch reduction, and without inflating the overall number of synthetic steps.

[0007] Specifically, there is a need for a benzyl-type protecting group that would be oxidatively cleavable in the presence of vinyl ethers and polyunsaturated bonds. This would address the issues found by Golding and Bittman and would therefore be suitable for a scaleable, general route to plasmalogens. Z-vinyl ethers:

[0008] In Nature, vinyl ethers are scarce with the structure often stabilised by conjugation with a carbonyl group or buried within a complex structure (T. B. Poulsen, Total Synthesis of Natural Products Containing Enamine or Enol Ether Derivatives, Acc. Chern. Res., 2021,54, 1830 - 1842). Rarely are they found as a standalone group, although rifamycins, plasmalogens, and aflatoxins do all possess such vinyl ether entities in theirstructures (S. H. Kirsch, F. P. J. Haeckl, R. Muller, Beyond the approved: target sites and inhibitors of bacterial RNA polymerase from bacteria and fungi, Nat. Prod. Rep., 2022, 39, 1226 - 1263; F. Dominger, E. R. Werner, J. Berger, K. Watschinger, Regulation of plasmalogen metabolism and traffic in mammals: The fog begins to lift, Cell Dev. Biol., 2022, 10, 1 - 22; A. Nazhand, A. Durazzo, M. Lucarini, E. B. Souto, A. Santini, Characteristics, Occurrence, Detection and Detoxification of Aflatoxins in Foods and Feeds, Foods, 2020, 9,1 -26). In particular, plasmalogens contain the thermodynamically less stable Z-vinyl ether. The synthesis of plasmalogens therefore requires a method to synthesise Z-vinyl ethers in high yield and high stereoselectivity.

[0009] There are mainly five reaction classes that afford either E- or Z-vinyl ethers, but there are problems with each reaction class (D. J. Wintemheimer, R. E. Shade, C. A. Medic, Methods for Vinyl Ether Synthesis, Synth., 2010, 15, 2497-2511). • Elimination reactions require an a- or p-leaving group adjacent to the ether oxygen. Under basic conditions loss of HX affords the vinyl ether with the stereo-outcome of this elimination depending on the substrate although precise stereocontrol is often poor. • Both copper(l) and copper(ll) catalysts have been used to couple alcohols and vinyl coupling partners (e.g. vinyl halide, vinyl boranes) (G. Nordmann, S. L. Buchwald, A domino copper-catalyzed C-O coupling-Claisen rearrangement process, J. Am. Chern. Soc., 2003, 125, 4978 - 4979; T. D. Quach, R. A. Batey, Copper(ll)-catalyzed ether synthesis from aliphatic alcohols and potassium organotrifluoroborate salts, Org. Lett., 2003, 5, 1381 - 1384). However, only E-vinyl ethers have ever been synthesised using this methodology. • Base-induced isomerisation of allyl ethers uses a strong base and an electrophile to trap the resulting carbanion (J. Shin, D. H. Thompson, Direct Synthesis of Plasmenylcholine from Allyl-Substituted Glycerols, J. Org. Chern., 2003, 68, 6760 - 6766). This affords mainly the Z-vinyl ether but competition between y- and unwanted a-addition of the electrophile can result in low yields. • Partial reduction of alkynyl ethers also gives the Z-isomer as the major product but it is never stereospecific. In Bittman’s plasmalogen synthesis the Lindlar catalysed reduction of an alkynyl ether was claimed to afford the Z-vinyl ether in a 66:1 Z.E ratio but only a single example was given (D. Qin, H. Byun, R. Bittman, Synthesis of Plasmalogen via 2,3-Bis-O-(4‘-methoxybenzyl)-sn-glycerol, J. Am. Chern. Soc., 1999,121,662-668). In general, Lindlar reductions afford 5-10% E-isomer which is not satisfactory enough (C. Oger, L. Balas, T. Durand, J. M. Galano, Are Alkyne Reductions Chemo-, Regio-, and Stereoselective Enough To Provide Pure (Z)-Olefins in Polyfunctionalized Bioactive Molecules, Chern. Rev., 2013, 113, 1313-1350). • Finally, olefinations of carbonyl substrates (e.g. by Wittig reaction) afford a mixture of E- and Z-isomers (M. Lakhrissi, Y. Chapleur, Wittig Olefination of Lactones, Angew. Chern., Int. Ed. Engl., 1996, 35, 750).

[0010] The Peterson olefination is a well-established method of stereoselectively synthesising alkenes. The first reported discovery (Peterson 1968) reacted trimethylsilylmethyl magnesium chloride with a carbonyl compound to afford a p-hydroxysilane (D. J. Peterson, Carbonyl olefination reaction using silyl-substituted organometallic compounds, 1968, 33, 780 - 784). This was then treated with base or acid to bring about the desired decomposition to the alkene. Since this discovery was published there have been many variations of the reaction reported (T. H. Chan, E. Chang, Synthesis of alkenes from carbonyl compounds and carbanions alpha to silicon. III. Full report and a synthesis of the sex pheromone of gypsy moth, J. Org. Chem., 1974, 39, 3264 - 3268; P. Hudrlik, D. Peterson, The synthesis of olefins from p-ketosilanes, Tetrahedron Lett., 1972,13, 1785 - 1787; J. J. Eisch, J. E. Galle, Stereospecific preparation of 1,2-epoxyalkyllithium reagents via the generalized lithiation of a-heterosubstituted epoxides, J. Organomet. Chem., 1976, 121, 10 - 14). The one commonality between all of these methods is that they proceed via a p-hydroxysilane intermediate: O M+ R" a-silyl carbanion + ketone MSiR3 < silyl reagent + epoxide P-hydroxy silane MR"" a-silyl ketone + organometallic + MR" silyl epoxide + organometallic

[0011] The four methods to synthesise the intermediate involve nucleophilic attack on an epoxide or ketone with the silyl functionality either pre-installed or added during the reaction. The resulting p-hydroxysilane can then be isolated and treated with acid or base, depending on the desired isomer, to afford an alkene (T. H. Chan, Alkene synthesis via beta-functionalized organosilicon compounds, Acc. Chem. Res., 1977, 10, 442 - 448). Under basic conditions a syn-elimination takes place, whereas under acidic conditions an anf / -elimination occurs. Therefore, one diastereoisomer can be treated either with base to afford one alkene isomer, or with acid to afford the other alkene isomer (P. F. Hudrlik, D. Peterson, R. J. Rona, Reactions of alpha,beta-epoxysilanes with organocuprate reagents. New stereospecific olefin synthesis, J. Org. Chem., 1975, 40, 2263 - 2264): bf3- RX°'H bf3 h R3Si R' HO SIR R" base anti diastereoisomers syn

[0012] Hudrlik reported in 1977 the synthesis of a methoxy Z-vinyl ether using the Peterson olefination (P. F. Hudrlik, A. M. Hudrlik, R. J. Rona, R. N. Misra, G. P. Withers, Stereospecific synthesis of heteroatom-substituted olefins from alpha,beta-epoxysilanes. Preparation of vinyl bromides, enol acetates, enol ethers, and enamides, J. Am. Chem. Soc., 1977, 99, 1993 - 1996). Brensted acid catalysed methanolysis of trimethyl((2S,3R)-3-propyloxiran-2-yl)silane, a c / s-silyl epoxide, afforded (1R,2R)-1-methoxy-1-(trimethylsilyl)pentan-2-ol, which was treated with potassium hydride to give (Z)-1-methoxypent-1-ene in an 86:14 Z:E ratio. Davies also used the Peterson reaction with methanolysis to synthesise an E-methoxy vinyl ether from a trans-silyl epoxide with greater stereocontrol (99:1 E:Z) (S. G. Davies, C. J. R. Hedgecock J. M. McKenna, A Formal Total Asymmetric Synthesis of (+)-Thienamycin, Tetrahedron: Asym. 1995, 6, 2507 -2510). Other reports of the Peterson being used for vinyl ether synthesis are rare and these were either simple unsubstituted vinyl ethers or methyl vinyl ethers (M. C. Croudace, N. E. Schore, General Synthesis of Acetylenic Vinyl Esters and Ethers, J. Org. Chem. 1981,46, 5357 - 5363; C. D. McCune , M. L. Beio, J. A. Friest, S. Ginotra, D. B. Berkowitz, A useful methoxyvinyl cation equivalent: a-t-butyldimethylsilyl-a-methoxyacetaldehyde, Tetrahedron Lett. 2015,56, 3575 - 3579). When methanolysis was performed, methanol was used as the solvent in large excess. For other alcohols methanol cannot be used as the solvent as it would outcompete nucleophilic attack from the desired alcohol. Therefore, the conditions used by Hudrlik and Davies are not applicable to most alcohols. There remains a need for a method suitable for synthesising more complex vinyl ethers with a range of alcohols for the epoxide ring-opening and subsequent elimination.

[0013] There is a need for an improved method for synthesising Z-vinyl ethers in high yield and high stereoselectivity. Phosphate head group:

[0014] Plasmalogens contain a phosphate head group at the sn-3 position with either choline or ethanolamine functionality that exists as a zwitterion: © ^\^NMe3 ------v-------' choline ethanolamine Plasmalogen phosphate head group structure.

[0015] All previous plasmalogen syntheses introduced the choline phosphate head group by reacting a glycerol alcohol with 2-chloro-1,3,2-dioxaphospholane 2-oxide (COP) to afford a cyclic phosphate ester, which is ring-opened by trimethylamine (NMes) to give the phosphocholine (D. H. Qin, H. S. Byun and R. Bittman, Synthesis of Plasmalogen via 2,3-Bis-O-(4‘-methoxybenzyl)-sn-glycerol, J. Am. Chem. Soc., 1999, 121,662-668; J. Shin and D. H. Thompson, Direct Synthesis of Plasmenylcholine from Allyl-Substituted Glycerols, J. Org. Chem., 2003, 68, 6760-6766; J. M. Zeidler, W. Zimmermann, H. J. Roth, Synthesis of azathia-analogues of platelet activating factor containing a methioninol backbone, Chem. Phys. Lipids, 1990, 56,175- 183). BRIEF SUMMARY OF THE DISCLOSURE

[0016] Disclosed herein is a methodology to synthesise natural and artificial plasmalogens: 0 A MD R'^d °© 0 Acylation 0 R,'X=XO / Xr^OH __________\ R“ O Z Phosphorylation g Protecting Group O Protecting Group Peterson Protected glycerol

[0017] Given the limited solubility of phosphocholine or phosphoethanolamine it may be advantageous to add the phosphate head group at the sn-3 position last. To avoid acyl migration it may be advantageous that the primary alcohol be protected prior to phosphorylation. To avoid intramolecular attack, on the Z-vinyl ether it may be advantageous for the sn-2 alcohol to be protected before acylation. With two protecting groups in the route, it is advantageous for these groups to be orthogonal (e.g. a novel benzyl-type protecting group, DIMON, at sn-3 and silyl at sn-2, respectively). As cleavage of a silyl protecting group will catalyse acyl migration, it is advantageous for DIMON to be the only protecting group present once the fatty chain is installed.

[0018] In accordance with compound of formula Y: a first aspect of the present invention there is provided a use of a (Y), to form a protected nucleophile, wherein a single substituent selected from R1-R4is -CH2-LG, or-CH2-OH, wherein LG is leaving group; at least one substituent selected from R'-R4 is selected from -O-(CH2CH2O)-C-.2-alkyl, and -Ci-2-alkyl; the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-(CH2CH2O)n-Ci-2-alkyl and -Ci-2-alkyl; and n is independently at each occurrence an integer selected from 0, 1,2, 3, 4 and 5.

[0019] In embodiments, the single substituent selected from R1-R4is -CH2-LG. In embodiments, the single substituent selected from R'-R4 is -CH2-OH.

[0020] In embodiments, at least one substituent selected from R1-R4 is -O-(CH2CH2O)n-Ci-2-alkyl; and the rest of the R1-R4 substituents are independently at each occurrence selected from H and -O-(CH2CH2O)n-Ci-2-alkyl.

[0021] In embodiments, n is independently at each occurrence an integer selected from 0,1 and 2.

[0022] In embodiments, each n is 0 such that at least one substituent selected from R1-R4 is selected from -O-Ci-2-alkyl and -Ci-2-alkyl; and the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-Ci-2-alkyl and -Ci-2-alkyl.

[0023] In embodiments, each n is 0 such that at least one substituent selected from R1-R4 is -O-C1 2-alkyl; and the rest of the R1-R4 substituents are independently at each occurrence selected from H and -O-C 1-2-alkyl.

[0024] In embodiments, each n is 1 such that at least one substituent selected from R1-R4 is -O-(CH2CH2O)-Ci-2-alkyl; and the rest of the R1-R4 substituents are independently at each occurrence selected from H and -O-(CH2CH2O)-Ci-2-alkyl.

[0025] In embodiments, each n is 2 such that at least one substituent selected from R1-R4 is -O-(CH2CH2O)2-Cb2-alkyl; and the rest of the R1-R4 substituents are independently at each occurrence selected from H and -O-(CH2CH2O)2-Ci-2-alkyl.

[0026] It may be that at least one -O-Ci-2-alkyl is -OMe. It may be that each -O-Ci-2-alkyl is -OMe. It may be that two substituents selected from R1-R4 are -O-Ci-2-alkyl and one substituent selected from R1-R4 is H.

[0027] At least one substituent selected from R'-R4 may be -Ci 2-alkyl, e.g. Me. R1 may be C1-2-alkyl, e.g. Me. At least one substituent selected from R1-R4 may be -O-Ci-2-alkyl, e.g. OMe. R1 may be -O-Ci-2-alkyl, e.g. OMe. R3 may be H. R4 may be Ci-2-alkyl, e.g. Me. R4 may be -O-Ci-2-alkyl, e.g. OMe.

[0028] It may be that R2 is -CH2-LG. Alternatively, it may be that R2 is -CH2-OH.

[0029] It may be that R3 is -CH2-LG. Alternatively, it may be that R3 is -CH2-OH.

[0030] Illustrative leaving groups include halo, such as Cl, Br, and I, and sulfonate esters such as tosylate (TsO). Preferably LG is Cl.

[0031] It may be that the compound of formula Y is DIMONCI: (DIMONCI).

[0032] It may be that the compound of formula Y is DIMONOH: (DIMONOH).

[0033] It may be that the protected nucleophile is a protected alcohol. For example, the protected alcohol may be a protected aliphatic or aromatic alcohol (e.g. a phenol). Aliphatic alcohols include benzylic, primary, and secondary alcohol. It may be that the protected nucleophile is a protected amine.

[0034] In an embodiment is provided a use of a compound of formula Y wherein the protected nucleophile is an intermediate in the synthesis of a plasmalogen.

[0035] In accordance with a second aspect of the present invention there is provided a method of forming a protected nucleophile, the method comprising; a) reacting a compound of formula Y as defined above, wherein a single substituent is selected from R1-R4is -CH2-LG, with a nucleophile; or b) reacting a compound of formula Y as defined above, wherein a single substituent is selected from R1-R4is -CH2-OH, with an electrophile, to form a protected nucleophile of formula Z: R1 wherein a single substituent selected from R1-R4 is -CH2-NU; at least one substituent selected from R1-R4 is selected from -O-(CH2CH2O)n-Ci-2-alkyl, and -Ci-2-alkyl; the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-(CH2CH2O)n-Cv2-alkyl and -Ci-2-alkyl; and n is independently at each occurrence an integer selected from 0,1,2, 3, 4, and 5; and Nu is a residue of a nucleophile.

[0036] In embodiments the method comprises option a). In alternative embodiments the method comprises option b).

[0037] It may be that the at least one substituent selected from R1-R4 selected from -O-(CH2CH2O)n-Ci-2-alkyl and -Ci-2-alkyl is as defined above in regard to the first aspect of the invention.

[0038] It may be that the rest of the R1-R4 substituents independently at each occurrence selected from H, -O-(CH2CH2O)n-Ci-2-alkyl and -Ci-2-alkyl are as defined above in regard to the first aspect of the invention.

[0039] It may be that n is as defined above in regard to the first aspect of the invention.

[0040] It may be that the compound of Formula Y is as defined above in regard to the first aspect of the invention.

[0041] It may be that the compound of formula Z is:

[0042] It may be that the protected nucleophile is a protected O-nucleophile. For example, the protected O-nucleophile may be a protected aliphatic alcohol. -CH2-NU may be wherein PG1 is a protecting group. Exemplary (hydroxyl) protecting groups include ethers, such as methoxymethyl ether, tetrahydropyranyl ether, / -butyl ether, allyl ether, benzyl ether, esters, such as acetic acid ester, pivalic acid ester, benzoic acid ester, and silyls. Preferably PG1 is a silyl protecting group, e.g. TMS, TES, TBDMS, TBDPS, TIPS. More preferably PG1 is TBDMS.

[0043] It may be that the protected O-nucleophile is a protected phenol. It may be that the protected nucleophile is a protected / V-nucleophile, such as a protected amine.

[0044] In embodiments in which the protected nucleophile is an aliphatic alcohol, option a) may be carried out in a suitable polar solvent. Common polar solvents include acetone, acetonitrile, dimethylformamide (DMF), tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), isopropanol, methanol, 2-methyltetrahydrofuran (2-MeTHF) and dimethyl carbonate (DMC). It may be that the polar solvent comprises DMF, THF, 2-MeTHF or mixtures thereof. It may be that the polar solvent comprises DMF. It may be that the polar solvent comprises THF. It may be that the polar solvent comprises 2-MeTHF.

[0045] In embodiments in which the protected nucleophile is an aliphatic alcohol, option a) may be carried out in the presence of a base. The base may be an alkali metal hydride, such as NaH. The base may be a Group 1 te / Y-butoxide, such as LiO‘Bu. It may be that the reaction is carried out in a solvent comprising THF and in the presence of an alkali metal hydride base, such as NaH. Alternatively, it may be that the reaction is carried out in a solvent comprising DMF and in the presence of a Group 1 te / Y-butoxide base, such as LiO^u.

[0046] In embodiments in which the protected nucleophile is an aliphatic alcohol, option b) may be carried out in a non-polar solvent, optionally wherein the non-polar solvent is toluene or trifluorotoluene, further optionally wherein the non-polar solvent is toluene.

[0047] In embodiments in which the protected nucleophile is an aliphatic alcohol, option b) may be carried out in the presence of a Lewis acid. The Lewis acid may be a metal salt. The Lewis acid may be selected from the group consisting of: aluminium-containing compounds, boron-containing compounds, and lanthanide-containing compounds. The Lewis acid may be boron trifluoride.

[0048] In preferred embodiments, the reaction is carried out in anhydrous, inert atmosphere to minimise the formation of by-products thereby improving yield. Anhydrous, inert conditions can be achieved by methods known in the art, such as by using oven-dried glassware and the Schlenk technique. It may be that the reaction is carried out at room temperature.

[0049] In embodiments in which the nucleophile is phenol, the reaction may be carried out in the presence of a weaker base, such as a carbonate (e.g. caesium, potassium, or sodium carbonate). It may be that the base is caesium carbonate. The reaction may be carried out in a suitable solvent, such as acetonitrile. In these embodiments the method preferably comprises option a).

[0050] In embodiments in which the nucleophile is an amine the method comprises option a). In these embodiments, option a) may be carried out in a suitable solvent, such as DCM. The reaction may be carried out in the presence of a tertiary amine base, such as NEts. In these embodiments, the amine may be a secondary amine.

[0051] In accordance with a third aspect of the present invention there is provided a method of deprotecting a protected nucleophile of formula Z: wherein a single substituent selected from R1-R4 is -CH2-Nu; at least one substituent selected from R1-R4 is selected from -O-(CH2CH2O)n-Ci-2-alkyl, and -Ci-2-alkyl; the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-(CH2CH2O)n-Ci-2-alkyl and -Ci-2-alkyl; n is independently at each occurrence an integer selected from 0,1,2,3,4 and 5; and Nu is a residue of a nucleophile, the method comprising treating the protected nucleophile with an acid, an oxidant or a reductant to form NuH.

[0052] It may be that the compound of formula Z is as defined above in regard to the second aspect of the invention.

[0053] It may be that -CH2-NU is 0 and / or , wherein R5 is a fatty acid residue; and R6 is an C624-alkyl or C6-24-alkenyl. Therefore, it may be that NuH is

[0054] In embodiments R5 is a Ce-22-alkyl. In embodiments R5 is a Ce-2i-alkyl. In embodiments R5 is a Ce-20-alkyl. In embodiments R5 is a Ce-w-alkyl. In embodiments R5is a Ce-is-alkyl. In embodiments R5 is a C7-22-alkyl. In embodiments R5 is a Cs-22-alkyl. In embodiments R5 is a Cg-22-alkyl. In embodiments R5 is a C10 22-alkyl. In embodiments R5 is a C? 21-alkyl. In embodiments R5 is a Cs 20-alkyl. In embodiments R5is a Cg-19-alkyl. In embodiments R5is a Cio-18-alkyl. In embodiments R5 is selected to correspond to the desired plasmalogen. For example, in embodiments R5 is -Cu-alkyl.

[0055] In embodiments R5is a C6-22-alkenyl. In embodiments R5is a Ce-2i-alkenyl. In embodiments R5 is a C6-2o-alkenyl. In embodiments R5is a Ce-ig-alkenyl. In embodiments R5is a Ce-is-alkenyl. In embodiments R5is a C7-22-alkenyl. In embodiments R5is a Cs-22-alkenyl. In embodiments R5is a Cg-22-alkenyl. In embodiments R5is a Cio 22-alkenyl. In embodiments R5is a C? 2i-alkenyl. In embodiments R5is a C8 2o-alkenyl. In embodiments R5is a Cg-19-alkenyl. In embodiments R5is a Cio-18-alkenyl. In embodiments R5 is selected to correspond to the desired plasmalogen. For example, in embodiments R5 is -Ci4-alkenyl. For example, in embodiments R5 is -Ci5-alkenyl. For example, in embodiments R5 is -Ci6-alkenyl. For example, in embodiments R5 is -Ci7-alkenyl. For example, in embodiments R5 is -Cis-alkenyl. For example, in embodiments R5 is -Ci9-alkenyl. For example, in embodiments R5 is -C2o-alkenyl. For example, in embodiments R5 is -C2i-alkenyl. For example, in embodiments R5 is -C22-alkenyl. In an embodiment, the alkenyl group includes 1,2, 3, 4, 5, or 6 unsaturated bonds.

[0056] R5 may be an oleic acid, arachidonic, or a docosahexaenoic acid residue.

[0057] In embodiments R6 is a C6-22-alkyl. In embodiments R6 is a Ce-2i-alkyl. In embodiments R6 is a C6 2o-alkyl. In embodiments R6 is a Ce-19-alkyl. In embodiments R6is a Ce-is-alkyl. In embodiments R6 is a C? 22-alkyl. In embodiments R6 is a Cs 22-alkyl. In embodiments R6 is a C=22-alkyl. In embodiments R6 is a Cio-22-alkyl. In embodiments R6 is a C7-2i-alkyl. In embodiments R6 is a C8-20-alkyl. In embodiments R6is a Cg-19-alkyl. In embodiments R6is a Ciow-alkyl. In embodiments R6 is selected to correspond to the desired plasmalogen. For example, in embodiments R6 is -Cw-alkyl.

[0058] In embodiments R6is a Ce-22-alkenyl. In embodiments R6is a Ce-2i-alkenyl. In embodiments R6 is a Ce 2o-alkenyl. In embodiments R6is a Ce 19-alkenyl. In embodiments R6is a Cws-alkenyl. In embodiments R6is a C? 22-alkenyl. In embodiments R6is a Cs 22-alkenyl. In embodiments R6is a C9-22-alkenyl. In embodiments R6is a Cio-22-alkenyl. In embodiments R6is a C7-2i-alkenyl. In embodiments R6is a Cs-2o-alkenyl. In embodiments R6is a Cg-ig-alkenyl. In embodiments R6is a Cio-18-alkenyl. In embodiments R6 is selected to correspond to the desired plasmalogen. For example, in embodiments R6 is -Ci4-alkenyl. For example, in embodiments R6 is -Cis-alkenyl. For example, in embodiments R6 is -Ci6-alkenyl. For example, in embodiments R6 is -Cv-alkenyl. For example, in embodiments R6 is -Cis-alkenyl. In an embodiment, the alkenyl group includes 1,2, 3, 4, 5, or 6 unsaturated bonds.

[0059] R6 may be selected from saturated Cw-alkyl, saturated Cw-alkyl, saturated Cw-alkyl, and monounsaturated Cis-alkenyl, e.g. cis-9-octadecenenyl.

[0060] It may be that the method comprises treating the protected nucleophile with an acid to form NuH. The acid may be trifluoroacetic acid (TFA). When TFA is the acid, it may be that the protected nucleophile is also treated with a carbocation scavenger, such as triethylsilane or anisole. Preferably, the carbocation scavenger is anisole. Alternatively, the acid may be hydrochloric acid. When the acid is HCI, the method may comprise refluxing a solution comprising the protected nucleophile and HCI. The solution will comprise a suitable solvent, such as methanol. In these embodiments, NuH may be an alcohol.

[0061] It may be that the method comprises treating the protected nucleophile with an oxidant to form NuH. In preferred embodiments, the oxidant is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). Advantageously, the reaction is carried out in a wet solvent, such as wet DCM. In these embodiments, NuH may be an alcohol.

[0062] It may be that the method comprises treating the protected nucleophile with a reductant to form NuH. It may be that the method comprises hydrogenating the protected nucleophile. For example, the reductant may be palladium on carbon (Pd / C). In these embodiments, NuH may be an O-nucleophile or an amine. When NuH is an amine it may be that the protected nucleophile is also treated with an acid, e.g. TFA. Typically, when the method comprises treating the protected nucleophile with a reductant, NuH will not comprise functionality that can be reduced (e.g. alkene, nitro, nitrile, etc).

[0063] In accordance with a fourth aspect of the present invention there is provided a method for synthesising a compound of formula IVa and / or IVb: the method comprising reacting a compound of formula Illa or lllb: with R9OH in the presence of a Lewis acid and a solvent, wherein R7 is selected from the group consisting of: Ci-28-alkyl and C2-28 alkenyl; R8 is a silyl protecting group; and R9 is an organic group.

[0064] In embodiments, the Lewis acid is a metal salt. The Lewis acid may be selected from the group consisting of: aluminium-containing compounds, boron-containing compounds, and lanthanide-containing compounds.

[0065] In embodiments, the Lewis acid is selected from the group consisting of boron trifluoride and lanthanide triflate, optionally wherein the lanthanide triflate is Yb(OTf)3. Preferably, the Lewis acid is boron trifluoride.

[0066] In embodiments when the Lewis acid is a lanthanide triflate (e.g. Yb(OTf)3) a minimum of 30 mol% catalyst is required to induce sufficient reactivity.

[0067] In embodiments when the Lewis acid is a lanthanide triflate (e.g. Yb(OTf)3), the solvent is ideally non-polar. Preferably, the non-polar solvent is (a,a,a-trifluoromethylbenzene (trifluorotoluene, TFT).

