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WO2006008493A1 - Synthèse des alcaloïdes polyhydroxylés - Google Patents

Synthèse des alcaloïdes polyhydroxylés Download PDF

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Publication number
WO2006008493A1
WO2006008493A1 PCT/GB2005/002800 GB2005002800W WO2006008493A1 WO 2006008493 A1 WO2006008493 A1 WO 2006008493A1 GB 2005002800 W GB2005002800 W GB 2005002800W WO 2006008493 A1 WO2006008493 A1 WO 2006008493A1
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Prior art keywords
alkaloid
mmol
pyrrolidine
casuarine
product
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PCT/GB2005/002800
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English (en)
Inventor
Robert James Nash
George William John Fleet
Jeroen Van Ameijde
Graeme Horne
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Mnl Pharma Limited
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Priority claimed from GB0416419A external-priority patent/GB0416419D0/en
Priority claimed from GB0427926A external-priority patent/GB0427926D0/en
Application filed by Mnl Pharma Limited filed Critical Mnl Pharma Limited
Publication of WO2006008493A1 publication Critical patent/WO2006008493A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to processes for the production of bicyclic polyhydroxylated alkaloids comprising the cyclisation of intermediates having three or more free hydroxyl groups.
  • the invention provides processes for the synthesis of polyhydroxylated pyrroiizidine or indolizidine alkaloids comprising the cyclisation of pyrrolidine or piperidine intermediates having three or more free hydroxyl groups.
  • alkaloid is used sensu stricto to define any basic, organic, nitrogenous compound which occurs naturally in an organism (particularly in a plant). However, unless otherwise indicated, the term alkaloid is used herein sensu lato to define a broader grouping of compounds which include not only the naturally occurring alkaloids, but also their synthetic and semi-synthetic analogues and derivatives.
  • alkaloids are phytochemicals, present as secondary metabolites in plant tissues (where they may play a role in defence), but some occur as secondary metabolites in the tissues of animals, microorganisms and fungi.
  • polar alkaloids see below
  • microbes including bacteria and fungi, particularly the filamentous representatives
  • alkaloids exhibit great diversity. Many alkaloids are small molecules, with molecular weights below 250 Daltons. The skeletons may be derived from amino acids, though some are derived from other groups (such as steroids). Others can be considered as sugar analogues. It is becoming apparent (see Watson ef a/. (2001 ) Phytochemistry 56: 265-295) that the water soluble fractions of medicinal plants and microbial cultures contain many interesting novel polar alkaloids, including many carbohydrate analogues. Such analogues include a rapidly growing number of so-called polyhydroxylated alkaloids.
  • alkaloids are classified structurally on the basis of the configuration of the N-heterocycle. Examples of some important alkaloids and their structures are set out in Kutchan (1995) The Plant Cell 7:1059-1070.
  • Watson et al. (2001) Phytochemistry 56: 265-295 have classified a comprehensive range of polyhydroxylated alkaloids inter alia as piperidine, pyrroiine, pyrrolidine, pyrroiizidine, indolizidine and nortropanes alkaloids (see Figs. 1-7 of Watson et al. (2001), the disclosure of which is incorporated herein by reference).
  • alkaloids are pharmacologically active, and humans have been using alkaloids (typically in the form of plant extracts) as poisons, narcotics, stimulants and medicines for thousands of years.
  • alkaloids typically in the form of plant extracts
  • the therapeutic applications of polyhydroxylated alkaloids have been comprehensively reviewed in Watson et al. (2001), ibidem: applications include cancer therapy, immune stimulation, the treatment of diabetes, the treatment of infections (especially viral infections), therapy of glycosphingolipid lysosomal storage diseases and the treatment of autoimmune disorders (such as arthritis and sclerosis).
  • Alexine (1) and australine (2) were the first pyrrolizidine alkaloids to be isolated with a carbon substituent at C-3, rather than the more common C-1 substituents characteristic of the necine family of pyrrolizidines.
  • alexines occur in all species of the genus Alexa and also in the related species Castanospermum australe. Stereoisomers of alexine, including 1 ,7a-diepialexine (3), have also been isolated (Nash et al. (1990) Phytochemistry (29) 111) and synthesised (Choi ef al. (1991) Tetrahedron Letters (32) 5517 and Denmark and Cottell (2001) J. Org. Chem. (66) 4276-4284).
