WO2014168698A1

WO2014168698A1 - Mono-ethers of isohexides and process for making the same

Info

Publication number: WO2014168698A1
Application number: PCT/US2014/020579
Authority: WO
Inventors: Kenneth STENSRUD
Original assignee: Archer Daniels Midland Company
Priority date: 2013-04-09
Filing date: 2014-03-05
Publication date: 2014-10-16
Also published as: JP2016516770A; AU2017213555A1; US9802950B2; EP2983660A4; BR112015024368A2; US20160289241A1; MX2015014270A; KR20150139942A; AU2014251315A1; CN105101960A; RU2015144627A; CA2907640A1; EP2983660A1

Abstract

A method of making a mono-ether of an isohexide and art assemblage of novel. Song - chain isohexide mono-ethers are deseribed. In particular, the method involves reacting an isohexide stereoisomer with a Bronsted base and an alky! species. The resultant mono-ethers can serve as attractive antecedents or chemical scaffolds tor making a derivative compound, such as various amphiphiles with potential uses as surfactants, dispersants, and lubricants, among others.

Description

MONO-ETHERS OF ISOHEX!DES AND PROCESS

FOR MAKING THE SAME

PRIORITY CLAIM

The present application claims benefit of priority of U.S. Provisional Application No. 6.1/809,949, filed on April 9, 2013. the contents of which are incorporated herein.

FIELD OF INVENTION

The present application relates to cyclic bifunetional ethers of isohexides that are useful as amphophilic compounds and intermediates generally, and to particular methods by which such compounds are made,

BACKGROUND

Traditionally, polymers and commodity chemicals have been prepared from petroleum-derived feedstock. As petroleum supplies have become increasingly costly and difficult to access, interest and research has increased to develop renewable or "green"¹ alteraative materials from biologically-derived sources for chemicals that will serve as commercially acceptable alternatives to conventional, petroleum-based or -derived counterparts, or for producing the same materials as produced from fossil, non-renewable sources.

One of the most abundant kinds of biologically-derived or renewable alternative feedstock for such materials is carbohydrates. Carbohyd ates, however, are generall unsmted to current high temperature industrial processes. As compared to petroleum- based, hydrophobic, aliphatic, or aromatic feedstocks having a low degree of fimctionalkation, carbohydrates such as polysaccharides are complex, over-functionalized hydrophilic materials. As a consequence, researchers have sought to produce biologically-based chemicals that can be derived from carbohydrates, but which are less highly functionaiized, including more stable bi~funciional compounds, such as 2,5-furandicarboxylic acid (FDCA), levuHme acid, and 1,4:3, 6-dianh.ydrohexitols.

L4:3,6T>ianhydrohexitois (also referred to herein as isohexides) are derived, from renewable resources from cereal-based polysaccharides, isohexides embody a class of bicyclic furanodiols that derive from the corresponding reduced sugar alcohols (D-sorbito!, D-mavmitoL and D-iditol respectively). Depending on the chirality, three isomers of the isohexides exist., namely: A) isosorbide, B) isomaonide, and C) isoidide. respectively; the structures of which are illustrated in Scheme 1.

Scheme 1 :

isosorbide isonmr ide isoidide from D-sorbito! _r0m D-mannito^'i from D-iditoi These molecular entities have received considerable interest and are recognized as valuable, organic chemical scaffolds for a variety of reasons. Some beneficial attributes include relative facility of their preparation and purification, the inherent economy of the parent feedstocks used in their preparation, owing not only to their renewable biornass origins, which affords great, potential as surrogates for non-renewable petrochemicals, but perhaps most significantly the intrinsic chiral bi-iunctionalities that permit a virtually limitless expansion of derivatives to be designed and synthesized.

The isohexides are composed of two m- fused tetrahydrofurati rings, nearly planar and V-shaped with a 120° angle between rings. The hydroxy! groups are situated at carbons 2 and 5 and positioned on either inside or outside the V~shaped molecule. They are designated, respectively, as end or exo. Isoidide has two exo hydroxy! groups, while the hydroxyi groups are both endo in isomannide, and one exo and one endo hydroxyi group in isosorbide. The presence of the exo snbstituents increases the stability of the cycle to which i is attached. Also exo and endo groups exhibit different reactivities since they are more or less accessible depending on the steric requirements of the derivatizing reaction,

As interest in chemicals derived from natural resources is increases, potential industrial applications have generated interest in the production and use of isohexides. For instance, in the field of polymeric materials, the industrial applications have included use of these diois to synthesize or modify poiycondensat.es. Their attractive features as monomers are linked to their rigidity, ch rality, non-toxicity, and the fact that they are not derived from petroleum. For these reasons, the synthesis of high glass transition temperature polymers with good ihermo-meehanieal resistance and/or with special optical properties is possible. Also the innocuous character of the molecules opens the possibility of applications in packaging or medical devices. For instance, production of isosorbide at the industrial scale with a purity satisfying the requirements for polymer synthesis suggests that isosorbide can soon emerge in industrial polymer applications. (See e.g., F. Fenouiiiot et al., "Polymers From Renewable 1 ,4:3,6-Dianhydrohexitols (Isosorbide, Isommanide and tsoidide); A Review," PROGRESS IN POLYMER SCIENCE, vol. 35, pp.578-622 (2010), or X. Feng ei L, "Sugar-based Chemicals for Environmentally sustainable Applications " CONTEMPORARY SCIENCE OF POLYMERIC MATERIALS, Am. Chem. Society, Dec. 2010, contents of which are incorporated herein by reference.)

Another application that has received limited interest involves isohexide-derived ampftiphiles, compounds that manifest: discrete hydrophilic and hydrophobic zones that afford unique inter and intramolecular self-assemblies in response to environmental stimuli. Conventionally, isohexide-based. amphophilic esters are predisposed to hydrolyze, particularly in commonly employed, non-neutral aqueous matrices. An alternative domain can offer a much greater robustness to hydrolytic conditions include alkyi ethers.

To better utilize isohexides as a gree feedstock, a clean and simple method of preparing the isohexides as a mono-ether that can be subsequently modified to synthesize other compounds would be welcome by those in the green or renewable chemicals industry.

