THEREOF

FIELD OF INVENTION

[0001] The present disclosure relates to certain cyclic bi-functional materials that are useful as monomers in polymer synthesis, as well as intermediate chemical compounds. In particular, the present invention pertains to halogenated furanic molecules, particular methods by which such molecules are prepared, and certain derivative compounds or materials that incorporate these molecules.

BACKGROUND

[0002] In recent years, researchers have devoted effort to find ways to employ biomass as feedstock for the production of organic chemicals because of its abundance, renewability, and worldwide distribution. Biomass contains carbohydrates or sugars (i.e., hexoses and pentoses) that can be converted into value added products. Organic compounds that are readily derived from sugars include furans, robust cyclic ethers that possess structural features that can be useful for making certain polymers, pharmaceuticals, or solvents, among other industrial constituents. A related compound that has received considerable attention of late is 5-(hydroxymethyl)furfural (HMF), a major dehydration product of fructose, an abundant, inexpensive monosaccharide (Scheme A).

Scheme A. HMF synthesis from acid-catalyzed dehydration of fructose

A B

[0003] HMF is a versatile chemical antecedent to various furanic ring-based derivatives that are known intermediates for various chemical syntheses, and are plausible surrogates for aromatic hydrocarbons that derive from petroleum resources. Due to the diverse functionalities of HMF, some have proposed that HMF be used to produce a wide range of commodities such as polymers, solvents, surfactants, pharmaceuticals, and plant protection agents. As substitutes, derivatives of HMF are comparable to benzene -based aromatic compounds or to other compounds containing a furan or tetrahydrofuran (THF). HMF and 2,5-disubstituted furans and THF analogs, therefore, have great potential in the field of intermediate chemicals from renewable agricultural resources.

[0004] HMF itself, however, is rather unstable and tends to polymerize or decompose under thermo- oxidative conditions with prolonged storage at ambient conditions. Thus, one should look to derivatives of HMF for practical commercial utility. Two derivatives of interest are: furan-2,5- dimethanol (abbreviated as FDM) and 2,5-bis-(hydroxymethyl)-tetrahydrofuran (abbreviated as bHMTHF), also known colloquially as THF-diols, presented in Scheme B.

Scheme B. Chemical structures of FDM and cis, trans isomers of bHMTHF

Furan-2,5-dimethanol (FDM) cis, trans 2,5-bis-(hydroxymethyl)tetrahydrofuran (bHMTHF)

[0005] These cyclic bifunctional molecules have potential to be chemical feedstock or platforms from which various derivative compounds can be synthesized. These chemical entities can serve as valuable glycolic antecedents for the preparation of polymers, solvents, additives, lubricants, and plasticizers, etc. Furthermore, the inherent, immutable chirality of bHMTHFs makes these

compounds useful as potential species for pharmaceutical applications or candidates in the emerging chiral auxiliary field of asymmetric organic synthesis.

[0006] Conventional preparation of halogenated furanic compounds have involved rather complex and exotic conditions. For instance, Peng et al. used 1,5-hexadiene and iodine as starting materials in preparing 2,5 -bis(iodomethyl)-tetrahydrofuran through a nickel-mediate stereocontrolled synthesis (Peng, Yu; Xu, Xiao-Bo; Xiao, Jian; Wang, Ya-Wen, "Nickel-mediated stereocontrolled synthesis of spiroketals via tandem cyclization-coupling of β-bromo ketals and aryl iodides," Chemical

Communications (Cambridge, United Kingdom) (2014), 50(4), pp. 472-474.) Others have used a rather harsh protocol involving reacting bHMTHF with thionyl chloride, a highly toxic and corrosive reagent, and pyridine under high temperatures to make 2,5-bis(chloromethyl)-tetrahydrofuran. (E.g., Cope, Arthur C, Anderson, Burton C, Journal of the American Chemical Society (1955), 77, pp. 995-8; Wiggins, L. F., Wood, D. J. C, Journal of the Chemical Society (1950), pp. 1566-75; Cope, Arthur C, Baxter, Warren N., Journal of the American Chemical Society (1955), 77, pp. 393-6; U.S. Patent No. 6,027355 (Mano et al)) These processes tend to be limited in their production and none of these reactions describe a way of making mono- or bis-(halomethyl)-tetrahydrofuran directly from sugar derived compounds according to a mild, non-toxic protocol. Given the potential uses, a cost efficient and simple process that can make bHMTHFs more accessible and easily manipulated for preparation of derivative would be appreciated by manufacturers of both industrial and specialty chemicals alike as a way to better utilize biomass-derived carbon resources.

