WO1992021657A1 - Sucres omega-desoxy-aza - Google Patents

Sucres omega-desoxy-aza Download PDF

Info

Publication number
WO1992021657A1
WO1992021657A1 PCT/US1992/004409 US9204409W WO9221657A1 WO 1992021657 A1 WO1992021657 A1 WO 1992021657A1 US 9204409 W US9204409 W US 9204409W WO 9221657 A1 WO9221657 A1 WO 9221657A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydrogen
hydroxyl
alkyl
azapyranose
methyl
Prior art date
Application number
PCT/US1992/004409
Other languages
English (en)
Inventor
Chi-Huey Wong
Tetsuya Kajimoto
Kun-Chin Liu
Lihren Chen
Original Assignee
The Scripps Research Institute
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US07/835,237 priority Critical patent/US5276120A/en
Priority claimed from US07/835,237 external-priority patent/US5276120A/en
Application filed by The Scripps Research Institute filed Critical The Scripps Research Institute
Priority to AU21459/92A priority patent/AU2145992A/en
Publication of WO1992021657A1 publication Critical patent/WO1992021657A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/94—Oxygen atom, e.g. piperidine N-oxide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

Definitions

  • the present invention relates to azasugar compounds, and more particularly to omega-deoxy-azapyranose and azafuranose compounds, their manufacture and use.
  • Carbohydrates are a large class of natural substances that structurally are polyhydroxycarbonyl compounds and their derivatives. Carbohydrates
  • Monosaccharides are simple carbohydrates that cannot be further hydrolyzed into simpler types of carbohydrate.
  • a monosaccharide having a six-membered ring is referred to as a pyranose, whereas a five-membered ring monosaccharide is referred to as furanose.
  • a pyranose or furanose lacking one or more hydroxyl groups normally present in a carbohydrate is referred to as a deoxy-pyranose or deoxy-furanose, with the carbon chain position at which the hydroxy is absent being indicated.
  • Azasugars are a class of saccharides in which the ring oxygen is replaced by an imino group (-NH-).
  • a six-membered ring azasugar can be referred to as an azapyranose or a polyhydroxylated piperidine compound.
  • a five-membered ring azasugar can be referred to as an azafuranose or a polyhydroxylated pyrrolidine.
  • An azasugar can also be named as an aza derivative of an otherwise systematically or trivially named pyranose or furanose monosaccharide.
  • azasugars described herein are derived from piperidines (azapyranoses), can be
  • hyrdroxylated at the 3-, 4- and 5-positions have hydrogen at the 6-position and can have a methyl group or hydrogen at the 2-position, the 1-position being the nitrogen atom, in piperidine nomenclature.
  • Dideoxy-azapyranoses are the polyhydroxylated piperidines as discussed above, that have either a methyl group or hydrogen at the 5-position, hydrogen at the 1-position and can have hydroxyl groups elsewhere on the ring, as above, in pyranose nomenclature. Pyranose nomenclature and numbering will usually be used herein for six-membered ring compounds, unless otherwise specified.
  • azasugars described herein are derived from pyrrolidines (azafuranoses). These compounds can be hydroxylated at the 3 and 4 positions, have a hydroxymethyl group at the 5-position, and a methyl or hydroxymethyl at the 2-position, the
  • Dideoxy-azafuranoses are the polyhydroxypyrrolidines discussed above that have a methyl or hydroxymethyl at the
  • azasugars can be useful for treating metabolic disorders such as diabetes [Liu, J. Org. Chem. 1987, 52, 4717; Bayer et al., Ger. Offen. DE 3620645; Anzeveno et al., J. Org. Chem. 1989, 54, 2539; Yoshikuni et al., J. Pharmacobio-Dyn 1988, 111. 356] or as antiviral agents [Karpas et al., Proc. Natl. Acad. Sci. 1988, 85, 9229; Walker et al., Proc Natl. Acad. Sci. 1987, 84, 8120; Winkler et al., J. Med. Chem.
  • Naturally occurring azasugars include 1-deoxynoj irimycin (1,5-dideoxy-1,5-imino-D-glucitol), 1-deoxymannojirimycin (1,5-dideoxy-1,5-imino-D-mannitol), and castanospermine (1,6,7,8- tetrahydroxyoctahydroindolizine).
  • 1-Deoxynojirimycin was isolated from plants of the genus Morus [Yagi et al., Nippon Nogei Kagaku Kaishi 1976, 50, 5751; Vasella et al., Helv. Chim. Acta.
  • glucose was used in the synthesis of 1-deoxynojirimycin and 1-deoxymannojirimycin [Fleet, Chem. Br. 1989, 25, 287 and references cited therein; Bernotas et al.,
  • DHAP dihydroxyacetone phosphate
  • 1-deoxynojirimycin can then be easily converted into castanospermine [Hamana et al., J. Org. Chem. 1987, 52, 5494].
  • the latter compound has been shown to inhibit the processing of the AIDS virus gpl60 envelope protein precursor, and to modify the envelope glycoprotein, thus affecting the ability of the virus to enter cells [Walker et al., Proc. Natl. Acad. Sci. 1987, 84, 8120].
  • Each of the above azapyranoses and azafuranoses thus far prepared has had two hydrogens at the 1-position of the azapyranose (or azafuranose) ring and a hydroxyl group at the 6- or 5-position (omega-position) carbon atom of the pyranose or furanose chain; i.e., the last carbon in the chain or the omega-position.
  • naturally occurring pyranose and furanose sugars found in man and other mammals contain a 6- or 5-position hydroxyl group, respectively.
  • the present invention contemplates omega-deoxy azapyranose compounds, their use, processes of
  • omega-deoxy-azapyranose manufacture of omega-deoxy-azapyranose and omega-deoxy-azafuranose compounds, and intermediate compounds. More particularly, an omega-deoxy-azapyranose is contemplated. That compound has the formula I:
  • R is hydrogen, hydroxymethyl, C 1 -C 6 alkyl, -CHOHCH 2 OH or carboxylic acid
  • R 1 is hydrogen, hydroxyl, C 1 -C 4 alkoxy, halide, or NR 6 R 7 where R 6 is hydrogen or C 1 -C 4 alkyl and R 7 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 acyl or NR 6 R 7 together form a cyclic imido group that contains 4-8 carbon atoms;
