Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2002-09-19
2003-09-16
Barts, Samuel (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S115000, C536S119000, C536S018500, C536S018600, C536S124000, C536S017100
Reexamination Certificate
active
06620921
ABSTRACT:
This is the National Phase Application of PCT/N200/0028, filed Nov. 16, 2000.
This invention relates to a perpropanoylated glucofuranose, its preparation from glucose, and its use in the preparation of other compounds. In particular, the invention relates to crystalline 1,2,3,5,6-penta-O-propanoyl-&bgr;-D-glucofuranose, a process for preparing it, and its use in the preparation of various glycosides and other compounds.
BACKGROUND
A large number of carbohydrate compounds are cheap and readily available starting materials useful in the synthesis of a wide variety of substances. One particularly desirable feature of carbohydrate compounds is that they are a source of one or more chiral carbon atoms. Many compounds useful in the pharmaceutical, agrochemical, and other industries, contain one or more chiral carbon atoms. Such compounds can be prepared in a more effective manner from carbohydrate starting materials than from non-chiral starting materials which therefore require the introduction of chirality during the synthetic route.
Examples of monosaccharide carbohydrates often used as starting materials include glucose, mannose, galactose, ribose, and arabinose. Disaccharides, for example lactose, trisaccharides, and other higher order saccharides, are also useful starting materials for the preparation of desirable compounds.
Most carbohydrate compounds contain several hydroxyl groups. Monosaccharides typically have four or five hydroxyl groups. The selective reaction of one or more of the hydroxyl groups of a monosaccharide is usually required during the synthetic route to a desired product. It is therefore often necessary to protect some or all of the hydroxyl groups of a monosaccharide in the form of ester groups, or other protecting groups.
Protection of one or more of the hydroxyl groups is often the first reaction of a sequence performed on the unprotected monosaccharide starting material.
Most readily available monosaccharide starting materials have a pyranose structure, although in solution the monosaccharide will interconvert between the pyranose form and the furanose form. The pyranose form contains a 6-membered oxygenated ring whereas the furanose form contains a 5-membered oxygenated ring. Both forms may have either an &agr; or &bgr; orientation of the hydroxyl group at C-1.
In many instances it is useful to convert the starting material monosaccharide into a protected furanose compound. The cheapest and most readily available monosaccharide starting material is glucose. Glucose can be protected by acetylating each hydroxyl group of glucose to give peracetylated glucopyranose. Peracetylated glucopyranose can be readily prepared in one step from glucose. However, the preparation of the furanose form is less straight forward.
The preparation of peracetylated glucofuranose is known but usually requires several reaction steps and has a low overall yield of product. A common method is to constrain the glucose to the furanose form by formation of diacetone glucose. Partial hydrolysis, acetylation and subsequent acetolysis gives peracetylated glucofuranose. Another method involves the initial preparation of glucose diethyl dithioacetal followed by cyclisation in the presence of mercury salts and then acetylation.
Peracetylated glucofuranose can be also prepared from glucose in one step in the presence of a reagent such as FeCl
3
or Montmorillonite clays. However, these one-step methods proceed in low yields and the products are unavoidably contaminated by significant amounts of pyranose products.
It is known to prepare perbenzoylated glucofuranose from glucose, but in several steps. For example, glucose can be treated with boric acid to give a boron complex of the glucose. The complex can be reacted with benzoyl chloride to give dibenzoylated glucose. Successive repetitions of similar procedures lead ultimately to the perbenzoylated glucofuranose.
The known methods of preparing a protected glucofuranose from an unprotected monosaccharide starting material require several reaction steps and are therefore laborious, time consuming and consequently expensive.
Additionally, a problem with many glucofuranose derivatives is that they are oils at normal temperatures and pressures, rather than crystalline solids. This means that it can be very difficult and time consuming to purify the glucofuranose. Often the &agr;- and &bgr;- forms of a glucofuranose have very similar physical properties making it difficult to separate one from the other by standard methods, such as chromatography. However, if one or both of the &agr;- and &bgr;- forms is crystalline, either may be readily separated from the other by recrystallisation from a suitable solvent.
Furthermore, peracylation of an unprotected saccharide typically gives a mixture of C-1 &agr; and &bgr; products. Often only one of the &agr; and &bgr; products is desired for further reaction. For example, a C-1 &bgr; acetate on a glucose ring can be more reactive than the C-1&agr; counterpart towards displacement by nucleophiles due to the effect of neighbouring group participation. Thus, the comparatively mild conditions needed for the synthesis of furanosides from a C-1 &bgr; acetate can minimise any undesired anomerisation during the reaction, leading to a predominance of &bgr;-furanoside product over the &agr;-furanoside form. &bgr;-Furanosides are of particular synthetic interest because, for example, the nucleotides in RNA contain &bgr;-furanoside moieties.
It is therefore an object of this invention to provide a novel peracylated glucofuranose, or to at least provide a useful alternative.
STATEMENTS OF INVENTION
In a first aspect of the invention there is provided a peracylated glucofuranose which is 1,2,3,5,6-penta-O-propanoyl-&bgr;-D-glucofuranose, preferably in crystalline form.
In a second aspect of the invention there is provided a process for the preparation of 1,2,3,5,6-penta-O-propanoyl-&bgr;-D-glucofuranose from D-glucose. Preferably, the process includes the steps of reacting D-glucose with boric acid, or an equivalent thereof, to give a boron-glucose intermediate and reacting the intermediate with a propanoylating reagent, such as propanoic anhydride.
In a third aspect of the invention there is provided a use of 1,2,3,5,6-penta-O-propanoyl-&bgr;-D-glucofuranose in the preparation of another compound, preferably a &bgr;-D-glucofuranoside.
DETAILED DESCRIPTION
The term “unprotected saccharide” includes any saccharide which is fully or at least partially unprotected. Such compounds will have at least two free hydroxyl groups including the hydroxyl group at the C-1 position of the reducing-sugar residue. Generally, unprotected saccharides are fully unprotected, for example, each oxygen function at positions C-1, C-2, C-3, C-4 and C-6 of a pyranose monosaccharide will be in the form of hydroxyl groups rather than ethers, esters and the like. Unprotected saccharides may have fewer hydroxyl groups, such as 1-6 disaccharides which have the C-6 oxygen function of the reducing ring linked to a monosaccharide, for example, isomaltose, allolactose and gentiobiose.
The term “peracylated” means that all hydroxyl groups of the corresponding unprotected saccharide have been converted to an ester group. The term “peracetylated” therefore means that each available hydroxyl group of the unprotected saccharide has been converted to an acetate group.
The term “disaccharide” refers to a compound in which two monosaccharides are joined by a glycosidic linkage. The term “oligosaccharide” refers to those saccharides having a well-defined structure comprising a known number (greater than 2) of known monosaccharides joined by glycosidic linkages.
The term “reducing-sugar residue” refers to the residue of a saccharide that has, in its unprotected form, a C-1 hydroxyl group and which is capable of being in an aldehydic form.
The terms &agr; and &bgr; relate to the stereochemical arrangement of an atom or group of atoms relative to the plane of the monosaccharide ring structure. Thus, for example, a C-1 &agr; acetate means that the acetate group li
Furneaux Richard Hubert
Rendle Phillip Martin
Sims Ian Michael
Barts Samuel
Henry Michael C.
Industrial Research Limited
Merchant & Gould P.C.
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