SUMMARY OF THE INVENTION

[0007] The present disclosure relates in part to a method for making an alkyl halide, exemplified by brominated furanic molecules, from 2,5-bis-(hydroxymethyl)-tetrahydrofuran (bHMTHF) according to mild and non-toxic protocols. The method involves contacting 2,5-bis-(hydroxymethyl)- tetrahydrofuran (bHMTHF) with a triphenylphosphine and tetrahalomethanes (CC , CBr4, CI4) at a temperature and for a time sufficient to convert the bHMTHF to corresponding mono or 2,5- bis(halomethyl)tetrahydrofurans (HMT). The temperature is in a range from about 0°C to about 50°C, and the duration is at least 4 hours.

[0008] In another aspect, the present disclosure pertains to the halomethyl-tetrahydrofuran compounds made from the synthesis described herein. In particular, the mono or di-alkyl halide furanic compounds have a general structure:

,0

p - ^""

._ x

wherein R is either -OH, CI, Br, or I, and X is CI, Br, or I when the furanic compound has a trans configuration, and that when both R and X are either CI or I then the furanic compound is not in a cis configuration, and X is Br when the furanic compound has a cis configuration.

[0009] In yet another aspect, the present disclosure describes a process for making a derivative compound. The process includes contacting either mono- or bis(halomethyl-tetrahydrofurans with a regent that a) displaces nucleophilically, b) eliminates, or c) substitutes at least an alcohol moiety or a halide moiety of the mono- or bis(halomethyl)-tetrahydrofurans under conditions sufficient to produce a derivative compound. In particular, the mono- or bis(halomethyl)-tetrahydrofurans are subjected to a reaction that involves at least: C-nucleophile displacement, N-nucleophile displacement, O- nucleophile displacement, S-nucleophile displacement, dimerization, esterification, etherification, epimerization, fluorination, Gilman's reaction, Grinard reaction, and oxidation.

[0010] Additional features and advantages of the present synthesis process and material compounds will be disclosed in the following detailed description. It is understood that both the foregoing summary and the following detailed description and examples are merely representative of the invention, and are intended to provide an overview for understanding the invention as claimed.

BRIEF DESCRIPTION OF FIGURES

[0011] FIG. 1, is a generic schematic of the present method for preparing a mono or di-alkyl furnaic compound under Appel reaction conditions.

[0012] FIG. 2, is a schematic illustrating the mechanism according to the Appel reaction.

[0013] FIG. 3, is a schematic representing a particular reaction according to an embodiment of the present process for preparing 2,5-bis(bromomethyl)tetrahydrofurans (BMT) diastereomers from bHMTHF diastereomers.

[0014] FIG. 4, is a general schematic that illustrates various synthesis pathways to make derivative compounds, such as thioethers, amines, halides, alkyl/aryl chain extensions, by nucleophilic displacement reactions, for example, from 2,5-bis(bromomethyl)tetrahydrofurans (BMT)

diastereomers. [0015] FIG. 5, is a general schematic that illustrates alternate synthesis pathways in which an alcohol moiety of a tetrahydrofluranic mono-halide (prepared according to the present disclosure) reacts while preserving the halogenated moiety.

[0016] FIG. 6, is a general schematic that illustrates other synthesis pathways in which a halide moiety of a tetrahydrofluranic mono-halide reacts while the alcohol moiety remains.

[0017] FIG. 7, is a gas chromatogram of a product mixture prepared according to an embodiment of the present invention.

[0018] FIG. 8, is a mass spectrum of the brominated furanic compound as eluted in Fig. 7.

