CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 USC § 119(e) of U.S. Provisional

Application Serial No. 62/059,197, filed on October 3, 2014, the entire disclosure of which incorporated herein by reference

TECHNICAL FIELD

The invention described herein pertains to processes for selectively alkylating methyl alpha- L-rhamnopyranoside and preparing methyl 3-O-(alkyl or alkenyl) alpha- L- rhamnopyranoside substantially free of 2-O-(alkyl or alkenyl) alpha-L-rhamnopyranoside.

Selective alkylation of specific hydroxyl groups in carbohydrates has been described previously in the literature; however, there remains a continued need for methods that provide improved safety, improved yields, and improved selectivities. Selective 3-O-alkylation methods for methyl pyranosides have been previously reported, but the need remains for improved methods for the selective preparation of methyl 3-O-(alkyl or alkenyl) alpha-L- rhamnopyranosides such as those used as intermediates in the preparation of several recently described insecticidal compounds (US 2010/0204165).

A two-step process for selective 3-O-alkylation of methyl alpha-L-rhamno- pyranoside using a stoichiometric tin promoter has been reported (Carbohyr. Res, 211 (1991) 179-182, Scheme 1). A stannylene acetal of methyl alpha-L-rhamnopyranoside was prepared and subsequently treated with allyl bromide or benzyl bromide to afford the desired 3-O-alkyl alpha-L-rhamnopyranoside in good or acceptable yields. It was further reported that no 2-0- alkyl or di-O-alkyl derivatives were detected in the case of the manno- and rhamno- pyranosides.

Scheme 1

isolated A preparation of methyl 3-O-allyl alpha-L-rhamnopyranoside in 40% isolated yield using similar reaction conditions has also been reported (Carbohydr. Res., 356 (2012) 115-131). A disadvantage of this and related procedures is the use of stoichiometric quantities of toxic stannanes and the generation of tin(IV) by-products, which are often difficult to remove from the reaction products.

Methods for mono-alkylation of symmetrical 1,2-diols not requiring tin have been reported (Onomura, et al., Tetrahedron Letters, 50(2009), 1466). For example, Onomura reported that a symmetrical 1,2-diol treated with an alkyl halide, a metal promoter, and potassium carbonate in dimethylformamide at ambient temperature results in >90% isolated yield of the mono-alkylation product. Onomura indicates that the metal promoter must be able to form a bidentate chelate with the 1,2-diol. Although Onomura postulated that a copper(II) salt could be used for this purpose, he only employed aryl boronic acids as promoters. Only the alkylation of symmetrical 1,2-diols was described and the alkylation of pyranosides was not evaluated. Subsequently it has been discovered that application of Onomura' s method to asymmetrical pyranosides containing 1,2-diols, namely methyl alpha-L-rhamnopyranoside, results in inferior yields and prolonged reaction times (See Comparative Example CE1).

It has also been reported that use of one equivalent of potassium iodide, with potassium carbonate as base in the presence of a catalytic amount of boron promoter, 2,2- diphenyl-l,3,2-oxazaborolidin-3-ium-2-uide, results in efficient monoalkylation of symmetrical 1,2-diols with benzyl bromide in acetonitrile at 60 °C (Taylor, et al., J. American Chemical Society, 134(2012), 8260-8267, Scheme 2). However, these conditions were not applied to pyranosides containing asymmetrical 1,2-diols.

Scheme

Regio selective alkylations (methyl, benzyl, and allyl) of carbohydrate diols using copper(II) chelates has been reported (Eby, et al., Carbohydrate Research, 729(1984), 111-120). The reported conditions for this alkylation process requires preparation of the sodium salt of the diol with sodium hydride, followed by addition of copper(II) chloride, followed by addition of the alkylating agent. For carbohydrates containing free hydroxyl groups at the 2- and 3-position, only gluco-, galacto-, and manno- pyranoses and pyranosides were reported undergoing these reactions in high yields. It also was reported that these conditions result in 3-0-:2-0- selectivities ranging from 2.3: 1 to 4.3: 1 for allyl iodide, 1.8: 1 to 5.7: 1 for benzyl iodide, and 3: 1 for methyl iodide. In one instance, methyl 4,6-di-O-benzyl-a-D-mannopyranoside was benzylated with benzyl iodide in high yield with a 3-0-:2-0-selectivity of greater than 19: 1 (Scheme 3).

Scheme 3

DETAILED DESCRIPTION

Described herein are processes for preparing compounds I or II substantially free of the compounds III or IV, respectively.

An illustrative example of the processes described herein is shown in Scheme 4.

Scheme 4

Advantages of this process relative to prior reported processes include (a) the reaction yields the 3-O-alkylated product with improved yield while maintaining selectivity and (b) the avoidance of stoichiometric amounts of tin. Isolated yields are as high as 90% with >3: 1 selectivity for alkylation at the 3-OH relative to the 2-OH.

