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Title:
SELECTIVE 3-O-ALKYLATION OF METHYL ALPHA-L-RHAMNOPYRANOSIDE
Document Type and Number:
WIPO Patent Application WO/2016/054539
Kind Code:
A1
Abstract:
Methyl alpha-L-rhamnopyranosides are selectively alkylated in the 3-position with catalytic amounts of dialkyltin compounds in the presence of halide additives and base.

Inventors:
LI, Xiaoyong (606 Senic Drive, Midland, Michigan, 48642, US)
DEAMICIS, Carl (11321 Echo Ridge Lane, Indianapolis, Indiana, 46236, US)
LORSBACH, Beth (6034 Haverford Avenue, Indianapolis, Indiana, 46220, US)
CROUSE, Gary D. (5069 East 146th Street, Noblesville, Indiana, 46062, US)
Application Number:
US2015/053776
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; B01J23/14; C07H1/00
Domestic Patent References:
WO2009102736A12009-08-20
Other References:
HEIDECKE CHRISTOPH D. ET AL.: "Regioselective Phthalimidopropyl-Modification of Carbohydrates in One Step", SYNTHESIS, vol. 1, pages 161 - 165
OKABE HIKARU ET AL.: "Studies on Resin Glycosides. II. Unhomogeneity of ''Pharbitic Acid'' and Isolation and Partial Structures of Pharbitic Acids C and D, the Major Constituents of ''Pharbitic Acid", CHEM. PHARM. BULL., vol. 19, no. 11, 1971, pages 2394 - 2403
MURAMATSU WATARU ET AL.: "Regio- and Stereochemical Controlled Koenigs-Knorr- Type Monoglycosylation of Secondary Hydroxy Groups in Carbohydrates Utilizing the High Site Recognition Ability of Organotin Catalysts.", ADV. SYNTH. CATAL., vol. 355, 2013, pages 2518 - 2524
YANG GUANGBIN ET AL.: "Selective 3-O-allylation and 3-O-benzylation of methyl a-D- manno-, a-L-rhamno- and b-L-fuco-pyranoside.", CARBOHYDRATE RESEARCH, vol. 211, 1991, pages 179 - 182
Attorney, Agent or Firm:
ADDISON, Bradford G. et al. (Barnes & Thornburg LLP, 11 South Meridian StreetIndianapolis, Indiana, 46204, US)
Download PDF:
Claims:
WHAT IS CLAIMED IS:

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

O' '"'CH 3 (I)

wherein R1 is alkyl, alkenyl, or alkylaryl each of which is optionally substituted; the process comprising:

(a) the step of contacting compound (A)

in a polar aprotic solvent, at a temperature of about 25 °C to about 90 °C, with

an amount of an alkylating agent (Rx-X), where R1 is as previously defined and X is CI, Br, or I, wherein the amount of alkylating reagent is about 1 mole-equivalent to about 2 mole- equivalents based on the amount of compound (A): and

an amount of dialkytin catalyst, wherein the amount of dialkytin catalyst is about 0.2 mole-equivalents to about 0.5 mole-equivalents based on the amount of compound (A); and an amount of halide additive, wherein the amount of halide additive is about 0.2 mole- equivalents to about 0.5 mole-equivalents based on the amount of compound (A); and

an amount of base, wherein the amount of base is about 1.0 mole-equivalent to about 2.0 mole-equivalents based on the amount of compound (A).

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

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)

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

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

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

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

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 ), where R 2 is as previously defined and X 2 is CI, Br, I, OS(0)2CF3, or OS(0)2OCH3 wherein the amount of alkylating agent is about 2 mole- equivalents to about 3 mole-equivalents of based on the amount of compound (I); and

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

5. The process of claim 2 or 3, 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) o

7. The process of any one of the preceding claims, wherein the amount of dialkytin catalyst is about 0.3 mole-equivalents to about 0.5 mole-equivalents based on the amount of (A).

8. The process of any one of the preceding claims, wherein the amount of dialkytin catalyst is about 0.4 mole-equivalents to about 0.5 mole-equivalents based on the amount of (A).

9. The process of any one of the preceding claims, wherein the dialkytin catalyst is a dialkyltin oxide or dialkyltin dihalide.

10. The process of any one of the preceding claims, wherein the dialkytin catalyst is di-w- butyltin oxide.

11. The process of any one of the preceding claims, wherein the amount of halide additive is about 0.3 mole-equivalents to about 0.5 mole-equivalents based on the amount of (A).