  • R 2 is hydrogen or hydroxyl
  • R 3 is hydrogen, hydroxyl or methyl
  • R 4 is hydrogen or methyl; with the provisos (i) that only one of R 3 or R 4 is methyl, and (ii) where one of R or R 4 is methyl, the other of R or R 4 is hydrogen and R 1 , R 2 and R 3 are hydroxyl, the stereoconfiguration of R and R 1-4 is other than that of glucose, mannose or fucose;
  • R 5 is selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 7 -C 10 aralkyl and C 1 -C 12 acyl, or >N-R 5 is a C 1 -C 12 alkyl or C 7 -C 10 aralkyl N-oxide; and the deoxy-azapyranose contains at least two hydroxyl groups.
  • R is hydrogen or hydroxymethyl and, preferably hydrogen. Where R is hydrogen, R 2 and R 3 are each preferably hydroxyl. In other preferred compounds, R 4 is methyl.
  • Another aspect of this invention contemplates a general process of forming a 5- or 6-deoxy-azasugar; i.e., an omega-deoxy-azasugar.
  • an azido-substituted ⁇ -ketose compound having a five- or six-carbon chain is hydrogenated in the presence of a palladium catalyst.
  • the azido-substituted ⁇ -ketose phosphate compound Preferably, the azido-substituted ⁇ -ketose phosphate compound.
  • the carbon atom of the azido substituent and the carbon of the keto group are separated in the chain by two or three carbon atoms, respectively.
  • the 6-deoxy- azapyranose or 5-deoxy-azafuranose thus prepared is preferably recovered.
  • compositions that comprises a glycosidase inhibiting amount of a before-described omega-deoxy-azapyranose compound dispersed in an aqueous medium.
  • the aqueous medium is preferably pharmaceutically acceptable.
  • a compound of the invention is an omega-deoxy-azapyranose.
  • azapyranose in the name implies that a compound of the invention contains a 6-membered ring having a nitrogen atom in the ring in place of the oxygen of a pyranose.
  • the nitrogen atom is an imino nitrogen (-NH-) in the parent azasugar and in many preferred compounds but the remaining valances of the nitrogen can be used as is discussed hereinafter.
  • pyranose also indicates that a compound of the invention, unless otherwise specified, is a carbohydrate, and therefore corresponds to the chemical formula (C) n (H 2 O) n , as discussed before.
  • a contemplated azapyranose has a plurality of hydroxyl groups, or is a polyhydroxy piperidine compound, unless otherwise indicated.
  • a contemplated azapyranose contains at least two hydroxyl groups.
  • a compound of the invention is also an omega- deoxy compound. By that it is meant that the last or “omega" carbon atom of the chain that makes up the azapyranose backbone lacks a hydroxyl group.
  • Particularly preferred compounds contain a chain of six carbon atoms, so that particularly preferred compounds are 6-deoxy-azapyranose compounds.
  • a compound of the invention has structural formula I:
  • R is hydrogen, hydroxymethyl (-CH 2 OH), C 1 -C 6 alkyl, dihydroxyethyl (-CHOHCH 2 OH) or carboxylic acid (-CO 2 H);
  • R 1 is hydrogen, hydroxyl, C 1 -C 4 alkoxy, halide, or NR 6 R 7 where R 6 is hydrogen or C 1 -C 4 alkyl and R 7 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 acyl or NR 6 R 7 together form a cyclic imido group that contains 4-8 carbon atoms;
  • R 2 is hydrogen or hydroxyl
  • R 3 is hydrogen, hydroxyl or methyl
  • R 4 is hydrogen or methyl; with the provisos (i) that only one of R 3 or R 4 is methyl ; and (ii) where one of R or R 4 is methyl, the other of R or R 4 is hydrogen and R 1 , R 2 and R 3 are hydroxyl, the stereoconfiguration of R and R 1-4 is other than that of glucose, mannose or fucose;
  • R 5 is selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 7 -C 10 aralkyl and C 1 -C 12 acyl, or >N-R 5 is a C 1 -C 12 alkyl or C 7 -C 10 aralkyl N-oxide; and;
  • the deoxy-azapyranose contains at least two hydroxyl groups.
  • An azido ketose used in a process of the invention would normally contain a hydroxyl group on each carbon atom of the chain except for the carbon of the keto group.
  • the azido group replaces one hydroxyl group and an azido ketose is properly named as a deoxy-azido ketose.
  • an azapyranose where any of R and R 1-4 is other than hydroxyl should also be named as a deoxy compound. Such proper names are long and
  • omega-and 1, omega-deoxy name will be used in most places, with other sub ⁇ tituents being named without the use of
  • the above structural formula also does not show the orientation of groups R and R 1-4 relative to the plane of the ring.
  • Each of the ⁇ - and ⁇ -orientations is contemplated for each of R and R 1-4 , so those substituent groups are shown generally.
  • the straight lines between the ring and the substituent groups are meant to imply that substituents can be in the ⁇ - or ⁇ -configuration.
  • Darkened wedge-shaped lines indicate that a substituent is in a ⁇ -configuration, extending upwardly from the plane of the ring, whereas dashed wedge-shaped lines indicate a substituent in the ⁇ -configuration, extending downwardly from the plane of the ring.
  • the orientation of a substituent is a function of the precursor molecule, and the substituent
  • orientation can be varied as desired. As will be discussed hereinafter, particular orientations of R and R 1-4 are preferred.
  • C 1 -C 4 alkyl group is also present in a C 1 -C 4 alkoxy group, so only the alkyl groups will be discussed.
  • Contemplated C 1 -C 4 alkyl groups include methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and t-butyl.
  • C 1 -C 4 acyl groups are the corresponding acyl groups to C1-C 4 alkyl groups, with the understanding that sec- and t-butyl have no corresponding acyl groups.
  • Preferred C 1 -C 4 alkyl and alkoxy groups are methyl, ethyl and methoxy and ethoxy, respectively.
  • a preferred C 1 -C 4 acyl group is acetyl.
  • R 5 is hydrogen. Hydrogen is. thus a preferred R 5 group.