Described herein is the use of from about 0.5 equivalents to about 3 equivalents of a metal carbonate, from about 0.1 equivalents to about 1 equivalent of a boron promoter, from about 0.1 equivalents to about 2 equivalent of an additive, from about 1 equivalent to about 2 equivalents of an alkylating agent, a polar aprotic solvent, at a temperature of from about 40 °C to about 110 °C at times ranging from about 20 hours to about 72 hours. Under these conditions, high yield and selectivity for 3-O-alkylation over 2-O-alkylation has been observed.

Illustrative metal carbonates useful in the processes described here include sodium carbonate, potassium carbonate, cesium carbonate, and the like. It has been discovered that the alkylation reaction does not proceed to an appreciable degree when the metal carbonate is replaced with a tertiary amine base (See Comparative Example CE2, Entry 1). It has also been discovered that a metal carbonate is necessary for the reaction to proceed efficiently (See Comparative Example CE2, Entry 2).

Boron promoters used in the processes described herein include optionally substituted phenyl boronic acids and diphenylborinates. Illustrative examples include, phenylboronic acid, 2,6-difluoro-phenylboronic acid, 2-methoxyphenylboronic acid,

2-methylphenylboronic acid, 3-methoxyphenylboronic acid, 4-trifluoromethylphenylboronic acid, and 2-aminoethyl diphenylborinate. It has been discovered that the boron promoters improve the efficiency of the reaction (See Comparative Example CE2, Entry 3 and 4).

Additionally, it has been discovered that use of diphenylborinates in catalytic amounts results in improved yields (See Example 5) compared to yields obtained with the use of stoichiometric amounts (See Example 6, Entry 7).

Additives used in the processes described herein include iodide salts, tertiary amine bases, and transition metal salts. Illustrative examples of additives used in the processes described herein include potassium iodide, tetrabutylammonium iodide, triethylamine, diisopropylamine, copper(II) chloride, copper(II) bromide, copper(II) iodide, copper(I) iodide, copper(I) bromide, copper(I) chloride, copper(I) oxide, zinc(II) acetate, and silver(I) chloride. It has been discovered that the use of additives is useful for increasing the rate of the reaction when using activated alkylating agents such as allyl bromide (See Example 6, Entry 3 and 6). It has also been discovered that additives are less effective when non-activated alkylating agents such as iodopropane are employed (See Comparative Example CE2, Entry 6 and Example 6, Entry 1 and Entry 2).

Alkylating agents used in the processes described herein include alkyl bromides, alkyl iodides, alkenyl bromides, alkenyl iodides, alkylaryl bromides and alkylaryl iodides. Illustrative examples include bromopropane, iodopropane, allyl bromide, allyl iodide, benzyl bromide, and benzyl iodide.

Polar aprotic solvents used in the processes described herein include alkyl nitriles. Illustrative examples include acetonitrile and propionitrile. It has been discovered that use of nitrile solvents provides improved yields compared to the yields obtained with the use of dimethylformamide (See Comparative Example CE2, Entry 5).

The selective alkylation processes described herein result in mixtures enriched in the 3-O-alkylated isomer of methyl alpha-L-rhamnopyranoside. However, use of a mixture of methyl 3-0-(alkyl or alkenyl) alpha-L-rhamnopyranoside containing the 2-0-(alkyl or alkenyl) isomer in subsequent process steps involved in the preparation of pesticidal compounds is complicated by difficulties in removing the 2-0-(alkyl or alkenyl) isomers that arise in each of those later steps from the desired 3-0-(alkyl or alkenyl) products. Described herein is a process for removing the 2-O-(alkyl or alkenyl) isomer formed in the alkylation of methyl alpha-L- rhamnopyranoside. It has been discovered that a simple process comprising an oxidation step can be used to remove the unwanted isomer. Described herein is the process of contacting a solution or suspension of the reaction product formed in the alkylation step with an oxidant that selectively reacts with vicinal hydroxyl groups allowing for the purification of the 3-O-alkylated isomer via aqueous extraction.

Described herein is the treatment of a solution or suspension containing a mixture of methyl 3-0-(alkyl or alkenyl) alpha-L-rhamnopyranoside and methyl 2-0-(alkyl or alkenyl) alpha-L-rhamnopyranoside with a solution of suspension of sodium periodate followed by an aqueous extraction to yield the 3-O-alkylated rhamnose derivative substantially free of the 2-O-alkylated isomer. It is appreciated that other oxidants may be used for the selective removal of the undesired isomer. It has been observed that not all oxidizers are suitable (See Comparative Example CE3).