12. The process of any one of the preceding claims, wherein the amount of halide additive is about 0.4 mole-equivalents to about 0.5 mole-equivalents based on the amount of (A).

13. The process of any one of the preceding claims, wherein the halide additive is a quaternary ammonium halides, a quaternary phosphonium halides, or an alkaline metal halide.

14. The process of any one of the preceding claims, wherein the halide additive is tetrabutylammonium fluoride, tetrabutylammonium bromide, or tetrabutylammonium iodide.

15. The process of any one of the preceding claims, wherein the halide additive is potassium bromide or potassium iodide.

16. The process of any one of the preceding claims, wherein the amount of base is about 1.2 mole-equivalents to about 2.0 mole-equivalents based on the amount of (A).

17. The process of any one of the preceding claims, wherein the amount of base is about 1.5 mole-equivalents to about 2.0 mole-equivalents based on the amount of (A).

18. The process of any one of the preceding claims, wherein the base is an alkali metal carbonate, alkali metal bicarbonate, alkali metal phosphate, or an amine compounds.

19. The process of any one of the preceding claims, wherein the base is an alkali metal carbonate.

20. The process of any one of the preceding claims, wherein the base is tri-w-butylamine or l,8-bis(dimethylamino)naphthalene (proton sponge).

21. The process of any one of the preceding claims, wherein the temperature of the step (a) is about 50 °C to about 90 °C.

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

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

24. The process of any one of the preceding claims, wherein Rl-X is a (C3) alkyl iodide.

25. The process of any one of the preceding claims, wherein Rl-X is iodopropane.

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

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

28. The process of any one of the preceding claims, wherein R is a (C3) alkenyl.

29. The process of any one of the preceding claims, wherein R -X is allyl bromide.

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

31. The process comprising of any one of the preceding claims, wherein the polar aprotic solvent is selected from acetonitrile, propionitrile, dimethylformamide, orN-methyl pyrrolidone.

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

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

34. The process of any one of the preceding claims, wherein the periodate salt of step (b) is sodium periodate.

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

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. 62/059,199, 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. 2010/0204165) remains.

A two-step process for selective 3-O-alkylation of methyl alpha-L-rhamno- pyranoside using tin as the stoichiometric promoter has been reported (Carbohyr. 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

isolated 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.

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 2.

Scheme 2

CH 3 CN

la Ilia

Advantages of this process relative to prior reported processes include (a) the reaction yields the 3-O-alkylated product with improved yield while maintaining high selectivity and (b) as little as about 0.2 equivalents of dialkyltin catalyst can be used, as compared with the stoichiometric amounts reported by others (See Comparative Examples). Isolated yields are as high as 72% with >6: 1 selectivity for alkylation at the 3-OH relative to the 2-OH.

Described herein is the use of from about 0.2 equivalents to about 0.5 equivalents of dialkytin catalyst, from about 0.2 equivalents to about 0.5 equivalents of halide additive, from about 1 equivalent to about 2 equivalents of base, from about 1 equivalent to about 2 equivalents of an alkylating agent, a polar aprotic solvent, at a temperature of from about 25 °C to about 90 °C, at times ranging from about 6 hours to about 48 hours. Under these conditions, high selectivity for 3-O-alkylation over 2-0- alkylation has been observed, with no observable over- alkylation (the yield of bis-alkylated product is <2%, within the limits of detection by GCMS).

Dialkyltin catalysts useful in the processes described herein include dialkyltin oxides and dialkyltin dihalides. Illustrative examples include di-w-butyltin oxide, di-w-butyltin dichloride, and combinations thereof.

Halide additives useful in the processes described herein include quaternary ammonium halides, quaternary phosphonium halides, and alkaline metal halides. Illustrative examples include tetrabutylammonium fluoride, tetrabutylammonium bromide,

tetrabutylammonium iodide, tetrabutylphosphonium bromide, potassium bromide, potassium iodide, and combinations thereof.

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 w-propyl bromide, w-propyl iodide, allyl bromide, allyl iodide, benzyl bromide, and benzyl iodide.

Bases useful in the processes described herein include alkali metal carbonates, alkali metal bicarbonates, and alkali metal phosphates and amine compounds. Illustrative examples of amine bases include tri-w-butylamine, l,8-bis(dimethylamino)naphthalene (proton sponge), and combinations thereof.