DETAILED DESCRIPTION OF THE INVENTION

Section I. - Description

A. Preparation of mono and 2,5-bis(halomethyl)tetrahydrofurans

[0019] In the present invention, alkyl-halide furanic compounds can be prepared directly from 2.5- bis-(hydroxymethyl)-tetrahydrofuran (bHMTHF) derived from the hydrogenation of HMF in a simple and elegant reaction that can achieve high yields. One can attain significant levels to near complete conversion of the starting materials (e.g., 50%-98% wt./wt.) and a yield of at least 25% relative to the starting materials of either the desired mono- or di-halogenated furanic compound. Typically, the percent yield is in a range from about 30% to about 60% or greater, such as about 35%, 40%, 45%, 50% 55%, or 63%. With process optimization one can achieve even higher yields, for example, about 65% or 70%) to about 75%> or 85%> or more.

[0020] Whereas previous syntheses involves complicated reactions with toxic reagents and produced di-halogenated cis -configured molecules, an advantage of the present reaction over the previously synthesis is the ability to generate both mono and dialkyl furanic halide molecules having both cis and frara- -configured molecules according to a non-toxic reaction protocol under mild conditions. Figure 1 shows a general reaction for preparing mono- and di-halide furanic compounds under Appel reaction conditions according to the present disclosure. The Appel reaction, as illustrated generally in Scheme 1, involves a reaction of triphenylphosphine (PPI13) and tetrahalomethanes (CX4: CC , CBr4, CI4,) with alcohols is a ready method to convert an alcohol to the corresponding alkyl halide under mild conditions. The yields are normally high.

Scheme 1.

[0021] The reaction proceeds by activation of the triphenylphosphine (PPI13) by reaction with the tetrahalomethane, followed by attack of the alcohol oxygen at phosphorus to generate an

oxyphosphonium intermediate. The oxygen is then transformed into a leaving group, and an SN2 displacement by halide takes place, proceeding with inversion of configuration if the carbon is asymmetric. Figure 2 shows this mechanism. Alternative phosphine reagents one may use in the Appel reaction may include commercially available alkyl phosphines, such as tributylphosphine.

[0022] To maximize the amount of mono-halogenated bHMTHF, one can either moderate the amount of CX ₄ /PPI13 used or halt the reaction at an earlier time, thus precluding further halogenation to the di-halogenated analogs. It is believed that the reaction is collision controlled. Some amount of di-halogenated species will be present and its concentration increases over time if sufficient halogenating agent is available regardless of the amount of mono-halogenated molecules. To optimize yields of the mono-halogenated species one can limit the amount of halogenating agent available. Hence, to increase the amount of mono-halogenated species one can use one

stoichiometric equivalent or less, instead of two or more equivalents, of CX4/PPI13.

[0023] Figure 3, presents a reaction according to an embodiment of the present process for preparing 2,5-bis(bromomethyl)tetrahydrofurans (BMT) diastereomers from bHMTHF diastereomers. The synthesis process of the present disclosure are equally applicable for the other halide species (i.e., chlorine and iodine).

[0024] The reaction can be performed in a temperature range from about 0°C to about 60°C. In certain embodiments, the temperature is in a range from about 10°C or 12°C to about 40°C or 50°C. Certain desirable temperatures are about 15°C or 18°C to about 22°C or 30°C, specifically ambient room temperature (e.g. ~20°C).

[0025] The duration of the reaction can be at least 3 or 4 hours. Typically, the reaction time is between about 5 hours to about 12 hours. In certain embodiments, the time is about 6 or 7 hours to about 9 or 10 hours; more typically, about 6 to 8 hours.

[0026] The mono or di -alkyl halide furanic compounds have a general structure:

\

X

wherein R is either -OH, CI, Br, or I, and X is CI, Br, or I when the furanic compound has a trans configuration, and that when both R and X are either CI or I then the molecule is not in a cis configuration. X is Br when the furanic compound has a cis configuration. The mono or di-alkyl halide furanic compounds are in a 90%: 10% ratio of cis:trans configured molecules. The alkyl halide furanic compounds that can be generated according to the present method of synthesis may include, for example: cis 2,5-bis(bromomethyl)tetrahydrofuran trans 2,5 -bis(bromomethyl)tetrahydrofur cis and trans (5-(bromomethyl)-tetrahydrofuran-2-yl)-methanol trans 2,5 -bis(cloromomethyl)tetrahydrofuran CI

and trans (5-(iodomethyl)-tetrahydrofuran-2-yl)-methanol

B. Derivatives of mono- and di-halides of tetrahydrofuranic molecules

[0027] The alkyl halide furanic compounds produced according to the present synthesis process are versatile molecules for further chemical synthesis. The materials can serve as precursor chemicals for various other reactions to generate an array of derivative compounds, such as thioethers, amines, halides, alkyl/aryl chain extensions, all achieved by nucleophilic displacement reactions as illustrated in Figure 4. The example shows 2,5-bis(bromomethyl)-tetrahydrofuran as the starting material, but can apply equally to other halogenated species. The derivative compounds are represented in generic notation.

