WO2016054568A1

WO2016054568A1 - Selective 3-o-alkylation of methyl alpha-l-rhamnopyranoside

Info

Publication number: WO2016054568A1
Application number: PCT/US2015/053821
Authority: WO
Inventors: Gary D. Crouse; Andrew Ward; Carl Deamicis; Jerod Patzner; Beth Lorsbach
Original assignee: Dow Agrosciences Llc
Priority date: 2014-10-03
Filing date: 2015-10-02
Publication date: 2016-04-07

Abstract

The present application provides processes for making compounds useful in the making of pesticidal compounds.

Description

SELECTIVE 3 -O- ALKYLATION OF METHYL ALPHA-L-RHAMNOPYRANOSIDE

CROSS-REFERENCE TO RELATED APPLICATIONS

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

Application Serial No. 62/059196, 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 profiles, improved yields, and improved selectivities. More

specifically, selective 3-O-alkylation methods for methyl pyranosides have been previously reported, but the need 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 Patent Appl. Publ. 2010/0204165) remains.

A two-step process for selective 3-O-alkylation of methyl alpha-L-rhamnopyranoside using tin as the stoichiometric promoter has been reported (Carbohydr. Res, 277(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-O-alkyl or di-O-alkyl derivatives were detected in the case of the manno- and rhamno- pyranosides.

Scheme 1

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.

Regio selective alkylations (methyl, benzyl, and allyl) of carbohydrate diols using copper chelates has been reported (Eby, et al., Carbohydrate Research, 729(1984), 111-120). The reported conditions for these alkylation processes require 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 mannopyranoses and pyranosides were reported undergoing these reactions in high yields. It also was reported that these conditions result in -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 2).

Scheme 2

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 3.

Scheme 3

DIPEA CH₃CN

Described herein is the use of from about 1 equivalent to about 3 equivalents of a copper(I) promoter, from about 1 equivalent to about 2 equivalents of an aryl boronic acid, from about 1 equivalent to about 2 equivalents of a tertiary amine base, and from about 1 equivalent to about 3 equivalents of an alkylating agent (all based on 1 equivalent of the starting methyl alpha-L-rhamno-pyranoside), in a polar aprotic solvent, at a temperature of from about 70 °C to about 130 °C, using conventional heating or microwave irradiation, for times ranging from about 30 minutes to about 30 hours to selectively prepare methyl 3-O-(alkyl or alkenyl) alpha- L-rhamnopyranoside . Under these conditions, high selectivity for 3-O-alkylation over 2-0- alkylation has been observed.

Illustrative examples of copper(I) promoters useful in the processes described herein are copper(I) oxide, copper(I) chloride, copper(I) bromide, and copper(I) iodide. Aryl boronic acids useful in the processes described herein include optionally substituted phenyl boronic acids. Illustrative examples include, phenylboronic acid,

2,6-difluoro-phenylboronic acid, 2-methoxyphenylboronic acid, 2-methylphenylboronic acid, 3-methoxyphenylboronic acid, and 4-trifluoromethylphenylboronic acid.

Tertiary amine bases are useful in the processes described herein. Illustrative examples include triethylamine, diisopropylamine (DIPEA), and the like. Described herein is the discovery that use of a base, such as a tertiary amine compounds is necessary for the reaction to occur in good yields (See Comparative Example CE1, Entry 1).

Alkylating agents useful 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 useful in the processes described herein include alkyl nitriles. Illustrative examples include acetonitrile, propionitrile, butyronitrile, and the like.

Described herein is the discovery that use of temperatures below about 110 °C in the alkylation of methyl 3-O-alpha-L-rhamnopyranoside with alkylating agents such as bromopropane or iodopropane results in low yields (See Comparative Example CE1, Entries 2 through 6).

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-O-(alkyl or alkenyl) alpha-L-rhamnopyranoside containing the 2-O-(alkyl or alkenyl) isomer in subsequent process steps involved in the preparation of pesticidal compounds is complicated by difficulties in removing the 2-O-(alkyl or alkenyl) isomers that arise in each of those later steps from the desired 3-O-(alkyl or alkenyl) products. Described herein is a process for selectively 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 the reaction product formed in the alkylation of methyl 3-O-alpha-L-rhamnopyranoside with an oxidant that selectively reacts with vicinal hydroxyl groups resulting in 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-O-(alkyl or alkenyl) alpha-L-rhamnopyranoside and methyl 2-O-(alkyl or alkenyl) alpha-L-rhamnopyranoside with a solution or suspension of sodium periodate followed by aqueous extraction to yield the 3-O-alkylated rhamnose derivative substantially free of the 2- O-alkylated isomer. It is appreciated that other oxidizers may be used for the selective removal of the undesired isomer, though it has been discovered that not all oxidizers are suitable (See Comparative Example CE2).