SUMMAR Y OF THE INVENTION

The present invention, i part, provides a method for preparing a mono-ether of an isohexide. The method involves reacting an isohexide with a Bronsted base and an alkyl-X species, according to the following equation:

wherein: "X" is a leaving group; "n" is an integer from 0 to 23, and "CA" is a conjugate acid of the Br0nsted base. The leaving group " " is at least one of the following: a halide, mesylate (OlVls), tosylate (OTs), and irifluoromethanesulfonate, also known by the name triflaie (OTf). The isohexide stereoisomer and a conjugate acid of the Brensted base each have an acid disassoeiation constant p a. and the absolute value of the difference (Δ pKa ^~ p Bronsted base - pKa isohex ide -OH) bet ween the pKa of the isohexide stereoisomer and the conjugate acid of the Bronsted base is at least 0. The synthesis reaction can produce a variety of mono-alkyl ethers in a control led manner which maximizes the yield of mono-ether product. In another aspect, the invention pertains to compounds that can he derivatized from the isohexide mono-ethers. T hese compounds have a general formula as follows:

wherein R is H. or d - C₂? and R' is SO3H and corresponding anion, PO3H2 and

corresponding anion(s). and an alkyl, alkyl-ether or alkyl-polyether with a chain of€4

DETAILED DESCRIPTION OF THE INVENTION

Section i. - Description

As biomass derived compounds that afford great potential as surrogates for non- renewable petrochemicals, 1 ,4:3,6-dianhydrohexito1s are a class of bicyclic furanodiols that are valued as renewable molecular entities. (For sake of convenience, 1,4:3,6- dtanhydrohexitols will be referred to as "isohexides" or "'isohexide stereoisomer" in the Description hereinafter.) As referred to above, the isohexides are good chemical platforms that have recently received interest because of their intrinsic chirai bi-funetionalities, which can permit a significant expansion of both existing and new derivative compounds that can be synthesized.

Isohexide starting materials can be obtained by known methods of making

respectively lsosorbide. isomannide, or isoidide. lsosorbide and isomannide can be derived from the dehydration of the corresponding sugar alcohols, D-sorbitol and D mannitoi. As a commercial product, isosorbide is also available easily from a manufacturer. The third isomer, isoidide, ca be produced from L-idose, which rarely exists in nature and cannot be extracted from vegetal biomass. For this reason, researchers have been acti vely exploring different, synthesis methodologies for isoidide. For example, the isoidide starting material can be prepared by epimerization from isosorbide. In L. W. Wright, I. D. Brandner, J. Org. Chem. , 1964, 29 (10), pp. 2979-2982, epimerization is induced by means of Hi catalysis, using nickel supported on diatomaceous earth. The reaction is conducted under relatively severe conditions, such as a temperature o.f220°C to 240°C at a pressure of 150 atmospheres. The reaction reaches a steady state after about two hours, with an equilibrium mixture containing isoidide (57-60%), isosorbide (30-36%) and isomannide (5-7-8%). Comparable results were obtained when starting from isoidide or isomannide. Increasing the pH to 10-1 1 was found to have an accelerating effect, as well, as increasing the temperature and nickel catalyst concentration. A similar disclosure can be found in U.S. Patent No. 3,023,223. which proposes to isomerize isosorbide or isomannide. More recently, P. Fueries proposed a method for obtaining L-iditol (precursor for isoidide), by chromatographic fractionation of mixtures of L-iditol and L-sorbose (U.S. Patent Publication No. 2006/0096588; U.S. Patent No. 7,674,38 ! B2). L-iditol is prepared starting from sorbitol In a first step sorbitol is converted by fermentation into L-sorbose, which is subsequently hydrogenaied into a. mixture of D~sorbitol and L.-idifol, This mixture is then converted into a mixture of L-iditol and L- sorbose. After separation from the L-sorbose, the L-iditol can be convened into isoidide. Thus, sorbitol is converted into Lsoidide in a four- step reaction, in a yield of about 50%. (The contents of the cited references are Incorporated herein by reference, )

A. Mono-ether Synthesis Reaction

The present invention provides, in pan, an efficient, and facile process for making mono-ethers of isohexides. The process involves the reaction of an isohexide stereoisomer with a Bronsted base and an aiky! or aliphatic species. The isohexide stereoisomer Is at least one of the following: isosorbide, isomannide, and isoidide, or a mixture of two or all three of these. The respective isohexide compounds can be obtained either commercially or synthesized from relatively inexpensive, widely-available biologically -derived feedstocks. The general reaction is presented in Scheme 1.

Scheme 1 : General Synthesis Reaction

wherein: ^*'X^" is a leaving group, "n" is an integer from 0 to 23, and "CA" is a conjugate acid of the Br0nsted base. Typically, "n" is an. integer from 2, 3 or 4 through 18, 19, or 20, inclusive of any value in between. The total length of the aliphatic portion of the alkyl-X species can range from about€? or (¾ up to about C_¾ or€.^'¾. Typically, the carbon chain is betwee about (¾,€4 or Q to about C^, Cj? or Css, or a combination of different ranges therein. In the synthesis, the isohexide stereoisomer and alky! species are reacted generally in 1 : 1 molar equivalents. In the alkyl-X species, " " serves as a leaving group or nucleofuge. in certain embodiments, "X^" is an alkyl halkle, such as a chloride, bromide or iodide. As one of the more economical and commercial sources of aliphatic haiides, bromides are more

favored. Aliphatic iodides and chlorides can he used also, but are not. as favored

commerciall , in other embodiments, one can em loy other nueieofuges, such as mesylates

(-i⁾Ms

}, or trilluoromethanesulfonates, also

known by the name triflates (-OT^'f

These species, however, are not as readily available commercially as the ai.ky l-halides and may need to be synthesized.