Polar aprotic solvents useful in the processes described herein include alkyl nitriles, ethers, amides, and sulfoxides. Illustrative examples include acetonitrile, propionitrile, dioxane, dimethylformamide, N-methyl-pyrrolidinone, dimethyl sulfoxides, and combinations thereof. In one embodiment the polar aprotic solvent is acetonitrile or dioxane.

The selective alkylation processes described herein result in mixtures enriched in the 3-O-alkylated isomer of methyl alpha-L-rhamnopyranoside. However, it is preferable for pesticidal compounds to be substantially free of isomeric impurities. 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 currently requires the chromatographic removal of the 2-0-(alkyl or alkenyl) isomer from the desired 3- 0-(alkyl or alkenyl) product at a later stage in the process. 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 the reaction product formed in the alkylation step 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 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 equivalent 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 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 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 a 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 3

Several illustrative embodiments of the invention are described by the following delineated 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) contacting compound (A)

in a polar aprotic solvent, at a temperature of about 25 °C to about 90 °C, with

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

an amount of dialkytin catalyst, wherein the amount of dialkytin catalyst is about 0.2 mole-equivalents to about 0.5 mole-equivalents based on the amount of compound (A); and an amount of halide additive, wherein the amount of halide additive is about 0.2 mole- equivalents to about 0.5 mole-equivalents based on the amount of compound (A); and

an amount of base, wherein the amount of base is about 1.0 mole-equivalent to about 2.0 mole-equivalents based on the amount of compound (A).

• A process (process II) for preparing a 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)

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

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

an amount of base, where the amount of 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 amount of dialkytin catalyst 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 amount of dialkytin catalyst is about 0.4 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 dialkytin catalyst is a dialkyltin oxide or dialkyltin dihalide.

• The process of any one of the preceding clauses wherein the dialkytin catalyst is di-n- butyltin oxide.

• The process of any one of the preceding clauses wherein the dialkytin catalyst is di-n- butyltin dichloride.

• The process of any one of the preceding clauses wherein the amount of halide additive 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 amount of halide additive is about 0.4 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 halide additive is a quaternary ammonium halide, a quaternary phosphonium halide, or an alkaline metal halide.

• The process of any one of the preceding clauses wherein the halide additive is tetrabutylammonium fluoride, tetrabutylammonium bromide, or tetrabutylammonium iodide. · The process of any one of the preceding clauses wherein the halide additive is tetrabutylphosphonium bromide.

• The process of any one of the preceding clauses wherein the halide additive is potassium bromide or potassium iodide.

• The process of any one of the preceding clauses wherein the amount of base is about 1.2 mole-equivalents to about 2.0 mole-equivalents based on the amount of (A).

• The process of any one of the preceding clauses wherein the amount of base is about 1.5 mole-equivalents to about 2.0 mole-equivalents based on the amount of (A).

• The process of any one of the preceding clauses wherein the base is an alkali metal carbonate, alkali metal bicarbonate, alkali metal phosphate, or an amine compounds.

· The process of any one of the preceding clauses wherein the base is an alkali metal carbonate.

• The process of any one of the preceding clauses wherein the base is tri-w-butylamine or l,8-bis(dimethylamino)naphthalene (proton sponge).

• The process of any one of the preceding clauses wherein the temperature of the step (a) is about 50 °C to about 90 °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 -C4) 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 1 -X is allyl bromide.

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

• The process comprising of any one of the preceding clauses wherein the polar aprotic solvent is acetonitrile, propionitrile, dimethylformamide, or N-methyl pyrrolidone. • The process of any one of the preceding clauses wherein the oxidant of step (b) is a periodate salt or manganese dioxide.

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

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

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

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

· The process of any one of the preceding clauses wherein R is methyl.

• 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 (c) 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 (c) is an inorganic base.

• The process of any one of the preceding clauses wherein the base of step (c) 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 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 (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 -C 4 ). Illustrative alkyl and alkenyl groups are, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-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

Isomeric ratios were estimated by 1 H NMR, or quantitative 13 C NMR or GC using conditions described below.

NMR analysis was conducted on a Bruker 400 MHz NMR spectrometer equipped with a

B-ACS 60 autochanger and a 5 mm PABBO broadband probe with Z-gradients. Deuterated

NMR solvents were obtained from Cambridge Isotope Laboratories, Inc.