[0028] When in the presence of powerful nucleophiles, such as thiols and amines, the 2,5- bis(bromomethyl)tetrahydrofurans undergoes rapid second order substitutions to form thioethers and secondary or tertiary amine products. Another example of a transformation is to induce a polarity inversion (umpolung) of the 2,5-bis(bromomethyl)tetrahydrofurans with magnesium (Grignard) and lithium dialkylcuprates (Gilman) reagents. This can generate easily powerful carbon centered nucleophiles. In another reaction, when a strong base is added (e.g., hydride, amide, organolithiates) to a solution of 2,5-bis(bromomethyl)-tetrahydrofurans at reduced temperature, an elimination generates a diolefin, 2,5-dimethylenetetrahydrofuran.

[0029] Further illustration of the versatility of tetrahydrofluranic mono-halide molecules are presented in Figure 5 and 6, which show some other representative reactions and compounds. In Figure 5, the tetrahydrofluranic mono-halide undergoes alcohol modifications, in which the alcohol moiety reacts while preserving the halogenated moiety. Figure 6 shows halide displacement reactions, in which the halide moiety reacts while the alcohol moiety remains. Other alternate derivative compounds can be prepared with some of the displacement, elimination, or substitution reactions described in International Patent Application No. PCT/US2014/070012, the contents of which are incorporated herein by reference, mutandis mutatis.

[0030] The following molecules present some representative derivative compounds that can be prepared from mono and bis(halomethyl)tetrahydrofurans according to some of the nucleophilic displacement, elimination or substitution reactions disclosed in the forgoing section above. Examples of some derivatives may include either a cis or frara- -configured molecule. For purposes of illustration, the following compounds numbered 1-27 and 35, depicted cis configured derivative molecules, and compounds 28-34, 36, 37, show trans configured molecules:

1. -5-(bromomethyl)tetrahydrofuran-2-yl)methyl trifluoromethane sulfonate

2. 1 -(((2S,5R)-5 -(bromomethyl)tetrahydrofuran-2-yl)methoxy)ethan- 1 -ol

3. (2R,5S)-2-(bromomethyl)-5-(fluoromethyl)tetrahydrofuran

4. (2R. -2-(bromomethyl)-5-(chloromethyl)tetrahydrofuran

(2 5-(methoxymethyl)tetrahydrofuran

((2S -5-(bromomethyl)tetrahydrofuran-2-yl)methyl acetate

(2S,5R)-5-(bromomethyl)tetrahydrofuran-2-carboxylic acid

(2S.5R)-5-(bromomethyl)tetrah} drofuran-2-carbaldehyde

((2S,5S)-5-propyltetrahydrofuran-2-yl)methanol

10. ((2R.5 S)-5 -(hydroxymethyl)tetrahydrofuran-2 -yl)methyl butyrate ((2S,5R)-5-((((2S,5R)-5-(bromomethyl)tetrahydrofuran-2-yl)me thoxy):

tetrahydrofuran-2-yl)methanol

((2R,5S)-5-((((2R,5S)-5-(hydroxymethyl)tetraliydrofuran-2 -yl)methoxy)methyl)- tetrahydrofuran-2-yl)methanol

'S,5S,5'S)-(oxybis(methylene))bis(tetrahydrofLiran-5,2-diyl) )dimethanol

((2R,5R)-5-((((2S,5S)-5-(hydroxymethyl)tetrahydrofuran-2- yl)methoxy)methyl)- tetrahydrofuran-2-yl)methanol (((2R,5 S)-5 -(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2- yl)methyl)magnesium bromide