The isohexide stereoisomer and a conjugate acid of the Bronsted base each have an acid dissociation constant pKa, wherein an absolute value of the difference (Δ pKa -^~ pKa Bronsted base - pKa isohexide -OH) betwee the pKa values of the isohexide stereoisomer and the conjugate acid of said Bronsted base is at least 0. As used herein, the absolute value (or modulus) | x \ of a real number x refers to the non-negative value of x without regard to its sign. Namely, \ x \ ~ x for a positive x, \ x \ ~ -x for a negative Λ\ and j 0 i ^:::: 0. For example, the absolute value of 3 is 3. and the absolute value of -3 is also 3. Hence, the absolute value of a number may be though of as its distance from zero. The absolute value of x is always either positive or zero, but never negative. Each hydroxy! moiety of isohexide has an individual pKa, and the average pKa of isohexide is about 16. Generally, the conjugate acids of suitable Breasted bases can have a pKa from a minimum of about 4 or 5 to a maximum of about 30 or 32. Typically, the pKa of the conjugate acid of the Bronsted base is about 9, 10 or 12 up to about 20-28. In certain preferred embodiments, the pKa of the conjugate acid of the Bransted base is greater than 16 (e.g., about 17 or 18 to about 20 or 25). in certain embodiments, suitable Bronsted bases may include, for example: -butoxides (pKa ^~ 17), hindered or tertiary amines (e.g., tri-ethyl amine, di-isopropy!-ethylamine, or iri-propylanune), hydroxides, or carbonates.

Although various Bronsted bases are suitable and can perform well in the present reaction, not all kinds of species should be used. One of the issues facing the synthesis of mono-ethers from isohexide stereoisomers has been to avoid uncontrolled or rapid

depotonaiion of both hydroxy! moieties of the isohexide molecule, since both hydroxy 1 moieties have equal reactivity, and the reaction is entirely collision based. The present synthesis process attempts to minimize the generation of di-ether side products. As the positive difference between the p a of the alcohol moieties of the isohexide stereoisomer and mild Bronsted base increases, deprotonation is favored and the reaetion kinetics is driven to the right to produce the mono-ether. However, Bransted bases that exhibit positive Δ pKa values that are too great relative to that of the isohexide stereoisomer are not desirable for a controlled synthesis and tend to work less effectively at generating good yields of target isohexide mono-ethers. When positive Δ pKa is too great, double deportonation of isohexide ^•••OH moieties (dianion) tends to occur, which gives rise to reaction conditions that generates the predominantly di-ethers. such as illustrated in Comparative Example 1 .

In Comparative Example 1 , below, a di-ether is the primary product when an a!kyl hydride is used as the Bresnsted base, even when stringently controlling reaction conditions. This result it is believed, stems from a heightened reactivity due to a sizable Δ pKa between the hydride and isohexide. As it is known, hydrides are more basic than alcohols (by > 18-20 orders of magnitude); consequently, hydrides will deprotonate almost immediately each of the alcohol moieties of the isohexide without stereo-specificity, irrespective of the solution temperature, thus producing a reaetion setting that favors di-ethers. Hence, in general Bmusted bases with higher pKa values such as alky! hydrides (pKa ^:::: 42), alky! lithiums (pKa > 53), alky I magnesiums (pKa - 51 ), aikyi euprates, or metal amides should be avoided.

Thus, the conjugate acid of Bronsted bases should ha ve a pKa that is not more than about 15 or 16 orders of magnitude greater than the pKa of the alcohol {hydroxy!) moieties of an isohexide, which is about 16-17. According to certain iterations, the absolute value of the difference in pK (Δ pKa) is in a range from about 1 or 2 to about 8 or 10 (e.g., desirably about I -9, 1-7, I -3, 2-4, 2-5, or 2-6), so as to better control the deprotonation of the isohexide molecule in favor of a single over a double deprotonation.

in embodiments that use conjugate acids of Bronsted bases having a pKa greater (i.e., about 17 or greater) than that of the alcohol moieties of the isohexide, the reactions are highly exothermic, necessitating control of the initial temperature conditions. The reagents are added initially at low temperatures of about PC or less. Then, the reaction temperature is allowed gradually io rise to ambient room temperature (e.g., -~20°C-25°C). In certain embodiments, the initial temperature is typically in a range between about 0°C or about -5°C and about -65°C or ~78°C. In some embodiments, the initial temperature can range between about -2°C or -3°C and about -60°C or -70°C (e.g., -10°C, -15°C, ~25*C, or -55°C).

Particular temperatures can be from about -7°C or -8°C to about -4Q°C or ~50^C'C (e.g., -12°C_; ~20°C, -28°C, or -36°C). In other words, the cool to cold initial temperature helps lower the initial energy of the system, which increases control of the kinetics of the reaction, so that one can produce selectively more of the mono-ether species than of the di~ether species, hi an embodiment, for example, the Bransted base is potassium t-butoxide; f-butanol, the conjugate acid of /-butoxide, has a K_s of about 18 or 19, as il lustrated in Scheme 2, below.

The embodiments of this kind, in which the value of the Δ pKa of the alcohol moieties of the isohexide and the Breasted bases is positive and will self-propel the reaction to the ether product, are preferred.

One can make use of a relatively slow induction period (i.e., between about 20 or 30 minutes up to about 40 or 45 minutes), which permits the base to dissolve in the polar aprotic solvent and the acid-base equili bration to occur. Slow or gradual addition of reagents at lower temperatures will minimize unwanted side products that arise from elimination.

During the induction period the desired mono-ether product is formed in large excess without need for additional energy input. As another benefit, a relatively low reaction temperature reduces the propensity for base-induced eliminations, which can form alkenes from alkyl- halides.

in other embodiments, when conjugate acids of non-nucleophilic bases that have a pKa of either the same or lower value than the pKa of the alcohol, moieties of the isohexide, external energy input is required to drive the reaction forward, ameliorating the

competitiveness of isohexide alkyiation with isohexide reprotonation. As the pKa differences between Isohexide -OH and Breasted bases wil l not react readily to generate significant amounts of oxide, the inherently slower kinetics can he helpful i controlling mono-ether synthesis. Hence, in reactions using a) a species with a pKa of about 4-9 will require heating the reaction to at least abou 50°C or 60°C to about 70^oC-80°C, or more; or b) a species with a pK a of about 10-16 will require some heating to about ambient room temperature or up to about 50*C. With proper modulation of the higher reaction temperatures, one can tailor the reaction to generate less undesired side products.