Described herein is the treatment of a solution or suspension of methyl 3-0- alkylated rhamnopyranoside, contaminated with from about 5% to about 25% of the 2-0- alkylated rhamnopyranoside, with an aqueous solution or suspension of sodium periodate (from about 1 to about 3 equivalents relative to the amount of 2-0-(alkyl or alkenyl) isomer present). Upon completion of the oxidation, the resulting mixture is extracted with an organic solvent, which results in extraction of the unreacted 3-0-(alkyl or alkenyl) rhamnopyranoside. Removal of solvent leaves methyl 3-0-(alkyl or alkenyl) rhamnopyranoside substantially free of methyl 2-0-(alkyl or alkenyl) rhamnopyranoside. Illustrative organic solvents for extraction include ethyl acetate, methyl tert-butyl ether, and the like. Described herein is treatment of a dimethylsulfoxide solution of methyl 3-0-(alkyl or alkenyl) rhamnopyranoside which is substantially free of methyl 2-0-(alkyl or alkenyl) rhamnopyranoside with a base such as powdered potassium hydroxide and an additional alkylating agent. Illustrative additional alkylating agents include methylating agents dimethyl sulfate, iodomethane, bromomethane, chloromethane, methyl trifluoromethylsulfonate, and the like. Extraction of the

dimethylsulfoxide solution, upon completion of alkylation, with a hydrocarbon or ethereal solvent results in isolation of methyl 3-0-(alkyl or alkenyl) 2,4-di-O-methyl alpha-L- rhamnopyranoside substantially free of methyl 2-0-(alkyl or alkenyl) 2,4-di-O-methyl alpha-L- rhamnopyranoside. Illustrative hydrocarbon solvents include heptane, hexane, cyclohexane, and the like. Illustrative ethereal solvents include diethyl ether, methyl tert-butyl ether, and the like. Scheme 5

Several illustrative embodiments of the invention are described by the following clauses:

A process (process I) for preparing a compound (compound I) having the formula

wherein R is alkyl, alkenyl, or alkylaryl each of which is optionally substituted; the process comprising:

(a) contacting compound (A)

in a polar aprotic solvent, at a temperature of about 22 °C to about 110 °C, with

an amount of an alkylating agent (R ^x -X), wherein the amount the alkylating agent is about 1 mole-equivalent to about 2 mole-equivalents based on the amount of compound (A), wherein R ¹ is as previously defined and X is CI, Br, or I; and

an amount of a metal carbonate, wherein the amount of the metal carbonate is about 0.5 mole-equivalent to about 3 mole-equivalents based on the amount of compound (A); and

an amount of a boron promoter, wherein the amount of the boron promoter is about 0.1 mole-equivalents to about 1 mole-equivalent based on the amount of compound (A); and

an amount of an additive, wherein the amount of the additive is about 0.2 mole- equivalents to about 2 mole-equivalent based on the amount of compound (A) when Ri-X is activated; or

no additive when R ^l -X is unactivated.

• A process (process II) for preparing a compound (compound I) having the formula

wherein R is alkyl, alkenyl, or alkylaryl each of which is optionally substituted; the process comprising:

(a) contacting a mixture of compounds (I) and (III)

(III)

with a liquid containing an oxidant at a temperature from about 15 °C to about 40 °C.

• The process of the preceding clause wherein the resulting compound (I) is substantially free of compound (III).

A process (process III) for preparing a compound (compound II) having the formula

wherein R is alkyl, alkenyl, or alkylaryl each of which is optionally substituted; and R is alkyl;

the process comprising:

(a) contacting a mixture of compounds (I) and (III)

with a liquid containing an oxidant at a temperature from about 15 °C to about 40 °C, and (b) contacting the resulting compound (I)

in a polar aprotic solvent, at a temperature of about 20 °C to about 60 °C, with

an amount of an additional alkylating agent (R 2 -X 2 ), wherein the amount of an additional alkylating agent is about 2 mole-equivalents to about 3 mole-equivalents based on the amount of compound (I),

wherein R 2 is as previously defined and X 2 is CI, Br, I, OS(0) ₂ CF3, or

OS(0) ₂ OCH ₃ ; and

an amount of a base, where the amount of the base is about 3 mole-equivalents to about 4 mole-equivalents based on the amount of compound (I).

• The process of the preceding clause wherein the resulting compound (II) is substantially free of compound (IV).

• The process of any one of the preceding clauses wherein the mixture of compounds (I) and (III) is formed by process I.

• The process of any one of the preceding clauses wherein the polar aprotic solvent of step (a) is acetonitrile or propionitrile.

• The process of any one of the preceding clauses wherein the temperature of step (a) is about 60 °C to about 80 °C.

The process of any one of the preceding clauses wherein R ¹ is alkyl.

The process of any one of the preceding clauses wherein R ¹ is a (Ci-C ₄ ) alkyl.

The process of any one of the preceding clauses wherein R ¹ -X is a (C ₃ ) alkyl iodide.

The process of any one of the preceding clauses wherein R ¹ -X is iodopropane.

The process of any one of the preceding clauses wherein R ¹ is alkenyl.

The process of any one of the preceding clauses wherein R ¹ is a (C ₂ -C ₄ ) alkenyl.