O

MgBr

/

((2 S -5 -((benzylthio)methyl)tetrahydrofuran-2 -yl)methanol

((2S,5R)-5-((propylamino)methyl)tetrahydrofuran-2-yl)meth anol

((2S,5R)-5-((hexyloxy)methyl)tetrahydrofuran-2-yl)methano l

Diethyl (((2S,5R)-5-(h _} droxymethyl)tetrahydrofiiran-2-yl)methyl) phosphate

20. (2R,5 S)-2,5 -dihexyltetrahydrofuran

21. 2,5-dimethylenetetrahydrofuran

^ O

22. ethyl)tetrahydrofuran-2-yl)-N-methylmethanamine

23. 2,5-diyl)dimethanethiol

24. (2R -2,5 -bis((ethylthio)methyl)tetrahydrofuran

25. '-(((2R,5S)-tetrahydrofuran-2,5-diyl)bis(methylene))bis(prop an-l-amine)

26. -tetraliydrofuran-2,5-diyl)bis(methylene)) bis(phosphate)

27. Tetraeth l (((2R,5S)-tetrahydrofuran-2,5-diyl)bis(methylene))bis(phosph onate)

28. l-((2S,5S)-5-((ethylthio)methyl)tetrahydroftiran-2-yl)-N-met hylmethanamine -((2R,5R)-5-((ethylthio)methyl)tetrahydrofuran-2-yl)-N-methy lmethanamine 2S.5S)-2 ^" , ^" 5ί-bis(τ(ethylthio)methyl)tetrahydroftiran ,N'-(((2S,5S)-tetrahydrofuran-2,5-diyl)bis(methylene))bis(pr opan-l-amine)

(2S.5S)-tetrahydrofuran-2.5-diyl)dimethanethiol

ieth l (((2R,5R)-5-(hydroxymethyl)tetrahydrofuran-2-yl)methyl) phosphate

iethyl (((2S,5S)-5-(hydroxymethyl)tetrahydrofuran-2-yl)methyl) phosphate

ieth l (((2S,5R)-5-(hydroxymethyl)tetrahydrofuran-2-yl)methyl)phosp honate

ieth l (((2R,5R)-5-(hydroxymethyl)tetrahydrofuran-2-yl)methyl)phosp honate

ieth l (((2S,5S)-5-(hydroxymethyl)tetrahydrofuran-2-yl)methyl)phosp honate Section II. - Examples

A.

[0031] Example 1. Preparation of 2,5- bis(halomethyl)tetrahydrofurans

[0032] Experimental: A flame-dried, 50 cc three-necked round-bottomed flask equipped with a PTFE magnetic stir bar was charged with 1.00 g of a 9: 1 cis/trans diastereomeric mixture of bHMTHFs (7.57 mmol), 5.95 g of triphenylphosphine (22.7 mmol, 3 eq.), 7.53 g of carbon tetrabromide (22.7 mmol, 3 eq.), and 25 mL of dry methylene chloride. The leftmost neck of the flask was capped with a rubber septum imbued with five 12" stainless steel needles, the centermost neck stoppered with a thermowell adapter, and the leftmost affixed to an argon inlet. Stirring commenced at room temperature while under an argon blanket. The reactants were observed to readily dissolve in methylene chloride and appeared as a light yellow tinged solution. After approximately 3 h, prodigious solids were observed suspended in the methylene chloride solution. The reaction proceeded overnight, after which time the solids were filtered and vestigial solution analyzed by GC/MS, ¹ P NMR, ¾ NMR, and ¹ C NMR. Purification entailed pouring the diluted crude solution onto a pre -fabricated column with hexane/ethyl acetate as the eluting solvents. Gradient flash chromatography furnished the target compounds at a 2: 1 hexanes/ethyl acetate proportion, Rf = 0.44, as 1.02 g of a colorless liquid (52% yield).

[0033] Figure 7 shows the gas chromatogram of the results with a peak at 8.909 minutes represents the 2,5-bis(bromomethyl)tetrahydrofuran, and a second peak at 15.791 minutes represents any remaining unreacted bHMTHF. Figure 8 presents the corresponding mass spectrum of the compound eluting at 8.909 minutes in Figure 7. The molecular ion, representing the relative molar mass of the targets) is ostensible at m/z 255.9 along with salient signals denoting concerted bromine atom losses (M-Br = 170.0 m/z; M-2Br = 96.1 m/z).

B.