An excess amount of Bronsted base can he employed with some species such as hindered amines or carbonates. Any acid that may be formed in the reaction (e.g., protonated form of isosorbide) immediately will be deprotonatecl hence the pH will he alkaline (i.e., greater than 7).

An organic solvent is used to facilitate the reaction. I some embodiments, the organic solvent is a non-nucieophilic species with a dielectric constant (ε, permittivity) of at least 20. Typically, the permittivity of a suitable solvent is within a range from about 20 to about 50, with solvent having a higher permittivity being more preferred. Some suitable polar, aprotic organic solvents include lor example, in the order of utility in terms of decreasing dielectric constants: dimethyl sulfoxide (DMSO) (ε - 46.7), itromethane (C¾N(>2) (ε ^::: 39.4), Ν,Ν-dimethylacetamide (s - 37.8), acetonitrile «¾CN) (ε = 37.5 ), , -dimethyl-forniamide (DMF) (s - 36.7 ), hexamefhylphosphoramide ( MPA) (ε - 31 .3), or acetone (ε 20.7). Hence, lor example, DMSO is preferred over nitromethane, over DMF, etc. In an example, reactions conducted in dimethylformamide, DMF, furnished the highest yield of isohexide mono-ethers, although several solvents were evaluated, including acetone, ietrahydfoihran, acetonitrile, methanol and ethanol.

As an exception to these general parameters, tetrahydrofuran (11 IF) ( ^::: 7.58) or 1 ,4 dioxane (ε ~ 2.25) also may be used as a solvent, even though they possess a relatively low dielectric constant, because of the very polarized C-Q bonds which will induce significant negative charge on the oxygen atoms, enabling the solvent to complex vvith cations, thus freeing the anionic base to better deprotonaie the hydroxy! moieties of the isohexides.

Neither alcohol-based nor aqueous solvents are suitable for the present reactions. Although alcohols are organic, nonetheless, they will react with the alky ! species which is undesired. Water is not a compatible solvent because it is nucleophilic and can react with the alk ! halides or sulfonates to form alcohols. Also, alkyl halides or sulfonates tend to be insoluble in water. In certain embodiments, water can solvate the Bronsted base, for instance, a -butoxide and deter its basicity.

In addition to being a clean and simple synthesis process, the present method of synthesis possesses several other advantages. For instance, in certain preferred embodiments, the bulk.iness of a r-butoxide limits its inherent nucieophiiieity, which decreases the likelihood of forming i-hutyi-ethers vvith alkyl halides or other species, A gradual addition of aikyi-halides (e.g., drop-wise or in portions), for instance, can prevent saturation and permi the desired nucleophilic substitutions to occur at least as readily as other random, collision- induced (elimination) processes.

Depending on the particular alkyl species, one may run the present synthesis reaction for a time period that, generates the most mono-ether. The reaction time can be, for instance, between about 30 minutes up to about 48 hours or more. The type of aikyl species used in the synthesis is the time-sensitive or yield-limiting reagent for making the mono-ether. For example, certain alky! reagents having shorter (e.g., < C_¾o or C<■) aliphatic carbon chains can react for shorter durations, as they tend to react more quickly than longer ie.g, > C;? or Cu) aliphatic species, This phenomenon may he due in part to sterte effects, but is not necessarily direct, a linear relationship.

The present synthesis process can result in satisfactory yields of corresponding mono- ethers, as demonstrated in the accompanying examples. The process is able to produce primarily isohexide mono-a kyl ethers in reasonably high molar yields, depending on the kind of alkyl species, from about 10% or 12% to about 50% or 60% from the starting materials, typically abot.it 15% or 17% to about 43% or 47%. With proper control of the reaction conditions and time, one can achieve yields up to about 70%-7S% of the mono-ether species. Di-ethers will be the predominant side products (e.g., -25-30%), and the quantity of d -ether will be typically the same as unreacted isohexides.

B. Mono-ethers of Isohexide Stereoisomers

In another aspect, the present invention pertains to the isohexide mono-ethers prepared from the reac tion of an isohexide stereoisomer with a Bronsted base and an alk i species. As the process for preparing these molecular entities is new, the various isohexid mono-ethers prepared according to the present invention are novel compositions of matter. The isohexide mono-ether has a general formula:

wherein "h" is a integer from 0 to 23. One can employ these mono-ethers as a chemical scaffold or platform from which various kinds of derivative compounds can be prepared, illustrative examples of some mono-ethers are presented in the Section H, - Examples, below.

C. Derivative Compounds from isohexide Mono-ethers

In another aspect, the present invention provides derivative compounds that can be synthesized from the mono-ethers of isohexides. The derivative of the mono-ether has a general formula as follows:

wherein R is H, or€_.¾ -€¼_?.; find R' is SChH and corresponding ankm, PO.d and

corresponding anion(s), and an alkyi, alkyl-eiher or a!kyl-po!yeiher with a chain of C4-C25. Particular examples of W as an alkyl-polyether can include€ Y\;_:C H-OC l C I W and CHsCHsOCHiCHjOCHiCHiOH.

The derivative of mono-ethers that can be made according io the present invention may include various organic moieties, for example, one or more of the following ~groups: alkyL allyl, aryl, or benzyl groups. Of particular interest, however, are mono-alky 1 ethers. Mono-alky 1 ethers of isohexides are desirable as precursors for amphiphiles (i.e., a molecule having a water-soluble or hydrophilic polar moiety and a hydrophobic organic moiety) or other derivative chemical compounds, such as surfactants or dispersants.