[0068] In embodiments when the Lewis acid is a lanthanide triflate (e.g. Yb(OTf)3), it is advantageous to conduct the reaction at a concentration of 0.5 M or less, preferably 0.25 M or less, more preferably 0.2 M.

[0069] In embodiments when the Lewis acid is a lanthanide triflate (e.g. Yb(OTf)3), the ratio of epoxide : alcohol is 1 : 1.0 to 1: 1.5, preferably 1 : 1.1 to 1 : 1.3, more preferably 1 : 1.2.

[0070] In embodiments when the Lewis acid is boron trifluoride, the mol% catalyst is between 1 and 5 mol%, preferably 5 mol%.

[0071] In embodiments when the Lewis acid is boron trifluoride, the solvent is ideally non-polar. Preferably, the non-polar solvent is trifluorotoluene (TFT) or toluene.

[0072] In embodiments when the Lewis acid is boron trifluoride, it is advantageous to conduct the reaction at a concentration of 0.1 M to 1 M or more.

[0073] In embodiments the ratio of the compound of formula Illa or lllb : R9OH is from 1: 1 to 1 : 4, preferably 1 : 1.2 to 1 : 4, more preferably 1 :1.2 to 1 : 3.

[0074] In embodiments the method comprises adding a solution comprising the compound of formula Illa or lllb to a solution comprising R9OH and the Lewis acid.

[0075] In embodiments the ratio of the compound of formula Illa or lllb : Lewis acid is from 1 : 0.01 to 1 : 0.50.

[0076] In embodiments the compound of formula Illa or lllb is reacted with R9OH at a temperature in the range from 15 °C to 35 °C.

[0077] In embodiments R7 is a Cs 22-alkyl. In embodiments R7 is a C6-2i-alkyl. In embodiments R7 is a Ce-2o-alkyl. In embodiments R7 is a C6-i9-alkyl. In embodiments R7 is a Ca-is-alkyl. In embodiments R7 is a C7-22-alkyl. In embodiments R7 is a C8-22-alkyl. In embodiments R7 is a C9-22-alkyl. In embodiments R7 is a Cio-22-alkyl. In embodiments R7 is a C7-2i-alkyl. In embodiments R7 is a C8-20-alkyl. In embodiments R7 is a C9-i9-alkyl. In embodiments R7 is a Cio-w-alkyl. In embodiments R7 is selected to correspond to the desired plasmalogen. For example, in embodiments R7 is selected from the group consisting of: -Cw-alkyl, -Ci6-alkyl and -Cis-alkyl.

[0078] In embodiments R7 is a Ce-22-alkenyl. In embodiments R7 is a C6-21- alkenyl. In embodiments R7 is a Ce-20-alkenyl. In embodiments R7 is a Ce-19-alkenyl. In embodiments R7 is a Ce-is-alkenyl. In embodiments R7 is a C?-22-alkenyl. In embodiments R7 is a Cs-22-alkenyl. In embodiments R7 is a C9-22-alkenyl. In embodiments R7 is a Cio-22-alkenyl. In embodiments R7 is a C?~2i-alkenyl. In embodiments R7 is a Cb-20-alkenyl. In embodiments R7 is a Cg-19-alkenyl. In embodiments R7 is a C® 18-alkenyl. In embodiments R7 is selected to correspond to the desired plasmalogen. For example, in embodiments R7 is -Cn-alkenyl. For example, in embodiments R7 is -Cis-alkenyl. For example, in embodiments R7 is -Ci6-alkenyl. For example, in embodiments R7 is -Ci7-alkenyl. For example, in embodiments R7 is -Cis-alkenyl. In an embodiment, the alkenyl group includes 1, 2, 3, 4, 5, or 6 unsaturated bonds.

[0079] R7 may be selected from saturated Ci4-a Ikyl, saturated Cw-alkyl, saturated Cw-alkyl, and monounsaturated Cis-alkenyl, e.g. cis-9-octadecenenyl.

[0080] In embodiments R8 is a silane group such that the compound of formula IVa and IVb is a p-hydroxy silane. For example, in embodiments, R8 is trimethylsilyl.

[0081] In embodiments R9 has a molecular mass below 1000 g mol1. In embodiments R9 is a moiety having 25 or fewer carbon atoms. In embodiments R9 has a single hydroxyl group. In embodiments the identity of the R9OH alcohol is selected to ensure sufficient solubility in the solvent employed.

[0082] In embodiments R9 is the organic portion of a benzylic, primary, or secondary alcohol, optionally wherein R9 is the organic portion of a primary aliphatic alcohol. In embodiments, R9 is the organic portion of a primary aliphatic alcohol of formula Z: wherein a single substituent selected from R1-R4 is and / or OPG1 at least one substituent selected from R1-R4is selected from-O-(CH2CH2O)-C-.2-alkyl, and -Ci-2-alkyl; the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-(CH2CH2O)n-Ci-2-alkyl and -Ci-2-alkyl; n is independently at each occurrence an integer selected from 0,1,2,3,4 and 5; and PG1 is a protecting group, optionally wherein PG1 is a silyl protecting group.

[0083] It may be that the compound of formula Z is as defined above in regard to the second aspect of the invention.

[0084] In embodiments, when R9 is a cyclic secondary alcohol, the beta carbon atoms of the cyclic secondary alcohol exclude an alkyl group substituent that is branched at the point of attachment to the beta carbon atom of the cyclic secondary alcohol; optionally wherein the beta carbon atoms of the cyclic secondary alcohol include a substituent selected from the group consisting of: H, -CH3 and -CH2CH3. In this embodiment, hindered alcohols such as : HO are excluded.

[0085] In embodiments the compound of formula Illa or IIlb is produced by reacting a compound of formula II: with an epoxidation reagent, optionally wherein the epoxidation reagent is meta-chloroperbenzoic acid (mCPBA).

[0086] In embodiments the compound of formula II is produced by reacting a compound of formula I: R7 =—R8 (i), with a reducing agent, optionally wherein the reducing agent is diisobutylaluminium hydride (DIBAL-H).

[0087] In accordance with a fifth aspect of the present invention there is provided a method for synthesising a compound of Formula V: R7 OR9 (V). the method comprising reacting a compound of Formula IVa or IVb: R8                R8 HO VaH HO Vh V^OR9 H d7           Hn? R (IVa) or R (IVb), with a base in a non-polar solvent, wherein R7 is selected from the group consisting of: Ci-2s-alkyl and C2-28 alkenyl; R8 is a silyl protecting group; and R9 is an organic group.

[0088] In embodiments the base is selected from the group consisting of: a metal hydride or metal alkoxide base, optionally potassium hydride or potassium alkoxide, e.g. potassium tert-butoxide.

[0089] In embodiments the non-polar solvent has an Et(30) value of 40 or less, optionally 38.5 or less. In embodiments the non-polar solvent is trifluorotoluene.

[0090] In embodiments the reaction is heated, optionally wherein the reaction is heated to 35°C or more, for example 40°C or 45°C.

[0091] In embodiments the compound of formula IVa and / or IVb is produced by the process of the present invention according to the fourth aspect.

[0092] In embodiments R7 is a Ce-22-alkyl. In embodiments R7 is a Ce-2i-alkyl. In embodiments R7 is a Ce-20-alkyl. In embodiments R7 is a Ce-19-alkyl. In embodiments R7 is a Cs-is-alkyl. In embodiments R7 is a C7-22-alkyl. In embodiments R7 is a Cs-22-alkyl. In embodiments R7 is a Cg-22-alkyl. In embodiments R7 is a Cio-22-alkyl. In embodiments R7 is a C7-2i-alkyl. In embodiments R7 is a C8-20-alkyl. In embodiments R7 is a Cg-19-alkyl. In embodiments R7 is a Cio-is-alkyl. In embodiments R7 is selected to correspond to the desired plasmalogen. For example, in embodiments R7 is selected from the group consisting of: -Cw-alkyl, -Cw-alkyl and -Cis-alkyl.

[0093] In embodiments R7 is a Ce-22-alkenyl. In embodiments R7 is a C6-21- alkenyl. In embodiments R7 is a Ce-20-alkenyl. In embodiments R7 is a Ce-ig-alkenyl. In embodiments R7 is a Ce-is-alkenyl. In embodiments R7 is a C7-22-alkenyl. In embodiments R7 is a Cs-22-alkenyl. In embodiments R7 is a Cg. 22-alkenyl. In embodiments R7 is a Cio22-alkenyl. In embodiments R7 is a C7 2i-alkenyl. In embodiments R' is a Cs 20-alkenyl. In embodiments R7 is a C^ig-alkenyl. In embodiments R' is a C-g 18-alkenyl. In embodiments R7 is selected to correspond to the desired plasmalogen. For example, in embodiments R7 is -Ci4-alkenyl. For example, in embodiments R7 is -Cis-alkenyl. For example, in embodiments R7 is -Ci6-alkenyl. For example, in embodiments R7 is -Ci7-alkenyl. For example, in embodiments R7 is -Cis-alkenyl. In an embodiment, the alkenyl group includes 1,2 or 3 unsaturated bonds. In an embodiment, the alkenyl group includes 1,2, 3, 4, 5, or 6 unsaturated bonds.

[0094] R7 may be selected from saturated Cu-alkyl, saturated Cw-alkyl, saturated C-s-alkyl, and monounsaturated Cis-alkenyl, e.g. cis-9-octadecenenyl.

[0095] In embodiments R8 is a silane group such that the compound of formula IVa and IVb is a p-hydroxy silane. For example, in embodiments, R8 is trimethylsilyl.

[0096] In embodiments R9 has a molecular mass below 1000 g mol1. In embodiments R9 is a moiety having 25 or fewer carbon atoms. In embodiments R9 has a single hydroxyl group. In embodiments the identity of the R9OH alcohol selected to ensure sufficient solubility in the solvent employed.

[0097] In embodiments R9 is the organic portion of a benzylic, primary, or secondary alcohol, optionally wherein R9is the organic portion of a primary aliphatic alcohol.

[0098] In embodiments, when R9 is a cyclic secondary alcohol, the beta carbon atoms of the cyclic secondary alcohol exclude an alkyl group substituent that is branched at the point of attachment to the beta carbon atom of the cyclic secondary alcohol; optionally wherein the beta carbon atoms of the cyclic secondary alcohol include a substituent selected from the group consisting of: H, -CHa and -CH2CH3. In this embodiment, hindered alcohols such as : HO are excluded.

[0099] In embodiments, R9 is the organic portion of a primary aliphatic alcohol of formula Z: (Z), \ O Y OH wherein a single substituent selected from R1-R4 is OPG1 and / or 6pg1 ; at least one substituent selected from R1-R4 is selected from -O-(CH2CH2O)n-Ci-2-alkyl, and -Ci-2-alkyl; the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-(CH2CH2O)n-Ci-2-alkyl and -Ci-2-alkyl; and n is independently at each occurrence an integer selected from 0,1,2, 3, 4, and 5; and PG1 is a protecting group, optionally wherein PG1 is a silyl protecting group.

[00100] It may be that the compound of formula Z is as defined above in regard to the second aspect of the invention.

[00101] The primary aliphatic alcohol of formula Z may be made according to the seventh method of the invention.

[00102] In embodiments the method of the fifth aspect further includes any one of steps (A) to (D): (A) deprotecting the compound of formula V to yield a compound of formula VI at least one substituent selected from R1-R4 is selected from -O-(CH2CH2O)n-Ci-2-alkyl, and -Ci-2-alkyl; the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-(CH2CH2O)n-C- 2-alkyl and -Ci 2-alkyl; n is independently at each occurrence an integer selected from 0,1,2, 3, 4, and 5; and R7 is selected from the group consisting of: Ce-22-alkyl and Ce-22-alkenyl; and / or (B) acylating the compound of formula VI to provide a compound of formula VII: and / or the at least one substituent selected from R1-R4 is selected from -O-(CH2CH2O)n-Ci^-alkyl, and -Ci-2-alkyl; the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-(CH2CH2O)n-Ci-2-alkyl and -Ci-2-alkyl; n is independently at each occurrence an integer selected from 0,1,2, 3, 4, and 5; and R7 is selected from the group consisting of: Ce 22-alkyl and Ce 22-alkenyl; and R5 is a fatty acid residue; and / or (C) deprotecting the compound of formula VII to yield a compound of formula Villa and / or Vlllb: (Vlllb); R7 is selected from the group consisting of: Ce-22-alkyl and C6-22 alkenyl; and R5 is a fatty acid residue; and / or (D) phosphorylating the compound of formula Villa and / or VII lb to yield a plasmalogen of formula Xa and / or Xb: and / or R5 is a fatty acid residue; R7 is selected from the group consisting of: Ce-22-alkyl and C6-22 alkenyl; and each R10 is selected from the group consisting of: H and C1-12 alkyl; or one R10 is selected from the group consisting of: H and C1-12 alkyl, and two R10, together with the N-atom to which they are bonded form a 5-6 membered heterocyclic ring.

[00103] In embodiments step (D) involves two sub-steps (D1) followed by (D2): (D1) reacting the compound of formula Villa and / or Vlllb with 2-chloro-1,3,2-dioxaphospholane 2-oxide (COP) to form a compound of formula IXa and / or IXb: wherein: R7 is selected from the group consisting of: Ce-22-alkyl and C6-22 alkenyl; and R5 is a fatty acid residue; (D2) reacting the compound of formula IXa and / or Xlb with N(R10)3 to form the plasmalogen of formula Xa and / or Xb.

[00104] In embodiments each R10 is H. In embodiments each R10 is Me. Preferably, step (D) is carried out under anhydrous conditions. Water may be removed from the reaction by method known in the art, e.g. by oven-drying the reaction vessel(s) or the addition of molecular sieves or an anhydrous metal salt (e.g. magnesium sulphate) to the reaction.

[00105] In accordance with a sixth aspect of the present invention there is provided a plasmalogen obtainable by the method of the fifth aspect.

[00106] In accordance with a seventh aspect of the present invention there is provided method of forming a protected glycerol of formula XIII: wherein a single substituent selected from R1-R4 is ^^^O^^^^OPG2 OH 'O ^J^OPG2 OH and / or at least one substituent selected from R1-R4 is selected from -O-(CH2CH2O)n-Ci-2-alkyl, and -Ci-2-alkyl; the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-(CH2CH2O)n-Ci-2-alkyl and -Ci-2-alkyl; and n is independently at each occurrence an integer selected from 0,1,2, 3, 4, and 5, the method comprising reacting a compound of formula XI: R1 wherein a single substituent selected from R1-R4 is -CH2OH; at least one substituent selected from R1-R4 is selected from -O-(CH2CH2O)n-Ci-2-alkyl, and -Ci-2-alkyl; the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-(CH2CH2O)n-Cv2-alkyl and -Ci-2-alkyl; and n is independently at each occurrence an integer selected from 0,1,2, 3, 4, and 5, with an epoxide of formula Xlla and / or Xllb: 0 (Xlla); 0 (Xllb), wherein PG2 is a protecting group, to form the compound of formula XIII.

[00107] The method may further comprise protecting the compound of formula XIII to yield a compound of formula XIV: wherein a single substituent selected from R1-R4 is O^^^OPG2 OPG1 and / or \^O^^^OPG2 OPG1 at least one substituent selected from R1-R4 is selected from -O-(CH2CH2O)n-Ci-2-alkyl, and -Ci-2-alkyl; the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-(CH2CH2O)n-Cv2-alkyl and -Ci-2-alkyl; n is independently at each occurrence an integer selected from 0,1,2, 3, 4, and 5; and PG1 is a protecting group, optionally wherein PG1 is a silyl protecting group.

[00108] The method may further comprise deprotecting the compound of formula XIV to yield a primary aliphatic alcohol of formula Z: wherein a single substituent selected from R1-R4 is OPG1 and / or OPG1 at least one substituent selected from R1-R4 is selected from -O-(CH2CH2O)n-Ci-2-alkyl, and -Ci-2-alkyl; the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-(CH2CH2O)n-Cv2-alkyl and -Ci-2-alkyl; and n is independently at each occurrence an integer selected from 0,1,2, 3, 4, and 5.

[00109] Reacting the compound of formula XI with the epoxide of formula XI la and / or Xllb may be carried out in the presence of a Lewis acid, e.g. boron trifluoride. Reacting the compound of formula XI with the epoxide of formula Xlla and / or Xllb will typically be carried out in a solvent, e.g. a nonpolar solvent such as toluene.

[00110] PG1 may be as defined above in regard to the second aspect of the invention. The method of protecting the compound of formula XIII to yield the compound of formula XIV will depend on the PG1 protecting group. This step can be achieved by conventional methods known to the person skilled in the art. For example, where PG1 is a silyl group (e.g. triethylsilyl or t-butyldimethylsilyl), the protection step can be conducted using an appropriate silylating reagent such as a silyl triflate or silyl chloride. When PG1 is t-butyldimethylsilyl, the protection step can be achieved by reacting the compound of formula XIII with TBDMS-OTf in the presence of pyridine.

[00111] Illustrative PG2 (hydroxyl) protecting groups include ethers, such as methoxymethyl ether, tetrahydropyranyl ether, f-butyl ether, allyl ether, benzyl ether, esters, such as acetic acid ester, pivalic acid ester, benzoic acid ester, and silyls. Preferably PG2 is a silyl protecting group, e.g. TMS, TES, TBDMS, TBDPS, TIPS. More preferably, PG2 is TBDMS.

[00112] The method of deprotecting the compound of formula XIV to yield the primary aliphatic alcohol of formula Z will depend on the type of PG2 protecting group. This step can be achieved by conventional methods known to the person skilled in the art. For example, where a PG2 is a silyl group (e.g. triethylsilyl or t-butyldimethylsilyl), the deprotection step can be conducted using a suitable fluoride source (e.g. ammonium fluoride, tetrabutylammonium fluoride, fluorosilicic acid or HF).

[00113] It may be that the at least one substituent selected from R1-R4 selected from -O-(CH2CH2O)n-Ci-2-alkyl and -Ci-2-alkyl (in the compound of formulae XI and XIII and, optionally, XIV and Z) is as defined above in regard to the first aspect of the invention.

[00114] It may be that the rest of the R1-R4 substituents independently at each occurrence selected from H, -O-(CH2CH2O)n-Ci~2-alkyl and -Ci 2-alkyl (in the compound of formulae XI and XIII and, optionally, XIV and Z) are as defined above in regard to the first aspect of the invention.

[00115] It may be that n (in the compound of formulae XI and XIII and, optionally, XIV and Z) is as defined above in regard to the first aspect of the invention. SUMMARY OF THE FIGURES:

[00116] Figure 1 shows the 1H NMR spectrum (5.4 - 6.4 ppm) of (Z)-hexadec-1-en-1-yltrimethylsilane 44.

[00117] Figure 2 shows the 1H NMR spectrum (1.9 - 3.2 ppm) of cis-trimethyl(3-tetradecyloxiran-2-yl)silane 42.

[00118] Figure 3 shows the stacked 1H NMR spectra of intermediates leading toi cis-silyl epoxide 42.

[00119] Figure 4 shows the 1H NMR of 1-((4-methoxybenzyl)oxy)-1-(trimethylsilyl)hexadecan-2-ol 47.

[00120] Figure 5 shows the stacked 1H NMRs (2.0 - 4.0 ppm) of 1-((4-methoxybenzyl)oxy)-1-(trimethylsilyl)hexadecan-2-ol 47 before (bottom) and after (top) D2O shake.

[00121] Figure 6 shows the 1H NMR of hexadecane-2-one 48 by-product.

[00122] Figure 7 shows the 1H NMR of by-product 1-((1-((4-methoxybenzyl)oxy)-1-(trimethylsilyl)hexadecan-2-yl)oxy)-1-(trimethylsilyl)hexadecan-2-ol 49, suspected to form after the desired product ring opens a remaining epoxide molecule.

[00123] Figure 8a shows the NMR spectrum of the PMB Z-vinyl ether 46.

[00124] Figure 8b shows the zoomed in 1H NMR spectrum of the PMB Z-vinyl ether 46 from 4.3 to 6.4 ppm.

[00125] Figure 9 shows the zoomed in NMR spectrum of the Z-vinyl ether product 46 from Table 15, Entry 6.

[00126] Figure 10 shows the stacked 1H NMR spectra of intermediates leading to 2-(chloromethyl)-1,4-dimethoxynapthalene.

[00127] Figure 11 shows the 1H NMR spectrum of suspected c / s- and trans-N-^ ,4-dimethoxynaphthalen-2-yl)methyl)- / V-methylbenzamide 37c.

[00128] Figure 12 shows the stacked 1H NMRs of A / -((1,4-dimethoxynaphthalen-2-yl)methyl)-A / -methylbenzamide 37c at various temperatures from 20 - 80 °C.

[00129] Figure 13 shows the stacked 1H NMR spectra of (S)-1 -((1,4-dimethoxynaphthalen-2-yl)methoxy)-3-(((Z)-hexadec-1 -en-1 -yl)oxy)propan-2-yl (4Z,7Z, 10Z,13Z,16Z, 19Z)-docosa-4,7,10,13,16,19-hexaenoate 46b and (S)-1-(((Z)-hexadec-1-en-1-yl)oxy)-3-hydroxypropan-2-yl (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate 47b.

[00130] Figure 14 shows the stacked 1H NMR spectra of the products forthe synthesis of R-4.

[00131] Figure 15 shows the 1H NMR spectrum of (S,Z)-tert-butyl((1-((1,4-dimethoxynaphthalen-2-yl)methoxy)-3-(hexadec-1 -en-1 -yloxy)propan-2-yl)oxy)dimethylsilane S-18.

[00132] Figure 16 shows the 1H NMR spectra of compounds S-19 and S-20.

[00133] Figure 17 shows the 1H NMR spectra of compounds S-21 and S-22.

[00134] Figure 18 shows the comparison of compound S-19 1H NMR spectra in treated and untreated CDCI3.

[00135] Figure 19 shows the 1H NMR spectra of compounds S-23-25.

[00136] Figure 20 shows the 1H and 31P NMR of suspected (R)-3-(((Z)-hexadec-1-en-1-yl)oxy)-2-(oleoyloxy)propyl (2-(trimethylammonio)ethyl) phosphate R-56.

[00137] Figure 21 depicts the set-up used to generate NMea gas forthe ring-opening reaction.

[00138] Figure 22 shows the 'H and 31P NMR and LCMS analysis of plasmalogen R-56.

[00139] Figure 23 shows the 1H and 31P NMR of plasmalogen R-60.

[00140] Figure 24 shows the 1H and 31P NMR and LCMS of plasmalogen R-61. DETAILED DESCRIPTION

[00141] The term “residue” of a molecule, e.g. the residue of a nucleophile, is intended to mean the monovalent species formed by removing a hydrogen atom from the molecule. The residue of a nucleophile is the monovalent species formed by removing a hydrogen atom from the nucleophilic group (e.g. -OH, -NH-, -SH) of the nucleophile.

[00142] An O-nucleophile (oxygen nucleophile) is a reactant that can donate a pair of electrons from an oxygen atom (typically the oxygen atom of an oxygen containing functional group) to form a new covalent bond. Examples of O-nucleophiles are water (H2O), hydroxide anion, alcohols, alkoxide anions, hydrogen peroxide, and carboxylate anions. The O-nucleophile may be an aliphatic alcohol, such as a primary, secondary (cyclic or non- cyclic), or tertiary (cyclic or non- cyclic) alcohol, or an aromatic alcohol, such as a phenol.

[00143] An / V-nucleophile (oxygen nucleophile) is a reactant that can donate a pair of electrons from a nitrogen atom (typically the nitrogen atom of an nitrogen containing functional group) to form a new covalent bond. / V-nucleophiles include ammonia, azide, amines, nitrites, hydroxylamine, hydrazine, carbazide, phenylhydrazine, semicarbazide, and amides. The / V-nucleophile may be an amine, e.g. a primary, secondary or tertiary amine, or an amide, e.g. a primary, secondary or tertiary amide.

[00144] The Et(30) parameter is an empirical polarity scale. The Et(30) parameter is defined as the molar absorption energy in kcal / mol of Reichardt's betaine B30 (2,6-diphenyl-4-(2,4,6-triphenyl-1-pyridinio)-phenolate 1 dissolved in the relevant solvent: , . , 28591 ET(3Q)(kcal mol )= —--- ^max The Et(30) can therefore be easily determined by the skilled person using UVA / is absorption spectroscopy.

[00145] “Fatty acids” are aliphatic monocarboxylic acids derived from animal or vegetable fat, oil or wax. Fatty acids commonly have a chain of 4 to 28 carbons (usually unbranched and even-numbered), which may be saturated or unsaturated.

[00146] Saturated fatty acids include butyric acid, butanoic acid, caproic acid, hexanoic acid, caprylic acid, octanoic acid, capric acid, decanoic acid, lauric acid, dodecanoic acid, myristic acid, tetradecanoic acid, palmitic acid, hexadecanoic acid, stearic acid, octadecanoic acid, arachidic acid, icosanoic acid, behenic acid, docosanoic acid, lignoceric acid and tetracosanoic acid. Monounsaturated fatty acids include caproleic acid, lauroleic acid, myristoleic acid, palmitoleic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic acid, erucic acid, brassidic acid or nervonic acid. Polyunsaturated fatty acids include linoleic acid, dienoic acid, alpha-Linolenic acid, gamma-Linolenic acid, columbinic acid, stearidonic acid, mead acid, dihomo-y-linolenic acid, arachidonic acid, eicosapentaenoic acid, docosapentaenoic acid or docosahexaenoic acid.

[00147] The nitrogen atom of a primary amine is directly bonded to a single carbon atom of any hybridization which is not carbonyl carbon. The nitrogen atom of a secondary amine is directly bonded to two carbon atoms of any hybridization, neither of which is a carbonyl carbon. The nitrogen atom of a secondary amide is directly bonded to two carbon atoms, at least one of the carbon atoms being a carbonyl carbon. The secondary amide may be a lactam, e.g. a-, p-, y-, 6-, and e-lactam. The nitrogen atom of a tertiary amide is directly bonded to three carbon atoms, at least one of the carbon atoms being a carbonyl carbon. The aforementioned “carbon atom(s)” will typically be the carbon atom of an alkyl or aryl group, or a carbon atom within a heterocyclyl.

[00148] Included within the scope of the present invention are all stereoisomers and geometric isomers of the compounds of the invention, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof (e.g. racemates), unless explicitly stated otherwise (e.g. via the use of wedge-and-dash bonds).

[00149] The sn-2 carbon atom in natural plasmalogens has the (R)-stereoconfiguration as depicted below: In embodiments, any of the plasmalogen intermediates in the methods or compounds of the invention depicted herein have the natural stereoconfiguration.

[00150] The term Cm-Cn refers to a group with m to n carbon atoms.

[00151] The term “alkyl” refers to a monovalent linear or branched saturated hydrocarbon chain. For example, Ci-Ce-alkyl may refer to methyl, ethyl, n-propyl, / so-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.

[00152] The term “alkenyl” refers to a branched or linear hydrocarbon chain containing at least one double bond. The double bond(s) may be present as the E or Z isomer. The double bond may be at any possible position of the hydrocarbon chain. For example, “C2-C6-alkenyl” may refer to ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

[00153] The term “cycloalkyl” refers to a monocyclic or bicyclic saturated hydrocarbon ring system. Bicyclic cycloalkyls include spirocyclic, fused and bridged bicyclic cycloalkyls. For example, “Cs-Cs-cycloalkyl” may refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl or cyclooctyl.