The process of any one of the preceding clauses wherein R ¹ is a (C ₃ ) alkenyl. • The process of any one of the preceding clauses wherein R -X is allyl bromide.

• The process of any one of the preceding clauses wherein the amount of metal carbonate is about 1 mole-equivalent to about 2 mole-equivalents based on the amount of (A).

• The process of any one of the preceding clauses wherein the amount of metal carbonate is about 1 mole-equivalent to about 1.5 mole-equivalents based on the amount of (A).

• The process of any one of the preceding clauses wherein the metal carbonate is potassium carbonate or cesium carbonate.

• The process of any one of the preceding clauses wherein the amount of boron promoter is about 0.1 mole-equivalents to about 0.8 mole-equivalents based on the amount of (A).

• The process of any one of the preceding clauses wherein the boron promoter is an aryl boronic acid or a diphenylborinate.

• The process of any one of the preceding clauses wherein the boron promoter is

wherein R ^a is H, F, CH ₃ , OCH , or CF , and n is 1 or 2.

· The process of any one of the preceding clauses wherein R ^a is H, 2-F, 2-OCH ₃ , 2-CB 3-OCH ₃ , or 4-CF ₃ , and n is 1.

• The process of any one of the preceding clauses wherein the aryl boronic acid is 2,6- difluorophenyl boronic acid.

• The process of any one of the preceding clauses wherein the boron promoter is a diphenylborinate.

The process of any one

The process of any one of the preceding clauses wherein the amount of the additive of ) is about 0.2 mole-equivalents to about 0.5 mole-equivalents based on the amount of (A).

The process of any one of the preceding clauses wherein there is no additive in step • The process of any one of the preceding clauses wherein the additive of step (a) is an iodide salt.

• The process of any one of the preceding clauses wherein the additive of step (a) is potassium iodide.

• The process of any one of the preceding clauses wherein the additive of step (a) is a tertiary amine base.

• The process of any one of the preceding clauses wherein the additive of step (a) is triethylamine or diisopropylethylamine.

• The process of any one of the preceding clauses wherein the additive of step (a) is a transition metal salt.

• The process of any one of the preceding clauses wherein the additive of step (a) is selected from copper(II) chloride, copper(II) bromide, copper(II) iodide, copper(I) iodide, copper(I) bromide, copper(I) chloride, copper(I) oxide, zinc(II) acetate, and silver(I) chloride.

• The process of any one of the preceding clauses wherein the additive of step (a) is selected from copper(II) chloride or copper(I) bromide.

• The process of any one of the preceding clauses wherein the temperature of step (a) is from about 20 °C to about 35 °C.

• The process of any one of the preceding clauses wherein the oxidant of step (a) is a periodate salt or manganese dioxide.

• The process of any one of the preceding clauses wherein the oxidant of step (a) is a periodate salt.

• The process of any one of the preceding clauses wherein the periodate salt of step (a) is sodium periodate.

• The process of any one of the preceding clauses wherein the oxidant of step (a) is manganese dioxide.

• The process of any one of the preceding clauses wherein the polar aprotic solvent of step (b) is dimethylsulfoxide.

• The process of any one of the preceding clauses wherein the temperature of step (b) is from about 20 °C to about 40 °C.

• The process of any one of the preceding clauses wherein R is a (Ci-C4) alkyl.

• The process of any one of the preceding clauses wherein R 2 -X 2 is iodomethane or dimethylsulfate. • The process of any one of the preceding clauses wherein the amount of base of step (b) is about 3 mole-equivalents to about 3.5 mole-equivalents based on the amount of compound (I).

• The process of any one of the preceding clauses wherein the base of step (b) is an inorganic base.

• The process of any one of the preceding clauses wherein the base of step (b) is potassium hydroxide or sodium hydroxide.

It is to be understood that the preceding clauses do not include any process that contains a combination of mutually exclusive elements or conditions.

As used herein, the term "alkyl" includes a chain of carbon atoms, which is optionally branched. As used herein, the term "alkenyl" includes a chain of carbon atoms, which is optionally branched, and includes at least one double bond. It is to be further understood that in certain embodiments, alkyl is advantageously of limited length, (C Cg), (C - C ₆ ), and (Q-C. . It is to be further understood that in certain embodiments alkenyl may be advantageously of limited length, including (C ₂ -C ₆ ), and (C ₂ -C4). Illustrative alkyl and alkenyl groups are, but not limited to, methyl, ethyl, n-propyl, isopropyl, w-butyl, isobutyl, sec-butyl, ie/t-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl, and the like, and the corresponding groups containing one or more double bonds, or a combination thereof.

As used herein, the term "aryl" includes monocyclic and polycyclic aromatic carbocyclic groups, each of which may be optionally substituted. Illustrative aromatic carbocyclic groups described herein include, but are not limited to, phenyl, naphthyl, and the like.