  • An NR 6 R 7 group is seen to be a free amine (-NH 2 -), a mono- or di-alkyl substituted amine, an acyl amine, an acyl alkyl amine where the alkyl and acyl groups are as described before, or a cyclic imido group that contains 4-8 carbon atoms.
  • exemplary cyclic imido groups include succinimido, methylsuccinimido, maleimido and phthalimido groups.
  • an alkyl or acyl group can be longer than those discussed previously.
  • the same C 1 -C 4 alkyl or acyl groups can be utilized, as can longer groups such as hexyl, octyl, nonyl, decyl, undecyl, dodecyl and their corresponding acyl groups, as well as benzyl and benzoyl groups.
  • the presence of a C 1 -C 12 acyl or alkyl group improves lipid solubility for the dideoxy-azapyranose.
  • a contemplated C 7 -C 10 aralkyl group includes benzyl, phenethyl, (p-ethyl) phenethyl, and the like.
  • An >N-R 5 can also be a C 7 -C 12 alkyl or a C 7 -C 10 aralkyl N-oxide.
  • the alkyl group is as discussed above, and the alkylated tertiary nitrogen atom is oxidized to form the N-oxide.
  • the symbol ">" is used to show the remaining valences of the nitrogen that are bonded to ring carbon atoms.
  • R is hydroxymethyl; R 1 , R 2 and R 3 are all hydroxyl; R4 is hydrogen; R 5 is hydrogen; and the
  • That preferred compound is designated herein as Compound 124 and is named D-1-deoxytalonojirimycin.
  • R is hydrogen or hydroxymethyl and, more preferred that R is hydrogen.
  • the compounds of the present invention conform to structural formula II, below.
  • R 1 -R 5 are as defined for formula I, with the proviso that where R 4 is methyl and R 1 , R 2 and R 3 are all hydroxyl, the stereoconfiguration of R 1-4 is other than that of fucose. Turning to particular compounds, it is
  • each of R 2 and R 3 is hydroxyl.
  • R 1 can preferably also be hydroxyl, halide such as fluoride, or N-acyl such as N-acetyl.
  • a particularly preferred group of compounds of structural formula II have a six-carbon backbone chain and are 1,6-dideoxy-azapyranose compounds. Those compounds conform to structural formula III, below.
  • R 2 and R 5 are as before-defined, R 1 is as before, but excluding hydrogen and C 1 -C 4 alkyl, and R 3 is hydrogen or hydroxyl, with the proviso that where R 1 , R 2 and R 3 are hydroxyl, the stereoconfiguratic of CH 3 and R 1-3 is other than that of fucose.
  • R and R for these compounds are each preferably hydroxyl as is shown in structural formula IV, below, where R 1 and R 5 are as immediately above.
  • R 1 is hydroxyl, N-acetyl, fluoride or ethoxy.
  • a subgroup of compounds of Formula III in which R 2 and R 3 are each hydroxyl are the compounds in which R 1 , R 2 and R 3 are each hydroxyl.
  • R 1 is hydrogen or C 1 -C 4 alkyl
  • R 3 is hydrogen or hydroxyl
  • R 4 is hydrogen or methyl
  • R 5 is as described before.
  • R 5 in formula V is also preferably hydrogen.
  • Another aspect of the present invention relates to the synthesis of some of the above omega- deoxy azapyranoses as well as the synthesis of
  • an azido-substituted ⁇ -ketose phosphate compound having a five- or six-carbon chain is reductively cyclized by hydrogenation in the presence of a palladium catalyst.
  • the carbon atom of the azido substituent and the carbon atom of the keto group are separated in the chain by two or three carbon atoms, respectively, or counting differently, the keto group is separated from the azido substituent by 3 or 4 carbon atoms.
  • An azido-substituted ⁇ -ketose phosphate used to form an omega-deoxy-azapyranose can be prepared in a number of standard organic chemical manners, as is apparent from their relatively simple structures. Such standard preparations tend, however, to provide the desired azido ⁇ -ketose phosphate compounds in relatively low yields of mixtures. Those mixtures can be separated prior to reductive cyclization-hydrogenoiysis by usually used chromatographic techniques.
  • Enzymes that are particularly useful for such syntheses are the aldolases.
  • a phosphorylated donor ketone e.g. dihydroxyacetone phosphate, DHAP
  • an azido-aldehyde e.g. 2-azido-3-hydroxypropanal
  • the reaction mixture is then maintained under biological reaction conditions for a period of time sufficient to form the desired azido-substituted ⁇ -ketose phosphate compound.
  • Biological reaction conditions are those that maintain the activity of the aldolase as well as the structural integrity of the formed azido-substituted ⁇ -ketose phosphate compound. Those conditions include a temperature range of about 0oC to about 45oC, a pH value range of about 5 to about 9 and an ionic strength varying from that of distilled water to that of about one molar sodium chloride. Methods for optimizing such conditions are well known in the art.
  • palladium catalyst can be used.
  • Exemplary catalysts include palladium powder, palladium on activated carbon (Pd/C), palladium on alumina, palladium on barium sulfate and palladium on calcium carbonate.
  • Palladium on activated carbon (charcoal) is a preferred catalyst.
  • the hydrogenation is carried out at greater than atmospheric pressure such as at about 40-60 pounds per square inch (psi).
  • a usual hydrogenation solvent such as water, ethanol or methanol, or mixtures thereof is also used.
  • a compound that is reductively cyclized herein is an azido ⁇ -ketose phosphate.
  • an omega-hydroxyl group was present in the starting azido ketol adjacent to the keto group, and that hydroxyl was retained in the cyclized azasugar.
  • omega-hydroxyl azasugars have been prepared using an azido ⁇ -ketose phosphate as an intermediate.
  • that intermediate was always dephosphorylated prior to the reductive cyclization step so that it was previously unknown that an omega-deoxy-azapyranose could be directly prepared during a
  • the aldolase-catalyzed reaction of Scheme 1 is an aldol condensation.