For 1 H NMR analysis, a sample of products (~ 10 mg) was dissolved in CDC1 3 (0.7 ml) and analyzed directly at 25 °C. Olefin proton signals of both isomers (5.35 ppm and 5.28 ppm) were used for ratio analysis.

For quantitative 13 C NMR analysis, a sample of products (100-120 mg) was dissolved in DMSO- 6 (0.7 ml) and acquisition parameters were set as following : relaxation delay 30-40 seconds, 90 degree pulse of 8.25 micro-seconds, 900-1000 scans at 25 °C, acquisition time 7-13 hours. CI carbon signals of both isomers (101.1 ppm and 98.7 ppm) were used for ratio analysis. GC analysis was performed on an Agilent 6850 equipped with Agilent DB-WAX column (30 m x 320 μιη x 0.5 μιη, p/n 123-7033); inlet 250 °C; fid, 250 °C; helium constant flow: 3 mL/minute; hydrogen flow: 40 mL/minute; air flow: 450 mL/minute; nitrogen makeup: 30 mL/minute; injection volume: 1 μί; split ratio: 25; temperature programming: 50 °C-0 minute, 30 °C/minute to 200 °C then 5 °C/minute to 250 °C, hold 2 minute; maximum column temperature: 250 °C. The peaks at 10.0- 10.1 minute were used for ratio analysis.

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

To a 10 mL round bottom flask was added methyl alpha-L-rhamnopyranoside (0.178 g,

1.00 mmol, 1.0 eq.), di-w-butyltin oxide (0.125 g, 0.500 mmol, 0.5 eq.), tetrabutylammonium bromide (0.161 g, 0.500 mmol, 0.5 eq.), proton sponge (0.257 g, 1.20 mmol, 1.2 eq.) and dry acetonitrile (4.0 mL). Ally bromide (0.174 mL, 2.00 mmol, 2.0 eq.) was then added. The mixture was stirred at 60 °C for 48 hours. The resulting mixture was concentrated by rotavap and purified by flash column chromatography using 0-80% ethyl acetate/hexanes as eluent to furnish the title products as an oil (0.156 g, 72%) with an isomeric ratio of 19 : 1 (la : Ilia).

3-O-allylated isomer (la): 1H NMR(400 MHz, CDC1 3 ): δ 6.00-5.90 (m, 1H), 5.36-5.30 (m, 1H), 5.26-5.22 (m, 1H), 4.71 (d, 2H, J = 2.0 Hz), 4.22-4.17 (m, 1H), 4.09-4.05 (m, 1H), 4.01 (q, 1H, J = 4 Hz), 3.71-3.65 (m, 1H), 3.55-3.53 (m, 1H), 3.37 (s, 3H), 2.29 (d, 1H, J = 4.0 Hz, -OH), 2.18 (s, 1H, OH), 1.32 (d, 3H, J = 8.0 Hz); 13 C NMR(100 MHz, 6 -DMSO): δ 136.0, 115.9, 101.1, 78.5, 70.8, 69.6, 68.4, 67.2, 54.0, 17.9; GC-MS m/z 218 (M + ).

2-O-allylated isomer(IIIa): 1H NMR (400 MHz, CDC1 3 ): δ 5.96-5.87 (m, 1H), 5.33-5.28 (m, 1H), 5.25-5.21 (m, 1H), 4.72 (d, 2H, J = 2.0 Hz), 4.22-4.17 (m, 1H), 4.06-4.00 (m, 1H), 3.71-3.66 (m, 1H), 3.63-3.62 (d, 1H, J = 4.0, 2.0 Hz), 3.60-3.57 (m, 1H), 3.36 (s, 3H), 2.28-2.24 (br, 2H, -OH), 1.33 (d, 3H, J = 8.0 Hz); 13 C NMR(100 MHz, 6 -DMSO): δ 135.7, 116.1, 98.7, 78.1, 72.2, 71.5, 70.6, 68.3, 54.0, 17.9; GC-MS m/z 218 (M + ). EXAMPLE 2: Synthesis of 3-O-allyl alpha-L-rhamnopyranoside