[00154] The term “cycloalkenyl” refers to a monocyclic or bicyclic unsaturated carbocyclic ring system comprising at least one double bond. Bicyclic cycloalkyls include spirocyclic, fused and bridged bicyclic cycloalkenyls. For example, “C3-6 cycloalkenyl” may refer to cyclopropenyl, cyclobutenyl, cyclopentenyl, norbornenyl or cyclohexenyl. Monocylic cycloalkenyls comprising 8 or more carbon atoms may be the cis or trans isomer.

[00155] Aryl groups may be any aromatic carbocyclic ring system (i.e. a ring system containing 2(2n + 1 )tt electrons). The aryl may be monocyclic or polycyclic. The aryl group may have from 6 to 12 carbon atoms in the ring system. Aryl groups will typically be phenyl groups. Aryl groups may be also be naphthyl groups or biphenyl groups.

[00156] Aromatic heterocyclyl groups may be any aromatic (i.e. a ring system containing 2(2n + 1 )tt electrons) 5 to 12 membered ring system comprising from 1 to 4 heteroatoms independently selected from O, S and N (in other words from 1 to 4 of the atoms forming the ring system are selected from O, S and N, the rest being carbon). The aromatic heterocyclyl may be monocyclic or and polycyclic. Thus, aromatic heterocyclyl group may be independently selected from: 5 membered aromatic heterocyclyl groups in which the heteroaromatic ring is substituted with 1-4 heteroatoms independently selected from O, S and N; and 6-membered aromatic heterocyclyl groups in which the heteroaromatic ring is substituted with 1-3 (e.g. 1-2) nitrogen atoms. Specifically, aromatic heterocyclyl groups may be independently selected from: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl and pteridinyl. The term “aromatic heterocyclyl” is synonymous with the term “heteroaryl”.

[00157] The term “non-aromatic heterocyclyl” is intended to cover any non-aromatic (aliphatic) 5 to 12 membered ring system comprising from 1 to 4 heteroatoms independently selected from O, S and N (in other words from 1 to 4 of the atoms forming the ring system are selected from O, S and N, the rest being carbon). The ring may be monocyclic or polycyclic, e.g. bicyclic. The ring may be saturated or unsaturated, i.e. the ring may comprise at least one double bond. Examples of non-aromatic heterocyclyls include piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydrofuranyl, tetrahydropyranyl, dihydropyranyl, dioxanyl and azepinyl.

[00158] The term “heterocyclyl” covers both aromatic and non-aromatic heterocyclys.

[00159] The present invention also includes all pharmaceutically acceptable isotopically-labelled compounds of formulae (I) and (II), wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. The purpose of such an inclusion may be to modify therapeutic properties, in particular to limit the rate of metabolism.

[00160] Examples of stable isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H, carbon, such as13C, nitrogen, such as 15N and oxygen, such as 18O.

[00161] Isotopically-labelled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.

[00162] It may be that the compounds of the invention are occupied with deuterium (2H) instead of hydrogen at a certain position or positions at an isotopic abundance greater than deuterium’s natural isotopic abundance (e.g. greater than about 0.015%). The position or positions may be occupied with deuterium at an isotopic abundance of greater than 50%. The position or positions may be occupied with deuterium at an isotopic abundance of greater than 90%, e.g. greater than 95%. The position or positions may be occupied with deuterium at an isotopic abundance of greater than 99%, e.g. greater than 99.5%.

[00163] Isotopic abundance can be determined using conventional analytical methods known to a person skilled in the art, such as mass spectrometry and nuclear magnetic resonance spectroscopy.

[00164] Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[00165] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[00166] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference. EXAMPLES General Synthesis

[00167] The skilled person will appreciate that adaptation of methods known in the art could be applied in the manufacture of the compounds of the present invention.

[00168] For example, the skilled person will be immediately familiar with standard textbooks such as "Comprehensive Organic Transformations - A Guide to Functional Group Transformations", RC Larock, Wiley-VCH (1999 or later editions); "March's Advanced Organic Chemistry - Reactions, Mechanisms and Structure”, MB Smith, J. March, Wiley, (5th edition or later); “Advanced Organic Chemistry, Part B, Reactions and Synthesis”, FA Carey, RJ Sundberg, Kluwer Academic / Plenum Publications, (2001 or later editions); "Organic Synthesis - The Disconnection Approach", S Warren (Wiley), (1982 or later editions); "Designing Organic Syntheses" S Warren (Wiley) (1983 or later editions); “Heterocyclic Chemistry”, J. Joule (Wiley 2010 edition or later); ("Guidebook To Organic Synthesis" RK Mackie and DM Smith (Longman) (1982 or later editions), etc., and the references therein as a guide.

[00169] The skilled person is familiar with a range of strategies for synthesising organic and particularly heterocyclic molecules and these represent common general knowledge as set out in text books such as Warren “Organic Synthesis: The Disconnection Approach”; Mackie and Smith “Guidebook to Organic Chemistry”; and Clayden, Greeves, Warren and Wothers “Organic Chemistry”.

[00170] The skilled chemist will exercise his / her judgement and skill as to the most efficient sequence of reactions for synthesis of a given target compound and will employ protecting groups as necessary. This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the protection / deprotection steps. These and other reaction parameters will be evident to the skilled person by reference to standard textbooks and to the examples provided herein.

[00171] Sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional methods, for example as described in P. G. M. Wuts, Greene's Protective Groups in Organic Synthesis, John Wiley &Sons, Inc., Michigan, 2014, and references therein.

[00172] Certain compounds of the invention can be made according to or by methods analogous to the methods described in Examples 1 to 20. Example 1 - Synthesis of cis-trimethvl(3-tetradecvloxiran-2-vnsilane (1)

[00173] An aim of the present application is to synthesise natural plasmalogens and their analogues, it was therefore decided to synthesise c / s-trimethyl(3-tetradecyloxiran-2-yl)silane42. This would afford the simplest natural plasmalogen, with a palmitic acid (16:0) derived Z-vinyl ether at the sn-1 position. The silyl epoxide was readily synthesised from 1-bromotetradecane 30: a. C13H27 Br 30 SiMe3 d' C13H27 99:1 Z:E 44 Overall yield: 61% Synthesis of c / s-trimethyl(3-tetradecyloxiran-2-yl)silane 42: a. lithium acetylide, DMSO, N2, rt, 3 h, 93%; b.i. n-BuLi ii. TMSCI, THF, N2, 0 °C to rt, 5 h, 98%; c. DIBAL-H, Et2O, N2, 0 °C to rt, 48 h, 83%; d. m-CPBA, DCM, N2, 0 °C to rt, 3 h, 81%.

[00174] The overall synthesis proceeded excellently, with a higher overall yield of 61%. The DIBAL-H reduction proceeded with even greater stereoselectivity, to afford the Z-alkenyl silane 44 in a 99:1 Z.E ratio (Figure 1). The same vinyl peaks were present as in the previous synthesis, but now the Z-vinylic protons (J= 14.0 Hz) integrated to 1.00 relative to the E-vinylic protons (J = 18.0 Hz) which integrated to 0.01. This was achieved by better synthetic technique, ensuring the glassware was oven-dried, and adding the DIBAL at 0 °C rather than room temperature. This isomeric ratio was retained in the silyl epoxide after epoxidation (Figure 2). The resonances in the 1H NMR spectrum at 3.08 and 2.18 ppm correspond to the c / s-epoxide protons and have J values of 5.4 and 5.1 Hz respectively, which agrees with a cis relationship. The trans-epoxide protons at 2.80 and 2.43 ppm integrated to 0.01 relative to the c / s-protons, which confirms that the 99:1 ratio was retained after epoxidation.

[00175] The structure of each product in the synthetic route was confirmed by 1H NMR analysis (Figure 3).

[00176] The alkyne spectrum contained the expected peak for the propargyl protons at 2.18 ppm (2H, triplet of doublets, J = 7.1,2.7 Hz) and the terminal alkyne proton peak at 1.93 ppm (1H, triplet, J = 2.6 Hz). After silylation, the terminal proton peak dissapeared, being replaced by a singlet at 0.14 ppm (9H) for the trimethylsilane protons and simplifying the propargyl proton’s peak to a triplet at 2.21 ppm. Reduction of the triple bond with DIBAL- / 7 was evident by two new peaks in the vinyl region, a doublet of triplets at 6.30 ppm (1H, J = 14.0, 7.4 Hz) and a doublet of triplets at 5.47 ppm (1H, J = 14.0, 1.3 Hz). This complimented the slightly upfield methylene peak, now a quartet of doublets at 2.11 ppm (2H, J = 7.4, 1.3 Hz). Finally, upon epoxidation the vinyl peaks dissapeared and two new peaks appeared at 3.08 ppm (1H, quartet, J = 5.6 Hz) and 2.18 ppm (1H, doublet, J = 5.1 Hz) corresponding to the epoxide protons. Example 2 - Synthesis of cis-trimethvl(3-tetradecvloxiran-2-vnsilane (2> Hexadec-1-vne

[00177] An oven-dried flask purged with nitrogen was charged with lithium acetylide ethylenediamine complex (365 mg, 3.97 mmol). Dimethyl sulfoxide (10 mL) was added, and the resulting suspension was stirred at rt for 0.25 h. To this suspension, cooled to 0 °C, was added 1-bromotetradecane (1.00 g, 3.61 mmol) dropwise. The mixture was warmed to rt and stirred for 5 h. The mixture was cooled to 0 °C and quenched by addition of water (10 mL), then diluted with water (20 mL) and extracted with petrol (3 x 30 mL). The combined organics were dried over MgSOx, filtered, and solvent evaporated in vacuo. The residue was dissolved in petrol (30 mL) and vacuum filtered through a pad of silica to afford hexadec-1-yne (746 mg, 3.35 mmol, 93%) as a clear, colourless oil: Rf 0.87 (petrol, permanganate stain); 1H NMR 6 h (300 MHz, Chloroform-d) 6 2.17 (2 H, td, J = 7.0, 2.6 Hz, C / 72CCH), 1.92 (1 H, t, J = 2.6 Hz, CCH), 1.51 (2 H, p, J = 6.8 Hz, C / - / 2CH2CCH), 1.45 - 1.26 (22 H, m, 11 x CH2), 0.87 (3 H, t, J = 6.4 Hz, CW3); 13C NMR 5 c (75 MHz, Chloroform-d) 6 84.9 (CH2C=CH), 68.2 (CH2C=CH), 32.1 (CH2CH2CH3), 29.8 (5 x CH2), 29.7 (CH2), 29.5 (CH2), 29.3 (CH2), 28.9 (CH2), 28.7 (CH2), 22.9 (CH2CH3), 18.6 (CH2CECH), 14.3 (CH2CH3); IR Vmax / cm ' 3315, 2922, 2853, 1466, 721,625; HRMS (TOF MS AP+) calcd CwHso [M-Et]+ 193.1051, found 193.1082. Hexadec-1-yn- 1-yltrimethylsilane Cl t5iMe3

[00178] To an oven-dried flask, purged with nitrogen via Schlenk technique, was added a solution of hexadec-1-yne (7.49 g, 33.68 mmol) in anhydrous tetrahydrofuran (100 mL). The solution was cooled to 0 °C and n-butyllithium (2.5 M in hexanes, 14.82 mL, 37.04 mmol) was added dropwise. Upon addition, the reaction was stirred for 1.5 h. Then chlorotrimethylsilane (4.70 mL, 37.04 mmol) was added dropwise. The reaction was warmed to rt and stirred for a further 3 h. The reaction was quenched by addition of saturated aqueous sodium bicarbonate solution (20 mL), diluted with water (150 mL) and extracted with diethyl ether (3 x 100 mL). The combined organics were dried over MgSO4, filtered, and evaporated in vacuo to afford hexadec-1-yn-1-yltrimethylsilane (9.71 g, 32,98 mmol, 98%) as a clear, colourless oil: Rf 0.66 (petrol, permanganate stain); 1H NMR 6 h (300 MHz, Chloroform-d) 6 2.21 (t, J = 7.1 Hz, 2H, CH2CH2CEC), 1.51 (m, 2H, CH2CH2CEQ, 1.26 (br, s, 20H, 10 x CH2), 0.94-0.82 (t, J= 6.0 Hz, 3H, CHs), 0.14 (s, 9H, Si(CH3)3); 13C NMR 6 c (75 MHz, Chloroform-d) 6 107.9 (CECSiMe3), 84.4 (CECSiMe3), 32.1 (CH2CH2CH3), 29.9 (2 x CH2), 29.8 (2 x CH2), 29.8 (CH2), 29.7 (CH2), 29.5 (CH2), 29.3 (CH2), 29.0 (CH2), 28.8 (CH2), 22.9 (CH2CH3), 20.0 (CH2CEC), 14.3 (CH2CH3), 0.3 (Si(CH3)3); IR vmax I cm 1 2957, 2923, 2854, 2176, 1466, 1248, 1032, 839, 759, 639; HRMS (TOF MS AP+) calcd Ci9H38Si [M+Et]+ 324.2721, found 324.2729. (Z)-hexadec-1-en-1-vltrimethvlsilane SiMe3 Cl3H27^^^

[00179] To a flask purged with nitrogen via Schlenk technique was added a solution of hexadec-1-yn-1-yltrimethylsilane (4.85 g, 16.46 mmol) in anhydrous diethyl ether (32 mL). The solution was cooled to 0 °C and diisobutylaluminium hydride solution (1 M in hexane, 24.69 mL, 24.69 mmol) was added dropwise. Upon addition the reaction was warmed to rt and stirred for 48 h. The reaction was quenched by cautious addition of aqueous sodium hydroxide solution (1 M, 30 mL) at 0 °C, diluted with water (100 mL), and extracted with hexane (3 x 50 mL). The combined organics were dried over MgSO4, filtered, and evaporated in vacuo to afford (Z)-hexadec-1-en-1-yltrimethylsilane (4.63 g, 15.61 mmol, 95%) as a clear, colourless oil in a 99:1 Z:E isomeric ratio: Rf 0.98 (petrol, permanganate stain); 1H NMR 6 h (400 MHz, Chloroform-d) 6 6.30 (dt, J = 14.0, 7.4 Hz, 1H, CH2CHCH), 5.47 (dt, J= 14.0, 1.3 Hz, 1H, CH2CHC / - / ), 2.11 (qd, J= 7.4, 1.3 Hz, 2H, CH2CHCH), 1.27 (br, s, 24H, 12 x CH2), 0.92-0.85 (t, J = 7.1 Hz, 3H, CH3), 0.11 (s, 9H, Si(CH3)3); 13C NMR 5 c (75 MHz, Chloroform-d) 6 149.5 (CH2CHCH), 128.8 (CH2CHCH), 33.7 (CH2CH2CH3), 32.1 (CH2CHCH), 30.0 (CH2), 29.9 (3 x CH2), 29.8 (3 x CH2), 29.8 (CH2), 29.5 (2 x CH2), 22.9 (CH2CH3), 14.3 (CH2CH3), 0.4 (Si(CH3)3); IR vmax I cm1 2956, 2923, 2853, 1607, 1466, 1248, 856, 835, 762, 690; HRMS (TOF MS AP+) calcd Ci9H40Si [M+Et]+ 326.2892, found 326.2889. Cis-tnmethyl(3-tetradecyloxiran-2-yl)silane

[00180] To a solution of (Z)-hexadec-1-en-1-yltrimethylsilane (8.10 g, 27.31 mmol) in dichloromethane (270 mL) at 0 °C was added m-chloroperoxybenzoic acid (7.07 g, 40.96 mmol). The reaction was warmed to rt and stirred for 3 h. The reaction was quenched by saturated aqueous sodium sulphite solution (250 mL) and organics separated. The organics were washed with saturated aqueous sodium sulphite solution (3 x 100 mL), dried over MgSO4, filtered, and evaporated cautiously by nitrogen blow down. The product was purified by silica chromatography, eluting with 98:2 petrohdiethyl ether afforded trimethyl(3-tetradecyloxiran-2-yl)silane (6.95 g, 22.23 mmol, 81%) as a clear, colourless oil: Rt 0.79 (19:1 petrol:ethyl acetate, permanganate stain); 1H NMR b h (300 MHz, Chloroform-d) b 3.08 (m, 1H, CH2C(O)HC(O)H), 2.18 (d, J= 5.1 Hz, 1H, CH2C(O)HC(O)H), 1.60 - 1.20 (br, s, 26H, 13 x CH2), 0.93 - 0.82 (t, J= 7.1 Hz, 3H, CH2CH3), 0.13 (s, 9H, Si(C / 73)3); 13C NMR b c (75 MHz, Chloroform-d) b 57.9 (CH2C(O)HC(O)H), 50.8 (CH2C(O)HC(O)H), 32.1 (CH2CH2CH3), 31.7 (CH2C(O)HC(O)H), 29.9 (5 x CH2), 29.7 (3 x CH2), 29.5 (CH2), 27.2 (CH2), 22.8 (CH2CH3), 14.3 (CH2CH3), -1.6 (Si(CH3)3); IR Vmax I cm1 2956, 2922, 2853, 1466, 1261, 1249, 886, 838, 753; HRMS (TOF MS AP+) calcd Ci9H40OSi [M+Pr]+ 354.3198, found 354.3192. Example 3 - Silyl epoxide ring-opening

[00181] Acidic epoxide ring-opening conditions were investigated using PMB alcohol 45 (Example 2, Table 1). 42 45 47 Entry Acid Equiv. Conditions Yield % 1 H2SO4 1.20 rt to 50 °C, 6 h failed 2 10-CSA 1.20 rt to 50 °C, 24 h failed 3 AI(OTf)3 0.05 50 °C, 1 h failed 4 BF3.(OEt)2 0.05 rt, 0.5 h 20 5 Yb(OTf)3 0.30 rt, 1 h 55 Example 3 Table 1: Results of acidic screening reactions. For all five reactions 5 mol% of the acid was added initially; this was increased incrementally until some reaction progress was observed by TLC analysis. If, after a stoichiometric amount of acid was added no reaction had occurred, then the reaction was warmed to 50 °C. The exception was aluminium triflate, which was warmed to 50 °C immediately to achieve homogenous catalysis.

[00182] For both Brensted acids (Entries 1 and 2) no desired reaction was observed. As with the basic conditions (Example 2 Table, above) the silyl epoxide was destroyed without any evidence of the desired intermediate or vinyl ether in the 1H NMR spectrum. These acids were heterogenous even at elevated temperatures and it was proposed that homogenous catalysis would be more appropriate. Aluminium triflate (Entry 3) also failed to give the desired product. Warming the reaction to 50 °C was necessary to achieve a homogenous mixture but this did not result in the desired reaction. More promisingly, boron trifluoride (Entry 4) did yield the desired 1-((4-methoxybenzyl)oxy)-1-(trimethylsilyl)hexadecan-2-ol 47 but only in 20% yield. Greater success was observed with ytterbium triflate (Entry 5) which gave the product in a moderate 55% yield. Given this promising result, efforts were focussed on optimising the ytterbium triflate reaction conditions to improve the yield.

[00183] The silyl epoxide was a mixture of both the (R,S) and (S,R) enantiomers, which would afford both the (R,R) and (S,S) enantiomers, respectively, upon ring-opening. The intermediate’s structure was confirmed by 1H NMR analysis (Figure 4). It was necessary to ensure that the epoxide had ring opened to give the desired 1-alkoxy-2-hydroxyalkylsilane and not the other regioisomer as this would not subsequently result in the vinyl ether: Regioisomers from acid catalysed ring opening of the silyl epoxide with an alcohol.

[00184] The significant peaks of interest include: the two doublets at 4.51 (1H, J = 10.7 Hz) and 4.44 ppm (1H, J= 10.7 Hz) which supports diastereotopic protons at the benzylic position; the triplet of triplets at 3.68 ppm (1H, J = 7.6, 5.1 Hz) which is consistent with the proton neighbouring the hydroxyl group (Ha); the doublet at 3.03 ppm (1H, J = 5.2 Hz) agrees with the proton neighbouring the silane (Hb); and finally the doublet at 2.24 ppm (1H, J = 5.2 Hz) was proposed for the hydroxyl proton. The hydroxyl peak was confirmed by adding D2O to the NMR sample and comparing the spectra before and after (Figure 5).

[00185] The doublet peak at 2.24 ppm disappeared after the D2O shake, which confirms it is the hydroxyl proton now exchanged for a deuterium atom. To rule out the other regioisomer, it is necessary to consider where and how those protons would appear in a 1H NMR spectrum. For Ha of the regioisomer, the proton would be coupled to the hydroxyl proton and Hb, whereas Ha for the desired regioisomer is also coupled to the protons of the neighbouring methylene. Therefore, Ha (of the desired product) is coupled to three proton environments which would give its peak a triplet of doublet of doublets splitting pattern. However, the two smallest coupling constants are the same so the pattern is simplified to a triplet of triplets which is observed in the spectrum. This splitting pattern would not happen for Ha of the regioisomer (doublet of doublets or triplet). For Hb of the regioisomer this would be a quartet, doublet of triplets, or triplet of doublets. None of these splitting patterns are observed for any peaks in the spectrum, instead the expected doublet for the product Hb is seen. This was satisfactory evidence to confirm that the desired regioisomer had been made, which is supported by literature reports that attack at the a-carbon is favoured for silyl epoxides (A. P. Davies, G. J. Hughes, P. R. Lowndes, C. M. Robbins, E. J. Thomas, G. H. Whitham, Some epoxide ringopening reactions ofa,p-epoxysilanes, J. Chem. Soc., Perkin Trans. 1,1981,1934 -1941; P. F. Hudrlik, A. M. Hudrlik, R. J. Rona, R. N. Misra, G. P. Withers, Stereospecific synthesis of heteroatom-substituted olefins from alpha,beta-epoxysilanes. Preparation of vinyl bromides, enol acetates, enol ethers, and enamides, J. Am. Chem. Soc., 1977, 99, 1993 - 1996). A final proof of structure would be the vinyl ether itself, as only the desired regioisomer can afford the vinyl ether via a syn-elimination. Example 4 - Ytterbium triflate 30 mol% fiM®3 C14H29 <Ri SiMe3 MeO^^^ TFT, N2.rt C14H29 42                  45                          47 Entry Time I h Total Cone. / M Epoxide:Alcohol Yield % 1 1 0.2 1:1.2 55 2 3 0.2 1:1.2 38 3 3 1.0 1:1.2 15 4 4 0.2 1:3 32 5 16 0.2 3:1 0 Example 4 Table 1 Results of ytterbium triflate optimisation reactions.

[00186] An attempt to lower the mol% of catalyst was made, beginning with 5 mol% and increasing incrementally until reaction was observed by TLC. However, 30 mol% in TFT was the minimum amount of ytterbium triflate required to induce reactivity. The original reaction conditions were repeated but run for longer (Entry 1 vs 2) to ensure that the reaction had gone to completion. However, the yield was lower for a longer reaction time suggesting the product reacted further under these conditions and a shorter reaction is beneficial (see Scheme below). Concentrating the reaction (Entry 3) from 0.2 M to 1 M was also detrimental, so the reaction was maintained at 0.2 M for further experiments. As the product also possesses a hydroxyl group, it can compete with the PMB alcohol to attack remaining silyl epoxide molecules. Therefore, the ratio of epoxide:alcohol was increased from 1:1.2 to 1:3 (Entry 4) to favour ring opening by PMB alcohol. Surprisingly, this did not improve the yield. The opposite reaction was also performed (Entry 5), with an epoxide:alcohol ratio of 3:1, but no desired product was formed. For both reactions a longer reaction time was used which further supported that time was a critical variable for this reaction.

[00187] To investigate this further, a more thorough analysis of the reaction mixture was undertaken. The reaction was not proceeding cleanly by TLC and one other minor product was formed. This was separated by silica chromatography and analysed by 1H NMR (Figure 6).

[00188] The by-product was identified as hexadecan-2-one 48. It is proposed that the activated epoxide can ring open via an SNl-type mechanism to afford a carbocation stabilised by the adjacent silicon. This species undergoes a hydride shift to afford an a-silyl ketone. The ketone is again activated by the Lewis acid and nucleophilic attack of the silicon affords the observed ketone: stable carbocation O ketone Proposed mechanism of by-product formation via silyl epoxide.

[00189] Furthermore, it is proposed that the desired product can react to give the same ketone. The ether oxygen can be activated by ytterbium triflate which triggers a similar hydride shift to afford the same a-silyl ketone intermediate: (TfO)3Yb 3 (TfOhYb^ O by-product Proposed mechanism of by-product formation via 1-alkoxy-2-hydroxyalkylsilane.

[00190] The proposed mechanisms above might explain why Entries 2-5 had failed to improve the reaction yield. The longer reaction time had resulted in more ketone by-product formation. Particularly for Entry 5, which ran for 16 hours, the crude 1H NMR showed exclusively evidence of the ketone by-product. While time was clearly an important factor, the by-product was proposed to form via a charged intermediate, and therefore destabilising this should favour formation of the desired product. Charged species are more stable in polar solvents therefore a non-polar solvent should be favourable. To test this, a range of solvents was investigated (Example 4 Table 2). Entry Solvent Et(30) Product:Ketone Product Yield % 1 TFT 38.5 55:45 55 2 DCM* 40.7 33:66 4 3 MeCN 45.6 0:100 0 4 THF 37.4 0:100 0 5 DMC 38.2 0:100 0 6 Et2O 34.5 N / A No Reaction 7 hexane 31.0 N / A No Reaction 8 toluene* 33.9 N / A No Reaction Example 4 Table 2 Results of solvent screening (*reaction warmed to make catalyst homogenous, DCM at 30 °C and toluene at 50 °C).

[00191] Of the seven new solvents screened, none were an improvement on trifluorotoluene. Comparing Entries 1 - 3 it is clear that increasing solvent polarity (Et(30)) increased ketone formation as predicted. However, Entries 4 and 5 show that solvents with a similar polarity to trifluorotoluene can also give exclusively the ketone. Therefore, polarity is not the only factor for ketone formation. For less polar solvents (Entries 6 - 8) no reaction was observed at all.

[00192] During the experiment, it was noticed that the trifluorotoluene reaction appeared cloudy, while the THF reaction was a clear, colourless solution. Following this observation, the solubility of the catalyst at room temperature was measured. This was achieved by stirring a saturated solution of ytterbium triflate in each solvent at room temperature for 24 hours, then a 1 mL sample was filtered and evaporated, and the dried weight of catalyst was measured. Interestingly, ytterbium triflate in trifluorotoluene had low solubility (2.2 g / L), whereas in THF it had very high solubility (236 g / L). Given that the desired product is proposed to react further to the ketone, a higher mol% of catalyst would accelerate this process. Reviewing the experiment, despite adding 30 mol% of catalyst in 3 mL of trifluorotoluene, its low solubility means the actual homogenous mol% of catalyst was much lower (~5 mol%). For THF the homogenous mol% was truly 30 mol%. Relative to the trifluorotoluene reaction, this would accelerate ketone formation by ~ 6 times and explains the experimental result observed. Unsurprisingly, the catalyst had no solubility in the non-polar solvents (Entries 6 - 8). As the reaction does not work with a heterogenous catalyst this explains the lack of reaction observed for these solvents. The catalyst was also insoluble in DCM at room temperature therefore the reaction was warmed to achieve homogenous catalysis. This did afford the product in a very low 4% yield, but the crude 1H NMR showed the ketone was the major product. For toluene the reaction was also warmed but no reaction was observed even at elevated temperatures.