  • a phosphorylated donor ketone e.g.
  • FDP fructose-1,6-diphosphate
  • Rham-1-P rhamnulose-1-phosphate
  • DHAP dihydroxyacetone phosphate
  • aldehydes as acceptor substrates to form azido-substituted ⁇ -ketose phosphate compounds having new stereogenic centers with, for example, D-threo
  • the aldolase enzyme By selection of the aldolase enzyme and the configuration of an azido aldehyde, one can control the isomeric configuration of the azido-substituted ⁇ -ketose phosphate compound and, thus, the stereochemistry of the cyclized azasugar. If formation of an azasugar with a desired configuration about a particular bond is not favored by the enzymatic aldol condensation leading to the azido ⁇ -ketose phosphate, that stereochemistry can be changed in the azido ⁇ -ketose phosphate or azasugar by selective blocking of hydroxyl or other reactive groups and inversion of the configuration of the desired substituent using well known organic chemical
  • aldehydes azido ⁇ -ketose phosphate and azasugars are discussed hereinafter.
  • an azido-substituted ⁇ -ketose phosphate can exist in solution in a straight chain or cyclic, hemiacetal form.
  • the azido group Upon reductive cleavage of the azido group in forming a primary amine that becomes the nitrogen atom of the azapyranose, the hemiacetal rearranges to form a cyclic imine that is further reduced to the azasugar.
  • a primary amine substituent present in an azido ⁇ -ketose phosphate used to form an azapyranose could also form a cyclic imine that would form an undesired azasugar on further reduction
  • a primary amine present as an R 1 group of an azapyranose is blocked during the hydrogenation step as with a t-Boc, Cbz or similar group that is removed after the reductive cyclization-hydrogenolysis step.
  • An N-C 1 -C 4 acyl group needs no added blocking group for the amine.
  • substituent groups R and R 1-4 present in a final omega deoxy-azapyranose can be present during the reduction step of the synthesis and need no blocking groups. If desired, however, blocking groups insensitive to the hydrogenation reaction can be utilized and then removed or the substituent groups replaced, as desired. The freedom from the need for blocking groups is, however, one of the advantages of this synthetic method.
  • each of the above aldolase enzymes can also be used to form 1,5-dideoxy- azafuranose (pyrrolidine) compounds using DHAP as the donor enzyme substrate as shown below in Scheme 2, where R is defined above in formula I.
  • An exemplary acceptor substrate for formation of an azafuranose is 2-azido-3-hydroxypropanal.
  • the azasugar products prepared from each enzyme are
  • the stereochemistry of formed azasugars is controlled by the isomeric configuration of aldehyde substrates and the use of particular aldolase enzymes.
  • 3-Azido-2-hydroxypropanal can exist in four isomeric states: 3 (R) -azido-2(R)-hydroxypropanal; 3 (R) -azido-2 (S) -hydroxypropanal; 3 (S)-azido-2(S)-hydroxypropanal; and 3 (S) -azido-2 (R) -hydroxypropanal.
  • Those isomers are prepared by the acid hydrolysis of particular isomers of four-carbon epoxy compounds as shown below in Scheme 3, whose reagents and reactions are discussed hereinafter.
  • step a of Scheme 3 The acid hydrolysis of the epoxy compounds (step a of Scheme 3) is carried out by reacting such compounds with pyridinium chlorochromate (PCC), acidic ethanol (EtOH/H + ), sodium azide (NaN 3 ) and acid (H + ).
  • PCC pyridinium chlorochromate
  • EtOH/H + acidic ethanol
  • NaN 3 sodium azide
  • H + acid
  • Cis-2,3-epoxy-1-acetoxy-4-butanol and cis-2,3-epoxy-4- acetoxy-1-butanol are prepared from cis-2.3-epoxy-1-4- diacetoxybutane and cis-2.3-epoxy-1,4-butanediol.
  • FDP Fructose-1,6-diphosphate
  • step a to form azido-ketose-phosphate
  • step b Compounds X, XI, XII and XIII are then reductively cyclized by hydrogenation (step b) to yield azasugar Compounds 100, 101, 102 and 103, respectively.
  • Compounds 100, 101, 102 and 103 differ from each other only in the orientation of the hydroxymethyl at the C-1 position and the hydroxyl at the C-2 position. It can thus be seen that the isomeric form of the 3-azido-2- hydroxylpropanal dictates the orientation of the C-1 and C-2 substituent groups in the resulting azasugars.
  • FDP-Aldolase can be obtained from commercial sources (Sigma Chemical Co., St. Louis, MO) or isolated from animal tissues such as rabbit muscle (See Example 1 hereinafter) . 2. Rhamnulose-1-phosphate (Rham-1-P) Aldolase
  • Rham-1-P aldolase step a) to form azido-ketose-phosphate Compounds XIV, XV, XVI and XVII, respectively.
  • Compounds XIV, XV, XVI and XVII are then reductively cyclized by hydrogenation (step b) to yield azasugar Compounds 104, 105, 106 and 107, respectively.
  • Rham-1-P Aldolase can be obtained from commercial sources (Sigma Chemical Co., St. Louis, MO) or isolated from E. coli strain K-40 (See Example 6 hereinafter).
  • Fuculose-1-phosphate (Fuc-1-P) Aldolase As shown below in Scheme 6, Compounds VI, VII, VIII and IX from Scheme 3 can alternatively be condensed with DHAP in the presence of Fuc-1-P aldolase (step a) to form azido-ketose-phosphate Compounds XVIII, XIX, XX and XXI, respectively. Compounds XVIII, XIX, XX and XXI are then reductively cyclized by hydrogenation (step b) to yield azasugar Compounds 108, 109, 110 and 111, respectively.
  • Fuc-1-P Aldolase can be obtained from commercial sources (Sigma Chemical Co., St. Louis, MO) or isolated from E. coli.
  • Fuc-1-P Aldolase can also be obtained from a number of bacterial sources.
  • E. coli fuculose-1-phosphate aldolase has been cloned and overexpressed, providing an alternate source for the enzyme (Ozaki et al., J. Am. Chem. Soc. 1990, 112, 4970).
  • TDP Tagatose-1,6-diphosphate
  • D-G3P 2-deoxyribose 5-phosphate