As used herein, the term "optionally substituted" includes the replacement of hydrogen atoms with other functional groups on radical that is optionally substituted. Such other functional groups illustratively include, but are not limited to, amino, hydroxy, halo, thio, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonyl, sulfonic acids and derivatives thereof, carboxylic acids and derivatives thereof, and the like. It is to be understood that any of amino, hydroxy, thio, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, and/or heteroarylheteroalkyl is optionally substituted.

As used herein the term "substantially free of when used to describe a compound that may contain some amount of another compound as an impurity or contaminant generally means that the amount of the impurity or contaminant that is present is less than about 3%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.25%, or less than about 0.1%.

The following illustrative examples further illustrate specific embodiments of the invention. These examples should not be interpreted in any way to limit the invention.

EXAMPLES

EXAMPLE 1: Synthesis of methyl 3-O-allyl alpha-L-rhamnopyranoside

To a round-bottomed flask (100 mL) equipped with magnetic stirrer was added methyl alpha-L-rhamnopyranoside (5.0 g, 28 mmol, 1 equivalent), dry dimethylformamide (25 mL), 4-fluorophenylboronic acid (0.98 g, 7.0 mmol, 0.25 equivalents), potassium carbonate (7.8 g, 56 mmol, 2 equivalents), and allyl bromide (6.8 g, 56 mmol, 2 equivalents). The solution was heated at 40 °C for 48 hours, then it was cooled, partitioned between water (100 mL) and dichloromethane (3 x 100 mL). The organic layer was dried over magnesium sulfate and concentrated at 40 °C under high vacuum to remove the excess dimethylformamide, furnishing unreacted methyl alpha-L-rhamnopyranoside (-30%) and the title compound as a 5.25: 1 mixture of 3:2 O-alkylation products as determined by GCMS as a light tan oil (3.9 g, 44%): Methyl 3-0-allyl alpha-L-rhamnopyranoside: 1H NMR (400 MHz, CDC1 ₃ ) δ 6.04 - 5.87 (m, 1H), 5.33 (dd, J = 17.2, 1.5 Hz, 1H), 5.24 (dd, J = 10.4, 1.4 Hz, 1H), 4.72 (dd, J = 1.7, 0.6 Hz, 2H), 4.23 - 4.03 (m, 1H), 4.03 - 4.00 (m, 1H), 3.71 - 3.62 (m, 1H), 3.56 - 3.52 (m, 1H), 3.38 (s, 3H), 2.30 (d, J = 2.4 Hz, 1H), 1.33 (d, J = 6.2 Hz, 3H); ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 134.24, 118.07, 100.39, 79.41, 71.47, 70.47, 67.73, 67.57, 54.86, 17.66. Methyl 2- O-allyl alpha-L-rhamnopyranoside: 1H NMR (400 MHz, CDC1 ₃ ) δ 6.04 - 5.87 (m, 1H), 5.33 (dd, J = 17.2, 1.5 Hz, 1H), 5.24 (dd, J = 10.4, 1.4 Hz, 1H), 4.72 (dd, J = 1.7, 0.6 Hz, 2H), 4.23 - 4.03 (m, 1H), 4.03 - 4.00 (m, 1H), 3.71 - 3.62 (m, 1H), 3.56 - 3.52 (m, 1H), 3.38 (s, 3H), 2.30 (d, J = 2.4 Hz, 1H), 1.33 (d, J = 6.2 Hz, 3H).

EXAMPLE 2: Synthesis of 3-O-allyl-alpha-L-rhamnopyranoside

Methyl alpha-L-rhamnopyranoside (5.00 g, 28.1 mmol, 1 equivalent) and phenylboronic acid (3.42 g, 28.1 mmol, 1 equivalent) were dissolved in dry acetonitrile (250 mL) in a round-bottomed flask (500 mL). Cesium carbonate (10.1 g, 30.9 mmol, 1.1 equivalents), potassium iodide (4.66 g, 28.1 mmol, 1 equivalents), and allyl bromide (3.16 mL, 36.5 mmol, 1.3 equivalents) were added. The reaction was stirred and heated at 70 °C under nitrogen. After 24 hours, the solution was cooled to room temperature and poured onto water. The products were extracted into ethyl acetate and the aqueous layer was washed with ethyl acetate (3x). The combined organics were dried and concentrated to give a yellow oil with white solid impurities. The residue was washed with ether, filtered through Celite®, and dried to give the title compound as a 5.25: 1 mixture of 3:2 O-alkylation products as determined by 1H NMR as a yellow oil (3.28 g, 53% crude).

EXA -O-allyl-alpha-L-rhamnopyranoside

Methyl alpha-L-rhamnopyranoside (5.00 g, 28.1 mmol, 1 equivalent) and phenylboronic acid (3.42 g, 28.1 mmol, 1 equivalent) were dissolved in dry acetonitrile (250 mL) in a round-bottomed flask (500 mL). Potassium carbonate (4.27 g, 30.9 mmol, 1.1 equivalents), potassium iodide (4.66 g, 28.1 mmol, 1 equivalent), and allyl bromide (3.16 mL, 36.5 mmol, 1.3 equivalents) were added. The reaction was stirred and heated at 70 °C under nitrogen for 24 hours. The solution was then cooled and poured onto water. The organics were extracted and the aqueous layer was extracted with ethyl acetate (3x). The combined organics were dried and concentrated to give a yellow oil. The residue was dissolved with ether, filtered through Celite®, and concentrated to give the title compound as a 3.54: 1 mixture of 3:2 O- alkylation products as determined by 1H NMR as a yellow oil (5.67 g, 93% crude).

EXAMPLE 4: Synthesis of 3-O-allyl-alpha-L-rhamnopyranoside

In a 22 L reactor equipped with an overhead stirrer, a condenser, a temperature probe, and an addition funnel, were added methyl alpha-L-rhamnopyranoside (1.25 kg, 7.01 mol, 1 equivalent), potassium iodide (291 g, 1.75 mol, 0.25 equivalents), phenylboronic acid (171 g, 1.40 mol, 0.2 equivalents), and potassium carbonate (1.45 kg, 10.5 mol, 1.5

equivalents). The reactor was flushed with nitrogen and dry acetonitrile (7 L) was added. This mixture was stirred at 25 °C for 20 minutes and then heated at 60 °C for 30 minutes. Allyl bromide (911 mL, 10.5 mol, 1.5 equivalents) was then added to the mixture with efficient stirring and the mixture was heated at 75 °C for 48 hrs. Thin layer chromatography showed completion of the reaction. The reaction mixture was filtered through Celite® and the Celite® was washed with ethyl acetate (4 x 1 L). The combined filtrate was concentrated to give the title compound as a 3.3: 1 mixture of 3:2 O-alkylation products as a viscous brown oil (1.53 kg, 100% crude).

EXAMPLE 5: S nthesis of 3-O-allyl-alpha-L-rhamnopyranoside

In a round-bottomed flask (100 mL) equipped with a condenser were added methyl alpha-L-rhamnopyranoside (2.0 g, 11 mmol, 1 equivalent), 2-aminoethyl

diphenylborinate (0.252 g, 1.12 mmol. 0.1 equivalents), potassium iodide (1.86 g, 11.2 mmol, 1 equivalents), and potassium carbonate (1.71 g, 12.3 mmol, 1.1 equivalents). The round bottom flask was flushed with nitrogen and dry acetonitrile (10 mL) was added. The mixture was stirred at 25 °C for 20 minutes and allyl bromide (1.46 mL, 16.8 mmol, 1.5 equivalents) was added to the suspension. A nitrogen balloon was put on top of the condenser. The reaction mixture was heated at 60 °C for 24 hours. Thin layer chromatography showed completion of the reaction. The reaction mixture was cooled to 25 °C, filtered through Celite® and the Celite® was washed with ethyl acetate (3 x 20 mL) and the washings and filtrate were concentrated. This gave the title compound as a 3.3: 1 mixture of 3:2 O-alkylation products as a colorless oil (3.05 g, 127% crude).

EXAMPLE 6: Synthesis of 3-O-allyl/alkyl-alpha-L-rhamnopyranoside

A 100 mL round bottom flask was charged with solvent (25 mL), methyl alpha- L-rhamnopyranoside, metal carbonate or tertiary amine base, alkylating agent, boron promoter, and additive (see Table 1). The solution was stirred under nitrogen atmosphere and heated at the temperature listed for the time listed, then it was cooled, diluted with diethyl ether (50 mL), vacuum filtered, and concentrated. The resulting oil was purified by flash column

chromatography using dichloromethane followed by 3% methanol/dichloromethane as eluent. This purification removed most (or all) of the unreacted methyl alpha-L-rhamnopyranoside and other impurities, leaving the O-alkylated products which were collected and analyzed for yield and selectivity. Results of each trial are shown in Table 1.

Table 1

1. Unless otherwise noted, isomer ratio is measured by comparing proton peak areas for the anomeric-OMe substituent.

2. Isomer ratio was measured by comparing gas chromatography peak areas

3. HB = diisopropylethylamine; KI = potassium iodide

EXAMPLE 7: Purification of methyl 3-O-allyl alpha-L-rhamnopyranoside using sodium periodate

To a stirred solution of a 73:27 mixture of methyl 3-O-allyl alpha-L- rhamnopyranoside and methyl 2-O-allyl alpha-L-rhamnopyranoside (0.050 g, 0.23 mmol) in acetonitrile (7 mL)/water (3.5 mL) in a 20 mL vial was added sodium periodate (0.050 g, 0.23 mmol, 1 equivalent). The solution was stirred at ambient temperature under nitrogen for 24 hours. The reaction was monitored by thin layer chromatography (R/for the 2' isomer is 0.25; R/for the 3' isomer is 0.3 using a solvent system consisting of 3:3:3: 1 hexanes:ethyl acetate:dichloromethane:acetone, visualized by phosphomolybdic acid stain.) and by GCMS, which showed no detectable 2-isomer after 24 hours.