Although isohexi.de stereoisomers (i.e., isosorhide, isomamiide, and isoidlde) bear a signa ture fused antiparallel furofuran core, the three dimensional arrangement of hydroxy! moieties in each are different. The difference in geometric orientation between the functional groups imparts unique amphophilic properties to the mono ethers of the isohexides. Hence, an aspect of the present invention relates to the synthesis of a variety of either short (< C₆j, medium (CV-C^) o long (> Q3) carbon chain isosorhide, isomannide and isoidlde monoalkyl ethers. These scaffolds present attractive antecedents to different amphiphiles with potential uses, for instance, as surfactants, hydrophiles (e.g., carbon chain C Cgj, organogels, rheology adjusters, dispersants, emulsixiers, lubricants, plasticizers, chiral auxiliary compound with specific stereochemistry', among others. The derivatives may be produced efficiently up to quantitative yields from the mono-alkyl ether of isosorbide, isomannide, isoidlde or a mixture of two or all three of these.

Section 11. - Examples

The present inventio is further illustrated with reference to the following examples. The examples herein were prepared according to the fol lowing general reaction:

n = 6,8,10.16

A. Isomannide

Example 1 : Synthesis of {3R3aR,6R₅6al )-6-(octyIoxy)hexahydiOi½o 3₅2-b]ftiran-3~ol

Experimental: A 20 cc scintillation vial equipped with a ½" egg-shaped PTFE coated magnetic stir bar was charged with 108 mg of isomamiide (0.96 mrnol), 104 mg of potassium /-butoxide (0.96 mrnol), 5 ml. of dry DMF and stirred for 30 minutes. A rubber septum was then fitted to the vial mouih, the vial immersed in an ice/brine bath for 5 minutes, and 220 μΐ, of oci ibroniide (1.25 mrnol) added dropwise, followed by warming to room temperature and vigorous stirring for 6 hours. At. this time, an aliquot was removed, decocted, and

quantitatively analyzed by GC MS. The resulting spectrum evinced a signal for the title compound at 1 .2 mitx that corresponded to ~ 29% mass yield. Residual isomarmide, ociyibroniide, and some elimination product, oct- i -ene was also observed. Approximately -12% composition consisted of the ocl hdiether of isomannide near 23 min. Thin-layer chromatography ί 1 : 1 hexanes/ethyl acetate) employing a cerium molybdate stain manifested lour salient spots, one near the solvent front that was consistent with octylbromide (and oct- l~ene), one with an rf - 0.71 relating the octy!-diether variant, one with rf ^::: 0.29, consistent with the title compound, and one near the baseline, denoting unreacted isomannide.

Example 2: Synthesis of (3R,3aR,6R,6aR)-6-(decyloxy)hexahydrofuro 3,2-b]fuian-3-ol

Experimental: An oven dried, 50 cc boiling flask equipped with a 7/8" octagonal, PTFE coated magnetic stir bar was charged with 1.00 g of isomannide (6,8 mmol), 921 mg of potassium f-outoxide (8.2 mmol) and 25 mL of dry DMF, then capped with a rubber septum. After the mixture had been stirred for 30 minutes, the flask was immersed in a ice/brine bath for 5 min, and 1.57 mL of decylbromide (7/5 mmol) added dropwise via syringe throngh the septum. The mixture was stirred vigorously for a period of 6 h, after which an aliquot was removed, decocted, and quantitatively analyzed by GC/MS. The resulting spectrum evinced a signal for th title compound at 19.2 min thai corresponded to -31% mass yield. Residua! isomannide, decylbromide. and some elimination product, dec- l-ene was also observed in the chro atograrn. An exiguous amount ofdecyi dicther of isomannide, at ~25 min, was espied. Thin-layer chromatography (1 :1 hexan.es/et.hyl acetate) employing cerium moiybdate stain manifested three prominent spots, one near the solvent front consistent with decylbromide (and dee~^'i ~ene), one with an rf ~ 038 consistent with the title compound and one near the baseline, representing unreacied isomannide.

Example 3: Synthesis of^3R_>3aR,6R,6 lt)-6 dodecyloxy)hexah> ofuro ,2-b]fur n-3-ol

Experimental: A 20 cc scintillation vial equipped with a ½" egg-shaped PTFE coated magnetic stir bar was charged with. 121 mg of isomannide (0.83 mmol), 121 mg of potassium -butoxide (1.08 mmol). 5 mL of dry DMF and stirred for 30 minutes, A rubber septum was the fitted to the vial mouth, the vial immersed in an ice/brine bath for 5 minutes, arid 260 μΐ, of dodeeyi bromide (1.08 mmol) added dropwise. followed by warming to room temperature and vigorous stirring for 6 hours. At this time, an aliquot was removed, decocted, and quantitatively analyzed by GC/MS. The resulting spectrum evinced a signal for the title compound at 20.6 min thai corresponded to - 27% mass yield. Residual isomannide. dodeeyi bromide and some elimination product, dodec-l-ene was also observed. Thin-layer chromatography ( 1:1 hexanes/ethy! acetate) employing cerium moiybdate stain manifested three salient spots, one near the solvent front consistent with dodeeylbromide (and dodec-1- ene)„ one with rf- 039 consistent with the title compound and one near the baseline, signifying unreaeted isomannide,

Example 4: Synthesis of (3 aR,6R,6a )-6 octadecyloxy)hexa ydiofiiro[3,2-b]fijraii>3-o

Experimental: A 20 cc scintillation vial equipped with a ½" egg-shaped PTFE coated magnetic stir bar was charged with 1 10 rag of isomannide (0.75 ramol), 1 10 rag of potassium f-butoxide (0.98 mmoi), 5 mL of dry DMF and stirred for 30 minutes. The vial was capped and immersed in an ice/brine bath for 5 minutes, and 326 mg of ociadecyl bromide (0.98 ramol) added in portions, followed by warming to room temperature and vigorous stirring for 6 hours. At. this time, ait aliquot was removed, decocted, and quantitatively analyzed by GC/MS. The resulting spectrum evinced a signal for the title compound at 24.9 rain that, corresponded to ~ 22% mass yield. Residual isomannide, octdec l bromide and some damnation product, octadec-i-ene was also observed. Thin-layer chromatography (1 :1 hexanes/ethyl acetate) employing cerium molybdate stain manifested three salient, spots, one near the solvent front consistent with ociadecylbromide (and octadee-1 -ene), one with rf ^::: 0.46 consistent with the title compound and one near the baseline, specifying remnant isomannide.