  • swainsonine (4) is a potent and specific inhibitor of ⁇ -mannosidase and is reported to have potential as an antimetastic, tumour anti ⁇ proliferative and immunoregulatory agent (see e.g. US5650413, WO00/37465, WO93/09117).
  • indolizidine alkaloid castanospermine (5)
  • castanospermine (5) is a potent ⁇ -glucosidase inhibitor.
  • This compound along with certain 6-O-acyl derivatives (such as that known as Celgosivir or Bucast (6)), has been reported to exhibit anti-viral and antimetastatic activities.
  • Casuarine, (1 R,2R,3R,6S,7S,7aR)-3-(hydroxymethyl)-1 ,2,6,7-tetrahydroxypyrrolizidine (10) (also known as casuarin) is a highly oxygenated bicyclic pyrrolizidine alkaloid that can be regarded as a more highly oxygenated analogue of the 1 ,7a-diepialexine (shown in 3) or as a C(3) hydroxymethyl-substituted analogue of the 1 ⁇ ,2 ⁇ ,6 ⁇ ,7 ⁇ ,7a(S)-1,2,6,7-tetrahydroxypyrrolizidine (shown in 9).
  • Casuarine can be isolated from several botanical sources, including the bark of Casuarina equisetifolia (Casuarinaceae), the leaves and bark of Eugenia jambolana (Myrtaceae) and Syzygium guineense (Myrtaceae) (see e.g. Nash et al. (1994) Tetrahedron Letters (35) 7849-52).
  • Casuarina equisetifolia wood, bark and leaves have been claimed to be useful against diarrhoea, dysentery and colic (Chopra et a/. (1956) Glossary of Indian Medicinal Plants, Council of Scientific and Industrial Research (India), New Delhi, p. 55) and a sample of bark has recently been prescribed in Western Samoa for the treatment of breast cancer.
  • An African plant containing casuarine (identified as Syzygium guineense) has been reported to be beneficial in the treatment of AIDS patients (see Wormald et a/. (1996) Carbohydrate Letters (2) 169-74).
  • the casuarine-6- ⁇ -glucoside (casuarine-6- ⁇ -D-glucopyranose, 11) has also been isolated from the bark and leaves of Eugenia jambolana (Wormald et al. (1996) Carbohydrate Letters (2) 169-74).
  • a process for the production of a polyhydroxylated bicyclic (for example pyrrolizidine, indolizidine or quinolizidine) alkaloid comprising the cyclisation of a pyrrolidine or piperidine intermediate having three or more free hydroxyl groups.
  • the alkaloids produced according to the processes of the invention preferably have at least 3, 4, 5, 6 or 7 free hydroxyl groups on the ring system nucleus. Most preferred are alkaloid products having 3, 4 or 5 free hydroxyl groups on the ring system nucleus.
  • the alkaloids produced according to the processes of the invention are preferably polar and/or water-soluble.
  • the invention finds particular application in the synthesis of polyhydroxylated pyrrolizidine alkaloids, for example having the formula:
  • R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, hydroxyl, straight or branched, linear or cyclic, unsubstituted or substituted, saturated or unsaturated acyl, ether, alkyl, alkenyl, alkynyl and aryl groups, primary, secondary and tertiary amines, imines, sulphides, thiols, halides (e.g.