[00193] In conclusion, the more polarthe solvent and the more mol% of catalyst, the more ketone by-product was formed. Therefore, a low mol% and non-polar solvent is needed to maximise the yield, but ytterbium tritiate is not soluble in many non-polar solvents which results in no reaction. The best solvent, trifluorotoluene, still gave an ~ 1:1 ratio of product:ketone, therefore to improve on this ratio a suitable solvent would need to be less polar but still able to dissolve the catalyst. Example 5 - Boron trifluoride

[00194] While boron trifluoride (BF3) had initially seemed worse than ytterbium triflate (20% vs 55% yield), the discovery of the ketone by-product as mentioned in Example 4 gave new perspective. The crude 1H NMR of the BF3 reaction showed no evidence of the ketone by-product, therefore optimisation of this reaction would avoid the same issues as observed with ytterbium triflate. A range of conditions was explored to optimise the reaction (Example 5 Table 1). 42 45 Entry .............„ Cat. mol % ~~.............5 Time / h $ Total Cone. / M .........0.1 Temp / °C ...........20 Solvent Yield % ".......20 2 1 3 0.1 20 TFT 24 3 5 0.5 1.0 20 TFT 45 4 1 0.5 1.0 20 TFT 31 5 5 0.5 1.0 0 TFT 39 6 5 0.5 1.0 20 DCM 18 7 5 0.5 1.0 20 hexane 35 8 5 0.5 1.0 20 toluene 44 Example 5 Table 1 Results of boron trifluoride condition optimisation reactions. All reactions ran with 1 equiv. of epoxide and 1.2 equiv. alcohol.

[00195] An attempt to lower the catalytic mol% (Entry 1 vs 2) did marginally improve the yield but slowed the rate of reaction considerably from 30 minutes to 3 hours. Concentrating the reaction (Entry 3) from 0.1 M to 1.0 M had the remarkable effect of doubling the yield to 45%. To compliment this, the mol% was again lowered from 5 to 1 mol% (Entry 4), but this proved detrimental to the yield. Similarly, lowering the temperature to 0 °C (Entry 5) did not improve the yield so the reaction was always performed at room temperature and with 5 mol% for future reactions. Three alternative solvents were trialled (Entries 6-8) and toluene was found to be as effective as trifluorotoluene. As such, it was used for further experiments due to its availability and cost. While the ketone by-product was not present, the reaction was not proceeding cleanly by TLC so the other minor product was isolated by silica chromatography, analysed by 1H NMR, and identified as 1-((1-((4-methoxybenzyl)oxy)-1-(trimethylsilyl)hexadecan-2-yl)oxy)-1-(trimethylsilyl)hexadecan-2-ol 49 (Figure 7).

[00196] Analysis of the 1H NMR of the by-product agrees with the structure above. The expected silyl singlet peak at 0.08 ppm (18 H) is now a doublet, suggesting two trimethylsilane groups are present. Similarly, the broad peak at 1.26 ppm and triplet at 0.88 ppm associated with the long aliphatic chain also integrate to double the number of expected protons. The remaining peaks all agree with the proposed structure with the expected number of peaks, integrals, splitting patterns, and chemical shifts. The desired 1-alkoxy-2-hydroxyalkylsilane has a hydroxyl functionality that can compete with the PMB alcohol to ring open the epoxide and this results in the by-product seen above. Looking at the crude 1H NMR of this reaction, the productby-product ratio was 2:1. To optimise the reaction further, attention was focussed on minimising this by-product (Example 5 Table 2). o + 5 mol% "OH BF3OEt2 SiMe3 HO«. SiMe3 II J toluene, N2 rt, 0.5 h c ,4h: u 42 45 47 Entry E p oxi de: Alco hoi P ro d u ct: By- prod u ct Yield % 1 1:1.2 2:1 45 2a 1:1.2 3:1 40 3a,b 1:2 5:1 64 4a,b 1:3 6:1 61 ga.b.c 1:3 19:1 83 Example 5 Table 2 Results of boron trifluoride condition optimisation reactions.a Order of addition changed from ‘catalyst added to solution of alcohol and epoxide’to ‘solution of epoxide added to solution of alcohol and catalyst’.b Product no longer isolated by column chromatography.c Reaction scaled up by a factor of 2.

[00197] Initially, the order of addition was changed so that the epoxide was added to a solution of the alcohol and catalyst, rather than the catalyst being added to a solution of the alcohol and epoxide (Entry 1 vs 2). This improved the ratio of productby-product from 2:1 to 3:1 without being detrimental to the yield but was not as successful as we wanted. As the reaction progresses, the [alcohol] decreases and the [product] increases. If a slight excess of alcohol is used the [product] will eventually be greater than the [alcohol] and the product will be more likely to ring open the remaining epoxide molecules. To compensate for this, the excess of alcohol added to the reaction was increased from 1.2 equivalents to 2 (Entry 3) which improved product formation to 5:1 vs the byproduct. Increasing to 3 equivalents of alcohol (Entry 4) again increased product formation to 6:1. Notably, the overall yield for Entries 3 and 4 jumped to -60%. As the 1-alkoxy-2-hydroxyalkylsilane is sensitive to acidic and basic conditions, it was decided to purify the intermediate without column chromatography. Silica is mildly acidic, and it was believed that the intermediate was partially reacting during purification. This was verified by the jump in yield when column chromatography was avoided, therefore this purification method was avoided for future reactions. Finally, the reaction was scaled up by a factor of 2 from 0.16 to 0.32 mmol (Entry 5). The yield improved to 83% and therefore this chemistry works significantly better on a larger scale. Additionally, the productby-product ratio improved to 19:1. This was attributed to the addition of the epoxide, which was added dropwise slowly over a period of 5 minutes compared to previously adding the solution of epoxide all at once. With these optimisations, the overall yield was improved from 20% to 83%, and formation of the desired product was pushed from 2:1 to 19:1. This excellent result showed that formation of the 1-alkoxy-2-hydroxyalkylsilane intermediate was achievable in high yield with mild, fast, reaction conditions.

[00198] These conditions worked well for the model alcohol 15. However, this chemistry needs to work for a range of alcohols to be considered useful. To test this, 11 alcohols were reacted using these conditions (Example 5 Table 3). 3 equiv. ROH q|_| / \ / s) 5mol%BF3OEt2 I C14H29<^ ^SiMe3 ...... C14H297Rrf 14 2a J 1 M total cone. 1 toluene, N2, rt, 0.5 h 0R Entry Alcohol (ROH) Silyl epoxide mmol Yield % 1a HO'^^'Y^ 0.32 64 1b ^-^OMe 0.64 83 2 HO^Y^^i 0.32 87 MeO^^^^ Example 5 Table 3 Results of silyl epoxide ring opening with a range of alcohols.

[00199] In general, the chemistry works excellently for a range of benzylic, primary, and secondary alcohols. Ortho-, meta-, and para-substitution (Entries 1 - 3) makes no appreciable difference to the yield (83 - 87%). Primary aliphatic alcohols (Entries 4-7) work robustly with this chemistry; these reactions also show this methodology is compatible with silyl protecting groups and unsaturated bonds. Entry 7b highlights that a large-scale reaction (6.40 mmol) can proceed in near quantitative yield. Secondary alcohols (Entries 8 and 9) also work well, even with complex molecules like cholesterol. However, limitations were found. The structurally similar ergosterol (Entry 10) only showed trace evidence of the desired product in the 1H NMR spectrum. This was due to the alcohol being insoluble in toluene at room temperature therefore the epoxide was consumed without the desired reaction occurring. For menthol (Entry 11) solubility was not the issue, but instead steric effects. The bulky / so-propyl group neighbouring the hydroxyl group makes it sterically challenging for the alcohol to attack the epoxide, resulting in the epoxide being consumed in undesired sidereactions. Finally, a diol (Entry 12) was tested. This symmetrical cyclic diol has neighbouring hydroxyl groups and therefore after mono-addition reaction at the remaining free hydroxyl might be sterically impeded. However, analysis of the crude reaction showed a mixture of products in a low crude yield (21 %), which was attributed to the poor solubility of the diol in toluene and both mono- and di-addition occurring. From these results it is clear that this chemistry works excellently with different alcohols provided they are soluble in toluene, sterically unencumbered, and contain one hydroxyl group. Example 6 - Peterson Elimination

[00200] Basic conditions were investigated to induce the desired syn-elimination of the 1-alkoxy-2-hydroxyalkylsilanes described previously to prepare Z-vinyl ethers. Again, the PMB intermediate 47 was used as the model (Example 6 Table 1). 47 46 Entry Base Z:E ratio Time / h Temp. / °C Yield % 1 NaH - 24 45 No reaction 2 KH 9:1 1 20 78 3 LiO‘Bu - 24 45 No reaction 4 KO‘Bu 9:1 2 45 66 5 LDA - 24 45 No reaction Example 6 Table 1 Results of Peterson elimination reaction using different bases.

[00201] The reactions were monitored by TLC. Initially, all 5 reactions were carried out at room temperature but if no reaction was observed after 1 hour the mixture was warmed to 45 °C and stirred for a further 23 hours. Interestingly, sodium (Entry 1) and potassium hydride (Entry 2) were both tested but only the potassium salt afforded the desired Z-vinyl ether in 78% yield, while the sodium salt showed no reaction by TLC analysis. Potassium hydride is a stronger base than sodium hydride as the larger potassium ion has a smaller charge density and therefore a weaker ionic bond with the hydride ion. The weaker bond means the hydride is more accessible for deprotonation. Furthermore, the smaller sodium cation has a greater charge density and can form a stronger ionic bond with the deprotonated hydroxyl of the 1-alkoxy-2-hydroxyalkylsilane. As the syn-elimination is driven by the oxygen anion forming a strong O-Si bond the oxygen must overcome the oxygen-metal ionic bond strength, which is energetically easier with a weaker ionic bond. Similarly, lithium (Entry 3) and potassium tert-butoxide (Entry 4) were tested and again only the potassium salt afforded the vinyl ether in 66% yield. Lithium has a greater charge density than sodium, so it is unsurprising that the lithium base was not as effective as potassium by a similar argument as that for sodium vs potassium. Finally, lithium diisopropylamide (Entry 5) was tested but this also failed to induce the elimination and was not investigated further.

[00202] Despite potassium hydride and potassium butoxide successfully affording the Z-vinyl ether 46 in good yield, these conditions also gave the undesired E-isomer. This was discovered when the product was analysed by 1H NMR (Figure 8).

[00203] The product structure was confirmed by analysing the 1H NMR spectrum. The peak at 5.99 ppm (1H) is due to the vinylic proton neighbouring the ether oxygen. This peak was a doublet of triplets with J values of 6.2 and 1.5 Hz, respectively, which agrees with a cis proton environment. The complimentary peak to this is the triplet of doublets (1H, J = 7.3 and 6.2 Hz) at 4.37 ppm, which is due to the other vinylic proton. Additionally, the singlet (2H) at 4.87 ppm is due to the two benzylic protons, which was simplified from the two doublets observed in the starting material 47 (Figure 4) as the proton environments are now equivalent due to the lack of chirality. The peak at 2.08 ppm is a quartet of doublets (2H, J = 7.2 and 1.3 Hz) and agrees with the methylene that neighbours the vinylic protons. All other major peaks in the spectrum agree with the expected proton environments of the product. The remaining minor peaks in the spectrum agree with the E-isomer structure, these peaks integrate in a 9:1 Z:E ratio (Figure 8b). The two doublet of triplets at 6.30 ppm and 4.87 ppm have J values of 12.4 and 12.6 Hz, respectively, which agrees with a trans relationship.

[00204] As the Peterson olefination is highly stereoretentive and the silyl epoxide had a 99:1 Z:E ratio this was expected to carry forward to the Z-vinyl ether. Therefore, the observed 9:1 ratio was surprising and suggested these reaction conditions allow isomerisation to occur. The isomerisation may be caused by the potassium cation, or by the solvent (THF) as these are the common variables between the two reactions. However, the potassium cation was necessary to trigger the elimination so attention was focussed on changing the solvent to see if this affected the stereoselectivity of the reaction (Example 6 Table 2). 47 46 Entry Base Solvent Z:E ratio Temperature / °C Time / h Yield % 1 KO‘Bu THF 9:1 45 2 66 2 KO‘Bu DMSO 19:1 45 1 54 3 KO‘Bu trifluorotoluene 50:1 45 1 29 4 KH THF 9:1 20 1 78 5 KH DMSO 17:3 20 0.5 70 6 KH trifluorotoluene 99:1 45 2 77 Example 6 Table 2 Results of solvent screening reactions.

[00205] For both bases, the solvent did affect the stereoselectivity. For potassium tert-butoxide, DMSO (Entry 2) gave a 19:1 Z.E ratio and therefore the elimination was more stereoselective in this solvent than THF, however the yield dropped to 54%. Similarly, using trifluorotoluene (Entry 3) gave considerably better stereoselectivity (50:1) but the yield dropped significantly to 29%. For potassium hydride, using DMSO (Entry 5) resulted in a 17:3 Z.E ratio and was therefore less stereoselective than the original THF reaction. Excitingly, using trifluorotoluene (Entry 6) gave the product in 77% yield with an excellent isomeric ratio of 99:1 (Figure 9). Hence, these conditions gave total stereoretention from the c / s-silyl epoxide without impacting the yield. As the solvent was now highly non-polar, it was necessary to warm the reaction to 45 °C to induce reactivity within the heterogenous mixture.

[00206] For potassium hydride, the more polar the solvent the less stereoselective the reaction resulting in more E-isomer. This trend suggests that the isomerisation occurs via a charged intermediate as polar solvents stabilise charged species.

[00207] These conditions work excellently for synthesising a PMB Z-vinyl ether. Five more intermediates were subjected to the same conditions (Example 6 Table 3). 1 99:1 5 79 Example 6 Table 3 Results of reaction scope investigation using optimised conditions.

[00208] For all five reactions, the desired Z-vinyl ether was synthesised in high yield and with the expected 99:1 Z:E stereoselectivity. These conditions are compatible with silyl protecting groups (Entry 3), and unsaturated bonds (Entries 4 and 5). For the cholesterol product (Entry 5) a near quantitative yield of 96% was achieved which demonstrates how powerful this chemistry can be for synthesising Z-vinyl ethers. From these results we concluded that these conditions are applicable to a range of 1-alkoxy-2-hydroxyalkylsilanes and offer an elegant route to Z-vinyl ethers that was previously undiscovered. Example 7: Protecting Group Development

[00209] Oxidation of benzyl ethers with DDQ or CAN is initiated by a single electron transfer from the aromatic ring. Therefore, the lower the oxidation potential of the aromatic system, the more readily it will lose an electron and be oxidatively cleaved. An arylmethyl with a sufficiently low redox potential should be rapidly and selectively oxidised in the presence of vinyl ethers and polyunsaturation. To investigate this, the oxidation potentials of several aryl species were reviewed (Example 7, Table 1) (N. L. Weinberg and H. R. Weinberg, Electrochemical Oxidation of Organic Compounds, Chem. Rev., 1968, 68, 449-523): Entry Aryl Redox Potential E1 / 2 (V) 1 benzene 2.08 2 toluene (~Bn) 1.98 3 naphthalene 1.34 4 1 -methylnaphthalene 1.24 5 anisole (~PMB) 1.76 6 1,2-dimethoxybenzene (~DMB) 1.45 7 1 -methoxynaphthalene 1.38 8 1,3-dimethoxynapthalene 1.39 9 2,3-dimethoxynapthalene 1.39 10 1,4-dimethoxynapthalene 1.10 Example 7, Table 1. Oxidation potential of some aryl species measured in acetonitrile with a platinum anode against a silver reference electrode.

[00210] Comparing benzene and toluene (Entries 1 and 2), and naphthalene and 1-methylnaphthalene (Entries 3 and 4), the presence of a methyl group lowers the redox potential by 0.1 V. The value of the Bn PG can be approximated to be ~ 2.0 V based on toluene. Similarly, the PMB PG can be estimated from anisole’s redox potential (Entry 5) and the DMB PG from 1,2-dimethoxybenzene (Entry 6). 1-Methoxynapthalene (Entry 7) has a higher redox potential than its methyl equivalent (Entry 4), and addition of a second methoxy group at the 2- or 3- position (Entries 8 and 9) does not impact the oxidation potential. Interestingly, a 1,4-di meth oxy substitution pattern dramatically lowers the oxidation potential to 1.10 V which is significantly lower than the next best PG (DMB, ~1.45 V). A benzyl-type version of this aryl species would arguably have an oxidation potential closer to 1.0 V given the trend of a methyl substituent lowering the redox potential further.

[00211] Given these observations, 1,4-dimethoxynaphthalene-2-methyl (DIMON): was chosen as a novel benzyl-type PG.

[00212] Although an aim of the present invention is provide a protecting group that can be used in the synthesis of plasmalogens, DIMON may also have a broader application as a novel PG to protect a range of nucleophiles (alcohols, phenols, amines, amides, thiols etc). Example 8a: Protecting Group Precursor Synthesis

[00213] Synthesis of bromide 5 is possible in a 2-step synthesis via either quinone 2 or 1-naphthol 9 (G. A. Kraus and T. O. Man, An Improved Reductive Methylation Procedure for Quinones, Synth. Commun., 1986, 16, 1037-1042): 0 2 OMe OMe Route to bromide 5 via 1,4-naphthoquinone 2

[00214] This route involves a one-pot reduction and methylation of a quinone. Screening of conditions to achieve the one-pot reduction and methylation were carried out (Example 8, Table 1). O 1) Na2S2O4 2) KOH 3) methylating agent OMe OMe H2O:THF, rt O Entry Na2S2O4 equiv. KOH equiv. Methylating agent H2O:THF Time h Yield % 1a 3 10 2.5 equiv. MeOTs 1:2 6 15 2a 3 10 2.5 equiv. MeOTs 1:2 80 53 3a 3 10 3.0 equiv. MeOTs 1:2 36 49 4 3 10 2.5 equiv. MeOTs 1:2 100 35 5a 6 20 2.1 equiv. Me2SO4 1:2 20 18 6 4 10 10 equiv. Me2SO4 1:1 20 80 Example 8, Table 1. Reaction conditions screened for the reduction and methylation of 1,4-naphthoquinone; a denotes 10 mol% TBAI in reaction.

[00215] The conditions used were based on methodology by Kraus, with tetrabutylammonium iodide (TBAI) being used in place of tetrabutylammonium bromide. First, methyl tosylate was investigated as the methylating agent (Entries 1 - 4): the best yield achieved was 53% (Entry 2). This reagent was chosen as methyl tosylate is considerably less toxic than its alternatives (methyl iodide and dimethyl sulphate), which are known carcinogens. Wien the reaction was performed for 6 hours (Entry 1) the yield was low. A longer reaction time pushed the yield over 50% (Entry 2). Increasing the equivalence of methyl tosylate to 3 equivalents (Entry 3) resulted in a faster reaction but no improvement of the yield. The reaction was carried out in the absence of TBAI (Entry 4), but this proved detrimental to the yield due to its role as a phase transfer catalyst. Dimethyl sulphate was also investigated as the methylating agent (Entries 5 - 6). Initially, a stoichiometric equivalent of dimethyl sulphate was added, but this resulted in a low yield of 18% (Entry 5). More detailed methodology published by Moody used deoxygenated water as the solvent, a large excess of dimethyl sulphate, and vigorous stirring of the quinone and reducing agent (J. Padwal, W. Lewis, C. J. Moody, Synthesis of Balsaminone A, a Naturally Occurring Pentacyclic Dinaphthofuran Quinone, J. Org. Chem., 2011,76, 8082 - 8087). Mimicking these conditions (Entry 6) resulted in an excellent 80% yield of purified material. Bromination via NBS afforded intermediate 5 in 70% overall yield using this methodology.

[00216] The following route to alcohol 7 was explored (Example 8, Table 2). Entry n-BuLi equiv. (CH2O)n equiv. Temp. / °C Time / h Atmos. Yield % 1 1.2 1.3 -40 to 20 1 N2 8 2 1.2 2.0 -78 to 20 3 n2 52 3 1.2 2.0 -40 to 20 4 Ar 52 4 1.2 2.0 -78 to 20 4 Ar 62 Example 8, Table 2. Conditions screened for installation of the methanol functionality.

[00217] The best conditions were those of Entry 4.

[00218] Chlorination of alcohol 7 by thionyl chloride (SOCh) was carried out four times, with a yield range of 89 - 95%. Despite its success, an alternative method using concentrated hydrochloric acid (HCI) was trialled to avoid the toxic sulfur reagent: Synthesis of 2-(chloromethyl)-1,4-dimethoxynapthalene via hydrochloric acid.

[00219] This method also proceeded excellently, with an improved quantitative yield. Additionally, this route produced a crystalline, white product whereas SOCh produced a brown oil. This suggested that the SOCh product was impure although no impurities were observed in the 1H NMR spectrum. As this new method produced a purer product in higher yield and used a less toxic reagent, it was used instead of SOCh for subsequent chlorination reactions to yield DIMONC11.

[00220] The optimised route to DIMONCI is as follows: Synthesis of 2-(chloromethyl)-1,4-dimethoxynaphthalene: a. i) Na2S2O4 3 h ii) KOH, Me2SO4,16 h, 1:1 H2O:THF, r.t, 80%; b. NBS, DCM, r.t, 16 h, 88%; c. i) n-BuLi, -78 °C, 2 h ii) paraformaldehyde, 2 h, r.t., EbO, Ar, 62%; d. cone. HCI, Et2O, r.t., 1 h, 100%.

[00221] The products of each reaction were analysed by 1H NMR spectroscopy (Figure 10). The symmetrical 1,4-dimethoxynapthalene 4 had 4 proton environments: a singlet for the methoxy groups (6 H, 4.01 ppm), a singlet for the 2 aromatic protons on the dimethoxy ring (2 H, 6.73 ppm), and two downfield multiplets for the remaining two pairs of aromatic protons (2 H, 7.61 ppm and 2 H, 8.32 ppm). Upon bromination the molecule was now asymmetric: the two methoxy groups were no longer chemically equivalent and therefore two singlets were observed, one at 3.96 ppm (3 H) and one at 3.98 ppm (3 H). The dimethoxy aromatic proton peak was now further downfield (1 H, 6.89 ppm) as the neighbouring bromide deshielded this proton. After installation of the CH2OH group, two new peaks appeared: a doublet at 4.90 ppm (2 H, J = 5.9 Hz) and a triplet at 2.09 ppm (1 H, J = 6.0 Hz), due to the benzylic methylene and hydroxyl proton, respectively, which were coupled to each other. Upon chlorination, the benzylic peak simplified to a singlet (2 H, 4.85 ppm), whilst there was no OH peak. Example 8b: Synthesis of (1,4-Dimethoxynaphthalen-2-yl)methanol 1,4-Dimethoxynaphthalene OMe OMe

[00222] To a solution of 1,4-naphthoquinone (4.00 g, 25.29 mmol) in 1:1 water:tetrahydrofuran (200 mL) was added sodium dithionite (17.61 g, 101.17 mmol). The reaction mixture was stirred vigorously at r.t. for 2 h. Following this time, the reaction was cooled to 0 °C and potassium hydroxide (14.19 g, 252.92 mmol) was added portionwise. Upon addition the reaction was warmed to rt and stirred for 1 h. The reaction was cooled again to 0 °C and dimethyl sulfate (23.99 mL, 252.92 mmol) was added dropwise. Upon addition the reaction was warmed to rt and stirred overnight. The reaction was quenched by addition of aqueous ammonium hydroxide solution (1.5 M, 250 mL), diluted with water (1 L) and extracted with ethyl acetate (3 x 500 mL). The combined organics were washed with aqueous hydrochloric acid solution (2 M, 2 x 500 mL), water (2 x 500 mL), and brine (2 x 500 mL). The organic layer was dried over MgSO4, filtered, and solvent removed in vacuo. Purification by silica gel chromatography, eluting with ethyl acetate and 40-60 petrol (0:100 to 5:95 gradient), afforded 1,4-dimethoxynaphthalene (3.80 g, 20.23 mmol, 80%) as a white crystal: Rf 0.65 (9:1 40-60 petrokethyl acetate, UV active); mp: 86-87 °C 1H NMR: 6 h (300 MHz, CDCb) 6 8.35-8.13 (2 H, m, 2 x ArH), 7.61 -7.44 (2 H, m, 2 x ArH), 6.71 (2 H, s, 2 x ArH), 3.97 (6 H, s, 2 x OCH3); 13C NMR: 6 c (75 MHz, CDCb) 6 149.6 (2 x Ar), 126.4 (2 x Ar), 125.9 (2 x Ar), 121.9 (2 x Ar), 103.3 (2 x Ar), 55.7 (2 x OMe); IR: vmax I cm1 3071, 3012, 2955, 2840, 1630, 1593, 1462, 1446, 1382, 1269, 1233, 1085, 1022, 762; HRMS: (TOF MS ES+) calcd C12H12O2 [M+H]+: 189.0871, found 189.0884; 2-Bromo-1,4-dimethoxvnaohthalene OMe OMe

[00223] To 1,4-dimethoxynaphthalene (11.90 g, 63.22 mmol) in dichloromethane (200 mL) was added / V-bromosuccinimide (13.50 g, 75.86 mmol). The reaction mixture was stirred at r.t. for 16 h. Following this time, the solvent was evaporated in vacuo. The organic layer was dried over MgSO4, filtered, and evaporated in vacuo. Purification by silica chromatography, eluting with diethyl ether and 40-60 petrol (1:99), afforded 2-bromo-1,4-dimethoxynaphthalene (14.35 g, 53.72 mmol, 85%) as a white solid: Rf 0.85 (3:1 40-60 petrokethyl acetate, UV active); mp: 54-55 °C; 1H NMR: 5 h (300 MHz, CDCb) 6 8.27-8.16 (1 H, m, ArH), 8.15-8.00 (1 H, m, ArH), 7.64-7.43 (2 H, m, 2 x ArH), 6.89 (1 H, s, ArH), 3.97 (3 H, s, OCH3), 3.96 (3 H, s, OCH3); 13C NMR: 6 c (75 MHz, CDCb) 5 152.3(1 x Ar), 146.8(1 x Ar), 129.0 (1 x Ar), 127.4 (1 x Ar), 125.8 (2 x Ar), 122.6 (1 x Ar), 121.8 (1 x Ar), 111.9 (1 x Ar), 107.9 (1 x Ar), 61.4 (1 x OMe), 55.9 (1 x OMe); IR: vmax I cm1 3070, 2997, 2963, 2939, 2848, 1580, 1461, 1355, 1327, 1258, 1103, 1070, 989, 821, 767; HRMS: (TOF MS ES-) calcd Ci2HnBr79O2 [M-H]: 264.9869, found 264.9504. (1,4-Dimethoxynaphthalen-2-yl)methanol OMe OMe

[00224] An oven-dried 3-necked reaction flask was charged with 2-bromo-1,4-dimethoxynaphthalene (2.00 g, 7.49 mmol), sealed, and purged with argon. Anhydrous diethyl ether (10 mL) was added and the solution was cooled to -78 °C before addition of n-butyllithium (2.5 M in hexanes, 4.49 mL, 11.2 mmol) dropwise over 0.5 h. The reaction mixture was stirred at -78 °C for 1 h, then slowly warmed to r.t. over 1 h. Following this time, paraformaldehyde (337 mg, 11.2 mmol) was added and the mixture was stirred at r.t. for 2 h. The reaction was quenched by addition of water (20 mL) and stirred for 0.5 h. The mixture was extracted with diethyl ether (3 x 30 mL) and the combined organic extracts were dried over MgSO4, filtered, and evaporated in vacuo. Purification by silica chromatography, eluting with ethyl acetate and 40-60 petrol (0:100 to 30:70 gradient), afforded (1,4-dimethoxynaphthalen-2-yl)methanol (1.01 g, 4.63 mmol, 62%) as off-white crystals: Rf 0.16 (3:1 40-60 petrokethyl acetate, UV active); mp: 73-74 °C; 1H NMR: 6 h (300 MHz, CDCb) 6 8.29 - 8.19 (1 H, m, ArH), 8.09 - 8.00 (1 H, m, ArH), 7.60 - 7.43 (2 H, m, 2 x ArH), 6.82 (1 H, s, ArH), 4.90 (2 H, d, J = 5.9 Hz, CH2OH), 4.00 (3 H, s, OCH3), 3.93 (3 H, s, OCH3), 2.09 (1 H, t, J = 6.0 Hz, CH2OH); 13C NMR: 6 c (75 MHz, CDCb) 6 152.1 (1 x Ar), 146.8 (1 x Ar), 128.6 (1 x Ar), 128.4 (1 x Ar),126.7(1 x Ar), 126.2(1 x Ar), 125.5(1 x Ar), 122.4 (1 x Ar), 121.8(1 x Ar), 103.8 (1 x Ar), 62.6 (1 x OMe), 60.8 (1 x CH2OH), 55.7 (1 x OMe); IR: Vmax I cm1 3341,3067, 3000,2942,2887, 2833, 1597, 1452, 1366, 1266, 1225, 1211, 1155, 1119, 1092, 1032, 1021,844, 765; HRMS: (TOF MS ES+) calcd C13H14O3 [M+Na]+: 241.0836, found 241.0852. Example 9: Installation of DIMON Example 9.1: Installation of DIMON onto aliphatic alcohols

[00225] To test DIMON as a protecting group for hydroxyl functions, 1-eicosanol 11 was reacted with DIMONCI 1 (S. Czernecki, C. Georgoulis, and C. Provelenghiou, Nouvelle methode de benzylation d'hydroxyles glucidiques encombres, Tetrahedron Lett., 1976,17, 3535 - 3536): C19H39 OH 1) NaH, rt, 1 h 2) DIMONC11, 10 mol% TBAI reflux, 64 h THF, N2, 59% 12 11 Synthesis of 2-((icosyloxy)methyl)-1,4-dimethoxynaphthalene 12.