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 ie/t-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 base such as powdered potassium hydroxide and an alkylating agent. Illustrative alkylating agents include 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 4

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

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

wherein R¹ 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 70 °C to about 130 °C, with

an amount of an alkylating agent (R^x-X), wherein the amount of alkylating agent is about 1 mole-equivalent to about 3 mole-equivalents based on the amount of compound (A), wherein R¹ is as previously defined and X is CI, Br, or I; and

an amount of copper(I) promoter, wherein the amount of copper(I) promoter is about 1 mole-equivalent to about 3 mole-equivalents based on the amount of compound (A); and

an amount of aryl boronic acid, wherein the amount of aryl boronic acid is about 1 mole-equivalent to about 2 mole-equivalents based on the amount of compound (A); and

an amount of base, wherein the amount of base is about 0.3 mole-equivalents to about 1 mole-equivalent based on the amount of compound (A).

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

(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.

• 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 (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 alkylating agent (R 2 -X 2 ), wherein the amount of alkylating agent is about 2 mole-equivalents to about 3 mole-equivalents of based on the amount of compound (I), wherein R 2 is as previously defined and X 2 is CI, Br, I, OS(0)₂CF3, or

OS(0)₂OCH₃; and

an amount of base, where the amount of the base is from 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 selected from acetonitrile, propionitrile, and butyronitrile.

• The process of any one of the preceding clauses wherein the temperature of step (a) is from about 110 °C to about 130 °C.

• The process of any one of the preceding clauses wherein the temperature of step (a) is about 130 °C.

• The process of any one of the preceding clauses wherein the temperature of step (a) is attained by microwave irradiation of the reaction mixture.

• The process of any one of the preceding clauses wherein R¹ is alkyl.

• The process of any one of the preceding clauses wherein R¹ is a (Ci-C₄) alkyl.

• The process of any one of the preceding clauses wherein R¹ -X is a (C₃) alkyl iodide. · The process of any one of the preceding clauses wherein R¹ -X is iodopropane.

• The process of any one of the preceding clauses wherein R¹ is alkenyl.

• The process of any one of the preceding clauses wherein R¹ is a (C₂-C4) alkenyl.

• The process of any one of the preceding clauses wherein R¹ is a (C₃) alkenyl.

• The process of any one of the preceding clauses wherein R¹ -X is allyl bromide.

· The process of any one of the preceding clauses wherein the amount of the copper(I) promoter 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 the copper(I) promoter 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 copper(I) promoter is copper(I) oxide.

• The process of any one of the preceding clauses wherein the amount of the aryl boronic acid is about 1 mole-equivalent to about 1.1 mole-equivalents based on the amount of (A).

• The process of any one of the preceding clauses wherein the aryl boronic acid is

wherein R^a is H, F, CH₃, 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-OCH₃, 2-CH₃, 3-OCH₃, or 4-CF₃, 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 amount of base of step (a) is about 0.3 mole-equivalents to about 0.5 mole-equivalents based on the amount of (A).

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

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

• 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 alkyl.

• The process of any one of the preceding clauses wherein R is a (CrC₄) alkyl.

• The process of any one of the preceding clauses wherein R -X 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 (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 - C₆), and (C C₄). It is to be further understood that in certain embodiments alkenyl may be advantageously of limited length, including (C₂-C₆), and (C₂-C₄). Illustrative alkyl and alkenyl groups are, but not limited to, methyl, ethyl, w-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: S nthesis of 3-O-w-propyl alpha- L-rhamnopyranoside

To a round-bottomed flask (100 mL) equipped with magnetic stirrer was added methyl alpha-L-rhamnopyranoside (17.0 g, 95.0 mmol, 1 equivalent), dry propionitrile (80 mL), phenylboronic acid (11.6 g, 95.0 mmol, 1 equivalent), copper(I) oxide (20.0 g, 140 mmol, 1.5 equivalents), diisopropylamine (6.00 g, 46.0 mmol, 0.5 equivalents), and iodopropane (16.2 g, 95.0 mmol, 1 equivalent). The solution was heated at 110 °C for 30 hours, then it was cooled and filtered to remove copper salts. The filtrate was treated with ammonium hydroxide (2 N, 50 mL), then it was extracted with dichloromethane (3 x 150 mL). Concentration of the organic layer furnished the title compound as a 5.25: 1 mixture of 3:2 O-alkylation products as determined by GCMS as a light yellow oil (15.7 g, 75%): Methyl 3-O-n-propyl alpha-L- rhamnopyranoside: 1H NMR (400 MHz, CDC1₃) δ 4.72 (d, J= 1.8 Hz, 1H), 4.04 - 3.98 (m, 1H), 3.71 - 3.57 (m, 2H), 3.56 - 3.39 (m, 3H), 3.37 (s, 3H), 2.51 (dd, J = 11.3, 2.4 Hz, 2H), 1.72 - 1.57 (m, 2H), 1.33 (d, J= 6.2 Hz, 3H), 0.95 (t, J= 7.4 Hz, 3H); ¹³C NMR (101 MHz, CDC1₃) δ 100.42, 79.80, 71.32, 71.31, 67.69, 67.67, 54.77, 23.04, 17.62, 10.34. Methyl 2-O-n- propyl alpha-L-rhamnopyranoside: 1H NMR (400 MHz, CDC1₃) δ 4.72 (d, J= 1.3 Hz, 1H), 3.75 - 3.51 (m, 4H), 3.36 (s, 3H), 3.41-3.25 (m,2H), 2.66 (d, J = 2.6 Hz, 1H), 2.48 (d, J = 10.7 Hz, 1H), 1.70 - 1.55 (m, 2H), 1.32 (d, J = 6.2 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H); ¹³C NMR (101 MHz, CDC1₃) δ 98.04, 78.59, 73.76, 72.83, 71.46, 67.60, 54.72, 23.01,17.54, 10.36.