[0034] Example 2. Preparation of ((2R,5S)-tetrahydrofuran-2,5-diyl)dimethanethiol and ((2S,5S)-

A B C

Step 1 : Synthesis of (2R,5S)-2,5-bis((benzylthio)methyl)tetrahydrofuran and (2S,5S)-2,5- bis((benzylthio)methyl)tetrahydrofuran, B

A B

[0035] Experimental: A flame-dried, 25 mL round bottomed flask equipped with a PTFE magnetic stir bar was charged with 500 mg of a 9: 1 mixture of (2R,5S)-2,5-bis(bromomethyl)tetrahydrofuran and (2S,5S)-2,5-bis(bromomethyl)tetrahydrofuran A (1.94 mmol), 382 benzyl mercaptan (4.85 mmol), 2 mL pyridine, and 10 mL of chloroform. With vigorous stirring, the mixture was refluxed overnight. After this time, the deep yellow solution was dried under reduced pressure and vestigial yellow oil taken up in 2 mL of methylene chloride and charged to a pre-fabricated silica gel column, where flash chromatography with a hexanes/ethyl acetate gradient furnished 476 mg of a 9: 1 mixture of (2R,5S)-2,5-bis((benzylthio)methyl)tetrahydrofuran and (2S,5S)-2,5- bis((benzylthio)methyl)tetrahydrofuran as a pale yellow oil (71%). ¾ NMR (primary cis isomer, 400 MHz, CDC1 ₃ ) δ (ppm) 7.46 (d, J= 7.2 Hz, 4H), 7.27 (m, 4H), 7.12 (d, J= 7.0 Hz, 2H), 4.18 (m, 2H), 3.61 (s, 4H), 2.80 (dd, J= 9.2 Hz, J= 5.6 Hz, 2H), 2.59 (dd, J= 9.0 Hz, J = 5.6 Hz, 2H), 1.96 (m, 2H), 1.71 (m, 2H); ¹ C NMR (primary cis isomer, 100 MHz, CDC1 ₃ ) δ (ppm) 140.9, 131.1, 130.6, 129.3, 81.6, 45.0, 39.7, 34.8 ppm.

Step 2: Synthesis of ((2R,5S)-tetrahydrofuran-2,5-diyl)dimethanethiol and ((2S,5S)-tetrahydrofuran- 2,5-diyl)

B C

[0036] Experimental: A 75 cc 316 SS Parr reactor equipped with a glass enclosed magnetic stir bar was charged with 400 mg of a 9: 1 mixture of bis((benzylthio)methyl)tetrahydrofuran and (2S,5S)-2,5- bis((benzylthio)methyl)tetrahydrofuran B (1.16 mmol), 500 mg of 10% Pd/C and 25 mL of absolute ethanol. The vessel was sealed, purged with volumes of H ₂ (500 psi each), charged with ¾ to a pressure of 1000 psi and the solution stirred (500 rpm) at room temperature for 4 h. After this time, the catalyst was filtered and residual solution dried under reduced pressure, furnishing a yellow oil. The oil was taken up 2 mL of methylene chloride and charged to a pre-fabricated silica gel column, where flash chromatography with a gradient hexanes/ethyl acetate eluent furnished 156 mg of a 9: 1 mixture of ((2R,5S)-tetrahydrofuran-2,5-diyl)dimethanethiol and ((2S,5S)-tetrahydrofuran-2,5- diyl)dimethanethiol as a pale, loose oil (82%). ¾ NMR (principal cis isomer, 400 MHz, CDCI3) δ (ppm) 4.12 (m, 2H), 2.85 (dd, J= 9.4 Hz, J= 6.4 Hz, 2H), 2.60 (dd, J= 9.4 Hz, J= 6.4 Hz, 2H), 1.93 (m, 2H), 1.66 (m, 2H), 1.25 (broad s, 2H); ¹³ C NMR (principal cis isomer, 100 MHz, CDC1 ₃ ) δ (ppm) 83.9, 39.4, 32.5.

[0037] Example 3. Preparation of tetraethyl (((2R,5S)-tetrahydrofuran-2,5-diyl)bis(methylene)) bis(phosphate) and tetraethyl (((2S,5S)-tetrahydrofuran-2,5-diyl)bis(methylene)) bis(phosphate), B.