B, lsoiodi.de

Example 5: Synthesis of (3S3aR,6S,6ai<)-6-(octyloxy)hexah.ydrofeo[3,2~b]furaii-3-ol

Experimental: A 20 cc scintillation via! equipped with a ½" egg-shaped PTFE coated magnetic stir bar was charged with 141 mg of isoidide (0.96 mmoi), 140 mg of potassium t- butoxide ( 1.25 mrno!), 5 mL of dry DMF and stirred for 30 minutes. A rubber septum was then fitted to the vial mouth, the vial immersed in an ice/brine bath for 5 minutes, and 220 μΐ. of octy ihromide (1.25 mmoi) added dropwise, followed by wanning to room temperature and vigorous stirring for 6 hours. At this time, an aliquot was removed, decocted, and

quantitatively analyzed by GC/^'MS. The resulting spectrum evinced a signal for the title compound at 17.8 mm tha corresponded to - 36% mass yield. Residual isoidide,

octylbromide and some elimination product, oct-l-ene was also observed. Approximately '-10% composition consisted of the octy! die her variant of isoisoidide near 22 rain. Thin- layer chromatography (1 : 1 hexanes 'ethyl acetate) employing cerium molybdate stain manifested four salient spots, one near- the solvent front consistent with octylbromide (and oct-l-ene), one with an rf =···· 0,75 relating the oetyl-diether analog, one with rf ^ 0.32 consistent with the title compound and one near the baseline, indicating remnant isoidide.

Example 6: Synthesis of (3S aJ^6S,6aR)-6-(decyioxy)hexahydjofuro[3,2-bjfuran-3-ol

Experimental: A 20 ec scintillation vial equipped with a ½" egg-shaped PTFE coated magnetic stir bar was charged with 134 mg of isoidide (0.92 mmoi), 123 mg of potassium r-butoxide (1.10 mmoi), 5 mL of dry DMF and stirred for 30 minutes. A rubber septum was then fitted to the vial mouth, the vial immersed in an ice/brine bath for 5 minutes, and 210 μΐ. of decy!bromide (1 ,01 mmoi) added dropwise, followed by warming to room temperature and vigorous stirring for 6 hours. At this time, an aliquot was removed, decocted, and

quantitatively analyzed by GC/MS. The resulting spectrum evinced a signal for the title compound at 19.3 mm thai corresponded to -32% mass yield. Residual isoidide,

deeylbromide, and some elimination product, dee-l--ene was also evinced signals in the chromatograro. A small amount of decyl diether of isoidide, at --24.8 min, was descried, Thin-layer chromatography ( 1 : 1 hexanes/'ethyl acetate) employing cerium molybdate stain manifested four salient spots, one near the solvent front consistent with decyibromide (and dec-l-ene), one with an rf~ 0.80 representing the deeyl-dieiher variant, erne with an rf ^:::: 0.34 consistent with the title compound and one near the baseline demonstrating residual isoidide.

Example 7: Synthesis of (3S3aR )S )aR)-6-(dodecyloxy)hexahydrofuro 3,2-b]furari-3-o]

Experimental: A 20 cc scintillation vial equipped with a ½" egg-shaped PTFE coated magnetic stir bar was charged with 270 mg of isoidide (1.85 mmol), 271 mg of potassium t- butoxide (2.4 i mmol), 5 ml, of dry DMF and stirred for 30 minutes. A rubber septum was then fitted to the vial month, the via! immersed in an ice/brine bath for 5 minutes, and 583 aL of dodecyi bromide (2.41 mmol) added dropwise, followed by wanning to room temperature and vigorous stirring for 6 hours. At this time, an aliquot was removed, decocted, and quantitatively analyzed by GC/MS. The resulting spectrum evinced a signal for the title compound at 20.7 mm that corresponded to ~ 34% mass yield. Residual isoidide, dodecyi bromide and some elimination product, dodec-l-eue was also observed. Thin-layer chromatography (1:1 hexanes/ethyl acetate) employing cerium molybdate stain manifested three salient spots, one near the solvent front consistent with dodeey!bromide (and dodec-f- ene), one with rf- 0.42 consistent with the title compound and one near the baseline, representing residual isoidide.

Example 8: Synthesis of (SS^aR^S^aR^^oc ad c lox ^iexah drofur ^-bj-furan-S- l

HQ H / ^'

Experimental: A 20 cc scintillation vial equipped with a W egg-shaped PTFE coated magnetic stir bar was charged with 11 1 mg of isoidide (0.76 mmol), 1 10 mg of potassium (· butoxide (0.98 mmol), 5 ml, of dry DMF and stirred for 30 minutes. The vial was capped and immersed in an ice/brine bath for 5 minutes, and 326 mg of oetadeeyl bromide (0.98 mmol) added in portions, followed by warming to room temperature and vigorous stirring for 6 hours. At this time, an aliquot, was removed, decocted, mid quantitatively analyzed by GC/MS, The resulting spectrum evinced a signal for the title compound at 25.1 min that corresponded to -· 19% mass yield. Residual isoidide, oetdeeyl bromide and the elimination product, oetadec~l ~ene, also exhibited signals. Thin-layer chromatography (1 : 1

hexanes/ethyi acetate) employing cerium moly date stain manifested three salient spots, one near the solvent front consistent with octadecylbromi.de (and oetadec-i-ene), one with rf- 0.44 consistent with the title compound and one near the baseline, representing residual isoidide.