  • the invention finds particular application in the synthesis of polyhydroxylated indolizidine alkaloids, for example having the formula:
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen, hydroxyl, straight or branched, linear or cyclic, unsubstituted or substituted, saturated or unsaturated acyl, ether, alkyl, alkenyl, alkynyl and aryl groups, primary, secondary and tertiary amines, imines, sulphides, thiols, halides (e g chlorine, fluorine, iodine and bromine), phosphates, phosphonates, phosphinates, metal, nitrile, nitro, azido, sulphone, sulphoxide and sulphydryl groups, or a pharmaceutically acceptable salt or derivative thereof, and wherein the cyclisation is of a pyrrolidine or pipe ⁇ dine intermediate
  • the pyrrolidine or piperidine intermediate cyclised according to the invention may be produced by any convenient synthetic technique Particularly preferred are pyrrolidine or piperidine intermediates produced by azide reduction In such embodiments, the pyrrolidine or piperidine intermediates may be produced as the direct products of the azide reduction or indirectly via a lactam intermediate
  • alkaloid as applied to the products of the processes of the invention, is used to define the synthetic or semi-synthetic counterpart of any basic, organic, nitrogenous compound which occurs naturally in an organism (particularly in a plant), together with analogues and derivatives thereof
  • bicyclic polyhydroxylated alkaloid defines a class of highly oxygenated alkaloids having a double or fused ring nucleus ( ⁇ e having two or more cyclic rings in which two or more atoms are common to two adjoining rings)
  • alkaloids typically have at least 3, 4, 5, 6 or 7 (preferably 3, 4 or 5) free hydroxyl groups on the ring system nucleus
  • polyhydroxylated pyrrolidine alkaloid defines a highly oxygenated alkaloid (e g having at least 3, 4, 5, 6 or 7 (preferably 3, 4 or 5) free hydroxyl groups on the ring system nucleus) that comprises the nucleus
  • polyhydroxylated indolizidine alkaloid defines a highly oxygenated alkaloid (e g having at least 3, 4, 5, 6 or 7 (preferably 3, 4 or 5) free hydroxyl groups on the ring system nucleus) that comprises the nucleus
  • polyhydroxylated quinolizidine alkaloid defines a highly oxygenated alkaloid (e.g. having at least 3, 4, 5, 6 or 7 (preferably 3, 4, 5 or 6) free hydroxyl groups on the ring system nucleus) that comprises the nucleus:
  • heteroatom defines an atom of any element other than carbon or hydrogen.
  • Preferred heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
  • polar as applied to alkaloids, is used to define alkaloids which exhibit high solubility in polar solvents (which have an electric dipole moment and so display hydrophilicity) relative to non-polar solvents (which exhibit hydrophobicity).
  • polar alkaloids of the invention may therefore be soluble in water.
  • derivative and pharmaceutically acceptable derivative as applied to the alkaloids of the invention define compounds which are obtained (or obtainable) by chemical derivatization of the parent alkaloids of the invention.
  • the pharmaceutically acceptable derivatives are therefore suitable for administration to or use in contact with the tissues of humans without undue toxicity, irritation or allergic response (i.e. commensurate with a reasonable benefit/risk ratio).
  • Preferred derivatives are those obtained (or obtainable) by alkylatio ⁇ , esterification or acylation of the parent alkaloids.
  • the derivatives may be immunomodulatory perse, or may be inactive until processed in vivo. In the latter case, the derivatives of the invention act as pro-drugs.
  • Particularly preferred pro-drugs are ester derivatives which are esterified at one or more of the free hydroxyls and which are activated by hydrolysis in vivo.
  • the pharmaceutically acceptable derivatives of the invention retain some or all of the immunomodulatory activity of the parent compound.
  • the immunomodulatory activity is increased by derivatization.
  • Derivatization may also augment other biological activities of the alkaloid, for example bioavailability and/or glycosidase inhibitory activity and/or glycosidase inhibitory profile.
  • derivatization may increase glycosidase Inhibitory potency ancf/or specificity.
  • pharmaceutically acceptable salt as applied to the alkaloids of the invention defines any non-toxic organic or inorganic acid addition salt of the free base alkaloid which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and which are commensurate with a reasonable benefiVrisk ratio. Suitable pharmaceutically acceptable salts are well known in the art.
  • Examples are the salts with inorganic acids (for example hydrochloric, hydrobromic, sulphuric and phosphoric acids), organic carboxylic acids (for example acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, dihydroxymafeic, benzoic, phenylacetfc, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 2-phenoxybenzoic, 2-acetoxybenzoic and mandelic acid) and organic sulfonic acids (for example methanesulfonic acid and p-toluenesulfonic acid).
  • organic carboxylic acids for example acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic,
  • the drugs of the invention may also be converted into salts by reaction with an alkali metal halide, for example sodium chloride, sodium iodide or lithium iodide.
  • an alkali metal halide for example sodium chloride, sodium iodide or lithium iodide.