[0038] Experimental: A flame-dried, 25 mL round bottomed flask equipped with a PTFE magnetic stir bar was charged with 100 mg of a 9: 1 mixture of (2R,5S)-2,5-bis(iodomethyl)tetrahydrofuran and (2S,5S)-2,5-bis(iodomethyl)tetrahydrofuran A (0.284 mmol), 131 mg of diethyl hydrogen phosphate (0.852 mmol), 129 mg of cesium fluoride (0.852 mmol) and 10 mL of dry acetonitrile. The mixture was stirred vigorously for 8 hours. After this time, the acetonitrile was evaporated under reduced pressure and residual yellow oil uptaken in 1 mL of methylene chloride and charged to a prefabricated silica gel column, where flash chromatography with a hexanes/ethyl acetate gradient furnished 61 mg of tetraethyl (((2R,5S)-tetrahydrofuran-2,5-diyl)bis(methylene)) bis(phosphate) and tetraethyl (((2S,5S)-tetrahydrofuran-2,5-diyl)bis(methylene)) bis(phosphate)a 9: 1 mixture of as a colorless oil (53%). ¾ and ¹ C NMR validated the identities and purities of title compounds, B.

[0039] Example 4. Preparation of tetraethyl (((2R,5S)-tetrahydrofuran-2,5-diyl)bis(methylene))- bis(phosphonate) and tetraethyl (((2S,5S)-tetrahydrofuran-2,5-diyl)bis(methylene))bis(phosph onate), B

[0040] Experimental: A three neck, flame -dried 10 mL round bottomed flask equipped with a PTFE magnetic stir bar was charged with 200 mg of a 9: 1 mixture of (2R,5S)-2,5- bis(bromomethyl)tetrahydrofuran and (2S,5S)-2,5-bis(bromomethyl)tetrahydrofuran (0.775 mmol) and 2 mL of triethylphosphite. An argon inlet was attached to the flask, and while vigorously stirring and under argon, the mixture was heated to 125°C. The reaction was monitored by TLC (5: 1 hexanes/ethyl acetate, cerium molybdate visualization), and deemed complete after 4 hours. The solution was then cooled to room temperature and charged to a pre-fabricated silica gel column, where flash chromatography using gradient hexanes— >ethyl acetate afforded 182 mg of the title compound B as a loose colorless oil (63%). %). ¾, ¹ C, and ¹ P NMR validated the identities and purities of title compounds, B.

[0041] Example 5. Preparation of ((2R,5S)-5-((((2R,5S)-5-(hydroxymethyl)tetrahydrofuran-2-

[0042] Experimental: A flame-dried, 100 mL boiling flask was charged with 1 g of ((2R,5S)- tetrahydrofuran-2,5-diyl)dimethanol (A, 7.57 mmol)) and 25 mL of anhydrous THF. The flask was immersed in a saturated brine/ice bath (~ -10°C) and 302 mg of sodium hydride (60 wt.% in mineral oil, 7.57 mmol) added in 5 portions (-60 mg) over 15 min. After complete addition, the resultant suspension was stirred for 15 min, furnishing an intense green color. A septum was then placed over the neck of the flask, and 1.86 g of ((2R, 5S)-5-(iodomethyl)tetrahydrofuran-2-yl)methanol (B, 7.57 mmol) dissolved in 10 mL of THF was added dropwise via syringe over 15 min. After addition, the brine/ice bath was removed and reaction stirred overnight. After this time, solids were filtered and filtrate poured over a pre-fabricated silica gel column, where flash chromatography with a gradient hexanes— >hexanes/ethyl acetate furnished 1.08 g of the title compound as a colorless oil (58%). The structure was of the product was validated by NMR. ¾ NMR (400 MHz, CDC1 ₃ ) δ (ppm) 5.00 (broad s, 2H), 4.02 (m, 2H), 3.82 (m, 2H), 3.66-3.61 (m, 4H), 3.47-3.51 (m, 4H), 2.02 (m, 4H), 1.74 (m, 4H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ (ppm) 88.8, 85.4, 77.2, 65.1, 30.8, 29.4.

[0043] The present invention has been described in general and in detail by way of examples.

Persons of skill in the art understand that the invention is not limited necessarily to the embodiments specifically disclosed, but that modifications and variations may be made without departing from the scope of the invention as defined by the following claims or their equivalents, including other equivalent components presently known, or to be developed, which may be used within the scope of the present invention. Therefore, unless changes otherwise depart from the scope of the invention, the changes should be construed as being included herein.