  • DERA is the only aldolase that accepts two aldehydes in the condensation reaction: other aldolases require a ketone and an aldehyde.
  • DERA accepts at least two ketones as donor substrates, acetone and fluoroacetone, albeit at slower rates.
  • DERA expresses relaxed substrate specificities for both donor and acceptor components to form one (when acetaldehyde or acetone is the donor) or two (when propionaldehyde is used as donor) new stereogenic centers with 3S or 2R,3S-configurations.
  • the acceptor substrates have very little structural requirements.
  • the 2-hydroxyaldehydes appear to react the fastest, and the D-isomers are better substrates than the L-isomers.
  • the stereospecificity is absolute regardless of the chirality of 2-hydroxy-aldehydes.
  • the aldol reactions thus follow the Cram-Felkin mode of attack for D-substrates and anti-Cram-Felkin mode for L-substrates.
  • DERA can be obtained in recombinant form.
  • the overexpression of E. coli DERA has been achieved as a part of the cloned deo C system.
  • 1,omega-dideoxy azapyranoses can be prepared by aldolase-catalyzed condensation and palladium-catalyzed reductive
  • N-acetyl derivatives of an azasugar of Scheme 8, above proceeds similarly from the reaction of DHAP with 3-azido-2-acetamidopropanal diethyl acetal, which is prepared from 3-azido-2-hydroxypropanal as described in Pederson et al., J. Org. Chem. 1990, 55, 4897.
  • a key element in the synthesis of these N-acetyl dideoxy-azasugars is the preparation of Compound XXVI and its enantiomer as is shown in
  • step a J. org. Chem. 1990, 55, 489] in step a, followed by
  • Synthesis of Compounds 14a-c also begins with 3-azido-2-hydroxypropanal, with formation of the precursor azaketose being catalyzed by DERA.
  • DERA is unique in that it can catalyze the aldol condensation of two aldehydes. Therefore, in the case of Compound 14a the reactants were (RS) 3-azido-2-hydroxypropanal and acetaldehyde to provide Compound 13a; Compound 14b was formed via the reaction of (RS) 3-azido-2-hydroxypropanal and acetone to form Compound 13b; and Compound 14c was formed by reacting (RS)-3-azido-2-hydroxypropanal with propionaldehyde to form Compound 13c. None of the resulting azidoketoses or azidoaldoses contained phosphate groups, so reductive cyclization yielded Compounds 14a-c directly from parent Compounds 13a-c. Compounds 13a-c are shown below.
  • the isomeric of configuration of azapyranoses made in accordance with the process of the present invention is dependent inter alia upon the particular aldolase used to condense DHAP and the azido aldehyde.
  • isomeric omega-deoxy azafuranoses can be made from DHAP and 2-azido-3-hydroxypropanal by using different aldolases as shown in Scheme 11, below.
  • DHAP, 2-azido-3-hydroxypropanal and the azido-substituted ⁇ -ketose phosphate intermediate compound are not shown in Scheme 11 for purposes of clarity.
  • 1,Omega-dimethyl azafuranoses can be made in accordance with a process of the present invention using DHAP and 2-azido-propanal.
  • the isomeric configuration of the 1, omega-dimethyl azafuranoses made in accordance with that process is also dependent inter alia upon the particular aldolase used to condense DHAP and the azido aldehyde.
  • a variety of isomeric 1, omega-dimethyl azafuranoses can be made from DHAP and 2-azido-propanal by using different aldolases as shown in Scheme 12, below.
  • DHAP, 2-azido-propanal and the azido-substituted ⁇ -ketose phosphate intermediate compound are not shown in Scheme 12 for purposes of clarity.
  • DHAP and 2-azido-propanal are condensed in the presence of Rham-1-P aldolase, however, two pairs of diastereomeric products are formed.
  • One pair, diastereomeric Compounds 127 and 128, is formed from a kinetically produced azido-substituted ⁇ -ketose
  • diastereomeric Compounds 129 and 130 is formed from a thermodynamically produced azido-substituted ⁇ -ketose phosphate intermediate compound.
  • 1,omega-dimethyl azafuranoses can be made from a single ketone and single azidoaldehyde precursor.
  • a before-described omega-deoxy-azasugar is preferably also recovered once made. Recovery typically includes separation of the palladium catalyst from the reaction mixture used for reductive cyclization, followed by chromatographic or other separation of the formed dideoxy-azapyranose from any other materials present. Exemplary recoveries are provided hereinafter.
  • a R 5 group is added to a before-described azapyranose after reductive cyclization is completed.
  • a C 1 -C 12 alkyl group can be added by reductive alkylation of a corresponding aldehyde or ketone (See Example 19 hereinafter).
  • a leaving group-substituted alkane can also be used for the alkylation.
  • Exemplary leaving groups include halides, methanesulfonyl (mesyl) and p- toluenesulfonyl (tosyl) groups. Methods of N-alkylation are well known.
  • C 1 -C 12 Acyl groups can be added via an appropriate anhydride or acid halide such as lauroyl chloride. Acylation methods are also well known.
  • N-Oxide derivatives are readily prepared from the N-alkyl derivatives by oxidation with hydrogen peroxide.
  • compositions that comprises a glycosidase-inhibiting amount of a before-described omega-deoxy-azapyranose dispersed in an aqueous medium.
  • the aqueous medium is a pharmaceutically acceptable, non-toxic medium such as normal saline, phosphate-buffered saline, Ringer's solution or the like as are well known in the art.
  • the aqueous medium can also comprise blood, serum, plasma or lymph of a mammal such as a mouse, rat, rabbit, guinea pig, dog or human to which the
  • azapyranose is administered.
  • a glycosidase-inhibiting amount is an amount that inhibits a preselected glycosidase enzyme by at least 25 percent, more preferably by about 50 percent, and most preferably by about 75 percent or more.
  • a before-described azapyranose is dispersed in the aqueous medium.