C. Isosorbide

Example 9: Synthesis of (3S,3aR_i6R,6aR)-6^octyloxy)hexahydroi iro 3,2-b]fxiran-3" l somer

Experimental: A 20 cc scintillation vial equipped with a ½" egg-shaped PTFE coated magnetic stir bar was charged with 138 mg of isosorbide (0.94 mmol), 1.38 mg of potassium f-butoxide (1.23 mmol), 5 ml. of dry DMF and stirred for 30 minutes. A rubber septum was then fi ted to the vial month, the vial immersed in an ice/brine bath for 5 minutes, and 215 μΐ, of octyl bromide ( 1.23 mmol) added dropwise, followed by warming to room temperature and vigorous stirring for 6 hours. At this time, an aliquot was removed, decocted, and quantitatively analyzed by GC/MS. The resulting spectrum evinced signals for the title compounds at. 1.7.4 and 17.9 min that corresponded to mass yields of 14% and 17%

respectively. Residua! isosorbide. octyl bromide and some elimination product, oct- 1 -ene was also observed. Thin-layer chromatography (1 : 1 hexanes/ethyi acetate) employing cerium molybdate stain manifested four salient spots, one near the solvent front consistent with octylbromide (and oct-l -ene}, two with rfs =· 0.32, 0.34, consistent with the title compounds and one near the baseline, divulging remnant isosorbide. Example 10: Synthesis of (3S₅3a ,6R,6a )-6-(decyloxy)hex^ydrofiiro 3,2-b^']fiiran-3-oi +

Isomer

Experimental: A 20 cc scintillation vial equipped with a ½" egg-shaped PTFE coated magnetic stir bar was charged wit h 127 mg of isosorbide (0,87 mmol), 127 mg of potassium -butoxide ( 1.13 mmol), 5 mL of dry DMF and stirred for 30 minutes. A rubber septum was then fitted to the viai mouth, the vial immersed in an ice/brine bath tor 5 minutes, and 235 ,uL of decyl bromide ( 1.23 mmol) added dropwise, followed by warming to room temperature and vigorous stirring for 6 hours. At this time, an aliquot, was removed, decocted, and quantitatively analyzed by GC MS. The resulting spectrum evinced signals for the title compounds at 19.0 and 1 .4 min that corresponded to mass yield of -14% and -19% respectively. Residual isosorbide, decyl bromide and some elimination product, dec-i-ene was also observed. Thin-layer chromatography (1:1 hex arses/ethyl acetate) employing cerium molybdate stain manifested four salient spots, one near the solvent front consistent with decy (bromide (and dec-1 ~ene), two with rf - 0,38 and 0.40 consistent with the title

compounds and one near the baseline, indicating unreaete isosorbide. Example 1 1 : Synthesis of (3S a _i6R,6a )-6-{dodecyioxy}hexaiiydrofeo[3,2-b]furan-3-o1^■·^'■ somer

Experimental: A 20 cc scintillation vial equipped with a ½" egg-shaped PTFE coated magnetic stir bar was charged with 1 18 mg of isosorbide (0.81 mmol), 1 18 mg of potassium i-butoxide ί 1.05 mmol), 5 m.L of dry DMF and stirred for 30 minutes. A rubber septum was then fitted to the vial mouth, the vial immersed in an ice/brine bath for 5 minutes, and 254 μΐ of dodecyl bromide ( 1.09 mmol) added dropwise, followed by warming to room temperature and vigorous stirring for 6 hours. At this time, an aliquot was removed, decocted, and quantitativel analyzed by GO/MS. The resulting spectrum manifested signals for the title compounds at 20.4 and 20.8 mm that corresponded to mass yields of 15 and 1 8%

respectively. Residual isosorbide, dodecyl bromide and some elimination product, dodec-1- ene was also observed. Thin-layer chromatography (1 :1 hexanes/ethyl acetate) employing cerium molybdate stain manifested three salient spots, one near the solvent front consistent with dodecyihromide (and dodec~l ~ene), two with rfs - 0.40, 0.42 consistent, with the title compounds and one near the baseline, specifying residual isosorbide.

Example 12: Synthesis of (3S ^_>6 _{6aR)-6~(octadecy}oxy)hexahydrof iro 3,2-bjforan-3-ol

+ Isomer

Experimental: A 20 cc scintillation vial equipped with a egg-shaped PTFE coated magnetic stir bar was charged with 123 mg of isosorbide (0.84 mmol), 123 mg of potassium /-butoxide (1.09 mmol ), 5 ml, of dry DMF and stirred for 30 minutes. The vial was capped and immersed in an ice/brine bath for 5 minutes, and 365 mg of octadecyl bromide ( 1.09 mmol) added in portions, followed by warming to room temperature and vigorous stirring for 6 hours. At this time, an aliquo was removed, decocted, and quantitatively analyzed by GC/MS. The resulting spectrum revealed signals for the title compounds at 24.7 and 25.2 min that corresponded to mass yields of 1 1% and 13% respectively. Residual isosorbide, octadecyl bromide and some elimination product, octadec-l -ene was also observed. Thin- layer chromatography (1 : 1 hexanes ethyl acetate) employing cerium molybdate stain manifested three salient spots, one near the solvent front consistent with octadecylhromide (and octadee-l-ene). one with rf ^::: 0.44 consistent with the title compounds and one near the baseline, representing remnant isosorbide. Comparative Example 1 , Under the same reaction conditions, an experiment using sodium hydride, a highly reacti ve Bronsted base (p a - 36), in lieu of potassium /-butoxide was performed and evinced isomanmde dioctyl diether with an exiguous amount, o monooctyl ether.

Synthesis of (3R,3aR,6 ,6aR)~6^octyloxy)hexahydrof ro[3 ,2~b]furan-3-ol

Major product

Experimental: A 20 cc scintillation vial equipped with a ½" egg- shaped PTFE coated magnetic stir bar was charged with 1 10 mg ofisomanni.de (0.97 mmol), 43 mg of sodium hydride (60% in mineral oil, 1 ,06 mmol), 5 ml, of dry DMF and stirred for 30 minutes. A rubber septum was then fitted to the vial mouth, the vial immersed in an ice/brine bath for 5 minut.es, and 222 μL· of octylbromide ( 1.26 mmoi) added dropwi.se, followed by wanning to room temperature and vigorous stirring for 6 hours. At this time, an aliquot was removed, decocted, and quantitatively analyzed by GC/MS, The resulting spectrum evinced a signal for the title compound at 16.3 mm that corresponded to - 6% mass yield. The primary product was disclosed as the octyl diether of isomamiide with ~27% mass yield and retention of 23.1 mi Significant amounts of residua! isomannide and octylbromide were also observed.