To a 25 mL round bottom flask was added methyl alpha-L-rhamnopyranoside (0.356 g, 2.00 mmol, 1.0 eq.), di-w-butyltin oxide (0.250 g, 1.00 mmol, 0.5 eq.), potassium iodide (0.166 g, 1.00 mmol, 0.5 eq.), proton sponge (0.514 g, 2.40 mmol, 1.2 eq.) and dry acetonitrile (8.0 mL). Ally bromide (0.348 mL, 4.00 mmol, 2.0 eq.) was then added. The mixture was stirred at 60 °C for 48 hours. The resulting mixture was concentrated by rotavap and passed through a short plug of silica gel using 0-80% ethyl acetate/hexanes as eluent to furnish the title products as oil (0.310 g, 71%) with an isomeric ratio of 16 : 1 (la : Ilia)

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

K 2 C0 3 (1 .2 eq.)

la Ilia

CH 3 CN, 38 °-C

To a 10 mL round bottom flask was added methyl alpha-L-rhamnopyranoside (0.178 g, 1.00 mmol, 1.0 eq.), di-w-butyltin oxide (0.0500 g, 0.200 mmol, 0.2 eq.), tetrabutylammonium bromide (0.161 g, 0.500 mmol, 0.5 eq.), potassium carbonate (0.152 g, 1.10 mmol, 1.1 eq.) and dry acetonitrile (4 mL). Ally bromide (0.0960 mL, 1.10 mmol, 1.1 eq.) was then added. The mixture was stirred at 38 °C for 24 hours. The resulting mixture was concentrated by rotavap and passed through a short plug of silica gel using 0-80% ethyl acetate/hexanes as eluent to furnish the title products as oil (0.152 g, 70%) with an isomeric ratio of 6 : 1 (la : Ilia). EXAMPLE 4: Synthesis of 3-O-allyl alpha-L-rhamnopyranoside

CH 3 CN , 90 °-C

To a 10 mL round bottom flask was added methyl alpha-L-rhamnopyranoside (0.178 g, 1.00 mmol, 1.0 eq.), di-w-butyltin oxide (0.0500 g, 0.200 mmol, 0.5 eq.), tetrabutylammonium bromide (0.161 g, 0.500 mmol, 0.5 eq.), proton sponge (0.257 g, 1.20 mmol, 1.2 eq.), molecular sieves (30 wt%, 4 A, 0.0540 g), and dry acetonitrile (4.0 mL). AUyl bromide (0.0960 mL, 1.10 mmol, 1.1 eq.) was then added. The mixture was stirred at 90 °C for 24 hours. Analysis by 1H NMR indicated 38% conversion with an isomeric ratio of 14 : 1 (la : Ilia). No isolation was performed.

EXAMPLE 5: Synthesis of 3-O-allyl alpha-L-rhamnopyranoside

To a 10 mL round bottom flask was added methyl alpha-L-rhamnopyranoside (0.178 g, 1.00 mmol, 1.0 eq.), di-w-butyltin oxide (0.0500 g, 0.200 mmol, 0.5 eq.), tetrabutylammonium fluoride- trihydrate (0.316 g, 1.00 mmol, 1.0 eq.), proton sponge (0.257 g, 1.20 mmol, 1.2 eq.) and dry acetonitrile (4.0 mL). Ally bromide (0.174 mL, 2.00 mmol, 2.0 eq.) was then added. The mixture was stirred at 50 °C for 24 hours. Analysis by 1H NMR indicated 56% conversion with an isomeric ratio of 11 : 1 (la : Ilia). No isolation was performed.

EXAMPLE 6: Purification of methyl 3-O-allyl rhamnopyranoside using sodium periodate

To a stirred solution of a 2.7: 1 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 7: Purification of methyl 3-O-allyl alpha-L-rhamnopyranoside using manganese dioxide

To a stirred solution of a 2.7: 1 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 8: 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 an additional 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 an additional 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-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,3S,5S,6S)-3-(allyloxy)-5-hydroxy-2-methoxy-6- methyldihydro-2H-pyran-4(3H)-one.