EXAMPLE 2: Synthesis of 3-O-w-Propyl-alpha-L-rhamnopyranoside varying copper(I) oxide amount, aryl boronic acid, iodopropane amount, temperature, and time.

A solution of methyl alpha-L-rhamnopyranoside, arylboronic acid, diisopropylethylamine (1 equivalent), and iodopropane in acetonitrile (identity, amounts, and equivalents listed in Table 1) was stirred at the temperature listed for the time listed. Ratios of mixtures were determined prior to or following workup by 1H NMR and/or GCMS. Results of each trial are shown in Table 1.

Table 1

1. These reactions were conducted under microwave irradiation.

2. Isomer ratio is measured by comparing proton peak areas for the anomeric-OMe substituent.

EXAMPLE 3: Synthesis of 3-O-propyl-alpha-L-rhamnopyranoside varying scale, copper(I) oxide amount, phenylboronic acid amount, diisopropylethylamine amount, electrophile amount, temperature, and time.

A solution of methyl alpha-L-rhamnopyranoside, phenylboronic acid, diisopropylethylamine, and 1-iodopropane in solvent (solvent, amounts, and equivalents listed in Table 2) was stirred at the temperature listed for the time listed. Ratios of mixtures were determined prior to or following workup by 1H NMR and/or GCMS. Results of each trial are shown in Table 2.

Table 2

1. Base = diisopropylethylamine

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

3. Reactions heated with microwave irradiation.

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

EXAMPLE 4: Synthesis of 3-O-allyl/alkyl-alpha-L-rhamnopyranoside varying scale, copper(I) oxide amount, phenylboronic acid amount, diisopropylethylamine amount, electrophile amount, temperature, and time.

A solution of methyl alpha-L-rhamnopyranoside, phenylboronic acid, diisopropylethylamine, and allyl bromide in solvent (solvent, amounts, and equivalents listed Table 3) was stirred at the temperature listed for the time listed. Ratios of mixtures were determined prior to or following workup by 1H NMR and/or GCMS. Results of each trial are shown in Table 3.

Table 3

1. Base = diisopropylethylamine

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

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

EXAMPLE 5: 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 6: 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 7: 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 at 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 2-0- 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 4 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-O-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_lS',5_lS^,,6_lS^,)-3-(allyloxy)-5-hydroxy-2-methoxy-6-methyldihydro-2H-pyran- 4(3H)-one.

Table 4

EXAMPLE 8: 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 Camlite 400, type E , 53 g, 616 mmol, black powder < 3 micron particle size, 6.4 equivalents) was added portionwise (3 equivalents, 2 equivalents, 1.4 equivalents every 3 hours). The black suspension was heated to 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-O: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-O:2-0-allyl isomer with acetonitrile solvent (20% by mass).

Table 5

EXAMPLE 9: Synthesis of methyl 3-0-allyl-2,4-di-0-methyl alpha-L- rhamno ranoside.

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 is 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 dimethylsulfoxide (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 of <35 °C. Stirring was continued overnight, then the solution was extracted with hexanes (2 x 75 mL) and concentrated to provide the title compound as a colorless oil (1.40 g, %). ^lH NMR, within the limits of detection, shows that this is the 3-O-allyl product, with no evidence of the 2-isomer: 1H NMR (400 MHz, CDC1₃) 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); ¹³C NMR (101 MHz, CDC13) 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 varying scale, copper(I) oxide amount, phenylboronic acid amount, diisopropylethylamine amount, electrophile, temperature, and time.

