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Title:
PROCESS FOR THE PREPARATION OF PURE METHYL 3-O-(ALKYL OR ALKENYL)- ALPHA-L-RHAMNOPYRANOSIDE AND 3-O-(ALKYL OR ALKENYL)-2,4-DI-O-ALKYL ALPHA-L-RHAMNOPYRANOSIDE
Document Type and Number:
WIPO Patent Application WO/2016/054505
Kind Code:
A1
Abstract:
The present application provides processes for making compounds useful in the making of pesticidal compounds.

Inventors:
CROUSE, Gary, D. (5069 East 146th Street, Noblesville, Indiana, 46062, US)
DEAMICIS, Carl (11321 Echo Ridge Lane, Indianapolis, Indiana, 46236, US)
LORSBACH, Beth (6034 Haverford Avenue, Indianapolis, Indiana, 46220, US)
Application Number:
US2015/053714
Publication Date:
April 07, 2016
Filing Date:
October 02, 2015
Export Citation:
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Assignee:
DOW AGROSCIENCES LLC (9330 Zionsville Road, Indianapolis, Indiana, 46268, US)
International Classes:
C07H15/04; C07H1/00
Domestic Patent References:
WO2009102736A12009-08-20
Other References:
OKABE HIKARU ET AL.: "Studies on Resin Glycosides. II.1) Unhomogeneity of ''Pharbitic Acid'' and Isolation and Partial Structures of Pharbitic Acids C and D, the Major Constituents of ''Pharbitic Acid:2", CHEM. PHARM. BULL., vol. 19, no. 11, 1971, pages 2394 - 2403
POZSGAY VINCE: "Synthesis of partially protected benzyl and methyl alpha-L- rhamnopyranosides by the phase-transfer technique", CARBOHYDRATE RESEARCH, vol. 69, 1979, pages 284 - 286
Attorney, Agent or Firm:
ADDISON, Bradford, G. et al. (Barnes & Thornburg LLP, 11 South Meridian StreetIndianapolis, Indiana, 46204, US)
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Claims:
WHAT IS CLAIMED IS:

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

(I)

wherein R is alkyl, alkenyl, or alkylaryl each of which is optionally substituted, substantially free of contamination by positional 0-(Rl) isomers;

the process comprising:

(a) the step of 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.

2. The process of claim 1 wherein the process yields compound (I) substantially free of compound (III).

3. A process (process II) 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 R 2 is as previously defined and X 2 is CI, Br, I, or OS(0)2OCH3, wherein in the amount of alkylating agent is about 2 mole- equivalents to about 3 mole-equivalents based on the amount of compound (I); and

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

4. The process of claim 3 wherein the compound (II) is substantially free of compound (IV).

wherein R is alkyl, alkenyl, or alkylaryl each of which is optionally substituted; and R 2 i ·s alkyl

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

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

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

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

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

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

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

12. The process of any one of the preceding claims wherein R is a (Q-C- alkyl.

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

14. 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).

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

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

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

18. The process of any one of the preceding claims wherein R1 is a (C1-C4) alkyl.

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

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

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

Description:
PROCESS FOR THE PREPARATION OF PURE METHYL 3-0-(ALKYL OR ALKENYL)- ALPHA-L-RHAMNOPYRANOSIDE AND 3-0-(ALKYL OR ALKENYL)-2,4-DI-0-ALKYL

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. 62/059,198, filed on October 3, 2014, the entire disclosure of which is incorporated herein by reference

TECHNICAL FIELD

The invention described herein pertains to processes for preparing methyl 3-0- (alkyl or alkenyl) alpha-L-rhamnopyranoside substantially free of 2-O-(alkyl or alkenyl) alpha- L-rhamnopyranoside.

DETAILED DESCRIPTION

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

An illustrative example of the processes described herein is shown in Scheme 1.

Scheme 1

Selective alkylation processes applied to methyl alpha-L-rhamnopyranoside result in mixtures of mono-O-alkylated products substantially enriched in the 3-O-alkylated isomer. 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) isomer from the desired 3-0-(alkyl or alkenyl) product. Described herein is a process for removing the 2-0-(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 mixture of methyl 3-0-(alkyl or alkenyl) alpha-L-rhamnopyranoside and methyl 2-0-(alkyl or alkenyl) 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 3-0-(alkyl or alkenyl) alpha-L-rhamnopyranoside and methyl 2-0-(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.

Described herein is the treatment of a solution or liquid suspension of methyl 3- O- 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-O-(alkyl or alkenyl) isomer present). The products resulting from oxidation of the 2-O-(alkyl or alkenyl) isomer are significantly more soluble in water, thereby providing a convenient means of removal. Upon completion of the oxidation, the resulting mixture is then extracted with an organic solvent, which results in extraction of the unreacted 3-O-(alkyl or alkenyl) rhamnopyranoside. Removal of solvent then 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 base such as powdered potassium hydroxide and an additional 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 2

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 R 1 is alkyl, alkenyl, or alkylaryl each of which is optionally substituted; the process comprising:

(a) the step of contacting a mixture of compounds (I) and (III) H 3 (m); and

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 process yields compound (I) substantially free of compound (III).

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

wherein R 1 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 R 2 is as previously defined and X 2 is CI, Br, I, or OS(0) 2 OCH3, wherein in the amount of alkylating agent is about 2 mole- equivalents to about 3 mole-equivalents based on the amount of compound (I); and

an amount of base, wherein the amount of 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 compound (II) is substantially free of compound (IV).

• 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 (C C 4 ) alkyl.

• The process of any one of the preceding clauses wherein R -X is iodomethane or dimethyl sulfate.

• 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.

• 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 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. 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 include 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 (C C 4 ). 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 -C 4 ). 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 replacement of one or more hydrogen atoms with other functional groups on the 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 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, 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, CDC1 3 ) 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); 13 C NMR (101 MHz, CDC1 3 ) 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, CDC1 3 ) 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); 13 C NMR (101 MHz, CDC1 3 ) 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 methyl 3-O-allyl alpha-L-rhamnopyranoside

To a 250 mL round bottomed-flask equipped with magnetic stirrer was added methyl alpha-L-rhamnopyranoside (5.00 g, 28.1 mmol, 1 equivalent) , dry acetonitrile (100 mL), phenylboronic acid (0.340 g, 2.80 mmol, 0.1 equivalents), silver oxide (4.50 g, 19.6 mmol, 0.7 equivalents), and allyl bromide (16.2 g, 950 mmol, 34 equivalents). The solution was heated at 50 °C for 24 hours, then it was cooled, filtered and concentrated. The concentrate was dissolved in ethyl acetate (100 mL), filtered, and re-concentrated to give the alkylated products as a light tan oil (5.30 g, 94.5%). The ratio of 3-0-allyl:2-0-allyl products was determined to be 94:6 by GCMS and 1H NMR: Methyl 3-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); 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 3: 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 complete removal of the 2-isomer after 24 hours. EXAMPLE 4: 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 complete removal of the 2-isomer after 24 hours.

EXAMPLE 5: 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. These analytical results 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 again 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 to 70 °C for 2 hours. Analytical results show less than 1% of the 2-O-allyl isomer (see Table 1 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 3:2-0-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 1

EXAMPLE 6: 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, 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. The mixture was 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-O:2-0-allyl isomer with acetonitrile solvent (20% by mass).

Table 2

EXAMPLE 7: S nthesis 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-O-allyl 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, the 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 the temperature below 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, %). 1H NMR analysis, within the limits of detection, showed no evidence of the 2-0- allyl 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). 1J C NMR (101 MHz, CDC1 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 CEl: 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 CEl). 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 CEl.

Table CEl