Table 1 Elapsed time

Mn0 2 (Total eq) Temp, °C 3:2 ratio GCMS 3:2 ratio 1HNMR

(hours)

0 0 25 2.8: 1 3: 1

1.0 2 70 4.9: 1 5.3: 1

2.2 4 70 11.5: 1 7.3: 1

3.5 6 70 99: 1 99: 1

EXAMPLE 9: 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 at 3 hour intervals). 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 3-0:2-0-a\\y\ isomer with acetonitrile solvent (20% by mass). Table 2

EXAMPLE 10: 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 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 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, lH), 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, 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 Example CE1: Typical procedure for allylation with dibutylstannylene acetal- Stoichiometric Method

To a 1 L round bottom flask was added alpha-L-rhamnopyranoside (15.0 g, 84.3 mmol, 1.0 eq.), di-w-butyltin oxide (20.3 g, 92.8 mmol, 1.1 eq.), and anhydrous methanol (420 mL). The suspension was heated to reflux and stirred for 4 hours. The resultant clear solution was cooled down and concentrated to afford colorless foam. The residue was azeotropically dried with toluene (2 x 50 mL) at 50 °C by rotavap to afford dibutylstannylene acetal as off-white solid powder (36.6 g, 100%) which was used directly for the next using following procedures.

Comparative Example CE2:

The crude di-w-butylstannylene acetal (0.578 g, 1.41 mmol) was dissolved in toluene (18 mL) leading to a clear solution. To a 25 mL round bottom flask was added tetrabutylammonium iodide (0.520 g, 1.41 mmol, 1.0 eq.), dibutylstannylene acetal solution (0.240 M, 6.00 mL, 1.0 eq.), and allyl bromide (0.244 mL, 2.82 mmol, 2.0 eq.). The mixture was heated at 60 °C for 24 hours. The homogenous dark brown solution was concentrated and the residue was purified by flash column chromatography using 0-80% ethyl acetate/hexanes as eluent to afford a mixture of two isomers with an isomeric ratio of 19.7 : 1.0 (la : Ilia) by quantitative 13 C NMR analysis and 19.4 : l(Ia : Ilia) by GC analysis.

Comparative Example CE3:

CH 3 CN , 60 S C

To a 25 mL round bottom flask was added di-w-butylstannylene acetal solid (0.578 g, 1.41 mmol), tetrabutylammonium iodide (0.520 g, 1.41 mmol, 1.0 eq.), dry acetonitrile (5.6 mL), and allyl bromide (0.244 mL, 2.82 mmol, 2.0 eq.). The solid becomes sticky at the beginning and gradually became homogenous clear solution after being heated to 60 °C. After 24 hours the solution was washed with saturated sodium thiosulfate solution (5 mL) and extracted with ethyl acetate (3 x 10 mL). Combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography using 0-80% ethyl acetate/hexanes as eluent to afford a mixture of two isomers as a colorless oil (0.252 g, 82%). The ratio of two isomers was determined to be 25.8 : 1 (la : Ilia) by

quantitative 13 C NMR analysis and 26.0 : 1 (la : Ilia) by GC analysis.

Comparative Example CE4:

CH 3 CN, 60 S C

la Ilia

To a 25 mL round bottom flask was added di-w-butylstannylene acetal solid (0.578 g, 1.41 mmol), tetrabutylammonium bromide (0.454 g, 1.41 mmol, 1.0 eq.), dry acetonitrile (5.6 mL), and allyl bromide (0.244 mL, 2.82 mmol, 2.0 eq.). The solid becomes sticky at the beginning and gradually became homogenous clear solution after being heated to 60 °C. After 24 hours the solution was washed with water (5 mL) and extracted with ethyl acetate (3 x 10 mL). Combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography using 0-80% ethyl acetate/hexanes as eluent to afford a mixture of two isomers as a colorless oil (0.227 g, 74%).

The ratio of two isomers was determined to be 20.0 : 1 (la : Ilia) by quantitative 13 C NMR analysis. Comparative Example CE5:

CH 3 CN, 75 S C

la Ilia

To a 25 mL round bottom flask was added di-w-butylstannylene acetal solid (0.578 g, 1.41 mmol), potassium iodide (0.234 g, 1.41 mmol, 1.0 eq), dry acetonitrile (5.6 mL), and allyl bromide (0.244 mL, 2.82 mmol, 2.0 eq.). The mixture was heated to 75 °C and gradually became homogenous clear solution. After 48 hours the solution was washed with saturated sodium thio sulfate solution (5 mL) and extracted with ethyl acetate (3 x 10 mL). Combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography using 0-80% ethyl acetate/hexanes as eluent to afford a mixture of two isomers as a colorless oil (0.224 g, 73%). The ratio of two isomers was determined to be 20.3 : 1 (la : Ilia) by quantitative 13 C NMR analysis and 19.5 : 1 (la : Ilia) by GC analysis.

Comparative Example CE6

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 CEl.

Table CEl