A solution of methyl alpha-L-rhamnopyranoside, phenylboronic acid, diisopropylethylamine, and the listed alkylating agent in solvent (solvent, amounts, and equivalents listed in Table CEl) was stirred at the temperature listed for the time listed. Ratios of mixtures were determined prior to or following workup by 1H NMR and/or GCMS. Results of each trial are shown in Table CEl.

Table CE1

5 1. Base = diisopropylethylamine

EXAMPLE CE2: 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 CE2). 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 CE2.

Table CE2

Claims

WHAT IS CLAIMED IS:

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

(a) contacting compound (A)

an amount of a copper(I) promoter, where the amount of the copper(I) promoter is about 1 mole-equivalent to about 3 mole-equivalents based on the amount of compound (A); and an amount of an aryl boronic acid, where the amount of the aryl boronic acid is about 1 mole-equivalent to about 2 mole-equivalents based on the amount of compound (A); and

an amount of a base, where the amount of the base is about 0.3 mole-equivalents to about 1 mole-equivalent based on the amount of compound (A).

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

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

3. The process of claim 2, wherein the resulting compound (I) is substantially free of compound (III).

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

wherein R¹ 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)

(b) contacting the resulting compound (I) in a polar aprotic solvent, at a temperature of about 20 °C to about 60 °C, with

OS(0)₂OCH₃; and

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

5. The process of claim 2, 3, or 4, wherein the mixture of compounds (I) and (III) is formed by the process of claim 1.

6. The process of any one of the preceding claims, wherein compound (II) is substantially free of compound (IV)

wherein R 1 is alkyl, alkenyl, or alkylaryl each of which is optionally substituted; and R 2 is alkyl.

7. The process of any one of the preceding claims, wherein the polar aprotic solvent of step (a) is selected from acetonitrile, propionitrile, and butyronitrile.

8. The process of any one of the preceding claims, wherein the temperature of step (a) is about 110 °C to about 130 °C. 9. The process of any one of the preceding claims, wherein the temperature of step (a) is about 130 °C.

10. The process of any one of the preceding claims, wherein the temperature of step (a) of is attained by microwave irradiation.

11. The process of any one of the preceding claims, wherein R¹ is alkyl.

12. The process of any one of the preceding claims, wherein R¹ is a (Ci-C4) alkyl. 13. The process of any one of the preceding claims, wherein R^l-X is a (C3) alkyl iodide.

14. The process of any one of the preceding claims, wherein R^l-X is iodopropane.

15. The process of any one of the preceding claims, wherein R¹ is alkenyl.

16. The process of any one of the preceding claims, wherein R is a (C₂-C₄) alkenyl.

17. The process of any one of the preceding claims, wherein R is a (C₃) alkenyl. 18. The process of any one of the preceding claims, wherein R^l-X is allyl bromide.

19. The process of any one of the preceding claims, wherein the amount of the copper(I) promoter is about 1 mole-equivalent to about 2 mole-equivalents based on the amount of (A). 20. The process of any one of the preceding claims, wherein the amount of the copper(I) promoter is about 1 mole-equivalent to about 1.5 mole-equivalents based on the amount of (A).

21. The process of any one of the preceding claims, wherein the copper(I) promoter is copper(I) oxide.

22. The process of any one of the preceding claims, wherein the amount of the aryl boronic acid is about 1 mole-equivalent to about 1.1 mole-equivalents based on the amount of (A).

23. The process of any one of the preceding claims, wherein the aryl boronic acid is

wherein R^a is H, F, CH₃, OCH₃, or CF₃, and n is 1 or 2.

24. The process of any one of the preceding claims, wherein the amount of base of step (a) is about 0.3 mole-equivalents to about 0.5 mole-equivalents based on the amount of (A).

25. The process of any one of the preceding claims, wherein the base of step (a) is a tertiary amine base.

26. The process of any one of the preceding claims, wherein the base of step (a) is diisopropylethylamine.

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

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

29. The process of any one of the preceding claims, wherein the oxidant of step (a) is a periodate salt. 30. The process of any one of the preceding claims, wherein the periodate salt of step (a) is sodium periodate.

31. The process of any one of the preceding claims, wherein the oxidant of step (a) is manganese dioxide.

32. The process of any one of the preceding claims, wherein the polar aprotic solvent of step (b) is dimethylsulfoxide.

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

34. The process of any one of the preceding claims, wherein R is alkyl.

35. The process of any one of the preceding claims, wherein R is a (Ci-C4) alkyl.

36. The process of any one of the preceding claims, wherein R 2 -X 2 is iodomethane or dimethylsulfate.

37. The process of any one of the preceding claims, wherein the amount of base of step (b) is about 3 mole-equivalents to about 3.5 mole-equivalents based on the amount of (I).

38. The process of any one of the preceding claims, wherein the base of step (b) is an inorganic base.

39. The process of any one of the preceding claims, wherein the base of step (b) potassium hydroxide or sodium hydroxide.