  • Such dispersal includes suspensions as well as true solutions, which are ultimate
  • the long chain alkyl and acyl groups that can be present as an R 5 group tend to lessen water-solubility while enhancing lipid solubility.
  • Enzymatic assay showed no DHAP remaining.
  • Hydrogen peroxide 42 mg, 50 percent by weight solution was added to a 1 mL H 2 O solution containing
  • KC1 potassium chloride
  • aldolase has been cloned and overexpressed, providing an alternate source for the enzyme (Ozaki et al., J. Am. Chem. Soc. 1990, 112. 4970).
  • DAST diethylaminosulfurtrifluoride
  • Compound 13b was recovered and hydrogenated over Pd/C as described above to provide Compound 14b.
  • Compound 14a was produced by the DERA-catalyzed condensation of (RS) 3-azido-2-hydroxypropanal, prepared as above, and acetaldehyde. Resulting Compound 13a was recovered and hydrogenated over Pd/C as
  • Compound 11 is prepared in a manner similar to that used for the preparation of Compound 6 (Example 6) except that (S)-3-azido-2-hydroxypropanal is utilized with DHAP and rhamnulose-1-phosphate aldolase.
  • Example 11 Cis-2, 3-epoxy-1,4-butane-diol;
  • Compound 18 is a less potent inhibitor than Compound 17 for ⁇ -glucosidase from sweet almond by an order of magnitude, although it is similar to Compound 17 for the inhibition of ⁇ -glucosidase from brewers yeast. It appears that addition of an oxygen atom to N in the N-oxide perturbs the binding to the enzyme, resulting in a weaker complex, as is also seen with N-methyl 1-deoxynojirimycin N-oxide (Compound 22). For in vivo inhibition, N-alkylation, however, may facilitate transport of the inhibitor across the cell membrane, thereby increasing the effectiveness of the inhibition [Walker et al., Proc. Natl. Acad. Sci. 1987, 84, 8120].
  • EDTA ethylenediaminetetraacetic acid
  • ⁇ -D-glucosidase from sweet almond
  • p-nitrophenyl ⁇ -D-glucoside from sweet almond
  • p-nitrophenyl ⁇ -D-glucoside from sweet almond
  • p-nitrophenyl ⁇ -D-glucoside from sweet almond
  • p-nitrophenyl ⁇ -D-glucoside from sweet almond
  • p-nitrophenyl ⁇ -D-glucoside from sweet almond
  • p-nitrophenyl ⁇ -D-glucoside from sweet almond
  • p-nitrophenyl ⁇ -D-glucoside from sweet almond
  • p-nitrophenyl ⁇ -D-glucoside from sweet almond
  • p-nitrophenyl ⁇ -D-glucoside from sweet almond
  • p-nitrophenyl ⁇ -D-glucoside from sweet almond
  • p-nitrophenyl ⁇ -D-glucoside from sweet almond
  • PIPES buffer (0.05 M with 0.01 mM EDTA, pH 6.5): To 1 liter (L) deionized H 2 O were added 15.1 g PIPES and 35.7 mg EDTA. The pH was adjusted to 6.5 with NaOH (10 M).
  • PIPES-NaOAc buffer (0.01 M PIPES, 0.2 M NaOAc and 0.01 mM EDTA, pH 6.5). This buffer was prepared according to the literature procedure [Dale et al.. Biochemistry 1985, 24, 3530].
  • ⁇ -D-Glucosidase The stock enzyme solution was prepared by dissolving 15 mg of solid protein (4 units/mg) in 1 mL PIPES-NaOAc buffer solution. This stock enzyme solution was diluted 5-fold for the enzymatic assay.
  • ⁇ -D-Mannosidase 5 mg of the solid protein were suspended in 1 mL of 3.0 M (NH 4 ) 2 SO 4 and 0.1 zinc acetate (ZnOAc), as distributed by Sigma.
  • E-nitrophenyl ⁇ -D-glucoside solution 100 mM in PIPES-NaOAc buffer, pH 6.5.
  • the solution was well mixed and 20 ⁇ L of the ,5-D-glucosidase solution were injected into the cuvette to start the reaction.
  • the reaction was monitored at 400 nm on a Beckman DU-70 photospectrometer for 45 seconds and the initial hydrolysis rate was calculated. The same procedure was repeated with five other substrate concentrations. After all the initial rates were accumulated, the corresponding Lineweaver-Burk plot at that inhibitor concentration was
  • PIPES-NaOAc buffer was used for all the enzymes except ,5-N-acetyl-D-glucosaminedase, for which PIPES buffer was used.
  • Type I (calf liver) 7 . 0 ⁇ 10 -8 ⁇ -Glucosidase (SA) 4 . 3 ⁇ 10 -5
  • Type I (calf liver) 1.0 ⁇ 10 -6a
  • the kinetic mechanism implicated from these experiments is uni-bi sequential ordered with p-nitrophenol being released first and fucose released second.
  • ⁇ -L-Fucosidase activity was measured by incubating the enzyme (0.005 Units) with fuc-pNP (0.2 -2.0 ⁇ M) in 0.4 ml of 50 mM acetate buffer, pH 5.5 for 20 minutes at 25 C in the absence and presence of the azasugars of the present invention. The reaction was stopped by the addition of 0.8 ml of 2 mM glycine buffer, pH 10.5. The amount of formed p-nitrophenol was determined by optical density spectroscopy at a
  • E. coli DH5a containing pVH17 was grown at 37oC with agitation. The cells were cooled to 4oC and harvested by centrifugation at 8K for 20 minutes. The cells (about 72 g) were resuspended in 200 mL of buffer containing 100 mM TRIS pH 7.6 and 2 mM EDTA (buffer A). The cells were lysed in a French Pressure apparatus (Aminco, Inc.) and centrifuged at 16,000xg for 30 minutes. The supernatant fluid was decanted and made 1% with streptomycin sulfate with stirring over a period of 20 min. The resulting solution was centrifuged as before.
  • DHAP (0.5 mmole) was added to an aqueous solution of (R) -3-azido-2-hydroxypropanal (1 mmole in 40 ml) and the pH value adjusted to 7.0 with 10 N NaOH.
  • fuculose-1-phosphate aldolase from E. coli (4 g), which had been treated with egg white lysozyme (40 mg) in Tris buffer (pH 7.5, 25 ml) for 1 hour at 35oC, to form a mixture and the mixture stirred slowly for 2 days. The stirred mixture was adjusted to a pH value of 4.7, and acid phosphatase (400 units) added.
  • 6-Azido-6-deoxy-D-xylo-hexulose (10mg, 0.048 mmole) prepared above was hydrogenated with 10% Pd/C under 45 psi of hydrogen for 1 day in 10 ml of water.
  • the catalyst was removed by filtration and the filtrate concentrated in vacuo and further purified with a Biogel P2 column to give Compound 124 in 67% yield (5 mg).
  • Example 19 Reductive Alkylation of Azasugars