EXAMPLE 8: Purification of methyl 3-O-allyl alpha-L-rhamnopyranoside using manganese dioxide

To a stirred solution of a 73:27 mixture of methyl 3-O-allyl alpha-L- rhamnopyranoside and methyl 2-O-allyl alpha-L-rhamnopyranoside (0.050 g, 0.23 mmol) in acetonitrile (7 mL) in a 20 mL vial was added manganese dioxide (0.26 g, 3.0 mmol, 13 equivalents). The solution was stirred at room temperature under nitrogen for 24 hours. The reaction was monitored by thin layer chromatography (R/for the 2-isomer is 0.25; R/for the 3- isomer is 0.3 using a solvent system consisting of 3:3:3: 1 hexanes:ethyl

acetate:dichloromethane:acetone, visualized by phosphomolybdic acid stain.) and by GCMS, which showed no detectable 2-isomer after 24 hours. EXAMPLE 9: Purification of methyl 3-O-allyl alpha-L-rhamnopyranoside examining time and manganese dioxide equivalents

Into a 100 mL round bottom flask equipped with a reflux condenser and a magnetic stirbar was added a mixture of methyl 3-0-allyl/2-O-allyl alpha-L-rhamnopyranoside (-3: 1, 1.0 g, 4.6 mmol), acetonitrile (25 mL), and Cams activated Carulite 400, type E manganese(IV) oxide (0.40 g, 4.6 mmol, black powder < 3 micron particle size, 1 equivalent). The black suspension was heated to 70 °C. After two hours of heating, the reaction was cooled and analyzed by GCMS, and 1H NMR. Analysis showed remaining 2-O-allyl isomer. Additional activated manganese dioxide (0.50 g, 5.7 mmol, 1.2 equivalents) was added and the mixture heated at 70 °C for 2 hours. Analysis by GCMS, and 1H NMR showed remaining 2-O-allyl isomer. Additional activated manganese dioxide (0.50 g, 5.7 mmol, 1.2 equivalents) was added and the mixture heated at 70 °C for 2 hours. Analytical results show less than 1% of remaining 2-O-allyl isomer (see Table 2 below). The mixture was vacuum filtered through a plug of Celite® and the Celite® pad rinsed with acetonitrile (2 x 25 mL). The filtrate and rinses were combined and concentrated to give a brown oil (0.74 g). Analysis by 1H NMR showed a 3:2-0- allyl ratio of 99: 1 with acetonitrile solvent (15% by mass). Analysis of the brown oil by GCMS showed a 3:2-O-allyl ratio of 99: 1 and 4% of an impurity tentatively assigned as the 3-keto derivative, (2R,3 _l S',5 _l S ^, ,6 _l S ^, )-3-(allyloxy)-5-hydroxy-2-methoxy-6-methyldihydro-2H- pyran- 4(3H)-one.

Table 2

EXAMPLE 10: Purification of methyl 3-O-allyl alpha-L-rhamnopyranoside examining time and manganese dioxide equivalents

Into a 500 mL three-necked round bottom flask equipped with a reflux condenser, a mechanical stirrer, and a thermocouple was added a solution of a mixture of methyl 3-0-allyl/2- O-allyl alpha-L-rhamnopyranoside in acetonitrile (-3: 1, 0.17% (w/w), 125 g solution, 21 g substrate, 96 mmol). Activated manganese dioxide (Cams activated Carulite 400, type E , 53 g, 616 mmol, black powder < 3 micron particle size, 6.4 equivalents) was added portionwise (in portions of 3 equivalents, 2 equivalents, and 1.4 equivalents every 3 hours). The black suspension was heated at 75 °C and analyzed by 1H NMR every 3 hours. After the addition of 6.4 equivalents of manganese dioxide and heating for a total of 12 hours, the ratio of 3-0:2-0- allyl isomer was 50: 1 by 1H NMR. The black suspension was cooled to 25 °C and the mixture was vacuum filtered through a plug of Celite® and the Celite® pad rinsed with acetonitrile (2 x 100 mL). The filtrate and rinses were combined (yellow solution) and concentrated to give a light brown oil (19.3 g). Analysis of the brown oil by 1H NMR showed a 50: 1 ratio of 3-0:2-0- allyl isomer with acetonitrile solvent (20% by mass). Table 3

EXAMPLE 11: Synthesis of methyl 3-O-allyl-2,4-di-0-methyl alpha-L-rhamnopyranoside.

