Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-10-01
2001-09-25
Fonda, Kathleen K. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S004100, C549S031000, C549S059000
Reexamination Certificate
active
06294666
ABSTRACT:
BACKGROUND OF THE INVENTION
Many biologically active molecules contain sugar moieties which are optically active. For example, mammalian glycoaminoglycans (e.g., heparin, heparan sulfates, and dermatan sulfate) and aminoglycoside antibiotics (e.g., neomycin B, paromomycin, and lividomycin A) all contain L-ido sugars. See Lindahl,
Pure & Appl. Chem.,
v. 69, 1897 (1997) and Fourmy et al.,
Science
vol. 274, 1367 (1996). To facilitate the development of new therapeutic sugar-containing compounds, there is a need for simple methods of preparing optically pure sugars.
SUMMARY OF THE INVENTION
An aspect of this invention relates to a method of preparing a compound of formula (I):
The method includes reacting a compound of formula (II):
with a hydroborating reagent to form a borane-containing intermediate, and reacting the borane-containing intermediate with a hydroperoxide in a basic aqueous medium to form a compound of formula (I). Each of R
1
, R
2
, R
3
, and R
4
, independently, is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl, aralkyl, heteroaralkyl, haloalkyl, or alkyloxyalkyl. Note that R
1
and R
2
, together, can optionally form a keto or, together with the carbon atom to which they are attached, optionally form a cyclic moiety. Similarly, R
3
and R
4
, together, can optionally form a keto or, together with the carbon atom to which they are attached, optionally form a cyclic moiety. The compound of formula (II) is prepared by reacting a compound of formula (III):
with a halogenating reagent to produce a halo-containing intermediate, and then reacting the halo-containing intermediate with a base to effect a double bond. As to the compound of formula (III), it is prepared by reacting a compound of formula (IV):
with a ketal- or an acetal-forming reagent.
Alternatively, the compound of formula (II), supra, is prepared by reacting a compound of formula (V):
wherein X is halo, with a base to effect a double bond. The compound of formula (V) is prepared by reacting a compound of formula (VI):
with a halogenating reagent.
Another aspect of this invention relates to a method of preparing an 1,6-anhydro-L-ido sugar. The method includes reacting a compound of formula (II), supra, with a hydroborating reagent to form a borane-containing intermediate; reacting the borane-containing intermediate with a hydroperoxide in a basic aqueous medium to form a compound of formula (I); and deprotecting the compound of formula (I) in an acidic medium. In this method, the compound of formula (II) and the compound of formula (I) are 1,2-O-Y-3,5-O-Z-&agr;-D-xylo-hex-5-enofuranoside and 1,2-O-Y-3,5-O-Z-&bgr;-L-idofuranoside, respectively, where Y is —C(R
1
)(R
2
)— and Z is —C(R
3
)(R
4
)—. Each of R
1
, R
2
, R
3
, and R
4
1
, independently, is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl, aralkyl, heteroaralkyl, haloalkyl, or alkyloxyalkyl. Note that R
1
and R
2
, together, can optionally form a keto or, together with the carbon atom to which they are attached, optionally form a cyclic moiety, and that R
3
and R
4
, together, optionally form a keto or, together with the carbon atom to which they are attached, optionally form a cyclic moiety. For example, if each of R
1
and R
2
is a methyl, then —C(R
1
)(R
2
)— is a isopropylidene.
A method of preparing a salt of a compound of formula (I) is also within the scope of this invention. For example, a salt of such a compound can be formed between an amino substituent of the benzene ring of a benzylidene group and a negatively charged anion, e.g., chloride, bromide, iodide, sulfate, or nitrate.
It should be recognized that a method of this invention includes preparing any optical isomers of formula (I).
As used herein, alkyl is a straight or branched hydrocarbon chain containing 1 to 8 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylpentyl, and 4-ethylhexyl. By cycloalkyl is meant a cyclic alkyl group containing 3 to 8 carbon atoms. Some examples of cycloalkyl are cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and norbornyl. Heterocycloalkyl is a cycloalkyl group containing 1-3 heteroatoms such as nitrogen, oxygen, or sulfur. Examples of heterocycloalkyl include piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuryl, and morpholinyl. As used herein, aryl is an aromatic group containing 6-12 ring atoms and can contain fused rings, which may be saturated, unsaturated, or aromatic. Examples of an aryl group include phenyl, naphthyl, biphenyl, phenanthryl, and anthracyl. Heteroaryl is aryl containing 1-3 heteroatoms such as nitrogen, oxygen, or sulfur and can contain fused rings. Some examples of heteroaryl are pyridyl, furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, and benzthiazolyl. A cyclic moiety is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. A cyclic moiety can also be fused rings and can be formed from two or more of the just-mentioned groups. An example of a cyclic moiety is phenanthryl.
An amino group can be unsubstituted, mono-substituted, or di-substituted. It can be substituted with groups such as alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. Halo refers to fluoro, chloro, bromo, or iodo.
A hydroborating reagent refers to a reagent which transforms a double bond-containing compound to a borane-containing compound. Examples of such a hydroborating reagent include borane.tetrahydrofuran, borane.dimethyl sulfide, disiamyl-borane, thexylborane, thexylchloro-borane.dimethyl sulfide, and 9-borabicyclo[3.3.1]nonane. The borane-containing compound can then be oxidized to an alcohol by reacting with a hydroperoxide such as hydrogen peroxide or t-butyl peroxide.
A halogenating reagent reacts with and transforms a compound with a suitable functionality, e.g., a good leaving group such as halide, into a halo-containing compound via reactions such as nucleophilic substitution. A halogenating reagent can be a chlorinating, a brominating, or an iodinating reagent. Examples of such a reagent include hydrogen halides (e.g., HBr), thionyl chloride, N-bromosuccinimide, and methyl iodide. The halo-containing compound can undergo dehydrohalogenation to form a double bond-containing compound in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene, diisopropylethylamine, triethylamine, or dimethylpyridine.
A ketal- or an acetal-forming reagent protect a pair of neighboring diols as a cyclic ketal or acetal group. Some commonly used ketal- or acetal-forming group include butylidene acetal, isopropyliene ketal, ethylidene acetal, methylene acetal, cyclohexylidene ketal, benzylidene acetal, o-nitrobenzylidene acetal, and 2,4-dimethoxybenzylidene acetal. More ketal- or acetal-forming groups can be found in references such as Greene, T. W.,
Protective Groups in Organic Synthesis,
John Wiley & Son, Inc., chapter 2 (1981).
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, suitable methods and materials are described below. All publications mentioned herein are incorporated by reference in their entirety.
Other features or advantages of the present invention will be apparent from the following detailed description of several embodiments, and also from the appending claims.
DETAILED DESCRIPTION OF THE INVENTION
Compounds of formula (I) can be prepared in their optically pure form by two methods of this invention, which are illustrated in Schemes 1 and 2 below.
In the method shown in Scheme 1, 1,2-O-isopropylidene-&agr;-D-glucofuranoside is used as an exemplary starting material. Selective benzylidene protection of 1,2-O-isopropylidene-&agr;-D-glucofuranoside affords a primary alcohol, i.e., 3,5-O-benzylidene-
Academia Sinica
Fish & Richardson P.C.
Fonda Kathleen K.
Maier Leigh C
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