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

L'invention se rapporte à des composés d'oméga-désoxy-azapyrannose, à des procédés de production et d'utilisation de ces composés, ainsi qu'à un procédé de production de composés d'oméga-désoxy-azafurannose.
PCT/US1992/004409 1991-05-30 1992-05-26 Sucres omega-desoxy-aza WO1992021657A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US07/835,237 US5276120A (en) 1991-05-30 1992-02-13 Process for forming omega-deuxy-azasugars
AU21459/92A AU2145992A (en) 1991-05-30 1992-05-26 Omega-deoxy-azasugars

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US70660091A 1991-05-30 1991-05-30
US706,600 1991-05-30
US07/835,237 US5276120A (en) 1991-05-30 1992-02-13 Process for forming omega-deuxy-azasugars
US835,237 1992-02-13

Publications (1)

Publication Number Publication Date
WO1992021657A1 true WO1992021657A1 (fr) 1992-12-10

Family

ID=27107709

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1992/004409 WO1992021657A1 (fr) 1991-05-30 1992-05-26 Sucres omega-desoxy-aza

Country Status (1)

Country Link
WO (1) WO1992021657A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995024391A1 (fr) * 1994-03-09 1995-09-14 Novo Nordisk A/S Piperidines et pyrrolidines
US5863903A (en) * 1994-03-09 1999-01-26 Novo Nordisk A/S Use of hydroxy alkyl piperidine and pyrrolidine compounds to treat diabetes
US10842784B2 (en) 2008-02-18 2020-11-24 Vida Pharma Limited Treatment of energy utilization disease