[00226] The alcohol was pre-stirred with sodium hydride to afford the alkoxide in situ before introduction of the benzylic halide. A catalytic quantity of TBAI was added to aid the reaction.

[00227] It was necessary to reflux with DIMONCI to observe any reactivity. This reaction was performed three times and the yield was improved with each repeat, the first attempt giving a 19% yield. It was suspected that the product partially deprotected during silica chromatography as the protecting group is expected to be acid labile and silica is weakly acidic. Therefore, 1% triethylamine was added to the column eluent when the reaction was repeated giving a 29% yield. In the third attempt a 59% yield was obtained by using a longer reaction time (64 h) compared to the first two attempts (16 h).

[00228] Benzyl alcohols are known to readily oxidise to benzaldehydes via oxygen as the oxidant (T. W. Greene, in Greene’s Protective Groups in Organic Synthesis, John Wiley &Sons, Inc., New Jersey, 4th edn, 2007, ch. 2, pp. 102-130). Metal catalysis is needed forthis to occur for known benzyl alcohols (e.g. Bn, PMB) but DIMON is more electron rich and therefore more susceptible to oxidation. Use of the Schlenk technique was tested as a method of delivering an inert atmosphere. The reaction vessel was oven-dried to remove any water present. Additionally, to minimise the generation of NaOH overtime NaH was added to a solution of DI MONCI and alcohol. The protection of 1-eicosanol 11 was carried out using this methodology: C19H39^ OH THF, N2, reflux 48 h, 93% DIMONC11, NaH, TBAI 12 11 Improved synthesis of 2-((icosyloxy)methyl)-1,4-dimethoxynaphthalene 12.

[00229] A good yield was obtained, affording the protected alcohol in 93% yield compared to the previous best of 59%. The reaction was refluxed but this may not have been necessary. To test this, all future reactions allowed the DIMON chloride and alkoxide to stir at room temperature for 1 hour. If a reaction was observed by TLC analysis, the reaction was left at room temperature. If no reaction was observed the reaction was refluxed. With excellent reaction conditions established, a range of aliphatic alcohols were tested (Example 9, Table 1). DIMONC11, NaH 10mol%TBAI THF, N2,16 h OMe OMe 17-23 24a-g Example 9, Table 1. Results for installation of DIMON onto aliphatic alcohols. The reactions used 1.0 equivalent of alcohol, 1.2 equivalents of DIMONCI, 1.2 equivalents of NaH, 10 mol% TBAI, and 3 mL / mmol THF.

[00230] Most of these reactions were successful at room temperature and for a shorter reaction time than previously used (16 h). Protection ofthe primary alcohols: octanol 17, E-oct-2-en-1-ol 18, and propargyl alcohol 19 (Entries 1 - 3) proceeded in good yield (75 - 82%). Protection of the benzylic alcohol (4-methoxyphenyl)methanol 20 afforded the ether in an excellent 93% yield (Entry 4). The sterically hindered secondary alcohol / .-menthol 21 (Entry 5) was protected in 71%. The steroid cholesterol 22 was protected in 91% yield. The related ergosterol 23 was protected in 70% yield (Entries 6 and 7). The lower yield for the ergosterol reaction was possibly due to the solubility of ergosterol, which required elevated temperatures to dissolve in THF whereas cholesterol did not. Only cholesterol and ergosterol required refluxing conditions to induce reactivity, whereas all other alcohols reacted at room temperature. In general, these conditions worked excellently for protecting a range of primary, secondary, and benzylic alcohols, the conditions described are suitable for a variety of alcohols. The skilled person could however tweak the conditions to optimise the yield for specific alcohols.

[00231] The same conditions were applied to the glycerol derivative glycidol 25. However, the initial reaction afforded the desired DIMON-glycidol product 26 in low yield (25%). As protection of a glycerol derivative was essential for plasmalogen synthesis, conditions were screened to improve this reaction (Example 9, Table 2). OMe 25                                  26 Entry NaH equiv. DIMONCI equiv. Solvent Time / h Temp / °C Yield % 1 1.2 1.2 THF 16 20 25 2 1.1 1.2 THF 16 Oto 20 27 3 1.2 2.0 DMF 1 0 78 4 1.2 1.2 DMF 16 Oto 20 85 5 1.2 1.2 DMF 2 0 84 Example 9, Table 2. Conditions screened for the DIMON protection of glycidol 25.

[00232] The reaction was initially carried out in THF, but addition of NaH at room temperature (Entry 1) and 0 °C (Entry 2) failed to afford the product in high yield. Upon deprotonation, the glycidol alkoxide could attack another epoxide intermolecularly. Despite DIMONCI being in excess, TLC analysis of the reaction showed DIMONCI had fully reacted while some glycidol remained unreacted. 1H NMR analysis showed dimer 16 was also present. The solvent was replaced with the more polar DMF to dissolve the NaH and ensure rapid, homogenous reaction. Using DMF, the yield was greatly improved to 78% (Entry 3). Adjustment of the reagent equivalents, temperature, and reaction time improved the yield marginally to 85% (Entry 4 and 5). This demonstrated that DMF was also a suitable solvent for installation of DIMON, and in this case was far superior to THF. DMF may also be a better solvent for some of the alcohols previously screened. To test this, installation of DIMON onto ergosterol was repeated in DMF. This afforded protected ergosterol in 89% (compared to 70% in THF) again highlighting DMF as a powerful alternative solvent.

[00233] Protection of glycidol in excellent yield made it an attractive glycerol derivative to use in plasmalogen synthesis. Natural plasmalogens are enantiopure compounds and therefore the conditions used for racemic glycidol were tested on (S)-glycidol S-25: DIMONCI 1, NaH 10 mol% TBAI OMe OMe R-26 u DMF, N2 0°C to rt, 16 h, 77% S-25 Synthesis of (R)-2-(((1,4-dimethoxynaphthalen-2-yl)methoxy)methyl)oxirane R-26

[00234] The reaction proceeded in a comparable 77% yield.

[00235] While sodium hydride was a suitable base for the installation of DIMON onto alcohols, it was also the cause of the by-products (aldehyde 6 and dimer 16). Lithium fe / Y-butoxide (LiO‘Bu) is a weaker, more hindered base that could also be suitable for alcohol deprotonation. To test LiO‘Bu as an alternative base, 3-(hexadecyloxy)propane-1,2-diol 27 was di-protected with DIMON: 1 M LiO‘Bu DIMONCI C16H33O oh c16h33o / Y^odimon OH THF, N2, reflux ODIMON 20 h, 72% 27                                     28 Synthesis of 2,2'-(((3-(hexadecyloxy)propane-1,2-diyl)bis(oxy))bis(methylene))bis(1,4-dimethoxynaphthalene) 28.

[00236] This reaction proceeded well in 72% yield. With this result, we concluded our study of DIMON installations onto aliphatic alcohols. We found that NaH in THF installed DIMON onto a range of alcohols in high yield. Importantly, we also found that these conditions were sometimes not optimal, and in those cases DMF was an alternative solvent that could be used, and LiO‘Bu was an alternative base. Critical to the success of the reaction was dry, inert conditions which we achieved by using oven-dried glassware and Schlenk technique. Fresh sodium hydride was also important, as the base hydrolyses to sodium hydroxide overtime. Example 9.2: Installation of DIMON onto phenols

[00237] Compared to aliphatic alcohols, phenols are acidic (pKa ~10), aromatic, O-nucleophiles and therefore deprotonation can be achieved with a weaker base (e.g. carbonate). To install DIMON onto phenols caesium carbonate was chosen as the base and performed the reactions in dry acetonitrile. This was due to the caesium salt offering better organic solubility than other carbonates (potassium, sodium) which enabled homogenous reaction at elevated temperatures. DIMON was thereby readily installed onto three phenols: 29-31 32a-c OH phenol 29, ether 32a, 91% phenol 30, ether 32b, 80% phenol 31, ether 32c, 89% Results for installation of DIMON onto phenols. The reactions used 1.0 equivalent of phenol, 1.2 equivalent DIMONCI, 1.1 equivalent CS2CO3, and 3 mL / mmol MeCN.

[00238] All three protections proceeded excellently to afford the protected phenols in 80 - 91% yield. Given this success, DIMON is a promising protecting group for O-nucleophiles. Example 9.3: Installation of DIMON onto N-nucleophiles

[00239] DIMON was installed onto two secondary amines, and two secondary amides (Example 9, Table 3). 37a-d 33-36 Entry / V-nucleophile No. Product Conditions Yield % 41 68 82 73 Example 9, Table 3. Installation of DIMON onto / V-nucleophiles. Conditions: A: NEts, DCM, N2, rt, 16 h; B: 10 mol% TBAI, NaH, THF, N2, rt, 16 h.

[00240] The protected amino acid methyl L-prolinate hydrochloride 33 was converted into its free base by triethylamine in situ and then treated with DIMONCI and an additional equivalent of base. This afforded the protected secondary amine in a moderate 41% yield (Entry 1). Protection of morpholine 34 proceeded better in 68% yield, which was comparable to O-nucleophiles. N-Methylbenzamide 35 was protected with the same conditions used for installation of DIMON onto aliphatic alcohols. This worked well, to give the protected amide in 82% yield. Similarly, the lactam pyrrolidin-2-one 36 was protected in 73% yield. 1H NMR analysis of the product / V-((1,4-dimethoxynaphthalen-2-yl)methyl)- / V-methylbenzamide 37c showed evidence of two rotational isomers (Figure 11).

[00241] From the NMR spectrum, four pairs of peaks were present in a 3:2 ratio due to rotamers. The presence of rotamers was confirmed by observing changes in the NMR spectrum with temperature (Figure 12).

[00242] At elevated temperature, each pair of peaks coalesced to one peak which confirmed two rotamers were present. This was due to higher temperature enabling rotation around the C-N bond to occur with a sufficient rate to cause coalescence of the resonances of the E and Z isomers. DIMON can therefore be successfully installed onto secondary amines and amides.

[00243] In summary, we have found conditions to install DIMON onto alcohols, phenols, amines and amides thiophenols in high yield have been found. Example 10: Removal of DIMON Example 10.1: Acid-catalysed cleavage of DIMON

[00244] Removal of a protecting group must be high yielding, synthetically easy, and afford the parent functional group. Acid-catalysed cleavage of electron rich benzyl ethers is a well-established method to achieve this goal (L. Yan, D. Kahne, P-Methoxybenzyl Ethers as Acid-Labile Protecting Groups in Oligosaccharide Synthesis, Synlett., 1995, 523 - 524). PMB and DMB are more acid labile than Bn due to the increased electron density that stabilises the generated benzylic carbocation. As DIMON is more electron rich than these protecting groups, it should be more acid labile. Typically, a 5-10% solution of trifluoroacetic acid (TFA) in dichloromethane is used to cleave benzyl-type protecting groups.

[00245] If required, the ester can be cleaved by methanol work-up to give the benzyl alcohol, allowing the protecting group to be recycled. These conditions were tested on various DIMON-protected substrates (Example 10, Table 1): none 42 none 33 triethylsilane 37 none 44 anisole 55 none no reaction none no reaction Example 10, Table 1. Results of TFA cleavage of DIMON.

[00246] 2-((lcosyloxy)methyl)-1,4-dimethoxynaphthalene 12 (Entry 1) was cleaved to afford 1-eicosanol in only 42% yield. Similarly, cleavage of protected ergosterol 24g (Entry 2) and protected 1-naphthol 32c (Entry 4) only afforded the free alcohols in 33% and 44% yield, respectively. This reaction generates a benzyl carbenium ion, a highly reactive species that can readily react with any nucleophile. For problematic acid-catalysed benzyl deprotections it is common to use a carbocation scavenger to trap the carbenium ion and allow the reaction to proceed cleaner (E. F. D. Medeiros, J. M. Herbert, R. J. K. Taylor, The synthesis and absolute configuration of the novel ichthyotoxic diacyiglycerols, umbraculumin A and umbraculumin C, J. Chem. Soc., Perkin. Trans. 1,1991,2725 - 2730; Y. Morimoto, M. Iwahashi, K. Nishida, Y. Hayashi, and H. Shirahama, Studies on the Asymmetric Synthesis of Stemona Alkaloids: Total Synthesis of (-)-Stenine, Angew. Chem., Int. Ed. Engl., 1996, 35, 904 - 906). Two carbocation scavengers were initially assessed. First, triethylsilane was added but this only marginally improved the yield to 37% (Entry 2 vs 3). The second scavenger, anisole, was slightly more effective, improving the yield to 55% (Entry 4 vs 5).

[00247] Hydrochloric acid as an alternative acid was tested (Example 10, Table 2): Example 10, Table 2. Results of HCI catalysed cleavage of DIMON.

[00248] L-menthol was deprotected in high yield.

[00249] TFA cleavage of DIMON ethers was moderately effective when carbocation scavengers were employed. Refluxing hydrochloric acid in methanol cleaved DIMON in high yield when the desired substrate possessed no acid sensitive functionality. Example 10.2: DDQ oxidative cleavage of DIMON

[00250] DIMON protected alcohols and phenols were treated with DDQ in wet dichloromethane at room temperature (Example 10, Table 3). Example 10, Table 3. Results of DIMON removal via DDQ oxidation.

[00251] DDQ cleavage of DIMON worked excellently to afford an alcohol or phenol in high yield (80 - 99%). The reaction was compatible with primary, secondary, benzylic, and phenolic hydroxyl groups including those that contained alkene (both isolated and conjugated), alkyne or chloro functionality.

[00252] The most interesting result was the reaction of 1,4-dimethoxy-2-(((4- methoxybenzyl)oxy)methyl)naphthalene 24d to afford 4-methoxybenzyl alcohol in 86% yield (Entry 3). This result shows that a DIMON ether is preferentially cleaved over a PMB ether. 1H NMR analysis showed that both 4-methoxybenzyl alcohol and 4-methoxybenzaldehyde were present in a 9:1 ratio. Therefore, the DIMON protecting group was oxidised with ca. 90% selectivity over PMB. DIMON can be used in parallel with PMB and orthogonally removed, allowing for selective deprotection between two benzyl-type protecting groups.

[00253] The protected lactam 1-((1,4-dimethoxynaphthalen-2-yl)methyl)pyrrolidin-2-one 37d was treated with DDQ at room temperature: 19:1 DCM:H2O rt, 72 h, 25% 37d DDQ 6 36 DDQ cleavage of 1-((1,4-dimethoxynaphthalen-2-yl)methyl)pyrrolidin-2-one 37d.

[00254] The reaction was slow, requiring 72 hours to be complete with a low 25% yield, possibly due to loss of material during aqueous work-up. This result showed it was possible to oxidatively remove DIMON from an amide. Example 10.3: Reductive cleavage of DIMON

[00255] Reductive cleavage of benzyl protecting groups via palladium on carbon (Pd / C) catalysed hydrogenation is an alternative benzyl deprotection method used when acidic or oxidative conditions are unsuitable (W. H. Hartung, R. Simonoff, Hydrogenolysis of Benzyl Groups Attached to Oxygen, Nitrogen, or Sulfur, Org. React., 2004, 7, 263 - 326). While effective, this methodology is restricted to substrates that do not possess functionality that can be reduced (alkenes, nitro, nitrile etc). To test if DIMON was cleavable under these conditions, we subjected four DIMON-protected compounds to hydrogenation conditions (Example 10, Table 4). H2, Pd / C 1:1 THF:MeOH, rt Entry Nucleophile Time / h Yield % Example 10, Table 4. Results of hydrogenation reactions.a denotes a stoichiometric amount of TFA was added to the reaction.

[00256] The hydrogenations of the DIMON-protected thymol and eicosanol compounds proceeded well to give the free phenol and alcohol in 86% and 91% yield, respectively. The same conditions were applied to the protected morpholine and A / -methylbenzamide compounds but after 24 hours no reaction was observed. A stoichiometric quantity of TFA was added to both reactions, which were stirred for an additional 48 hours. TFA assists by protonating the morpholine nitrogen and benzamide oxygen to encourage cleavage. Addition of TFA resulted in slow cleavage of morpholine to afford the morpholinium trifluoroacetate salt in 66% yield. Even under forceful acidic conditions the protected amide had not reacted after 48 hours.

[00257] Hydrogenation offers an alternative DIMON deprotection for acidic or oxidatively sensitive substrates. This method works well for O-nucleophiles, and amines when an acid is also added to the reaction. Example 10.4: Compatibility with Polvunsaturation

[00258] To prove that DIMON was compatible with polyunsaturation, three 1-alkyl-2-acyl-3-DIMON-substituted glycerol compounds with different degrees of unsaturation were synthesised: Synthesis of 1-alkyl-2-acyl-3-DIMON-glycerol compounds a. hexadecane-1-ol, 5 mol% BF3.OEt2, toluene, N2, rt, 16 h, 75%; b.i. oleic acid, DCC, DMAP, DCM, N2, rt, 24 h, 93%; b.ii. linoleic acid, DCC, DMAP, DCM, N2, rt, 24 h, 79%; b.iii. docosahexaenoic acid, DCC, DMAP, DCM, N2, rt, 24 h, 91%.

[00259] DIMON-protected glycidol 26 was ring-opened with hexadecan-1-ol under boron trifluoride catalysis to afford the 1,3-substituted glycerol intermediate 43 in 75% yield. The free hydroxyl was then acylated with three fatty acids: oleic acid (18:1) in 93% yield, linoleic acid (18:2) in 79%, and docosahexaenoic acid (22:6) in 91%. All three trisubstituted compounds were treated with DDQ: DDQ oxidative cleavage of DIMON in the presence of polyunsaturation: R = oleic acid, 86% yield; R = linoleic acid, 81 % yield; R = docosahexaenoic acid, 62% yield.

[00260] All three compounds were successfully deprotected to afford the primary alcohol in 86% (oleyl), 81% (linoleyl), and 62% (docosahexaenoyl) yield. Critically, by comparing the 1H NMR spectrum of each product against its starting material, the unsaturated functionality was unchanged. Furthermore, the acyl chain was retained at the sn-2 position and therefore acyl migration had been avoided. This was determined by the hydroxyl proton peak in the spectrum, which was a triplet because of coupling to a methylene peak. The oxidative cleavage of the linoleyl and docosahexaenoyl analogue would not be possible with PMB as the protecting group. Therefore, DIMON is cleavable oxidatively in the presence of polyunsaturation. This is particularly useful for phospholipid syntheses containing docosahexaenoic acid as this fatty acid is a major structural component of human brain, skin, and retina cells, and therefore plays a role in many pathologies involving these cells (M. R. Renk, The Emerging Field of Lipidomics, Nat. Rev. Drug Discovery, 2005, 4, 594-610).

[00261] To test whether DIMON is oxidatively cleavable in the presence of Z-vinyl ethers two 1-alkenyl-2-acyl-3-DIMON substituted glycerol compounds were treated with DDQ: DDQ oxidative cleavage of DIMON in the presence of a Z-vinyl ether: R = oleic acid, 92% yield; R = docosahexaenoic acid, 61% yield.

[00262] In both cases DIMON was oxidatively cleaved without oxidation of the Z-vinyl etherto afford the primary alcohols in 92% (oleyl) and 61% (docosahexaenoyl) yield. This was determined by comparing the 1H NMR of the product against the starting material (Figure 13).

[00263] The two vinyl ether proton peaks at 5.91 ppm (doublet of triplets, J = 6.2, 1.5 Hz) and 4.35 ppm (triplet of doublets, J = 7.3, 6.1 Hz), and the docosahexaenoyl alkene proton peak (12 H, 5.39 ppm) were retained after DIMON was cleaved. If the vinyl ether had been oxidised it would have undergone hydrolysis to afford an aldehyde. As no evidence of an aldehyde proton was present we were satisfied that the vinyl ether was untouched by DDQ. DIMON is therefore oxidatively cleavable in the presence of polyunsaturation and Z-vinyl ethers. Example 11a - Synthesis of (R)-2-((tert-butvldimethylsilyl)oxy)-3-((1,4-dimethoxynaphthalen-2-yl)methoxy)propan-1-ol R-4

[00264] The R-enantiomer (R-4) was synthesised from (R)-glycidol R-7 in 4-steps: Synthesis of (R)-2-((tert-butyldimethylsilyl)oxy)-3-((1,4-dimethoxynaphthalen-2-yl)methoxy)propan-1-ol R-4: a. TDBMSCI, imidazole, THF, N2, 16 h, 99%; b. DIMON-OH 11,5 mol% BF3.OEt2, toluene, N2, rt, 1 h, 53%; c. TBDMS-OTf, pyridine, DCM, N2, 0 °Cto rt, 16 h, 94%; d. NH4F, 1:1 MeOH:THF, N2, rt, 48 h, 83%.

[00265] (R)-Glycidol R-7 was silylated with te / Y-butyldimethylsilyl chloride (TBDMSCI) using imidazole as the base to afford protected glycidol S-14 in quantitative yield. This compound was subjected to acid-catalysed epoxide ring-opening with (1,4-dimethoxynaphthalen-2-yl)methanol (DIMON alcohol 11) to give (S)-1-((tert-butyldimethylsilyl)oxy)-3-((1,4-dimethoxynaphthalen-2-yl)methoxy)propan-2-ol S-15 in 53% yield. The alternative regioisomer, (S)-3-((tert-butyldimethylsilyl)oxy)-2-((1,4-dimethoxynaphthalen-2-yl)methoxy)propan-1-ol, was synthesised in 17% yield. Therefore, the ring-opening reaction had a total yield of 70% and a 3:1 ratio of regioisomers. The desired regioisomer was silylated again with TBDMS to give (8)-5-(((1,4-dimethoxynaphthalen-2-yl)methoxy)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane S-16 in 94% yield. Finally, the primary silyl group was selectively cleaved by ammonium fluoride to afford compound R-4 in 83% yield. The overall yield for this route was 41%.

[00266] The products of each step were analysed by 1H NMR (Figure 14). The silylation of (R)-glycidol R-7 resulted in three new singlet peaks at 0.90 (9 H), 0.08 (3 H) and 0.07 ppm (3 H), due to the te / Y-butyldimethylsilyl group. After reaction with DIMON alcohol 11 the epoxide protons from 2.5 - 3.0 ppm disappeared, replaced by glycerol peaks from 3.5 - 4.0 ppm. The desired regioisomer (S-15) spectrum possessed a doublet at 2.54 ppm (1 H, J = 4.8 Hz) assigned to the hydroxyl proton peak, which supported a secondary alcohol that neighboured only one proton. The other regioisomer spectrum had a triplet peak at 2.29 ppm (1 H, J = 6.1 Hz) that supported a primary alcohol that neighboured two protons. After the second silylation, the hydroxyl peak disappeared and two new singlet peaks appeared at 0.88 (9 H) and 0.04 ppm (6 H) due to the second TBDMS group. Finally, after selective cleavage of the primary silyl group, a new hydroxyl peak appeared at 2.04 ppm as a broad singlet. Due to the differences in the spectra of compounds S-15 and R-4 we were confident that the desired primary alcohol had been obtained.

[00267] (R)-Glycidol R-7 was purchased from a commercial source with a nominal 95% enantiomeric excess (ee). As a single plasmalogen enantiomer was desired, we wanted to ensure the chiral centre had not been perturbed during silylation or epoxide ring opening. Therefore, the optical rotation of S-14 was measured: [q]d20 = -2.04° (c = 1.08 in CHCb). This value agreed with its published value of-1.93° (c = 1.04 in CHCb at 20 °C), which indicated that compound S-14 had retained the initial chirality (C. P. Bold, C. Klaus, B. Pfeiffer, J. Schurmann, R. Lombardi, D. L. Agell, J. F. Diaz, K. H. Altmann, Studies toward the Synthesis of an Oxazole-Based Analog of (-)-Zampanolide, Org. Lett., 2021,23, 2238-2242). Additionally, compound S-15 was treated with DDQ to cleave the DIMON protecting group and afford (S)-3-((tert-butyldimethylsilyl)oxy)propane-1,2-diol S-17. The optical rotation of S-17 was measured: [a]D20 = -3.39° (c = 0.77 in CHCb). The optical rotation of this enantiomer had not published but the optical rotation of the R-enantiomer had a reported value of +3.50° (c = 0.73 in CHCb at 20 °C) (Z. X. Guistra, K. L. Tan, The efficient desymmetrization of glycerol using scaffolding catalysis, Chem. Commun., 2013,49,4370 - 4372). We were therefore confident that compound 17 was the desired S enantiomer. As no further chemistry involved the chiral carbon it will not be affected. Therefore, compound R-4 will afford a plasmalogen enantiomer which is assumed to have at least 95% ee. Example 11b): Synthesis of (R)-2-((tert-butvldimethvlsilvl)oxv)-3-((1,4-dimethoxynaphthalen-2-vl)methoxy)propan-1 -ol (S)-tert-butyldimethyl(oxiran-2-vlmethoxy)silane TBDMSO^^Ty O

[00268] To a flask, purged with nitrogen, was added a solution of (R)-glycidol (2.00 g, 27.00 mmol) in tetra hydrofuran (30 mL). The solution was cooled to 0 °C then imidazole (2.76 g, 40.50 mmol) and fe / t-butyldimethylsilyl chloride (6.10 g, 40.50 mmol) were added sequentially. Upon addition, the reaction was warmed to rt and stirred for 16 h. The reaction mixture was vacuum filtered through a pad of Celite® and the eluent was evaporated in vacuo. The product was purified by silica chromatography, eluting with 95:5 petrol:ethyl acetate afforded (S)-tert-butyldimethyl(oxiran-2-ylmethoxy)silane (5.03 g, 26.73 mmol, 99%) as a clear, colourless oil: [a]D20 = -2.04 (c = 1.08 in CHCb); 1H NMR 6 h (400 MHz, CDCb) 6 3.85 (1 H, dd, J = 11.9, 3.2 Hz, OCHH), 3.66 (1 H, dd, J = 11.9, 4.8 Hz, OCHH), 3.08 (1 H, dddd, J = 4.8, 4.0, 3.2, 2.7 Hz, CH(O)), 2.77 (1 H, dd, J = 5.1,4.0 Hz, CHH(O)), 2.63 (1 H, dd, J = 5.1,2.7 Hz, CHH(O)), 0.90 (9 H, s, SiC(CH3)3), 0.08 (3 H, s, SiCH3), 0.07 (3 H, s, SiCH3); HRMS (TOF MS AP+) calcd C9H2o02Si [3M+H]+ 565.3770, found 565.3756. Analysis corresponds with literature: C. P. Bold, C. Klaus, B. Pfeiffer, J. Schurmann, R. Lombardi, D. Diaz, and K. Altmann, Studies toward the Synthesis of an Oxazole-Based Analog of (-)-Zampanolide, Org. Lett. 2021,23, 2238-2242. (S)-1-((tert-butyldimethylsilvl)oxv)-3-((1.4-dimethoxynaphthalen-2-yl)methoxv)propan-2-ol OMe OMe

[00269] To a flask, purged with nitrogen via Schlenk technique, was added a solution of (1,4-dimethoxynaphthalen-2-yl)methanol (5.00 g, 22.91 mmol) in toluene (20 mL) and boron trifluoride diethyl etherate (47 pL, 382 pmol). To this was added a solution of (S)-te / Y-butyldimethyl(oxiran-2-ylmethoxy)silane (1.44 g, 7.64 mmol) in toluene (10 mL) dropwise. Upon addition, the reaction was stirred at rt for 1 h. The reaction was quenched by addition of minimal saturated aqueous sodium bicarbonate solution, then diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organics were dried over MgSO4, filtered, and evaporated in vacuo. The product was purified by silica chromatography, eluting with 85:15 petrokethyl acetate afforded (S)-1-((tert-butyldimethylsilyl)oxy)-3-((1,4-dimethoxynaphthalen-2-yl)methoxy)propan-2-ol (1.65 g, 4.05 mmol, 53%) as a pale yellow oil: Rf 0.30 (85:15 petrokethyl acetate, permanganate stain); [a]o19 = +4.0 (c = 1.01 in CHCb); 1H NMR 6 h (400 MHz, CDCb) 6 8.27 - 8.22 (1 H, m, ArH), 8.08 - 8.04 (1 H, m, ArH), 7.58 - 7.44 (2 H, m,2 x ArH), 6.84 (1 H, s, ArH), 4.79 (2 H, s, OCH2C), 4.00 (3 H, s, OCH3), 3.94 - 3.84 (4 H, m, OCH3, CHOH), 3.76 - 3.55 (4 H, m, CH2CHCH2), 2.43 (1 H, br, s, OH) 0.89 (9 H, s, SiC(CH3)3), 0.07 (6 H, s, 2 x SiCH3); 13C NMR 6 c (75 MHz, CDCb) 6 152.2 (Ar), 147.7 (Ar), 128.5 (Ar), 126.7 (Ar), 126.5 (Ar), 125.9 (Ar), 125.7 (Ar), 122.5 (Ar), 122.0 (Ar), 104.2 (Ar), 71.3 (CH2OCH2), 70.9 (CH(OH)), 68.2 (CH2OCH2), 64.3 (SiOCH2), 62.9 (OCH3), 55.7 (OCH3), 26.0 (SiC(CH3)3), 18.4 (SiC(CH3)3), -5.3 (2 x SiCHs); IR vmax / cm1 3453 br, 2929, 2856, 1597, 1461, 1369, 1252, 1214, 1088, 1000, 834, 768; HRMS (TOF MS AP+) calcd C22H34O5Si [M-H]+ 405.2092, found 405.2103. (S)-5-((( 1.4-dimethoxynaphthalen-2-yl)methoxy)methyl)-2,2,3.3.8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane

[00270] To a flask., purged with nitrogen, was added a solution of (S)-1-((te / Y-butyldimethylsilyl)oxy)-3-((1,4-dimethoxynaphthalen-2-yl)methoxy)propan-2-ol (1.49 g, 3.66 mmol) in dichloromethane (20 mL). The solution was cooled to 0 °C then pyridine (890 pL, 10.99 mmol) and te / Y-butyldimethylsilyl trifluoromethanesulfonate (1.68 mL, 7.33 mmol) were added sequentially. Upon addition, the reaction was warmed to rt and stirred for 16 h. The reaction was diluted with dichloromethane (30 mL) and washed with saturated aqueous sodium bicarbonate solution (3 x 30 mL). The organics were dried over MgSO4, filtered, and evaporated in vacuo. The product was purified by silica chromatography, eluting with 95:5 petrol:ethyl acetate afforded (S)-5-(((1,4-dimethoxynaphthalen-2-yl)methoxy)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (1.79 g, 3.44 mmol, 94%) as a pale yellow oil: [a]D19 = -8.4 (c = 1.01 in CHCb); 1H NMR 6 h (300 MHz, CDCb) 6 8.29 - 8.19 (1 H, m, ArH), 8.11 - 8.01 (1 H, m, ArH), 7.60 - 7.42 (2 H, m, 2 x ArH), 6.89 (1 H, s, ArH), 4.79 (2 H, dd, J= 14.8, 11.9 Hz, CH2OC / - / 2C), 4.00 (3 H, s, OCH3), 3.95-3.86 (4 H, m, OCH3, CHOSi), 3.72 - 3.48 (4 H, m, CH2CHCH2), 0.90 (9 H, s, SiC(CH3)3), 0.89 (9 H, s, SiC(CH3)3), 0.10 (6 H, s, 2 x SiCHs), 0.06 (6 H, s, 2 x SiCH3); 13C NMR 6 c (75 MHz, CDCb) 6 152.1 (Ar), 147.3 (Ar), 128.6 (Ar), 126.6 (Ar), 126.6 (Ar), 126.4 (Ar), 125.5 (Ar), 122.5 (Ar), 122.0 (Ar), 104.2 (Ar), 73.0 (CHSi), 72.9 (CHCH2O), 68.2 (CH2OCH2), 65.4 (SiOCH2), 62.8 (OCH3), 55.8 (OCH3), 26.1 (SiC(CH3)3), 26.0 (SiC(CH3)3), 18.5 (SiC(CH3)3), 18.4 (SiC(CH3)3), -4.4 (SiCH3), -4.6 (SiCH3), -5.2 (SiCH3), -5.3 (SiCH3); IR Vmax / cm1 2953, 2929, 2885, 2857, 1598, 1461, 1370, 1252, 1214, 1091, 1004, 831,768; HRMS (TOF MS AP+) calcd C28H48O5Si2 [M+NH4]+ 538.3379, found 538.3381. (R)-2-((tert-butvldimethvlsilvl)oxv)-3-((1,4-dimethoxvnaDhthalen-2-vl)methoxv)DroDan-1-ol

[00271] To a solution of (S)-5-(((1,4-dimethoxynaphthalen-2-yl)methoxy)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (1.70 g, 3.26 mmol) in 1:1 tetrahydrofuran:methanol (10 mL) under nitrogen was added ammonium fluoride (4.84 g, 130.6 mmol) and the reaction was stirred at rt for 48 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organics were dried over MgSO4, filtered, and evaporated in vacuo. The product was purified by silica chromatography, eluting with 85:15 petrokethyl acetate afforded (R)- 2-((tert-butyldimethylsilyl)oxy)-3-((1,4-dimethoxynaphthalen-2-yl)methoxy)propan-1-ol (1.11 g, 2.72 mmol, 83%) as a pale yellow oil: : [a]D19 = +13.8 (c = 0.99 in CHCb); 1H NMR 6 H (300 MHz, CDCb) 6 8.27 - 8.21 (1 H, m, ArH), 8.10 - 8.01 (1 H, m, ArH), 7.60 - 7.43 (2 H, m, 2 x ArH), 6.83 (1 H, s, ArH), 4.77 (2 H, s, CH2OCH2), 4.03 - 3.93 (4 H, m, OCH3, CHOSi), 3.90 (3 H, s, OCH3), 3.76 -3.53 (4 H, m, CH2CHCH2), 2.04 (1 H, s, br, OH), 0.90 (9 H, s, SiC(CH3)3), 0.11 (3 H, s, SiCH3), 0.10 (3 H, s, SiCH3); 13C NMR 6 c (75 MHz, CDCb) 6 152.2 (Ar), 147.5 (Ar), 128.5 (Ar), 126.7 (Ar), 126.5 (Ar), 126.0 (Ar), 125.7 (Ar), 122.5 (Ar), 122.0 (Ar), 104.0 (Ar), 72.3 (CHCH2O), 71.5 (CHOSi), 68.3 (CH2OCH2), 65.0 (CH2OH), 62.9 (OCHs), 55.8 (OCH3), 25.9 (SiC(CH3)3), 18.2 (SiC(CH3)3), -4.4 (SiCH3), -4.7 (SiCH3); IR vmax I cm1 3457 br, 2955, 2929, 2894, 2856, 1597, 1461,1370, 1253, 1213, 1124, 1088, 834, 768; HRMS (FTMS +p NSI) calcd C22H34O5Si [M+Na]+ 429.2068, found 429.2060. Example 12a -(S,Z)-tert-butvl((1-((1,4-dimethoxvnaphthalen-2-vl)methoxv)-3-(hexadec-1-en-1-vloxv)propan-2-vl)oxv)dimethvlsilane S-18 99:1 Z.E Synthesis of (S,Z)-tert-butyl((1-((1,4-dimethoxynaphthalen-2-yl)methoxy)-3-(hexadec-1-en-1-yloxy)propan-2-yl)oxy)dimethylsilane S-18: a. alcohol R-4, 5 mol% BF3.OEt2, toluene, N2, rt, 0.5 h, 77%; b. KH, TFT, N2, 45 °C, 1 h, 85%.

[00272] Reaction of glycerol compound R-4 with silyl epoxide 1 a diastereomeric mixture of compound 8c was produced. The subsequent Peterson elimination removed the chirality of the alkyl chain so all diastereoisomers of 8c can be used to synthesis the desired product. Treatment of compound 8c with potassium hydride afforded the Z-vinyl ether S-18 in 85% yield. The Z.E isomeric ratio for S-18 was determined by 1H NMR (Figure 15). The two vinyl ether protons were assigned to the doublet of triplets at 5.82 ppm (1 H, J= 6.2, 1.5 Hz) and the triplet of doublets at 4.19 ppm (1 H, J = 7.3, 6.2 Hz). The coupling constant for these peaks agreed with a c / s-relationship. The E-isomer vinyl ether peak at 6.12 ppm integrated to 0.01 relative to the Z-isomer peak which integrated to 0.99. Therefore, the ratio of Z.E isomers was an excellent 99:1. With this result we had shown that the modified Peterson reaction could be applied to the synthesis of plasmalogens to afford Z-vinyl ethers in high yield and high stereoselectivity. Example 12b: Synthesis of (S,Z)-tert-butyl((1-((1,4-dimethoxynaphthalen-2-yl)methoxy)-3-(hexadec-1 -en-1 -yloxy)propan-2-yl)oxy)dimethylsilane 1-((S)-2-((tert-butvldimethvlsiM)oxv)-3-((1A-dimethoxynaphthalen-2-vl)methoxv)propoxy)-1-drimethylsilyl)hexadecan-2-ol OMe

[00273] To a flask, purged with nitrogen via Schlenk technique, was added a solution of (R)-2-((tert-butyldimethylsilyl)oxy)-3-((1,4-dimethoxynaphthalen-2-yl)methoxy)propan-1-ol (1.95 g, 4.80 mmol) in toluene (4.80 mL) and boron trifluoride diethyl etherate (10 pL, 80 pmol). To this was added a solution of trimethyl(3-tetradecyloxiran-2-yl)silane (500 mg, 1.60 mmol) in toluene (1.60 mL) dropwise. Upon addition, the reaction was stirred at rt for 0.5 h. The reaction was quenched by addition of minimal saturated aqueous sodium bicarbonate solution and concentrated in vacuo. The product was isolated by vacuum filtration through a pad of silica, eluting with 95:5 petrokethyl acetate afforded 1-((S)-2-((fe / Y-butyldimethylsilyl)oxy)-3-((1,4-dimethoxynaphthalen-2-yl)methoxy)propoxy)-1-(trimethylsilyl)hexadecan-2-ol (909 mg, 1.26 mmol, 79%) as a clear, colourless oil and carried forward without further purification: Rf 0.21 (95:5 petrokethyl acetate, permanganate stain); 1H NMR 6 h (300 MHz, CDCb) 6 8.28 - 8.18 (1 H, m, ArH), 8.09 - 7.99 (1 H, m, ArH), 7.59 - 7.41 (2 H, m,2 x ArH), 6.87 (1 H, d, J = 7.5 Hz, ArH), 4.81 - 4.71 (2 H, m, CH2OCH2), 4.04 - 3.94 (4 H, m, OCH3, CHOSi), 3.88 (3 H, d, J = 0.7 Hz, OCH3), 3.78 - 3.40 (5 H, m, CH2CHCH2, CHOH), 2.81 (1 H, d, J = 6.7 Hz, CHSi(CH3)3), 1.48- 1.20 (26 H, m, 13 x CH2), 1.36 - 1.11 (24 H, m), 0.96 - 0.80 (12 H, m, SiC(CH3)3, CH3), 0.15 - 0.02 (15 H, m, Si(CH3)3, 2 x SiCHs); HRMS (FTMS +p NSI) calcd C4iH74O6Si2 [M+Na]+ 741.4916, found 741.4906. (S.Z)-tert-butyl(d-((1,4-dimethoxynaphthalen-2-vl)methoxv)-3-(hexadec-1-en-1-vloxv)propan-2- yl)oxv)dimethylsilane OMe OMe

[00275] To a flask, purged with nitrogen via Schlenk technique, was added potassium hydride (30 wt% dispersion in mineral oil, 1.67 g, 12.51 mmol). The solids were washed with hexane three times before a solution of 1-((S)-2-((fe / t-butyldimethylsilyl)oxy)-3-((1,4-dimethoxynaphthalen-2-yl)methoxy)propoxy)-1-(trimethylsilyl)hexadecan-2-ol (900 mg, 1.25 mmol) in trifluorotoluene (12.50 mL) was added. Upon addition, the reaction was warmed to 45 °C and stirred for 1 h. The reaction was cooled to rt and cautiously quenched by addition of minimal saturated aqueous ammonium chloride solution. The mixture was diluted with water (50 mL) and extracted with dichloro methane (3 x 50 mL). The combined organics were dried over MgSO4, filtered, and evaporated in vacuo. The product was purified by silica chromatography, eluting with 97:3 petrokethyl acetate afforded (S,Z)-tert-butyl((1-((1,4-dimethoxynaphthalen-2-yl)methoxy)-3-(hexadec-1-en-1-yloxy)propan-2-yl)oxy)dimethylsilane (669 mg, 1.06 mmol, 85%) as a clear, colourless oil: Rf 0.45 (95:5 petrokethyl acetate, permanganate stain); 1H NMR 0 h (300 MHz, CDCh) 6 8.28 - 8.19 (1 H, m, Ar / 7), 8.10 -8.01 (1 H, m, ArH), 7.60 - 7.42 (2 H, m, 2 x Ar / 7), 6.85 (1 H, s, ArH), 5.92 (1 H, dt, J= 6.2, 1.5 Hz, CH=C / 7O), 4.77 (2 H, dd, J = 13.6, 12.0 Hz, CH2OCH2), 4.29 (1 H, td, J = 7.3, 6.2 Hz, CH=CHO), 4.05 (1 H, p, J= 5.2 Hz, CHOSi) 3.99 (3 H, s, OCH3), 3.90 (3 H, s, OCH3), 3.83 (1 H, dd, J= 10.6, 4.6 Hz, CHCHHOCH2), 3.72 (1 H, dd, J= 10.6, 6.3 Hz, CHCHHOCH2), 3.56 (2 H, d, J= 5.3 Hz, CHOCH2CH), 2.03 (2 H, qd, J = 6.7, 1.5 Hz, CH2CH=CHO), 1.34-1.22 (24 H, s, br, 12 x CH2), 0.95 - 0.81 (12 H, m, SiC(CH3)3, CH3), 0.10 (6 H,s,2x SiCHs); 13C NMR 6 c (75 MHz, CDCh) 6 152.1 (Ar), 147.4 (Ar), 145.4 (CH=CHO), 128.6 (Ar), 126.7 (Ar), 126.5 (Ar), 126.3 (Ar), 125.6 (Ar), 122.5 (Ar), 122.0 (Ar), 106.8 (CH=CHO), 104.1 (Ar), 74.4 (CH2OCH2), 72.4 (CHOSi), 71.1 (CHOCH2), 68.2 (CH2OCH2), 62.9 (OCH3), 55.8 (OCH3), 32.1 (CH2), 30.0 (CH2), 29.8 (6 x CH2), 29.7 (CH2), 29.5 (CH?), 26.0 (SiC(CH3)3), 24.2 (CH2CH=CHO), 22.8 (CH2), 18.3 (SiC(CH3)3), 14.3 (CH3), -4.6 (2 x SiCH3);); IR Vmax I cm 1 HRMS (FTMS +p NSI) calcd C38H64O5Si [M+NH4]+ 646.4861, found 646.4866. Example 13a - Installation of acyl chain at the sn-2 position

[00276] Compound S-18 was reacted with tetrabutylammonium fluoride (TBAF) to cleave the silyl protecting group and give compound S-19 which was acylated with three fatty acids: OMe OMe OMe OMe S-19 S-18 oleic acid: arachidonic acid: docosahexaenoic acid: Installation of acyl chain at the sn-2 position: a. 1 M TBAF, THF, N2, rt, 16 h, 90%; b.i. oleic acid, DCC, DMAP, DCM, N2, rt, 20 h, 95%; b.ii. arachidonic acid, DCC, DMAP, DCM, N2, rt, 16 h, 93%; b.iii. docosahexaenoic acid, DCC, DMAP, DCM, N2, rt, 16 h, 92%.

[00277] Cleavage of the TBDMS group proceeded cleanly in 90% yield to afford the secondary alcohol S-19. The material was then split into three batches and acylated using Steglich esterification conditions [ / V,A / -dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP)] to activate the fatty acid for coupling. As natural plasmalogens were desired, oleic acid, arachidonic acid, and docosahexaenoic acid were chosen for the acylations. All three reactions worked well to afford the desired compounds in 95% (S-20), 93% (S-21) and 92% (S-22) yield, respectively. Compounds S-19, S-20, S-21 and S-22 were characterised by 1H NMR spectrometry (Figure 16 and 17).

[00278] The doublet peak at 2.55 ppm (1 H, J = 4.7 Hz) was assigned to the 2° hydroxyl proton of compound S-19 . After acylation with oleic acid, the hydroxyl peak disappeared and a new multiplet at 5.35 ppm (2 H) appeared due to the oleyl vinylic protons. Similarly, for compounds S-21 and S-22 each spectrum contained a new multiplet for the arachidonoyl (8 H, 5.38 ppm) and docosahexaenoyl (12 H, 5.37 ppm) vinylic protons. For all three acylation products, the peak assigned to the proton at the chiral centre had shifted significantly downfield from 4.05 to 5.24 ppm. It had also simplified from a complex multiplet to a quintet (J = 5.1 Hz). Therefore, we were satisfied that the sn-2 position had been acylated as desired. No evidence of reaction at the vinyl ether was present, and the ratio of ZE isomers remained at 99:1 for all four compounds.

[00279] It was important that for all compounds containing a Z-vinyl ether and free glycerol hydroxyl (e.g. S-19) the deuterated chloroform (CDCh) used was pre-treated with potassium carbonate (K2CO3) before NMR analysis (Figure 18). Example 13b: Synthesis of (S)-1-((1,4-dimethoxynaphtha len-2-yl)methoxy)-3-(((Z)-hexadec-1-en-1-yl)oxy)propan-2-yl oleate and (S)-1-((1,4-dimethoxynaphthalen-2-yl)methoxy)-3-(((Z)-hexadec-1 -en-1 -yl)oxy)propan-2-yl (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19- hexaenoate (S,Z)-1-((1,4-dimethoxynaphthalen-2-vl)methoxv)-3-(hexadec-1-en-1-Yloxv)propan-2-ol OMe OMe

[00280] To a solution of (S,Z)-te / Y-butyl((1-((1,4-dimethoxynaphthalen-2-yl)methoxy)-3-(hexadec-1-en-1-yloxy)propan-2-yl)oxy)dimethylsilane (650 mg, 1.03 mmol) in tetrahydrofuran (10 mL) under nitrogen was added tetrabutylammonium fluoride (1 M in tetrahydrofuran, 1.14 mL, 1.14 mmol) dropwise. Upon addition, the reaction was stirred at rt for 16 h. The reaction was diluted with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organics were dried over MgSO4, filtered, and evaporated in vacuo. The residue was vacuum filtered through a pad of silica, eluting with 75:25 petrol:ethyl acetate to afford (S,Z)-1 -((1,4-dimethoxynaphthalen-2-yl)methoxy)-3-(hexadec-1-en-1-yloxy)propan-2-ol (479 mg, 930 pmol, 90%) as a clear, colourless oil: Rf 0.47 (75:25 petrol:ethyl acetate, UV / Vis); [a]D19 = -2.0 (c = 1.03 in CHCh); 1H NMR 6 h (300 MHz, CDCh) 6 8.29 - 8.20 (1 H, m, ArH), 8.11 - 8.01 (1 H, m, ArH), 7.60 - 7.43 (2 H, m, 2 x ArH), 6.82 (1 H, s, ArH), 5.94 (1 H, dt, J = 6.2, 1.5 Hz, CH=CHO), 4.79 (2 H, s, CH2OCH2), 4.37 (1 H, td, J = 7.3, 6.2 Hz, CH=CHO), 4.12 - 3.98 (4 H, m, CH(OH), OCH3), 3.91 (3 H, s, OCH3), 3.86 - 3.74 (2 H, m, CHOCH2), 3.72 - 3.55 (2 H, m, CH2OCH2), 2.55 (1 H, d, J = 4.7 Hz, OH), 2.11 - 1.97 (2 H, m, CH2CH=CHO), 1.39 - 1.18 (24 H, s, br, 12 x CH2), 0.91 (3 H, t, J = 6.8 Hz, CH3); 13C NMR 6 c (75 MHz, CDCh) 6 152.2 (Ar), 147.8 (Ar), 144.9 (CH=CHO), 128.6 (Ar), 126.8 (Ar), 126.6 (Ar), 125.8 (Ar), 125.7 (Ar), 122.5 (Ar), 122.1 (Ar), 108.1 (CH=CHO), 104.1 (Ar), 73.0 (CHOCH2), 71.2 (CH2OCH2), 69.7 (CH(OH)), 68.3 (CH2OCH2), 63.0 (OCH3), 55.8 (OCH3), 32.1 (CH2), 29.9 - 29.4 (10 x CH2), 24.1 (CH2CH=CHO), 22.8 (CH2), 14.3 (CH3); IR Vmax / cm-1 3448 br, 2922, 2852, 1664, 1598, 1460, 1370, 1267, 1214, 1124, 1095, 768; HRMS (TOF MS AP+) calcd C32H50O5 [M+Na]+ 537.3550, found 537.3544. (S)-1-((1,4-dimethoxynaphthalen-2-yl)methoxY)-3-(((Z)-hexadec-1-en-1-yl)oxy)propan-2-Yl oleate

[00281] To a solution of (S,Z)-1-((1,4-dimethoxynaphthalen-2-yl)methoxy)-3-(hexadec-1-en-1-yloxy)propan-2-ol (150 mg, 291 pmol) in dichloromethane (3 mL) under nitrogen was added 4-dimethylaminopyridine (18 mg, 146 pmol) and A / , / V-dicyclohexylcarbodiimide (90 mg, 437 pmol). The mixture was stirred at rt for 0.5 h before addition of oleic acid (110 pL, 350 pmol) and then stirred for a further 16 h. The reaction was diluted with water (30 mL) and extracted with dichloromethane (3 x 30 mL). The combined organics were dried over MgSOi, filtered, and evaporated in vacuo. The product was purified by silica chromatography, eluting with 97:3 petrol:ethyl acetate afforded (5)-1-((1,4-dimethoxynaphthalen-2-yl)methoxy)-3-(((Z)-hexadec-1-en-1-yl)oxy)propan-2-yl oleate (216 mg, 277 pmol, 95%) as a clear, colourless oil: Rf 0.62 (90:10 petrol:ethyl acetate, UV / Vis); [a]D19 = +4.0 (c = 0.97 in CHCb); 1H NMR 5 h (300 MHz, CDCI3) 6 8.29 - 8.20 (1 H, m, ArH), 8.10 - 8.01 (1 H, m, ArH), 7.60 - 7.43 (2 H, m, 2 x ArH), 6.83 (1 H, s, ArH), 5.91 (1 H, dt, J = 6.2, 1.5 Hz, CH=CHO), 5.43 - 5.29 (2 H, m, CH=CH), 5.24 (1 H, p, J = 5.1 Hz, CH2CHCH2), 4.78 (2 H, d, J = 2.1 Hz, CH2OCH2), 4.35 (1 H, td, J= 7.3, 6.1 Hz, CH=CHO), 4.00 (3 H, s, OCH3), 3.94 - 3.88 (5 H, m, OCH3, CHOCH2), 3.71 (2 H, d, J = 5.1 Hz, CH2OCH2), 2.33 (2 H, t, J = 7.3 Hz, CW2C=O), 2.08 - 1.94 (6 H, m, 3 x CH=CHCH2), 1.63 (2 H, p, J = 7.5 Hz, CH2CH2C=O), 1.42 - 1.23 (48 H, s, br, 22 x CH2), 0.96 - 0.81 (6 H, m, 2 x CW3); 13C NMR 6 c (75 MHz, CDCb) 6 173.2 (C=O), 152.2 (Ar), 147.7 (Ar), 144.9 (CH=CHO), 130.1 (CH=CH), 129.8 (CH=CH), 128.5 (Ar), 126.7 (Ar), 126.6 (Ar), 125.7 (Ar), 125.7 (Ar), 122.5 (Ar), 122.0 (Ar), 108.0 (CH=CHO), 104.1 (Ar), 71.3 (CHOC=O), 70.4 (CH2OCH2), 68.6 (CHOCH2), 68.1 (CH2OCH2), 62.9 (OCH3), 55.7 (OCH3), 34.5 (CH2C=O), 32.1 (2 x CH2), 30.1 - 29.0 (19 x CH2), 27.3 (CH2CH=CHCH2), 25.1 (CH2), 24.0 (CH2CH=CHO), 22.8 (CH2), 14.2 (2 x CH3); IR Vmax I cm1 2922, 2853, 1740, 1665, 1598, 1461, 1370, 1267, 1214, 1163, 1124, 1093, 845, 768, 722; HRMS (TOF MS AP+) calcd C50H82O6 [M+H]+ 779.6184, found 779.6184. (S)-1-((1,4-dimethoxynaphthalen-2-vl)methoxy)-3-(((Z)-hexadec-1-en-1-yl)oxy)propan-2-yl (4Z, 7Z, 10Z. 13Z, 16Z, 19Z)-docosa-4.7.10,13,16,19-hexaenoate OMe O OMe

[00282] To a solution of (S,Z)-1 -((1,4-dimethoxynaphthalen-2-yl)methoxy)-3-(hexadec-1-en-1- yloxy)propan-2-ol (150 mg, 291 pmol) in dichloromethane (3 mL) under nitrogen was added 4- dimethylaminopyridine (18 mg, 146 pmol) and A / , / V-dicyclohexylcarbodiimide (90 mg, 437 pmol). The mixture was stirred at rt for 0.5 h before addition of docosahexaenoic acid (122 pL, 350 pmol) and then stirred for a further 16 h. The reaction was diluted with water (30 mL) and extracted with dichloromethane (3 x 30 mL). The combined organics were dried over MgSO4, filtered, and evaporated in vacuo. The product was purified by silica chromatography, eluting with 97:3 petrol:ethyl acetate afforded (5)-1-((1,4-dimethoxynaphthalen-2-yl)methoxy)-3-(((Z)-hexadec-1-en-1-yl)oxy)propan-2-yl (4Z,7Z, 10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate (228 mg, 277 pmol, 95%) as a clear, colourless oil: Rf 0.36 (95:5 petrol:ethyl acetate, UV / Vis); 1H NMR 6 h (300 MHz, CDCI3) 8.29 - 8.19 (1 H, m, ArH), 8.10 - 8.00 (1 H, m, ArH), 7.60 - 7.42 (2 H, m,2 x ArH), 6.82 (1 H, s, ArH), 5.90 (1 H, dt, J = 6.2, 1.5 Hz, CH=CHO), 5.48 - 5.35 (12 H, m, 6 x CH=CH), 5.24 (1 H, p, J =5.1 Hz, CHOC=O), 4.85 - 4.70 (2 H, m, CH2OCH2), 4.34 (1 H, td, J = 7.3, 6.1 Hz, CH=CHO), 3.99 (3 H, s, OCH3), 3.94 - 3.84 (5 H, m, OCH3, CHOCH2), 3.71 (2 H, d, J = 5.1 Hz, C / - / 2OCH2), 2.90 - 2.77 (10 H, m, 5 x CHCH2CH), 2.47 - 2.31 (4 H, m, CH2CH2C=O), 2.15 - 1.94 (4 H, m, CH2CH=CHO, CHCH2CH3), 1.26 (24 H, s, br, 12 x CH2), 0.98 (3 H, t, J = 7.5 Hz, CH3), 0.89 (3 H, t, J = 6.5 Hz, C / 73); 13C NMR 5 c (75 MHz, CDCh) 6 172.5 (C=O), 152.2 (Ar), 147.7 (Ar), 144.9 (CH=CHO), 132.2 (CH=CH), 129.4 (CH=CH), 128.7 (CH=CH), 128.5 (Ar), 128.4 - 127.9 (6 x CH=CH), 127.2 (CH=CH), 126.7 (Ar), 126.6 (Ar), 125.7 (2 x Ar), 122.5 (Ar), 122.0 (Ar), 108.1 (CH=CHO), 104.1 (Ar), 71.5 (CHOC=O), 70.3 (CH2OCH2), 68.5 (CHOCH2), 68.2 (CH2OCH2), 62.9 (OCH3), 55.8 (OCH3), 34.3 (CH2C=O), 32.1 (CH2), 30.2 - 29.1 (10 x CH2), 25.7 (5 x CHCH2CH), 24.0 (CH2CH=CHO), 22.8 (CH2CH2C=O, CH2), 20.7 (CHCH2CH3), 14.4 (CH3), 14.3 (CH3); IR Vmax / cm1 3012, 2923, 2856, 1738, 1664, 1600, 1464, 1370, 1155, 1093, 768; HRMS (FTMS +p NSI) calcd C54H80O6 [M+Na]+ 847.5847, found 847.5846. Example 14a - DDQ oxidative cleavage of DIMON to afford primary alcohols S-23-25

[00283] With the sn-1 and sn-2 functionality installed, all that remained was the phosphocholine or phosphoethanolamine headgroup at the sn-3 position. To install these groups, first the DIMON protecting group had to be cleaved oxidatively with DDQ. S-20-22 S-23-25 oleic acid: arachidonic acid: docosahexaenoic acid: DDQ oxidative cleavage of DIMON to afford primary alcohols S-23-25: R = oleic acid, 92% yield; R = arachidonic acid, 65% yield; R = docosahexaenoic acid, 61% yield.

[00284] All three reactions proceeded well to afford the desired primary alcohols in 92% (oleyl), 65% (arachidonoyl), and 61% (docosahexaenoyl) yield. To confirm that the vinyl ether was undisturbed, and the acyl group had not migrated, the products were analysed by 1H NMR (Figure 19).

[00285] As no evidence of an aldehyde proton was present, we were confident the Z-vinyl ether had not been oxidatively cleaved. For compound S-23 the hydroxyl proton was assigned to the triplet at 1.78 ppm (1 H, J = 6.2 Hz) which was coupled to the doublet of doublets peak at 3.75 ppm (2 H, J = 6.1,4.7 Hz) assigned to the neighbouring methylene protons. Therefore, the product contained a primary alcohol and no acyl migration had occurred. The other two spectra had broad or hidden hydroxyl peaks. Therefore, to show that acyl migration had not occurred the resonance at 5.04 ppm for the CH at the chiral centre was analysed. Migration from the secondary to primary hydroxyl would shift this proton peak upfield to ~4 ppm, as seen with compound S-19 which possessed a secondary hydroxyl (Figure 16). As the observed peak was still downfield at ~5 ppm we were satisfied that no acyl migration had occurred. To re-iterate, DIMON had been successfully oxidatively cleaved without perturbation of the Z-vinyl ether or migration of the acyl chain. These results showed that our new methodologies were highly satisfactory for the synthesis of plasmalogens. Example 14b: Synthesis of (S)-1-(((Z)-hexadec-1-en-1-yl)oxy)-3-hydroxypropan-2-yl oleate

[00286] To a solution of (S)-1-((1,4-dimethoxynaphthalen-2-yl)methoxy)-3-(((Z)-hexadec-1-en-1-yl)oxy)propan-2-yl oleate (200 mg, 257 pmol) in 19:1 dichloromethane:water (2.6 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (58 mg, 257 pmol) portionwise. Upon addition, the reaction was stirred at rt for 0.5 h. The reaction was quenched by addition of L-ascorbic acid (45 mg, 257 pmol), diluted with water (30 mL), and extracted with dichloromethane (3 x 30 mL). The combined organics were dried over MgSO4, filtered, and evaporated in vacuo. The product was isolated by a short silica column, eluting with 93:7 petrokethyl acetate separated the 1,4-dimethoxy-2-naphthaldehyde by-product, eluting with 75:25 petrokethyl acetate afforded the desired (S)-1-(((Z)-hexadec-1-en-1-yl)oxy)-3-hydroxypropan-2-yl oleate (137 mg, 236 pmol, 92%) as a clear, colourless oik Rf 0.30 (85:15 petrokethyl acetate, UV / Vis); [a]D19 = -3.6 (c = 1.02 in CHCb); 1H NMR 6 h (300 MHz, CDCb) 5 5.90 (1 H, dt, J = 6.2, 1.5 Hz, CH=CHO), 5.42 - 5.26 (2 H, m, CH=CH), 5.03 (1 H, qd, J = 5.2, 4.2 Hz, CHOC=O), 4.38 (1 H, td, J = 7.3, 6.2 Hz, CH=CHO), 3.88 (2 H, d, J = 5.3 Hz, CHOCH2), 3.80 (2 H, dd, J = 4.7, 3.5 Hz, CH2OH), 2.34 (2 H, t, J = 7.3 Hz, CH2C=O), 2.10-1.94 (6 H, m, 3 x CH=CHCH2), 1.68 - 1.55 (2 H, m, CH2CH2C=O), 1.40-1.15 (48 H, m, 24 x CH2), 0.93-0.81 (6 H, m, 2 x CH3); 13C NMR 0 c (75 MHz, CDCb) 0 173.7 (C=O), 144.7 (CH=CHO), 130.1 (CH=CH), 129.8 (CH=CH), 108.4 (CH=CHO), 73.2 (CHOC=O), 70.3 (CHOCH2), 62.2 (CH2OH), 34.5 (CH2C=O), 32.1 (2 X CH2), 30.3 - 28.9 (19 x CH2), 27.3 (CH2CH=CHCH2), 25.1 (CH2), 24.0 (CH2CH=CHO), 22.8 (CH2), 14.3 (2 x CHs); IR Vmax I cm1 3467 br, 2922, 2853, 1739, 1665, 1465, 1377, 1261, 1097, 1047, 802, 722; HRMS (TOF MS AP+) calcd C37H70O4 [M+H]+ 579.5347, found 579.5347. Example 14c: Synthesis of (S)-1-(((Z)-hexadec-1-en-1-vl)oxv)-3-hvdroxypropan-2-vl (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate

[00287] To a solution of (5)-1-((1,4-dimethoxynaphthalen-2-yl)methoxy)-3-(((Z)-hexadec-1-en-1-yl)oxy)propan-2-yl (4Z,7Z,10Z, 13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate (220 mg, 267 pmol) in 19:1 dichloromethane:water (2.7 mL)was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (61 mg, 267 pmol) portionwise. Upon addition, the reaction was stirred at rt for 0.5 h. The reaction was quenched by addition of L-ascorbic acid (47 mg, 267 pmol), diluted with water (30 mL), and extracted with dichloromethane (3 x 30 mL). The combined organics were dried over MgSO4, filtered, and evaporated in vacuo. The product was isolated by a short silica column, eluting with 93:7 petrohethyl acetate separated the 1,4-dimethoxy-2-naphthaldehyde by-product, eluting with 75:25 petrokethyl acetate afforded the desired (S)-1-(((Z)-hexadec-1-en-1-yl)oxy)-3-hydroxypropan-2-yl (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate (100 mg, 160 pmol, 60%) as a clear, colourless oil: Rf 0.55 (80:20 petrokethyl acetate, UV / Vis); 1H NMR 6 h (300 MHz, CDCb) 6 5.90 (1 H, dt, J = 6.2, 1.5 Hz, CH=CHO), 5.50 - 5.23 (12 H, m, 6 x CH=CH), 5.04 (1 H, qd, J = 5.2, 4.2 Hz, CHOC=O), 4.38 (1 H, td, J = 7.3, 6.2 Hz, CH=CHO), 3.88 (2 H, d, J = 5.2 Hz, CH2OH), 3.80 (2 H, dd, J = 4.7, 4.0 Hz, CHOCH2), 2.92 - 2.73 (11 H, m, 5 x CHCH2CH, OH), 2.48 - 2.35 (4 H, m, CH2CH2C=O), 2.15-1.96 (4 H, m, CH2CH=CHO, CHCH2CH3), 1.25 (24 H, s, br, 12 x CH2), 0.97 (3 H, t, J = 7.5 Hz, CH3), 0.88 (3 H, t, J = 6.5 Hz, CHs); 13C NMR 6 c (75 MHz, CDCb) 6 172.9 (C=O), 144.7 (CH=CHO), 132.2 (CH=CH), 129.6 (CH=CH), 128.7 (CH=CH), 128.5 (CH=CH), 128.4 (2 x CH=CH), 128.2 (2 x CH=CH), 128.1 (CH=CH), 128.0 (CH=CH), 127.9 (CH=CH), 127.1 (CH=CH), 108.4 (CH=CHO), 73.4 (CHOC=O), 70.2 (CHOCH2), 62.1 (CH2OH), 34.3 (CH2C=O), 32.1 (CH2), 30.3 - 29.2 (10 x CH2), 25.8 - 25.5 (5 x CHCH2CH), 24.0 (CH2CH=CHO), 22.9 (CH2), 22.8 (CH2CH2C=O), 20.7 (CHCH2CH3), 14.4 (CH3), 14.2 (CH3); IR vmax I cm1 3457 br, 3013, 2922, 2852, 1738, 1664, 1460, 1371, 1154, 1105, 718; HRMS (FTMS +p NSI) calcd C41H68O4 [M+Na]+ 647.5010, found 647.5005. Example 15a - Synthesis of hexadecvl phosphorodichloridate 44

[00288] A simple, long chain alcohol (hexadecan-1-ol 43) was initially used to mimic the fatty glycerol environment: POCI3 O NEt3 p C15H31 OH ---------* C1sH3i O'i''CI 15 31 DCM, N2 Cl 0 °C to rt 43 20 h, 96% 44 Synthesis of hexadecyl phosphorodichloridate 44.

[00289] The reaction of hexadecan-1-ol 43 with POCb proceeded cleanly to afford hexadecyl phosphorodichloridate 44 in 96% yield. Example 16 - Synthesis of hexadecvl (2^trimethvlammonio)ethyl) phosphate 50

[00290] The reaction between an alcohol and COP under basic conditions gives a cyclic phosphate ester intermediate that can be isolated. This species can then be ring opened by NMe3 to give the phosphocholine functionality. Typically, anhydrous gaseous NMe3 is condensed from a cylinder into a sealed microwave vial. A large excess of the amine is used (~200 equivalents) and the reaction is refluxed for upto 24 hours. However, for the duration of this project a cylinder of NMe3 could not be readily purchased in the UK and was not available on site. Therefore, we opted for a 2 M solution of NMes in acetonitrile, anticipating that this would be sufficient to ring-open the phosphate ester and that a smaller equivalent of amine could be used. Again, the alcohol hexadecan-1-ol 43 was used as a model to test the chemistry: Ci5H3i^OH —- C15H31 C15H31 O ii 5: © Ynmg3 43                   49 50 Synthesis of hexadecyl (2-(trimethylammonio)ethyl) phosphate 50: a. COP, py., TFT, N2, 3 h, 100%; b. 2 M NMe3 in MeCN, N2, reflux, 72 h, 46%.

[00291] Hexadecan-1-ol 43 was reacted with COP to afford cyclic phosphate ester 49 in quantitative yield. The intermediate had a single proton-decoupled 31P NMR singlet peak at 17.6 ppm, whereas the COP peak appeared at 22.5 ppm, confirming that a new phosphorus containing compound had been synthesised. The product structure was confirmed by 1H NMR analysis: the hexadecan-1-ol hydroxyl peak at 1.20 ppm (1 H, triplet, J = 5.4 Hz) had disappeared, the neighbouring methylene peak at 3.64 ppm (2 H, triplet of doublets, J = 6.5, 5.2 Hz) had shifted downfield to 4.15 ppm (2 H, doublet of triplets, J = 8.8, 6.6 Hz) and a new multiplet at 4.39 ppm (4 H) was present due to the phosphate ester ethylene protons. The reaction with NMes was attempted three times: the first two attempts used 10 and 15 equivalents of the amine, respectively, and both failed to yield the desired phosphocholine 50. When 50 equivalents of NMes was used the product was successfully synthesised and isolated, in a moderate 46% yield. The phosphocholine had a single proton-decoupled 31P NMR singlet peak at 0.2 ppm. The 1H NMR spectrum contained a characteristic singlet at 3.42 ppm (9 H) for the trimethylamine protons, and the phosphate ethylene protons had split from one multiplet at 4.39 ppm (4 H) to two multiplets at 4.34 (2 H) and 3.82 ppm (2 H). Example 17 - Synthesis of 3-(hexadecvloxv)-2-(oleovloxv)propyl (2-(trimethvlammonio)ethyl) phosphate 53

[00292] 1-(hexadecyloxy)-3-hydroxypropan-2-yl oleate 51 was reacted in a similar manner: Synthesis of 3-(hexadecyloxy)-2-(oleoyloxy)propyl (2-(trimethylammonio)ethyl) phosphate 53: a. COP, py. TFT, N2, 0 °C to rt, 1.5 h, 100%; b.2M NMe3 in MeCN, TFT, N2, reflux, 16 h, 43%.

[00293] Both steps proceeded similarly to the model hexadecan-1-ol reaction, to afford 3-(hexadecyloxy)-2-(oleoyloxy)propyl (2-(trimethylammonio)ethyl) phosphate 53 in 43% yield. The proton-decoupled 31P NMR spectrum of compound 53 contained a singlet peak at -1.1 ppm. Given the similarity between the alkyl phospholipid and the oleyl plasmalogen, we anticipated that the plasmalogen 31P NMR peak would also appear between 0 and -2 ppm. Example 18 - Synthesis of (R)-3-(((Z)-hexadec-1-en-1-vhoxv>-2-(oleovloxv)propyl (2-(trimethvlammoniotethvl) phosphate R-56 S-23 oleic acid: Synthesis of (R)-3-(((Z)-hexadec-1-en-1-yl)oxy)-2-(oleoyloxy)propyl (2-(trimethylammonio)ethyl) phosphate R-56: a. COP, py. TFT, N2, 0 °C to rt, 1 h, 100%; b. 2 M NMe3 in MeCN, TFT, N2, reflux, 16 h, 5%.

[00294] Reaction of alcohol S-23 with COP proceeded in quantitative yield to afford cyclic phosphate ester R-54. Importantly, the vinyl ether was retained and there was no evidence of an aldehyde in the 1H NMR spectrum. The expected phosphate ethylene multiplet at 4.41 ppm (4 H) was present and all other peaks supported the desired structure. The intermediate had a proton-decoupled 31P NMR singlet peak at 17.6 ppm which agreed with the signal seen for compound 49. The intermediate was subjected to the ring opening reaction with NMes which afforded plasmalogen R-56 in a low 5% yield. The product was analysed by 1H and 31P NMR after purification by normal phase column chromatography (Figure 20).

[00295] Despite isolating a single compound by TLC analysis, the proton-decoupled 31P NMR spectrum contained two peaks at -3.5 and 15.0 ppm in a 3:1 ratio, respectively, which indicated two phosphorus compounds were present. The 1H NMR spectrum also suggested two compounds were present, the desired plasmalogen and an unknown compound. This was particularly noticeable in the region from 3.0 - 4.5 ppm, which was predicted to correspond to 18 protons: 9 from the trimethylamine, 4 from the phosphate ethylene, 4 from the glycerol backbone, and 1 from the vinyl ether. However, the peaks in this region integrated to 21, indicating that another compound was present. It was likely that the phosphate had been hydrolysed under the reaction conditions to afford alcohol S-23 and 2-(trimethylammonio)ethyl hydrogen phosphate 57: R-56 57

[00296] Proposed hydrolysis of plasmalogen R-56 to alcohol S-23 and phosphate 57.

[00297] If water was present in the reaction this would hydrolyse the phosphate. A 1H NMR spectrum of the NMea solution (2 M in acetonitrile) showed the characteristic water signal at 1.56 ppm, in an approximate 1:1 ratio with NMea. The 1H NMR spectrum of the crude reaction mixture was compared against the starting material and this showed alcohol S-23 was present. Therefore, we were convinced that the product had been hydrolysed and the resulting phosphate 57 had coeluted with the plasmalogen product during column chromatography. To overcome this, water must be completely removed from the reaction, which could be achieved by addition of molecular sieves. We were also dissatisfied with the yield of the ring-opening reaction using the NMes solution; even on the hexadecan-1-ol model reaction the yield was only 46%. We aspired to use condensed NMes gas to mirror the conditions shown in literature where 50 - 75% yields are achieved (D. H. Qin, H. S. Byun and R. Bittman, Synthesis of Plasmalogen via 2,3-Bis-O-(4‘-methoxybenzyl)-sn-glycerol, J. Am. Chem. Soc., 1999,121,662-668; J. Shin and D. H. Thompson, Direct Synthesis of Plasmenylcholine from Allyl-Substituted Glycerols, J. Org. Chern., 2003, 68, 6760-6766). To do this, we set-up a system that could generate NMes gas and condense it directly into our reaction vessel (Figure 21).

[00298] Under a flow of nitrogen, a 12 M aqueous solution of sodium hydroxide (NaOH) was added dropwise cautiously to a flask containing trimethylamine hydrochloride (NMes.HCI, ~40 mmol) to liberate NMea gas. The gaseous NMea was passed through two flasks containing NaOH and sodium hydride (NaH), respectively, to capture any water present in the system. The NMea gas then flowed through a sealed microwave vial via a syringe needle. The vial was cooled to -78 °C with dry ice which condensed the NMes in the reaction vessel. Any remaining gas flowed out of an exit needle into two Drechsel bottles, the second containing a 1 M aqueous solution of HCI to trap NMes as the hydrochloride salt. After collecting the liquid NMes, the two needles were removed from the reaction vessel to seal the amine in the vial. To add the cyclic phosphate ester, a balloon was inserted into the vessel to relieve any pressure while a solution of compound R-54 in 3:1 acetonitrile:trifluorotoluene was injected into the vial. After addition, the balloon was removed and the reaction was refluxed for 16 hours. To ensure no water was present, 3 A molecular sieves were added to the microwave vial: R-54 C14H29 NMe3 3:1 MeCN:TFT, N2 3A molecular sieves -78 °C to reflux 16 h, 20% R-56 Synthesis of (R)-3-(((Z)-hexadec-1-en-1-yl)oxy)-2-(oleoyloxy)propyl (2-(trimethylammonio)ethyl) phosphate R-56.

[00299] With this set-up, the yield was improved to 20%. However, the 1H NMR spectrum of the crude reaction mixture showed evidence of vinyl ether hydrolysis as an aldehyde peak was present at 9.74 ppm (triplet, J = 1.9 Hz). Furthermore, when the plasmalogen was isolated by column chromatography the same impurity was observed (compound 55). Again, the proton-decoupled 31P NMR spectrum showed a 3:1 ratio of plasmalogen:impurity with the same chemical shifts at -3.5 and 15.0 ppm. Vinyl ether hydrolysis requires acidic (or oxidative) conditions and molecular sieves are acidic enough to catalyse reactions (N. Asakura, T. Hirokane, H. Hoshida, H. Yamada, Molecular sieves 5A as an acidic reagent: the discovery and applications, Tetrahedron Lett., 2011,52, 534 -537). While the presence of H2O will result in hydrolysis, the rate of hydrolysis is slower without an acid catalyst. The reaction was repeated without molecular sieves, and the reaction vessel was oven-dried overnight to remove all H2O. This afforded plasmalogen R-56 in 55% yield, a significant improvement. Importantly, there was no evidence of vinyl ether hydrolysis in the crude 1H NMR. The plasmalogen was analysed by 1H, 31P, 1H-1H COSY, 1H-13C HMBC and 1H-13C HSQC NMR, as well as LCMS (Figure 22).

[00300] From the analysis we were confident that plasmalogen R-56 had been synthesised and isolated in a highly pure state. The 1H NMR region from 3.0 - 4.5 ppm contained 18 protons as expected, and the proton-decoupled 31P NMR spectrum contained a single sharp peak at -1.7 ppm. Therefore, the impurity was not present and had been completely avoided by using strict anhydrous conditions whilst ensuring no acidic sources were present. 2D NMR analysis enabled the identification of each proton (and carbon) in the molecule. Importantly, the Z-vinyl ether protons were still present at 5.90 (1 H, doublet of triplets, J= 6.2, 1.5 Hz) and 4.31 ppm (3 H, multiplet, CH=CHO, CH2OP=O) and there was no evidence of the E-vinyl ether protons. The molecular mass was confirmed by LCMS analysis, the observed m / z 744.55 peak agreed with the molecule’s mass: [M+H]+ 744.59 m / z. Furthermore, the 522.35 m / z fragment peak agreed with the species arising from hydrolysis of the vinyl ether: [M+H]+ 522.36 m / z. With this result, we had successfully found conditions to install the phosphocholine head group onto a plasmalogen precursor in an acceptable yield and without destroying the vinyl ether. Example 19 - Synthesis of (R)-3-(((Z)-hexadec-1-en-1-vDoxv)-2-(((5Z,8Z,11Z,14ZHcosa-5,8,11,14-tetraenovhoxv)propyl (2-(trimethvlammonio)ethvl) phosphate R-60 and (R)-2-(((4Z.7Z.10Z,13Z.16Z,19Z)-docosa-4,7,10,13,16,19-hexaenovl)oxv)-3-(((Z)-hexadec-1 -en-1 -vl)oxv)propyl (2-(trimethvlammonio)ethvl) phosphate R-61

[00301] Plasmalogen precursors S-24 and S-25 were reacted with COP and pyridine, and then ring-opened with NMes to afford two more plasmalogens: S-24,25 R-58, R-59 R-60, R-61 arachidonic acid: docosahexaenoic acid: Synthesis of (R)-3-(((Z)-hexadec-1 -en-1 -yl)oxy)-2-(((5Z,8Z, 11Z, 14Z)-icosa-5,8,11,14-tetraenoyl)oxy)propyl (2-(trimethylammonio)ethyl) phosphate R-60 and (R)-2- (((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyl)oxy)-3-(((Z)-hexadec-1-en-1-yl)oxy)propyl (2-(trimethylammonio)ethyl) phosphate R-61: a. COP, pyridine, TFT, N2, 0 °C to rt, 5 h, 100%; b. NMe3, 3:1 MeCN:TFT, N2, reflux, 16 h, 45% (arachidonoyl) 41% (docosahexaenoyl).

[00302] Reaction with COP and pyridine afforded both intermediates (R-58 and R-59) in quantitative yield. The proton-decoupled 31P NMR analysis showed both products had a single, singlet peak at 17.5 ppm which agreed with the signal seen for compound R-54. The 1H NMR spectra contained the phosphate ethylene multiplet peak at 4.41 ppm (4 H) and showed no evidence of vinyl ether hydrolysis. The intermediates were subjected to the NMes ring-opening reaction, which afforded plasmalogens R-60 and R-61 in 45% and 41% yield, respectively. Plasmalogen R-60 was analysed to confirm its structure and purity (Figure 23).

[00303] The 1D and 2D NMR spectra of plasmalogen R-60 agreed with the desired structure. However, the same impurity (compound 57) was present as shown by the 31P NMR spectrum which showed the plasmalogen peak at -2.3 ppm and impurity peak at 15.3 ppm. The plasmalogen:impurity ratio was 10:1 indicating >90% purity for the plasmalogen. This result was attributed to the reaction vessel being insufficiently dried and showed the importance of stringent anhydrous operation. Plasmalogen R-61 was also analysed to confirm its structure and purity (Figure 24).

[00304] The 1H and 31P NMR spectra of plasmalogen R-61 did not contain any impurity peaks. The 31P NMR peak at -1.9 ppm was in good agreement with the other plasmalogen phosphate signals. The 1H NMR agreed with the desired structure and there was no evidence of vinyl ether hydrolysis with the expected 99:1 Z:E ratio. The observed LCMS ion at 790.71 m / z agreed with the molecular mass for the protonated adduct: [M+H]+ 790.57 m / z. To the best of our knowledge, this was the first time that plasmalogens R-56, R-60 or R-61 had been synthesised. Example 20: Synthesis of (R)-3-(((Z)-hexadec-1-en-1-vl)oxv)-2-(oleovloxv)propyl (2-(trimethvlammonio)ethyl) phosphate (Z) 9' xO. ©

[00305] To an oven-dried flask, purged with nitrogen via Schlenk technique, was added a solution of (S)-1-(((Z)-hexadec-1-en-1-yl)oxy)-3-hydroxypropan-2-yl oleate (135 mg, 233 pmol) in trifluorotoluene (4 mL). The solution was cooled to 0 °C and pyridine (38 pL, 466 pmol) and 2-chloro-1,3,2-dioxaphospholane 2-oxide (21 pL, 233 pmol) were added dropwise sequentially. Upon addition, the reaction was warmed to rt and stirred for 3 h. The solution was vacuum filtered through a pad of Celite® and the filtrate was evaporated and dried under high vacuum for 1 h to afford the intermediate (R)-1-(((Z)-hexadec-1-en-1-yl)oxy)-3-((2-oxido-1,3,2-dioxaphospholan-2-yl)oxy)propan-2-yl oleate (160 mg, 233 pmol, 100%) as a white solid. Following this, freshly distilled trimethylamine (~4 mL, 44 mmol) was added to a sealed, oven-dried, microwave vial cooled to -78 °C and under nitrogen. To the vessel was added a solution of (R)-1-(((Z)-hexadec-1-en-1-yl)oxy)-3-((2-oxido-1,3,2-dioxaphospholan-2-yl)oxy)propan-2-yl oleate (160 mg, 233 pmol) in 3:1 acetonitrile:trifluorotoluene (8 mL) with a nitrogen balloon inserted to relieve the internal pressure. Upon addition, the balloon was removed, and the reaction mixture was heated to reflux and stirred for 16 h. The mixture was cooled to rt and the vessel pressure was released cautiously. The solvent was evaporated in vacuo. Purification by silica chromatography, eluting with dichloromethane:methanol:water 70:30:0 to 70:30:4 afforded (R)-3-(((Z)-hexadec-1-en-1-yl)oxy)-2-(oleoyloxy)propyl (2-(trimethylammonio)ethyl) phosphate (92 mg, 124 pmol, 53%) as a white solid: Rf 0.40 (70:30:4 dichloromethane:methanol:water, permanganate stain); [q]d19 = -2.0 (c = 1.01, CHCh); 1H NMR 6 h (300 MHz, CDCh) 5 5.90 (1 H, dt, J = 6.2, 1.5 Hz, CH=CHO), 5.36 - 5.30 (2 H, m, CH=CH), 5.20 - 5.06 (1 H, m, CHOC=O), 4.37 - 4.24 (3 H, m, CH=CHO, CH2CH2OP=O), 3.99 - 3.77 (6 H, m, CHOCH:, CHCH2OP=O, CH2N(CH3)3), 3.36 (9 H, s, N(CH3)3), 2.29 (2 H, t, J= 7.6 Hz, CH2C=O), 2.06 - 1.94 (6 H, m, CH2CH=CHCH2, CH2CH=CHO), 1.56 (2 H, p, J = 7.3 Hz, CH2CH2C=O), 1.37 - 1.23 (44 H, m, 22 x CH2), 0.87 (6 H, t, J = 6.4 Hz, 2 x CH3); 13C NMR 6 c (176 MHz, CDCh) 6 173.4 (C=O), 145.0 (CH=CHO), 130.1 (CH=CH), 129.8 (CH=CH), 107.7 (CH=CHO), 72.0 (CHOC=O), 70.7 (CHOCH2), 66.5 (CH2N(CH3)3), 63.5 (CHCH2OP=O), 59.5 (CH2CH2OP=O), 54.6 (N(CH3)3), 34.6 (CH2C=O), 32.1 (2 x CH2), 30.5-28.8 (18 x CH2), 27.4 (CH2CH=CHCH2), 25.1 (CH2CH2C=O), 24.1 (CH2CH=CHO), 22.8 (2 x CH2), 14.3 (2 x CH3); 31P NMR 6 p (121 MHz, CDCh) -1.7; IR Vmax / cm 1 3370 br, 2958, 2921,2852, 1731, 1664, 1466, 1378, 1259, 1088, 1060, 969, 801; LCMS rt = 0.57 min, 100%, m / z 744.55 [M+H]+; HRMS (TOF MS AP+) calcd C42H82NO7P [M+H]+ 744.5902, found 744.5911. Example 21: Synthesis of ( / ?)-2-(((4Z,7Z,10Z,13Z,16Z.19Z)-docosa-4.7.10.13.16.19-hexaenovl)oxv)-3-(((Z)-hexadec-1-en-1-vl)oxv)propyl (2-(trimethvlammonio)ethyl) phosphate (Z) / O's. .R NMes

[00306] To an oven-dried flask, purged with nitrogen via Schlenk technique, was added a solution of (S)-1-(((Z)-hexadec-1-en-1-yl)oxy)-3-hydroxypropan-2-yl oleate (135 mg, 233 pmol) in trifluorotoluene (4 mL). The solution was cooled to 0 °C and pyridine (38 pL, 466 pmol) and 2-chloro-1,3,2-dioxaphospholane 2-oxide (21 pL, 233 pmol) were added dropwise sequentially. Upon addition, the reaction was warmed to rt and stirred for 3 h. The solution was vacuum filtered through a pad of Celite® and the filtrate was evaporated and dried under high vacuum for 1 h to afford the intermediate (R)-1-(((Z)-hexadec-1-en-1-yl)oxy)-3-((2-oxido-1,3,2-dioxaphospholan-2-yl)oxy)propan-2-yl oleate (160 mg, 233 pmol, 100%) as a white solid. Following this, freshly distilled trimethylamine (~4 mL, 44 mmol) was added to a sealed, oven-dried, microwave vial cooled to -78 °C and under nitrogen. To the vessel was added a solution of (R)-1-(((Z)-hexadec-1-en-1-yl)oxy)-3-((2-oxido-1,3,2-dioxaphospholan-2-yl)oxy)propan-2-yl oleate (160 mg, 233 pmol) in 3:1 acetonitrile:trifluorotoluene (8 mL) with a nitrogen balloon inserted to relieve the internal pressure. Upon addition, the balloon was removed, and the reaction mixture was heated to reflux and stirred for 16 h. The mixture was cooled to rt and the vessel pressure was released cautiously. The solvent was evaporated in vacuo. Purification by silica chromatography, eluting with dichloromethane:methanol:water 70:30:0 to 70:30:4 afforded (R)-3-(((Z)-hexadec-1-en-1-yl)oxy)-2-(oleoyloxy)propyl (2-(trimethylammonio)ethyl) phosphate (92 mg, 124 pmol, 53%) as a white solid: Rf 0.45 (70:30:4 dichloromethane:methanol:water, permanganate stain); [q]d19 = -3.1 (c = 1.04, CHCb); 1H NMR 6 h (300 MHz, CDCb) 5 5.90 (1 H, d, J = 6.3 Hz, CH=CHO), 5.47 - 5.25 (12 H, m, 6 x CH=CH), 5.16 (1 H, s, CHOC=O), 4.41 - 4.27 (3 H, m, CH=CHO, CH2CH2OP=O), 4.02 - 3.76 (6 H, m, CHOCH2, CHCH2OP=O, CH2N(CH3)3), 3.35 (9 H, s, N(CH3)3), 2.88-2.77 (10 H, m, 5 x CHCH2CH), 2.41 -2.34 (4 H, m, CH2CH2C=O), 2.04 (4 H, m, CH2CH=CHO, CHCH2CH3), 1.35-1.21 (24 H, s, br, 12 x CH2), 0.97 (3 H, t, J= 7.5 Hz, CH3), 0.87 (2 H, t, J= 6.5 Hz, CH3); 13C NMR 5 c (75 MHz, CDCb) 6 172.7 (C=O), 145.0 (CH=CHO), 132.1 (CH=CH), 129.4 (2 x CH=CH), 128.7 (2 x CH=CH), 128.4 (2 x CH=CH), 128.2 (2 x CH=CH), 128.0 (2 x CH=CH), 127.1 (CH=CH), 107.7 (CH=CHO), 72.2 (CHOC=O), 70.6 (CHOCH2), 66.5 (CH2N(CH3)3), 63.5 (CHCH2OP=O), 59.5 (CH2CH2OP=O), 54.5 (N(CH3)3), 34.3 (CH2C=O), 32.0 (CH2), 30.0 - 29.7 (8 x CH2), 29.5 (2 x CH2), 25.7 (5 x CHCH2CH), 24.1 (CH2CH=CHO), 22.8 (CH2, CH2CH2C=O), 20.7 (CHCH2CH3), 14.4 (CH3), 14.2 (CH3); 31P NMR 6 p (121 MHz, CDCb) -1.9; IR 3349 br, 3014, 2922, 2853, 1733, 1663, 1466, 1377, 1237, 1152, 1090, 1051,968, 926, 714; LCMS rt = 3.55 min, 100%, m / z 790.71 [M+H]+; HRMS (TOF MS AP+) calcd C46H80NO7P [M+H]+ 790.5745, found 790.5751.

Claims

1. A use of a compound of formula Y:(Y), to form a protected nucleophile,wherein a single substituent selected from R1-R4 is -CH2-LG or -CH2-OH, wherein LG is leaving group;at least one substituent selected from R1-R4 is selected from -O-(CH2CH2O)n-Ci-2-alkyl, and -Ci-2-alkyl;the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-(CH2CH2O)n-Ci-2-alkyl and -Ci-2-alkyl; andn is independently at each occurrence an integer selected from 0,1,2,3,4 and 5.

2. The use of claim 1, wherein at least one substituent selected from R1-R4 is -O-Ci-2-alkyl; and the rest of the R^R4 substituents are independently at each occurrence selected from H and -O-Ci-2-alkyl.

3. The use of claim 2, wherein at least one -O-Ci-2-alkyl is -OMe.

4. The use of claim 2 or claim 3, wherein each -O-Ci-2-alkyl is -OMe.

5. The use of any preceding claim, wherein two substituents selected from R1-R4 are -O-C1.2-alkyl and one substituent selected from R1-R4is H.

6. The use of any preceding claim, wherein R1 is -O-Ci-2-alkyl.

7. The use of any preceding claim, wherein R2 is -CH2-LG or -CH2-OH.

8. The use of any preceding claim, wherein R3 is H.

9. The use of any preceding claim, wherein R4 is -O-Ci-2-alkyl.

10. The use of any preceding claim, wherein LG is halo, optionally wherein LG is Cl.

11. The use of claim 1, wherein the compound of formula Y is:

12. The use of any preceding claim, wherein the protected nucleophile is a protected alcohol.

13. The use of any one of claims 1 to 12, wherein the protected nucleophile is an intermediate in the synthesis of a plasmalogen.

14. A method of forming a protected nucleophile the method comprising:a) reacting a compound of Formula Y as defined in any one of claims 1 -11, wherein a single substituent is selected from R1-R4is -CH2-LG, with a nucleophile; orb) reacting a compound of Formula Y as defined in any one of claims 1 - 11, wherein a single substituent is selected from R1-R4is -CH2-OH, with an electrophile,to form a protected nucleophile of formula Z:wherein a single substituent selected from R1-R4 is -CH2-NU;at least one substituent selected from R1-R4 is selected from -O-(CH2CH2O)n-Ci-2-alkyl, and -Ci-2-alkyl;the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-(CH2CH2O)n-Ci-2-alkyl and -Ci-2-alkyl;n is independently at each occurrence an integer selected from 0,1,2,3,4 and 5; andNu is a residue of a nucleophile.

15. The method of claim 14, wherein the protected nucleophile is a protected O-nucleophile, optionally wherein the protected O-nucleophile is a protected aliphatic alcohol.

16. The method of claim 15, wherein -CH2-NU is OPG1 and / orOPG1 , wherein PG1 is a protecting group, optionally wherein PG1 is a silyl protecting group.

17. The method of claim 15 or claim 16, wherein option a) is carried out in a polar solvent, optionally wherein the polar solvent comprises DMF, THF, 2-MeTHF, DMC or mixtures thereof; or wherein option b) is carried out in a non-polar solvent, optionally wherein the non-polar solvent is toluene.

18. The method of any one of claims 15 or claim 17, wherein option a) is carried out in the presence of a base, optionally wherein the base is NaH or LiO'Bu; or wherein option b) is carried out in the presence of a Lewis acid, optionally wherein the Lewis acid is boron trifluoride.

19. The method of any one of claims 15 to 18, wherein the reaction is carried out in an anhydrous, inert atmosphere.

20. A method of deprotecting a protected nucleophile of formula Z:wherein a single substituent selected from R1-R4 is -CH2-Nu;at least one substituent selected from R1-R4 is selected from -O-(CH2CH2O)n-Ci-2-alkyl, and -Ci-2-alkyl;the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-(CH2CH2O)n-Ci-2-alkyl and -Ci-2-alkyl;n is independently at each occurrence an integer selected from 0,1,2,3,4 and 5; andNu is a residue of a nucleophile,the method comprising treating the protected nucleophile with an acid, an oxidant or a reductant to form NuH.

21. The method of claim 20, wherein the nucleophile is an O-nucleophile, optionally wherein the O-nucleophile is an aliphatic alcohol.

22. The method of claim 21, wherein -CH2-NU is 0 and / or0 , wherein R5 is a fatty acid residue; and R6 is an Ce-22-a Iky I or C=22-alkenyl.

23. The method of any one of claims 20 to 22, wherein the method comprises treating the protected nucleophile with an oxidant, optionally wherein the oxidant is DDQ.

24. A method for synthesising a compound of formula IVa and / or IVb:the method comprising reacting a compound of formula Illa or lllb:o owith R9OH in the presence of a Lewis acid and a solvent,wherein R7 is selected from the group consisting of: Ci-28-alkyl and C2-28-alkenyl;R8 is a silyl protecting group; andR9 is an organic group.

25. The method of claim 24, wherein the Lewis acid is boron trifluoride or a lanthanide triflate, optionally wherein the lanthanide triflate is Yb(Otf)s.

26. The method of claim 24 or claim 25, wherein the Lewis acid is boron trifluoride.

27. The method of any one of claims 24 to 26, wherein the ratio of the compound of formulaIlla or lllb : Lewis acid is from 1 : 0.01 to 1 : 0.50.

28. The method of any one of claims 24 to 27, wherein the ratio of the compound of formula Illa or lllb : R3OH is from 1 : 2 to 1 : 4.

29. The method of any one of claims 24 to 28, wherein the solvent is a non-polar solvent.

30. The method of any one of claims 24 to 29, wherein the method comprises adding a solutioncomprising the compound of formula Illa or lllb to a solution comprising R9OH and the Lewis acid.

31. The method of any one of claims 24 to 30, wherein the compound of formula Illa or lllb is produced by reacting a compound of formula II:with an epoxidation reagent, optionally wherein the epoxidation reagent is mCPBA.

32. The method of claim 31, wherein the compound of formula II is produced by reacting a compound of formula I:with a reducing agent, optionally wherein the reducing agent is DIBAL-H.

33. A method for synthesising a compound of Formula V:the method comprising reacting a compound of Formula IVa or IVb:R8HO ir 'OR9H r7(IVa) or f' (IVb), with a base in a non-polar solvent,wherein R7 is selected from the group consisting of: Ci-28-alkyl and C2-28-alkenyl;R8 is a silyl protecting group; andR9 is an organic group.

34. The method of claim 33, wherein the base is selected from the group consisting of: a metal hydride or metal alkoxide base, optionally potassium hydride or potassium alkoxide, e.g. potassium tert-butoxide.

35. The method of claim 33 or 34, wherein the non-polar solvent has an Et(30) value of 40 or less, optionally wherein the solvent is trifluorotoluene.

36. The method of any one of claims 33 to 35, wherein the reaction is heated, optionallywherein the reaction is heated to 35°C or more.

37. The method of any of claims 33 to 36, wherein the compound of formula IVa and / or Ivb is produced by the method of any one of claims 24 to 32.

38. The method of any one of claims 24 to 37, wherein R7 is a Ce 22-aIkyI or Ce 22 alkenyl.

39. The method of any one of claims 24 to 38, wherein R8 is trimethylsilyl.

40. The method of any one of claims 24 to 39, wherein R9 has a molecular mass below 1000gmol'1.

41. The method of any one of claims 24 to 40, wherein R9 is the organic portion of a benzylic, primary, or secondary alcohol, optionally wherein R9 is the organic portion of a primary aliphatic alcohol.

42. The method of claim 41, wherein, when R9 is a cyclic secondary alcohol, the beta carbon atoms of the cyclic secondary alcohol exclude an alkyl group substituent that is branched at the point of attachment to the beta carbon atom of the cyclic secondary alcohol; optionally wherein the beta carbon atoms of the cyclic secondary alcohol include a substituent selected from the group consisting of: H, -CH3 and -CH2CH3.

43. A method of forming a protected glycerol of formula XIII:wherein a single substituent selected from R1-R4 is OH and / orY^O^^^OPG2OH ;at least one substituent selected from R1-R4 is selected from -O-(CH2CH2O)n-Ci 2-alkyl, and -Ci-2-alkyl;the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-(CH2CH2O)n-Ci-2-alkyl and -Ci-2-alkyl; andn is independently at each occurrence an integer selected from 0,1,2,3,4 and 5,the method comprising reacting a compound of formula XI:R1wherein a single substituent selected from R1-R4 is -CH2OH;at least one substituent selected from R1-R4 is selected from -O-(CH2CH2O)n-Ci-2-alkyl, and -Ci-2-alkyl;the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-(CH2CH2O)n-Cv2-alkyl and -Ci-2-alkyl; andn is independently at each occurrence an integer selected from 0,1,2,3,4 and 5,with an epoxide of formula Xlla and / or Xllb:0 (Xlla); 0 (Xllb),wherein PG2 is a protecting group, optionally wherein PG2 is a silyl protecting group,to form the compound of formula XIII,44. The method of claim 43 further comprising protecting the compound of formula XIII to yield a compound of formula XIV:wherein a single substituent selected from R'-R4 isO^^^OPG2OPG1 and / orOPG1at least one substituent selected from R1-R4 is selected from -O-(CH2CH2O)n-Ci-2-alkyl, and -Ci-2-alkyl;the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-(CH2CH2O)n-Ci-2-alkyl and -Ci-2-alkyl;n is independently at each occurrence an integer selected from 0,1,2,3,4 and 5; andPG1 is a protecting group, optionally wherein PG1 is a silyl protecting group.

45. The method of claim 44, further comprising deprotecting the compound of formula XIV toyield a primary aliphatic alcohol of formula Z:(Z),X^O'^Y^OH wherein a single substituent selected from R'-R4 is OPG1 and / orOPG1at least one substituent selected from R1-R4 is selected from -O-(CH2CH2O)n-Ci-2-alkyl, and -Ci-2-alkyl;the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-(CH2CH2O)n-Ci.2-alkyl and -Ci-2-alkyl; andn is independently at each occurrence an integer selected from 0,1,2,3,4 and 5.

46. The method of any one of claims 24 to 39, wherein R9 is the organic portion of a primaryaliphatic alcohol of formula Z:(Z),wherein a single substituent selected from R'-R4 isand / orOPG1at least one substituent selected from R1-R4 is selected from -O-(CH2CH2O)n-Ci-2-alkyl, and -Ci-2-alkyl;the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-(CH2CH2O)n-Ci-2-alkyl and -Ci-2-alkyl;n is independently at each occurrence an integer selected from 0,1,2,3,4 and 5; andPG1 is a protecting group, optionally wherein PG1 is a silyl protecting group.

47. The method of claim 46, wherein the primary aliphatic alcohol of formula Z is made according to the method of claim 45.

48. The method of claim 46 or claim 47, further comprising any one of steps (A) to (D):(A) deprotecting the compound of formula V to yield a compound of formula VIat least one substituent selected from R1-R4 is selected from -O-(CH2CH2O)n-Ci-2-alkyl, and -Ci-2-alkyl;the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-(CH2CH2O)n-Ci 2-alkyl and -Ci-2-alkyl;n is independently at each occurrence an integer selected from 0,1,2,3,4 and 5; andR7 is selected from the group consisting of: Ce-22-alkyl and Ge-22 alkenyl; and / or(B) acylating the compound of formula VI to provide a compound of formula VII:the at least one substituent selected from R1-R4 is selected from -O-(CH2CH2O)n-Ci~2-alkyl, and -Ci-2-alkyl;the rest of the R1-R4 substituents are independently at each occurrence selected from H, -O-(CH2CH2O)n-Ci-2-alkyl and -Ci-2-alkyl;n is independently at each occurrence an integer selected from 0,1,2,3,4 and 5;R7 is selected from the group consisting of: Ce-22-alkyl and Ce-22 alkenyl; andR5 is a fatty acid residue; and / or(C) deprotecting the compound of formula VII to yield a compound of formula Villa and / or Vlllb:wherein R7 is selected from the group consisting of: Ce 22-a Iky I and Ce 22 alkenyl; andR5 is a fatty acid residue; and / or(D) phosphorylating the compound of formula VIII to yield a plasmalogen of formula Xa and / or Xb:and / orR5 is a fatty acid residue;R7 is selected from the group consisting of: Ce-22-alkyl and C6-22 alkenyl; andeach R10 is selected from the group consisting of: H and C1-12 alkyl; or one R10 is selected from the group consisting of: H and C1-12 alkyl, and two R10, together with the N-atom to which they are bonded form a 5-6 membered heterocyclic ring.49.The method of claim 48, wherein each R10 is H or each R10 is Me.Application No: GB2312210.4Examiner:Dr S. David EvansClaims searched: 1-23, 43-45Date of search: 5 February 2025Patents Act 1977: Search Report under Section 17Documents considered to be relevant:Category Relevant to claims Identity of document and passage or figure of particular relevance X 1-9, 11, 12, 14, 15, 17-21 Journal of Organic Chemistry, Vol. 72(24), 2007, (Kostikov, Alexey P.; Popik, Vladimir V.), pages 9190-9194, ISSN: 0022-3263, DOI: 10.1021 / jo701426j. See Chern. Abs. Acc. No. 2007:1215546 and the whole paper, but especially the conversion of compounds 12 to 13a,b in Scheme 5a at page 9192. X 1-9, 11, 12, 14, 15, 17-21 WO 01 / 04130 Al (PURDUE RESEARCH FOUNDATION et al) See Chern. Abs. Acc. No. 2001:50656 and the entire document, but particularly the conversion of compounds 23a to 25a and compounds 23b to 25b at pages 22 and 30. X 1-9,11, 12, 14, 15, 17-21 WO 01 / 74827 Al (PURDUE RESEARCH FOUNDATION) See Chern. Abs. Acc. No. 2001:747799 and the whole document, but in particular, the reaction schemes shown at pages 22 and 29. X 1-9, 11, 12, 14, 15, 17-21 Journal of Medicinal Chemistry, Vol. 44(25), 2001, (Tobias, Sandra C.; Borch, Richard F.), pages 4475-4480, ISSN: 0022-2623, DOI: 10.1021 / jm010337r. See Chern. Abs. Acc. No. 2001:795459 and the entire article, but especially the preparation of compounds lb and 2b from 1,4-dimethoxy-2-hydroxymethylnaphthalene at pages 4478-4479. X 1-9,11, 12, 14, 15, 17-21 Journal of Medicinal Chemistry, Vol. 43(16), 2000, (Flader, Carolee; Liu, Jiwen; Borch, Richard F.), pages 3157-3167, ISSN: 0022-2623, DOI: 10.1021 / jm000179o. See Chem. Abs. Acc. No. 2000:481806 and the whole article, but especially the conversion of compounds Ila and 11b into 12 and 13a-c,d in Scheme 2a at page 3158.Categories: X Document indicating lack of novelty or inventive step A Document indicating technological background and / or state of the art. Y Document indicating lack of inventive step if combined with one or more other documents of same category. P Document published on or after the declared priority date but before the filing date of this invention. & Member of the same patent family E Patent document published on or after, but with priority date earlier than, the filing date of this application.Field of Search:International Classification:Subclass Subgroup Valid From C07C 0041 / 09 01 / 01 / 2006 C07B 0051 / 00 01 / 01 / 2006 C07C 0029 / 124 01 / 01 / 2006 C07C 0033 / 34 01 / 01 / 2006 C07C 0041 / 18 01 / 01 / 2006 C07C 0041 / 22 01 / 01 / 2006 C07C 0043 / 164 01 / 01 / 2006 C07C 0043 / 166 01 / 01 / 2006 C07C 0043 / 205 01 / 01 / 2006 C07C 0045 / 37 01 / 01 / 2006 C07C 0047 / 546 01 / 01 / 2006 C07C 0067 / 03 01 / 01 / 2006 C07C 0067 / 26 01 / 01 / 2006 C07C 0069 / 157 01 / 01 / 2006 C07C 0069 / 708 01 / 01 / 2006 C07C 0069 / 732 01 / 01 / 2006 C07C 0213 / 00 01 / 01 / 2006 C07C 0217 / 54 01 / 01 / 2006 C07D 0301 / 00 01 / 01 / 2006 C07D 0303 / 18 01 / 01 / 2006 C07F 0007 / 08 01 / 01 / 2006 C07F 0009 / 09 01 / 01 / 2006 C07F 0009 / 146 01 / 01 / 2006 C07J 0009 / 00 01 / 01 / 2006

Images