The present invention has been described in general and in detail by way of examples. Persons of ski ll in the art understand that the invention is not limited necessarily to the embodiments specifically disclosed, but. tha 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 know or to be developed, which may he used within the scope of the invention. Therefore, unless changes otherwise depart from the scope of the invention, the changes should he construed as being included herein.

Claims

We Claim:

1 . A method of making a mono-ether of an isohexide, comprising: reac ting an isohexide with a Bronsted base and an alky! species in a reaction system, said isohexide and a conjugate acid of said Bronsted base each having an acid disassociation consiani, pKa. wherein an absolute value of the difference (Δ pKa = pKa Bronsted base - p a isohexide -OH) between said pKa values of said isohexide stereoisomer and said conj ugate acid of said Brousted base is at least. 0.

2. The method according to claim L wherein said Δ pKa is about 1 to about 8.

3. The method according to claim 1, wherein said Bronsied base is a non~nucleophilic species.

4. lite method according to claim I , wherein said Bronsted base is at least one of the following: a ?~butoxide, a hindered amine, a carbonate, a hydroxide, a hydride, an alky I lithium, an alky! magnesium, an a!k i cupraie, and a metal amide.

5. The method according to claim 1, wherein said alkyl species is a halide or a sulfonate.

6. The method according to claim 1, wherein a polar, aptotic solvent is present.

7. The method according to claim 6, wherein said solvent is a non-nucleophilic species with a dielectric constant (permittivity) within a range from about 20 to about 50.

8. The method according to claim 6, wherein said solvent is at least one of the following: acetone, acetomtrile, Ν,Ν-dimethyi-formamide (DMF), dimethyl sulfoxide (DMSO), N,N-dimethyiacetamide, hexamethylphosphoramide (HMPA), nitromethane.

9. The method according to claim 6, wherein said solvent is tetrahyckofuran ίΤΉΡ , or 1 ,4 dioxane.

10. The method according to claim 1, further comprising introducing thermal energy into a reaction system when said pKa of said Bransted base is less than a pKa for each hydroxyl moiety of said isohexide.

1 1. The method according to claim 1 , further comprising heating said reaction system; a) to at least about 50°C when said Bronsted base has a pKa of about 4-9; or b) to abou ambient room temperature, up to about 50°C when said Bronsted base has a pK of about 10-16.

12. The method according to claim 1 , further comprising cooling a reaction system to a low temperature of about 0°C to about -78°C when said Bronsted base has a pKa of about 17 or ureater. A method of preparing an isohexide mono-ether comprising: reacting an isohexide with a Brousted base and an alkyl-X species according to the following:

wherein: "X" is a leaving group, "n" is an integer from 0 to 23, and "CA" is a conjugate acid of the Br«*nsted base.

1 . The method according to claim 13, wherein said X leaving group is at least one of the

following: a halide, -QMs

, and -O ff .

15. The method according to claim 1 , wherein said "n" is an integer from 2 to 20,

inclusive.

16. The method according to claim 13, wherein said alkyl-X species has an aliphatic portion with a total length that, ranges from to C₂₅.

17. The method according to claim 16, wherein said alkyl-X species has an aliphatic portion with a total carbon chain that is from C? to Cjg.

18. The method according to claim 13. wherein said isohexide and said conjugate acid of said Bronsted base each having an acid disassoeiation constant pKa, wherei the positive difference (Δ p a.) between said pKa of said isohexide stereoisomer and said conj ugate acid of said Bronsted base is about 1 to about. 10.

1 . An isohexide mono-ether prepared according to claim 13, from a reaction of an

isohexide stereoisomer wit a Bransted base and an aikyl species, said mono-ether comprising:

wherein "n" is an. integer from 0 to 23.

10. The isohexide mono-eiher according to claim 1 % wherein said mono-ether is at least one of the fol lowing compounds: where the isobexide corstams isoffiarmidei

-6-(octyloxy)bex^ydrof ro[3,2-bJfurai3-

-6-(decy!oxy)hexahydrofuro 3,2-b]furan~3-ol

3) (3R₅3aR,6R,6aR)-6-(dodecyloxy)hexahydrofuroP_>2-b]f«ran--3-o!

4) (3R3aR^R,0aR)~0-Cociadecytaxy^

b) where the isohexide contains isoiodide:

l ) (3S aR,6S,6aR 6-(octyloxy)hexahydrofufo[3,2-b3.furan.-3-oj.

2) ( -6 decyloxy)hexahydrofuro 3,2-b]furan-3-oi

3) (3S,3aK,6S,6aR)-6-(dodecyfoxy)hex.aiiydro&ro[3_>2-b]iuran-3-ol

4) (3S3aR_;6S,6aR)-6-(ociadecyloxy)hexa ydroforo[3,2-b)furan-3~oi

where the isohexide contains isosorbide:

1) (3S aR,6R_?6aR}~6'(octyIoxy)hexahydrofuro3,2 '>]furan-3--ol and Isomer

Ϊ) (3S aR_i6R,6aR)-6-(decyioxy}^iexahydroi¾ro[3,2~b]tiraa-

3) (3S aK,6R,6aR)-6-(dodecyloxy)hexahydrofuiO[3,2- |fuT¾n-3-ol mid Isomer

and

4) (SSJ R^R^a ^^ociadecyio y^exah drotWo ^-bJfurai S-ol and Isomer

21. A derivative prepared from an isohexide mono-ether, the derivative having a general form u 1 a compr i ng:

wherein is H, or C¾ - a d R' is selected from the group consisting of SOjH and corresponding anion, PO₃H₂ and corresponding anion(s), and an alkyi, alkyl-eiher, or alkyl-polyether with a chain of€<}-(¾.

22. The derivative according to claim 22, wherein said alkyi polyether is either

Ci ClbOC!IjCl Oi⁾ or C hClI i C!hOCIbC^} [ OIf.

23. lire derivative according to claim 22, wherein said derivative compound is an

amphophilic species.