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5017704A (en) * 1989-06-27 1991-05-21 Monsanto Company Fucosidase inhibitor
US5100797A (en) * 1989-06-27 1992-03-31 Monsanto Company Fucosidase inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5017704A (en) * 1989-06-27 1991-05-21 Monsanto Company Fucosidase inhibitor
US5100797A (en) * 1989-06-27 1992-03-31 Monsanto Company Fucosidase inhibitors

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF ORGANIC CHEMISTRY, Volume 56, No. 22, 1991, pp. 6280-6289, (AMERICAN CHEMICAL SOCIETY), LIU et al., "Use of Dihydroxyacetone Phosphate Dependent Aldolases in the Synthesis of Deoxyazasugars". *
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Volume 113, No. 16, pp. 6187-6196, (AMERICAN CHEMICAL SOCIETY), KAJIMOTO et al., "Enzyme-Catalyzed Aldol Condensation for Asymmetric Synthesis of Azasugars: Synthesis, Evaluation, and Modeling of Glycosidase Inhibitors". *
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Volume 113, No. 17, 1991, pp. 6678-6680, (AMERICAN CHEMICAL SOCIETY), KAJIMOTO et al., "Palladium-Mediated Stereocontrolled Reductive Amination of Azido Sugars Prepared from Enzymatic Aldol Condensation: A General Approach to the Synthesis of Deoxy Aza Sugars". *
LIEBIGS ANNALEN DER CHIMIE, Volume ID, pp. 953-963, PAULSEN et al., "Synthese von Modifizierten x-L- Fucosidase-Inhibitoren, die 1,5-Didesoxy- 1,5-Imino-L-Fucit als Basisstruktur Enthalten", see pages 954 and 957. *
TETRAHEDRON LETTERS, Volume 32, No. 32, 1991 (PERGAMON PRESS, GREAT BRITAIN), pp. 4867-4870, WONG et al., "Synthesis of Novel Disaccharides Based on Glycosyltransferases: B1, 4 Galactosyl transferase". *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995024391A1 (fr) * 1994-03-09 1995-09-14 Novo Nordisk A/S Piperidines et pyrrolidines
US5863903A (en) * 1994-03-09 1999-01-26 Novo Nordisk A/S Use of hydroxy alkyl piperidine and pyrrolidine compounds to treat diabetes
JP2008056688A (ja) * 1994-03-09 2008-03-13 Novo Nordisk As ピペリジン及びピロリジン
US10842784B2 (en) 2008-02-18 2020-11-24 Vida Pharma Limited Treatment of energy utilization disease

Similar Documents

Publication Publication Date Title
US5276120A (en) Process for forming omega-deuxy-azasugars
Molyneux et al. Australine, a novel pyrrolizidine alkaloid glucosidase inhibitor from Castanospermum australe
Liu et al. Use of dihydroxyacetone phosphate-dependent aldolases in the synthesis of deoxy aza sugars
Kajimoto et al. Enzyme-catalyzed aldol condensation for asymmetric synthesis of azasugars: synthesis, evaluation, and modeling of glycosidase inhibitors
US5593887A (en) Oligosaccharide enzyme substrates and inhibitors: methods and compositions
Ziegler et al. Enzyme-catalyzed synthesis of 1-deoxymannojirimycin, 1-Ddeoxynojirimycin, and 1, 4-Dideoxy-1, 4-imino-D-arabinitol
Okabe et al. Synthesis of the dideoxynucleosides" ddC" and" CNT" from glutamic acid, ribonolactone, and pyrimidine bases
Gerth et al. The soraphens: a family of novel antifungal compounds from Sorangium cellulosum (Myxobacteria) I. Soraphen A 1α: fermentation, isolation, biological properties
US5461143A (en) Oligosaccharide enzyme substrates and inhibitors: methods and compositions
Dondoni et al. Installation of the pyruvate unit in glycidic aldehydes via a Wittig olefination-Michael addition sequence utilizing a thiazole-armed carbonyl ylide. A new stereoselective route to 3-deoxy-2-ulosonic acids and the total synthesis of DAH, KDN, and 4-epi-KDN
US5795749A (en) Use of 2-deoxyribose-5-phosphate aldolase to prepare 2-deoxyfucose, analogues and derivatives
Tatsuta et al. Total syntheses of glucosidase inhibitors, cyclophellitols
Ernholt et al. Enantiospecific Synthesis of 1‐Azafagomine
US5352591A (en) Aldolase enzyme process for making 5-azido-5-deoxy-hexulose-1-phosphate
US5021427A (en) Novel pyrrolizidine alkaloid
WO1992021657A1 (fr) Sucres omega-desoxy-aza
Jarosz et al. Approaches to higher-carbon sugars, based on the use of sugar-derived, stabilized Wittig reagents
Lees et al. The enzymatic synthesis of 1, 5-dideoxy-1, 5-diimino-d-talitol and 1-deoxygalactostatin using fuculose-1-phosphate aldolase
WO1997031901A1 (fr) Hydroxyhexahydropyridazines
US5576426A (en) Aldolase catalyzed stereoselective synthesis of arabinohexulose, xyloheptulose, threohexulose and xylohexulose
Venkatasubbaiah et al. An epoxydon-derived ester from a Phoma sp. pathogenic to rhubarb
Petersen et al. Tandem asymmetric CC bond formations by enzyme catalysis
Matin et al. Synthesis and evaluation of the glycosidase inhibitory activity of 5-hydroxy substituted isofagomine analogues
Gabriel et al. Pyranosone dehydratase from the basidiomycete Phanerochaete chrysosporium: improved purification, and identification of 6-deoxy-D-glucosone and D-xylosone reaction products
EP0674706B1 (fr) Kdo aldolase et reactions de condensation associees

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA