CROSS-REFERENCE TO RELATED APPLICATIONS

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

Application Serial No. 62/059,193, 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 selectively alkylating methyl alpha-L-rhamnopyranoside and preparing methyl 3-0-(alkyl or alkenyl) alpha-L- rhamnopyranoside substantially free of 2-0-(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 yields as well as improved selectivities. More specifically, selective 3-0- 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- rhamnopyranoside using tin as the stoichiometric promoter has been reported (Carbohyr. Res, 1991, 211, 179-182, Scheme 1). A stannylene acetal of methyl alpha-L-rhamnopyranoside was prepared (step la) and subsequently treated with allyl bromide or benzyl bromide (step lb) 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 The preparation of methyl 3-O-allyl alpha-L-rhamnopyranoside in 40% isolated yield using similar reaction conditions has also been reported (Carbohydr. Res., 2012, 356, 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.

A two-step method for the selective 3-O-alkylation of methyl alpha-L- fucopyranoside that eliminates the need for tin reagents has been described by Aoyama, et al. (Tetrahedron Lett., 1997, 38, 5001-5004, Scheme 2). It was reported that treatment of methyl alpha-L-fucopyranoside with phenylboronic acid leads to the exclusive formation of an isolated 3,4-boronate ester. Subsequent treatment of the 3,4-boronate ester with excess silver(I) oxide (5 equivalents), triethylamine (1 equivalent), and iodobutane (1 equivalent) in refluxing benzene provided methyl 3-O-butyl alpha-L-fucopyranoside in 50% yield "as the sole sugar derivative other than starting material." It was further reported that the yield could be enhanced to -80% by an additional 1 equivalent of both triethylamine and iodobutane in small portions over about 24 hours. Slow addition of the amine and iodobutane in small portions was determined to be necessary to avoid formation of significant amounts of the 2,3-di-O-butyl product.

Scheme 2

methyl a-L-fucopyranoside isolated

It was further reported by Aoyama, et al. that: (1) silver(I) oxide is essential; no reaction takes place in its absence; (2) the presence of an appropriate tertiary amine such as triethylamine, a pyridine, or 4-dimethylaminopyridine is also important (only a small amount, -4%, of methyl 3-O-butyl alpha-L-fucopyranoside is obtained in the absence of an amine); (3) the choice of solvent and amine is important (use of acetone in place of benzene or quinuclidine in place of triethylamine lowers the yield of methyl 3-O-butyl alpha-L-fucopyranoside; (4) formation of the phenylboronate ester of the diol moiety is essential for the reaction to occur. They report that exposure of methyl alpha-L-fucopyranoside to the optimized alkylation conditions absent treatment with phenylboronic acid failed to provide the desired alkylated sugar.

Use of the method described by Aoyama, et al. to prepare methyl 3-O-propyl alpha-L-rhamnopyranoside using silver(I) oxide (3 equivalents) and toluene as a solvent has been reported by Crouse et al. (US 2010/0204165, Scheme 3). The selectivity between 2-0- and 3-0- alkylation was not reported.

Scheme 3

methyl -L-rhamnopyranoside isolated A one-step, selective 3-O-alkylation of pyranosides utilizing a catalytic amount of diphenylborinate, 2,2-diphenyl-l,3,2-oxazaborolidin-3-ium-2-uide (as the intramolecular complex), has been described by Taylor et al. (Org. Lett., 2011, 13, 3090-3093, Scheme 4). It was reported that 2,2-diphenyl-l,3,2-oxazaborolidin-3-ium-2-uide promoted a high-yield (90%) of the 3-O-monoalkylation product of the methyl 6-O-ieri-butyldimethylsilyl mannopyranoside. It was further reported by Taylor, et al. that use of catalysts such as boric acid and

phenylboronic acid resulted in the formation of methyl 3-O-benzyl 6-0- iert-butyldimethylsilyl mannopyranoside in lower yields (50%), in mixture with other alkylated by-products. Taylor, et al., identified acetonitrile as the optimal reaction solvent for these alkylation conditions. They also reported that, in contrast to the observations of Aoyama, et al., addition of an amine base, triethylamine, suppressed the formation of the desired methyl 3-O-benzyl 6-0- tert- butyldimethylsilyl mannopyranoside. Although the method described by Taylor, et al., appears to be applicable to other pyranosides such as rhamnose and fucose, they report that this method is limited to the use of activated alkyl halides (benzylic or alkoxymethyl). They state that use of iodomethane or bromobutane resulted in no alkylation of the pyranoside under their described conditions. It should further be noted that the method described by Taylor, et al., requires use of 1.1 equivalents of silver(I) oxide. Scheme 4

In summary, selective alkylation of pyranosides using the conditions described by Aoyama - catalytic amounts of boronic acids, nonpolar solvents, and amine bases - requires use of a several-fold excess of silver(I) oxide. It has been found that reducing the ratio of silver to pyranoside to around 1 : 1 results in reversal of the 3-O-alkyl to 2-O-alkyl selectivity in this reaction, and that Aoyama' s optimal conditions give poor selectivity when used for the alkylation of rhamnopyranosides (see Comparative Example CE2). Taylor, et al., report that using their preferred catalyst, 2,2-diphenyl-l,3,2-oxazaborolidin-3-ium-2-uide, and a polar solvent allows alkylation to proceed with 1.1 equivalents of silver(I) oxide to pyranoside in good yields with good selectivities, but that their conditions are not useful for alkylation with un- activated alkylating agents.

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 5.

Scheme 5

Advantages of this process relative to prior reported processes include (a) the reaction yields the 3-O-alkylated product in the absence of a tertiary amine base with improved yield while maintaining high selectivity; (b) as little as about 0.7 equivalents of silver oxide can be used, compared with 5 equivalents reported by Aoyama and 3 equivalents reported by Crouse; (c) a catalytic amount of a simple, inexpensive phenylboronic acid (10 mol relative to the pyranoside) can be used with unactivated alkylating agents.

Also described herein is the discovery that these conditions result in selective 3- O-allylation when allyl bromide is used instead of iodopropane (Scheme 6).

Scheme 6

Under conditions described herein, a 94% isolated yield of the 3-O-allyl alpha- L-rhamnopyranoside is obtained, with about a 11: 1 selectivity for alkylation at the 3-OH relative to the 2-OH. Other advantages of the processes described herein include avoidance of the use of a toxic tin reagent, and overall higher yields relative to the previously reported conditions.

Described herein is the use of from about 0.4 equivalents to about 3 equivalents of silver(I) oxide, from about 0.05 equivalents to about 1 equivalent of an aryl boronic acid, from about 1 equivalent to about 35 equivalents of an alkylating agent, a polar aprotic solvent, at a temperature of from about 50 °C to about 75 °C, at times ranging from about 6 hours to about 48 hours. Under these conditions, high selectivity for 3-O-alkylation over 2-O-alkylation is obtained, with no observable over- alkylation (the yield of bis-alkylated product is <2%, within the limits of detection by GCMS). Illustrative polar aprotic solvents include acetonitrile, propionitrile, N-methyl pyrrolidone, dimethylformamide, and the like. Illustrative alkylating agents include bromopropane, iodopropane, allyl bromide, and the like.

The selective alkylation processes described herein result in mixtures enriched in the 3-O-alkylated isomer of methyl alpha-L-rhamnopyranoside. However, use of a mixture of methyl 3-0-(alkyl or alkenyl) alpha-L-rhamnopyranoside containing the 2-0-(alkyl or alkenyl) isomer in subsequent process steps involved in the preparation of insecticidal compounds is complicated by difficulties in removing the 2-0-(alkyl or alkenyl) isomers that arise in each of those later steps from the desired 3-0-(alkyl or alkenyl) products. Described herein is a process for removing the 2-0-(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 solution of the reaction product formed in the alkylation step with an oxidant that selectively oxidizes one or more of the vicinal hydroxyl groups present in the 2-0-(alkyl or alkenyl) isomer allowing for the purification of the 3-O-alkylated isomer via aqueous extraction.

Described herein is the treatment of a solution or suspension containing a mixture of methyl 3-O-(alkyl or alkenyl) alpha-L-rhamnopyranoside and methyl 2-O-(alkyl or alkenyl) alpha-L-rhamnopyranoside with sodium periodate followed by a simple aqueous extraction to yield the 3-O-alkylated rhamnose derivative substantially free of the 2-O-alkylated isomer. Also described 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 manganese dioxide followed by a simple aqueous extraction to achieve the same result. It is appreciated that other oxidants may be used for the selective removal of the undesired isomer.

Described herein is the treatment of a solution or suspension of methyl

3-O-alkylated alpha-L-rhamnopyranoside, contaminated with from about 5% to about 25% of the 2-O-alkylated alpha-L-rhamnopyranoside, with an aqueous solution of sodium periodate (from about 1 to about 3 equivalents relative to the amount of 2-O-(alkyl or alkenyl) isomer present). The resulting solution or suspension is extracted with an organic solvent, which results in extraction of the unoxidized 3-O-(alkyl or alkenyl) alpha-L-rhamnopyranoside. Removal of solvent from the extract leaves methyl 3-0-(alkyl or alkenyl) alpha-L-rhamnopyranoside which is substantially free of 2-0-(alkyl or alkenyl) alpha-L-rhamnopyranoside. Illustrative organic solvent 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 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. For an illustrative example, see Scheme 7.

Scheme 7

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 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 45 °C to about 110 °C, with

an amount of an alkylating agent (R ^x -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 silver(I) oxide, wherein the amount of silver(I) oxide is about 0.4 mole- equivalents to about 3 mole-equivalents based on the amount of compound (A); and

an amount of an aryl boronic acid, wherein the amount of aryl boronic acid is about 0.05 mole-equivalents to about 1 mole-equivalent 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 the step of:

(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.

· 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 ), where R 2 is as previously defined and X 2 is CI, Br, I, OS(0) ₂ CF ₃ , 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 any one of the two preceding clauses wherein the mixture of (I) and (III) is prepared by process I.

• The process of any one of the preceding clauses wherein the polar solvent of step (a) is selected from acetonitrile, propionitrile, dimethylformamide and N-methyl pyrrolidone.

• The process of any one of the preceding clauses wherein the temperature of the step (a) is about 45 °C to about 70 °C.

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

· 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 -X is bromopropane.

· 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 is a (C ₂ -C ₄ ) alkenyl.

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

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

• The process of any one of the preceding clauses wherein the amount of silver(I) oxide is about 0.4 mole-equivalents to about 0.9 mole-equivalents based on the amount of (A).

• The process of any one of the preceding clauses wherein the amount of silver(I) oxide is about 0.5 mole-equivalents to about 0.9 mole-equivalents based on the amount of (A).

• The process of any one of the preceding clauses wherein the amount of silver(I) oxide is about 0.6 mole-equivalents to about 0.9 mole-equivalents based on the amount of (A).

• The process of any one of the preceding clauses wherein the amount of silver(I) oxide is about 0.6 mole-equivalents to about 0.8 mole-equivalents based on the amount of (A).

• The process of any one of the preceding clauses wherein the amount of silver(I) oxide is about 0.7 mole-equivalents to about 0.8 mole-equivalents based on the amount of (A).

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

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

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

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

• The process of any one of the preceding clauses wherein the aryl boronic acid is PhB(OH) ₂ .

• The process of any one of the preceding clauses wherein the amount of aryl boronic acid is about 0.05 mole-equivalents to about 0.4 mole-equivalents based on the amount of (A).

• The process of any one of the preceding clauses wherein the amount of aryl boronic acid is about 0.05 mole-equivalents to about 0.3 mole-equivalents based on the amount of (A).

• The process of any one of the preceding clauses wherein the amount of aryl boronic acid is about 0.05 mole-equivalents to about 0.2 mole-equivalents based on the amount of (A).

• The process of any one of the preceding clauses wherein the amount of aryl boronic acid is about 0.1 mole-equivalents to about 0.2 mole-equivalents based on the amount of (A). • The process of any one of the preceding clauses wherein no tertiary amine is added to the reaction.

• 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.

2 2

• 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 (A).

• 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 terms "alkenyl" each include 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, including (Ci-Cg), (C -C ), and (Ci-C ₄ ). It is to be further understood that in certain embodiments alkenyl may be advantageously of limited length, including (C ₂ -Cg), (C ₂ -C6), and (C ₂ -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.

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, alkylaryl, heteroalkylaryl, heteroaryl, alkylheteroaryl, heteroalkylheteroaryl, 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, alkylaryl, heteroalkylaryl, heteroaryl, alkylheteroaryl, and/or heteroalkylheteroaryl is optionally substituted.

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

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

EXAMPLES

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

To a 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(I) oxide (4.50 g, 19.6 mmol, 0.7 equivalents), and allyl bromide (16.2 g, 950 mmol, 34 equivalents). The solution was heated to 50 °C for 24 hours, then it was cooled, filtered and concentrated. The filtrate was dissolved in ethyl acetate (100 mL), filtered, and concentrated to give a mixture of the alkylated products as a light tan oil (5.30 g, 94.5%). The ratio of 3-0-allyl:2-O-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 ) 5 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).

EXA -O-allyl alpha-L-rhamnopyranosid

Acetonitrile (20 L), methyl alpha-L-rhamnopyranoside (1.00 kg, 5.61 mol, 1 equivalent), phenylboronic acid (0.0800 kg, 0.656 mol, 0.1 equivalents), silver(I) oxide (0.910 kg, 3.93 mol, 0.7 equivalents), and allyl bromide (1.02 kg, 8.42 mol, 1.5 equivalents) were charged into a reactor at 25-30 °C with stirring. The reaction mass was stirred and heated to 50 °C and then maintained at 48+2 °C for 15 hours. The reaction mass was cooled to 25-30 °C, vacuum filtered through a Celite® bed, rinsed with acetonitrile (1 L), and the filtrate collected. The filtrate was concentrated at 50-55 °C under vacuum (500-600 mm Hg) to give a dark yellow oil (1.15 kg, 93.8%) containing a 11 : 1 mixture of methyl 3-O-propyl alpha-L- rhamnopyranoside: methyl 2-O-propyl alpha-L-rhamnopyranoside.

EXAMPLE 3: Synthesis of 3-O-n-propyl alpha-L-rhamnopyranoside

Into a 30 L reactor equipped with an overhead stirrer, a temperature probe, a condenser, and a chiller, was added methyl alpha-L-rhamnopyranoside (1.50 kg, 8.40 mol, 1 equivalent), silver(I) oxide (1.37 kg, 5.89 mol, 0.7 equivalents) and phenylboronic acid (102 g, 0.842 mol, 0.1 equivalents). The reactor was then flushed with nitrogen and dry acetonitrile (8 L) was added. The mixture was stirred and iodopropane (1.23 L, 12.6 mol, 1.5 equivalents) was added to the suspension. The reaction mixture was heated to 45 °C for 3 hours. It was observed that the temperature of the reaction mixture increased by itself to 55 °C maximum. The fluid in the chiller remained at 45 °C and acted as a cooling system for the reaction. When the temperature started to decrease, the reaction mixture was heated to 55 °C for 3 hours. At this point, the temperature was stable. The reaction was heated at 58 °C for an additional 6 hours until thin layer chromatography showed completion of the reaction. After cooling of the reaction mixture to 25 °C, the mixture was diluted with ethyl acetate (2 L) and filtered through Celite®. The Celite® was washed with ethyl acetate (3 x 500 mL) and the washings and filtrate were concentrated. It was observed that some precipitate formed during the concentration. The residue was dissolved in ethyl acetate (2 L) and filtered a second time over Celite®. The Celite® was washed with ethyl acetate (3 x 500 mL) and the washings and filtrate were concentrated. The residue was then well dried under vacuum. The title compound was obtained as a viscous brown oil (2.20 kg, ) as a 10: 1 mixture of 3-O-propyl:2-0-propyl isomers: 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-w-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 = 1.4 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 4: S nthesis of 3-O-n-propyl alpha-L-rhamnopyranoside

Into a 25 mL round bottom flask containing a magnetic stirbar was added methyl alpha- L-rhamnopyranoside (1.00 g, 5.60 mmol, white solid) and bromopropane (15.0 mL, 168 mmol. 30 equivalents). This gave a fine white suspension with an internal temperature of 18.0 °C. To the suspension was added phenylboronic acid (0.100 g, 0.820 mmol, 0.1 equivalents) followed by silver oxide (1.30 g, 5.60 mmol, 1 equivalent). The reaction was heated to 60 °C and maintained at this temperature for 16 hours. The black suspension was filtered through a plug of Celite® and the Celite® pad was rinsed with ethyl acetate (2 x 25 mL). The colorless filtrate was rotary evaporated to give a colorless oil (1.30, 108% mass balance). GCMS analysis showed a ratio of 3-O-propyl/2-0-propyl (4.2: 1.0) and about 30% of the dialkylated L- rhamnose derivative. The mixture was purified by flash column chromatography using 20-60% B/A, where A = 1: 1 hexane/dichloromethane and B = (1: 1:0.05) ethyl acetate/acetone/methanol as eluent providing the title compound as a 4: 1 mixture of the 3-O-propyl and 2-O-propyl isomers (0.960 g, 76% yield) with an amount of 2 3-O-di-n-propyl alpha-L-rhamnopyranoside.

(0.260 g): ^1J C NMR (101 MHz, CDC13) δ 99.98, 99.35, 79.96, 79.83, 79.76, 75.01, 74.92, 73.16, 71.56, 70.99, 68.47, 68.17, 67.17, 54.74, 23.54, 23.33, 23.15, 17.80, 10.59, 10.46; EIMS m z 231 (M-31).

EXAMPLE 5: Synthesis of 3-O-allyl alpha-L-rhamnopyranoside varying scale, silver(I) oxide amount catalyst, base, allyl bromide, temperature, and time.

A solution of methyl alpha-L-rhamnopyranoside, silver(I) oxide, catalyst, allyl bromide, and base in acetonitrile (amounts and equivalents listed in Table 1) was stirred at the temperature listed for the time listed. Ratios of mixtures were determined by 1H NMR and/or GCMS prior to or following workup. Results of each trial are shown in Table 1. Table l ¹

1. All reaction performed using acetonitrile as solvent.

2. Catalyst: A = phenylboronic acid; B = 2,2-diphenyl-l,3,2-oxazaborolidin-3-ium-2-uide.

3. HB = diisopropylethylamine; TEA = triethylamine; DBU = l,8-diazabicyclo[5.4.0]undec-7-ene.

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

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

EXAMPLE 6: Synthesis of 3-O-allyl alpha-L-rhamnopyranoside varying scale, silver(I) oxide amount phenylboronic acid amount, base, iodopropane amount, temperature, and time.

A solution of methyl alpha-L-rhamnopyranoside, silver(I) oxide, phenylboronic acid, iodopropane, and base in acetonitrile (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

1. All reactions were performed using acetonitrile as solvent. All reactions were performed using microwave irradiation.

2. HB = diisopropylethylamine; Py = pyridine

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

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

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

To a stirred solution of a 73:27 mixture of methyl 3-O-allyl alpha-L- rhamnopyranoside and methyl 2-O-allyl alpha-L-rhamnopyranoside (0.050 g, 0.23 mmol) in acetonitrile (7 mL)/water (3.5 mL) in a 20 mL vial was added sodium periodate (0.050 g, 0.23 mmol, 1 equivalent). The solution was stirred at ambient temperature under nitrogen for 24 hours. The reaction was monitored by thin layer chromatography (R/for the 2' isomer is 0.25; R/for the 3' isomer is 0.3 using a solvent system consisting of 3:3:3: 1 hexanes:ethyl acetate:dichloromethane:acetone, visualized by phosphomolybdic acid stain.) and by GCMS, which showed complete removal of the 2' -isomer after 24 hours.

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

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

acetate:dichloromethane:acetone, visualized by phosphomolybdic acid stain.) and by GCMS, which showed complete removal of the 2-isomer after 24 hours.

EXAMPLE 9: Purification of methyl 3-O-allyl alpha-L-rhamnopyranoside examining time and manganese dioxide equivalents

Into a 100 mL round bottom flask equipped with a reflux condenser and a magnetic stirbar was added a mixture of methyl 3-0-allyl/2-O-allyl alpha-L-rhamnopyranose (-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 to 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 3 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 _l S ^, ,5 _l S ^, ,65 ^, )-3-(allyloxy)-5-hydroxy-2- methoxy-6-methyldihydro-2H-pyran-4 3H)-one.

Table 3

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

Into a 500 mL three-necked round bottom flask equipped with a reflux condenser, a mechanical stirrer, and a thermocouple was added a solution of a mixture of methyl 3-0- allyl/2-O-allyl alpha-L-rhamnopyranoside in acetonitrile (-3: 1, 0.17% (w/w), 125 g solution, 21 g substrate, 96 mmol). Activated manganese dioxide (Cams activated Carulite 400, type E , 53 g, 616 mmol, black powder < 3 micron particle size, 6.4 equivalents) was added portionwise (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-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 4 Elapsed time 3:2 ratio ^l H

Mn0 ₂ (Total eq) Temp, °C

(hours) NMR

0 0 25 3: 1

3.0 3 75 8.3: 1

3.0 6 75 8.3: 1

5.0 9 75 16.7: 1

6.4 12 75 50: 1

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

A solution of methyl 3-O-allyl alpha-L-rhamnopyranoside (2.60 g, 11.9 mmol) contaminated with 20+% of the 2-isomer was stirred in acetonitrile (25 mL). To this solution 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, within the limits of detection, showed no evidence of the 2-isomer. See NMR data listed in Example 12.

EXAMPLE 12: Synthesis of methyl 3-O-allyl-2,4-di-0-methyl alpha-L-rhamnopyranoside.

Charged acetonitrile (20.0 L, 20 volume), methyl alpha-L-rhamnopyranoside (1.00 kg, 5.61 mol, 1 equivalent), phenyl boronic acid (80.0 g, 0.0656 mol), silver(I) oxide (0.910 kg, 3.93 mol, 0.7 equivalents) and allyl bromide (1018.0 g, 0.842 mol) in to a reactor at 25 - 30 °C with stirring. The reaction mass was heated to 50 °C and maintained at 48+2 °C for 15 hrs. The reaction mass was cooled to 25 - 30 °C and vacuum filtered through a

diatomaceous earth bed and rinsed the bed with acetonitrile (1000.0 mL) and collected the filtrate. The filtrate was concentrated at 50 - 55 °C under vacuum (500 - 600 mm Hg) to give crude product as a 11: 1 mixture of methyl 3-O-allyl alpha-L-rhamnopyranoside: methyl 2-0- allyl alpha-L-rhamnopyranoside (1150 g, 93.8% yield, dark yellow oil). Charged crude mixture (1150.0 g), water (11.5 L) and sodium periodate (333.8 g, 1.58 mol, 0.3 eq) into reactor at 25 - 30 °C with stirring for 1.5 hrs. The reaction mass was extracted once with methyl tert- butyl ether (5.75 L) and the remaining aqueous layer was extracted with 10 % methanol in dichloromethane ( 7 x 5.0 volumes). Combined all the organic extracts, dried over sodium sulfate, filtered and concentrated at 50 - 55 °C under vacuum (500 - 600 mm Hg) to give crude 3-O-allyl alpha-L-rhamnopyranoside (860 g, 74.8% yield, 87% purity by GC analysis) of a yellow oil containing none of the 2-O-allyl isomer: 1H NMR (400 MHz, CDC1 ₃ ) δ 5.96 (ddt, J = 17.2, 10.3, 5.8 Hz, 1H), 5.33 (dq, J = 17.2, 1.5 Ηζ,ΙΗ), 5.24 (dq, J = 10.4, 1.3 Hz, 1H), 4.71 (d, J = 1.7 Hz, 1H), 4.19 (ddt, J = 12.6, 5.7, 1.4 Hz, 1H), 4.07 (ddt, J = 12.6, 5.9, 1.4 Hz, 1H), 4.01 (t, J = 2.1 Hz, 1H), 3.78 - 3.59 (m, 1H), 3.57 - 3.50 (m, 2H), 3.37 (s,4H), 2.56 (s, 2H), 1.33 (d, J = 6.2 Hz, 4H). 13C NMR (101 MHz, CDC13) δ 134.24, 118.07, 100.39, 79.41,

71.47, 70.47, 67.73, 67.57, 54.86, 17.66. Charged dimethylsulfoxide (4.6 L, 5.5 volume), crude 3-O-allyl-L-rhamnopyranoside (850 g, 3.89 mol) and potassium hydroxide (655 g, 11.7 mol) in to a reactor at 25 - 30 °C with stirring. The reaction mass was heated to 40 °C and iodomethane (1271 g, 8.50 mol) was added over 1 hrs and the temperature maintained at 40 °C for 20 hrs. The reaction mass was cooled to 25 - 30 °C, diluted with water, and extracted with hexane (3 x 5 L) and concentrated under reduced pressure to give (652 g, 68.0%) of a light brown oil (purity 97.5% by GC analysis). 1H NMR (400 MHz, CDC1 ₃ ) δ 6.07 - 5.85 (m, 1H), 5.40 - 5.25 (m, 1H), 5.24 - 5.09 (m, 1H), 4.73 - 4.63(m, 1H), 4.24 - 4.11 (m, 2H), 3.69 - 3.40 (m, 10H), 3.35 (s, 3H), 3.14 (t, 1H), 1.30 (d, 3H). ¹³ C NMR (101 MHz, 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 3-0- w-propyl alpha-L-fucopyranoside using Aoyama conditions

methyl alpha-L-fucopyranoside

A modified version of the Aoyama, et al., conditions (iodopropane (1.2 eq), silver(I) oxide (3 eq), triethylamine (1 eq), phenylboronic acid (1 eq), in benzene at reflux for 14 hours) was shown to result in a 65% yield of methyl 3-O-propy-fucopyranoside with a 3-0- alkyy:2-0-alkyl selectivity of greater than 32: 1.

EXAMPLE CE2: Synthesis of 3-0- w-propyl-alpha-L-rhamnopyranoside using Aoyama conditions

methyl alpha-L-rhamnopyranoside

The conditions of Example CE1 applied to the alkylation of methyl rhamnopyranoside resulted in a 72% yield of a mixture of methyl 3-O-propyl and 2-O-propyl alpha-L-rhamnopyranoside in a 1.6: 1 ratio. These results show that alkylation conditions that yield good regioselectivity when used in one pyranoside series cannot be relied upon to yield good regioselectivity when used in another pyranoside series.

EXAMPLE CE3: Synthesis of 3-0- w-allyl alpha-L-rhamnopyranoside using 0.1 equivalents of silver oxide

To a round-bottomed flask (100 mL) equipped with a condenser were added the methyl alpha-L-rhamnopyranoside (2.0 g, 11 mmol, 1 equivalent), silver(I) oxide (0.260 g, 1.1 mmol, 0.1 equivalents), and phenylboronic acid (1.4 g, 11 mmol, 1 equivalent). The round- bottomed flask was flushed with nitrogen and dry acetonitrile (10 mL) was added. The mixture was stirred and allyl bromide (1.5 mL, 17 mmol, 1.7 equivalents) was added to the suspension. A nitrogen balloon was put on top of the condenser. The reaction mixture was heated to 60 °C for 104 hours. The thin layer chromatography against standards showed conversion of the starting material to a mixture of 3-0/2-0 allylated compounds.

EXAMPLE CE4: 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 CE1). The solution was stirred at ambient temperature under nitrogen for 24 hr. The reaction was monitored by thin layer chromatography (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:ethyl acetate:dichloromethane:acetone, visualized by phosphomolybdic acid stain.) and by GCMS. Results of each trial are shown in the following Table CE1.

Table CE1