A solution of methyl 3-O-allyl alpha-L-rhamnopyranoside (2.60 g, 11.9 mmol) contaminated with 20+% of the 2-isomer was stirred in acetonitrile (25 mL). To this solution was added a solution of sodium periodate (0.750 g, 3.50 mmol) in water (20 mL). This solution was allowed to stir for 2 hours, then it was diluted with ethyl acetate (50 mL) and the aqueous layer removed and re-extracted with ethyl acetate (50 mL). The combined organic layers were concentrated under vacuum, then the remaining residual oil was dissolved in dimethyl sulfoxide (15 mL) and stirred at ambient temperature while powdered potassium hydroxide (2.00 g) was added. Methyl sulfate (total of 3.35 grams) was then added in 0.5 mL increments, maintaining a temperature below 35 °C. Stirring was continued overnight, then the solution was extracted with hexanes (2 x 75 mL). The combined hexane extracts were concentrated to provide the title compound as a colorless oil (1.40 g, 48%). 1H NMR, within the limits of detection, shows that this material is the 3-O-allyl isomer, with no evidence of the 2-isomer: 1H NMR (400 MHz, CDC1 ₃ ) δ 6.07 - 5.85 (m, 1H), 5.40 - 5.25 (m, 1H), 5.24 - 5.09 (m, 1H), 4.73 - 4.63(m, 1H), 4.24 - 4.11 (m, 2H), 3.69 - 3.40 (m, 10H), 3.35 (s, 3H), 3.14 (t, 1H), 1.30 (d, 3H). ¹³ C NMR (101 MHz, CDCI ₃ ) δ 135.25, 116.82, 98.35, 82.31, 79.31, 78.39, 71.33,67.88, 61.14, 59.37, 54.84, 17.91. COMPARATIVE EXAMPLES

EXAMPLE CE1: Synthesis of 3-O-allyl/alkyl-alpha-L-rhamnopyranoside using Onomura conditions.

A 100 mL round bottom flask was charged with dimethylformamide (25 mL), methyl alpha-L-rhamnopyranoside, allyl bromide, phenyl boronic acid, and metal carbonate 0 (see Table CE1). The solution was stirred under nitrogen atmosphere and heated at the

temperature listed for the time listed, then it was cooled, diluted with diethyl ether (50 mL), vacuum filtered, and concentrated. The resulting oil was purified by flash column

chromatography using dichloromethane followed by 3% methanol/dichloromethane as eluent. This purification removed most (or all) of the unreacted methyl alpha-L-rhamnopyranoside and 5 other impurities. The O-alkylated products were collected and analyzed for yield and

selectivity. Results of each trial are shown in Table CE1.

Table CE1

1. Yield is the combined isolated yield of 2-O-allyl and 3-O-allyl products.

0 2. Ratio of isomers was measured by comparing the integral for the anomeric -OMe peaks, which occur at 3.37 and 3.36 ppm, respectively. EXAMPLE CE2: Synthesis of 3-O-allyl/alkyl-alpha-L-rhamnopyranoside

A 100 mL round bottom flask was charged with acetonitrile (25 mL), methyl alpha-L-rhamnopyranoside, metal carbonate or tertiary amine base, alkylating agent, phenyl boronic acid, and additive (see Table CE2). The solution was stirred under nitrogen atmosphere and heated at the temperature listed for the time listed, then it was cooled, diluted with diethyl ether (50 mL), vacuum filtered, and concentrated. The resulting oil was purified by flash column chromatography using dichloromethane followed by 3% methanol/dichloromethane as eluent. This purification removed most (or all) of the unreacted methyl alpha-L- rhamnopyranoside and other impurities. The O-alkylated products were collected and analyzed for yield and selectivity. Results of each trial are shown in Table CE2.

Table CE2

1. Yield is the combined isolated yield of 2-O-allyl and 3-O-allyl products.

2. Ratio of isomers was measured by comparing the integral for the anomeric -OMe peaks, which occur at 3.37 and 3.36 ppm, respectively.

3. Performed in dimethylformamide.

EXAMPLE CE3: Attempted purification of methyl 3-O-allyl alpha-L-rhamnopyranoside using oxidants other than sodium periodate and manganese dioxide

To a stirred solution of a 73:27 mixture of methyl 3-O-allyl alpha-L- rhamnopyranoside and methyl 2-O-allyl alpha-L-rhamnopyranoside (0.050 g, 0.23 mmol) in acetonitrile (7 mL)/water (3.5 mL) in a 20 mL vial was added the oxidant and/or a co-oxidant (quantities are listed in the Table CE3). The solution was stirred at ambient temperature under nitrogen for 24 hr. The reaction was monitored by TLC (R _f for the 2' isomer is 0.25; R _f for the 3' isomer is 0.3 using a solvent system consisting of 3:3:3: 1

hexanes:EtOAc:dichloromethane:acetone, visualized by phosphomolybdic acid stain.) and by GCMS. Results of each trial are shown in the following Table CE3. Table CE3