  • the alkaloids of the invention are converted into their salts by reaction with a stoichiometric amount of sodium chloride in the presence of a solvent such as acetone.
  • salts and the free base compounds can exist in either a hydrated or a substantially anhydrous form.
  • Crystalline forms of the alkaloids of the invention are also contemplated and in general the acid addition salts of the alkaloids are crystalline materials which are soluble in water and various hydrophilic organic solvents and which in comparison to their free base forms, demonstrate higher melting points and an increased solubility.
  • the present invention contemplates all optical isomers, racemic forms and diastereoisomers of the alkaloid products.
  • the pyrrolidine and indolizidine alkaloids may be produced in optically active and racemic forms.
  • references to the pyrrolizidine and indolizidine alkaloid products of the present invention encompass the products as a mixture of diastereoisomers, as individual diastereoisomers, as a mixture of enantiomers as well as in the form of individual enantiomers.
  • a wide range of bicyclic polyhydroxylated alkaloid products may be synthesised using the processes of the invention.
  • the bicyclic polyhydroxylated alkaloids produced according to the invention may have a pyrrolizidine nucleus.
  • Such 5+5 alkaloids are based on a bicyclic nucleus derived from two fused pyrrolidine rings with N at the bridgehead, thus:
  • bicyclic polyhydroxylated pyrrolizidine alkaloids examples include those listed in Figure 5 of Watson ef a/. (2001) Phytochemistry 56: 265-295 (see page 274), the content of which is incorporated herein by reference.
  • the bicyclic polyhydroxylated alkaloid produced according to the invention may have an indolizidine nucleus.
  • Such 6+5 alkaloids are based on a bicyclic nucleus derived from fused piperidine and pyrrolidine rings with N at the bridgehead, thus:
  • bicyclic polyhydroxylated indolizidine alkaloids examples include those listed in Figure 6 of Watson ef a/. (2001) Phytochetnistry 56: 265-295 (see page 275), the content of which is incorporated herein by reference.
  • the bicyclic polyhydroxylated alkaloid produced according to the invention may have a quinolizidine nucleus.
  • Such 6+6 alkaloids are based on a bicyclic nucleus derived from fused piperidine rings with N at the bridgehead, thus:
  • the bicyclic polyhydroxylated alkaloids produced according to the processes of the invention may have at least 3, 4, 5, 6 or 7 free hydroxyl groups on the ring system nucleus.
  • the alkaloids Preferably, the alkaloids have 3, 4, 5 or 6 free hydroxyl groups on the ring system nucleus.
  • the number of hydroxyl groups present are typically sufficient to render the alkaloid molecule polar and/or soluble in polar solvents (e.g. water).
  • the nuclei of the bicyclic polyhydroxylated alkaloids produced according to the processes of the invention may have groups or substituents other than hydroxyl groups on the ring system nucleus.
  • groups/substituents include those selected from hydrogen, straight or branched, linear or cyclic, unsubstituted or substituted, saturated or unsaturated acyl, ether, alkyl, alkenyl, alkynyl and aryl groups.
  • Ether groups include epoxides, acetals (including glycosidyl moieties, e.g. glucosidyl moieties) and hemiacetals.
  • Hemiacetal groups include cyclic hemiacetals (for example, polyhydroxylated cyclic hemiacetal sugars).
  • Acyl groups include aldehydes and ketones (including polyhydroxylated aldehyde and ketone sugars, which may be aldose or ketose).
  • Other acyl groups include carboxylic acids and carboxylic acid derivatives. The latter include acid halides, acid anhydrides, esters, amides and imides.
  • Aryl groups include 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine.
  • Aryl groups containing heteroatoms include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, qum ' azoline, cinnoline, pteridine, carbazole, carboline, phenanth ⁇ dine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyr
  • the aryl groups may also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic (e.g. the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls).
  • graups/substituents include primary, secondary and tertiary amines, imines, sulphides, thiols, halides (e.g. chlorine, fluorine, iodine and bromine), phosphates, phosphonates, phosphinates, metal, nitrile, nitro, azido, sulphone, sulphoxide and sulphydryl groups.
  • the pyrrolidine alkaloid products of the processes of the invention may have the formula:
  • R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, hydroxyl, straight or branched, linear or cyclic, unsubstituted or substituted, saturated or unsaturated acyl, ether, alkyl, alkenyl, alkynyl and aryl groups, primary, secondary and tertiary amines, imines, sulphides, thiols, halides (e.g. chlorine, fluorine, iodine and bromine), phosphates, phosphonates, phosphinates, metal, nitrile, nitro, azido, sulphone, sulphoxide and sulphydryl groups, or a pharmaceutically acceptable salt or derivative thereof.
  • R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, hydroxyl, straight or branched, linear or cyclic, unsubstituted or substituted, saturated or unsaturated acyl, ether, alkyl, alkenyl
  • Suitable ether groups include epoxides, acetals (including glycosidyl moieties, e.g. glucosidyl moieties) and hemiacetals.
  • Hemiacetal groups include cyclic hemiacetals (for example, polyhydroxylated cyclic hemiacetal sugars).
  • Suitable acyl groups include aldehydes and ketones (including polyhydroxylated aldehyde and ketone sugars, which may be aldose or fcetose).
  • Other acyl groups include carboxylic acids and carboxylic acid derivatives. The latter include acid halides, acid anhydrides, esters, amides and imides.
  • Suitable aryl groups include 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine.
  • Exemplary aryl groups containing heteroatoms include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoiine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrol
  • the aryl groups may also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic (e.g. the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls).
  • any or all of R 1 , R 2 , R 3 and R 4 is a saccharide moiety and the alkaloid product is a glycoside.
  • particularly preferred are compounds in which any or all of R 1 , R 2 , R 3 and R 4 is a glucoside c arabinoside moiety.
  • the pyrrolizidine alkaloid products of the processes of the invention have the formula:
  • R is selected from the group comprising hydrogen, straight or branched, linear or cyclic, unsubstituted or substituted, saturated or unsaturated acyl, ether, alkyl, alkenyl, alkynyl and aryl groups, or a pharmaceutically acceptable salt or derivative thereof.
  • the pyrrolizidine ring bears a saccharide moiety and the alkaloid product is a glycoside.
  • the alkaloid product is a glycoside.
  • particularly preferred are compounds in which R is a glucoside or arabinoside moiety.
  • the derivative may be an acyl derivative.
  • the alkaloid may be:
  • the acyl derivative may be alkanoyl or aroyl.
  • alkanoyl derivatives selected from acetyl, propanoyl or butanoyl.
  • Preferred is 6-O-butanoylcasuarine having the formula:
  • R is selected from the group comprising hydrogen, straight or branched, unsubstituted or substituted, linear or cyclic, saturated or unsaturated acyl, ether, alkyl, alkenyl, alkynyl and aryl groups, or a pharmaceutically acceptable salt or derivative thereof.
  • the pyrrolizidine alkaloid product is 1R,2R,3R,6S,7S,7aR)-3- (hydroxymethyl)-1,2,6,7-tetrahydroxypyrrolizidirre (casuarirte), wherein R is hydrogen and having the formula:
  • the pyrrolizidine alkaloid product is casuarine glycoside, or a pharmaceutically acceptable salt or derivative thereof.
  • the alkaloid is preferably casuarine-6- ⁇ -D- g/ucoside of the formula:
  • pyrrolizidine alkaloid products include those selected from:
  • the invention contemplates diastereomers of the compounds of the invention.
  • diastereomers selected from 3,7- ⁇ fep/-casuarine (12), 7-ep/-casuarine (13), 3,6,7-triepi-casuarine (14), 6,7- ⁇ 7ep/-casuarine (15) and 3-ep/-casuarine (16), as well as pharmaceutically acceptable salts and derivatives thereof.
  • Other preferred diastereomers include 7a epimers selected from 3,7,7a-tr/ep/-casuarine, 7,7a-diep/-casuarine, 3,6,7, 7a-fefraep/-casuarine, 6,7,7a-triep/-casuarine and 3,7a-diep/-casuarine, as well as pharmaceutically acceptable salts and derivatives thereof.
  • the indolizidine alkaloid products of the processes of the invention may have the formula:
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen, hydroxyl, straight or branched, linear or cyclic, unsubstituted or substituted, saturated or unsaturated acyl, ether, alkyl, alkenyl, alkynyl and aryl groups, primary, secondary and tertiary amines, imines, sulphides, thiols, halides (e.g.
  • Suitable ether groups include epoxides, acetals (including glycosidyl moieties, e.g. glucosidyl moieties) and hemiacetals.
  • Hemiacetal groups include cyclic hemiacetals (for example, polyhydroxylated cyclic hemiacetal sugars).
  • Suitable acyl groups include aldehydes and ketones (including polyhydroxylated aldehyde and ketone sugars, which may be aldose or ketose).
  • Other acyl groups include carboxylic acids and carboxylic acid derivatives. The latter include acid halides, acid anhydrides, esters, amides and imides.
  • Suitable aryl groups include 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine.
  • Exemplary aryl groups containing heteroatoms include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrol
  • the aryl groups may also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic (e.g. the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls).
  • any or all of R 1 , R 2 , R 3 and R 4 is a saccharide moiety and the alkaloid product is a glycoside.
  • particularly preferred are compounds in which any or all of R 1 , R 2 , R 3 and R 4 is a glucoside or arabinoside moiety.
  • the indolizidine products obtainable by the processes of the invention include swainsonine (4), castanospermine (5), Bucast (6) and various derivatives and salts thereof.
  • the indolizidine alkaloid products of the processes of the invention have the formula:
  • R 1 is selected from the group comprising hydrogen, straight or branched, unsubstituted or substituted, linear or cyclic, saturated or unsaturated acyl, ether, alkyl (e g cycloalkyl), alkenyl, alkynyl and aryl groups and R 2 and R 3 are selected from hydrogen, hydroxy and alkoxy, or a pharmaceutically acceptable salt or derivative thereof
  • the indolizidine product has the formula
  • R 1 is selected from the group comprising hydrogen, straight or branched, unsubstituted or substituted, linear or cyclic, saturated or unsaturated acyl, ether, alkyl (e g cycloalkyl), alkenyl, alkynyl and aryl groups and R 2 is selected from hydrogen, hydroxy and alkoxy, or a pharmaceutically acceptable salt or derivative thereof
  • R 1 is selected from the group comprising hydrogen, straight or branched, unsubstituted or substituted, linear or cyclic, saturated or unsaturated acyl, ether, alkyl (e g cycloalkyl), alkenyl, alkynyl and aryl groups and R 2 is selected from hydrogen, hydroxy and alkoxy, or a pharmaceutically acceptable salt or derivative thereof
  • indolizidine alkaloid products having the formula
  • the indolizidine alkaloid product has the formula
  • the pyrrolidine or piperidine intermediates for cyclisation in the processes of the invention are preferably generated from carbon skeleton precursors having: (a) an N function; and (b) two electrophilic carbon atoms susceptible to nucleophilic attack by the N function.
  • the N function and electrophilic carbon atoms have the following configuration (relative spacing):
  • Suitable N functions include amino groups or precursors thereto (for example, azides or lactams).
  • the electrophilic carbon atoms may be carbonyl carbons and/or carbon atoms furnished with leaving groups. Any suitable leaving group may be employed, but preferred are sulphonate leaving groups (e.g. triflates, mesylates and tosylates).
  • sulphonate leaving groups e.g. triflates, mesylates and tosylates.
  • one preferred class of carbon skeleton precursors suitable for use in a process for the production of a range of different polyhydroxylated pyrrolizidine alkaloids are the ditosylateheptahydroxyazidooctanes.
  • the two electrophilic carbon atoms need not both be present simultaneously in any single precursor. Rather, they may be elaborated sequentially, the second being provided (for example via the addition of a leaving group) after the first has been subject to nucleophilic attack by the N function (which may be coincident with the creation of a first (5- or 6-membered) ring (and the formation of the pyrrolidine or piperidine intermediate or precursor thereof).
  • the carbon skeleton precursors are linear polyhydroxy alkanes (e.g. heptane, octane or nonane), precursors thereto or derivatives thereof.
  • any hydroxyl groups on the carbon skeleton precursors and/or the pyrrolidine or piperidine intermediates may be partially or fully protected during part of the synthesis, provided that the pyrrolidine or piperidine intermediate on which the cyclisation step is performed comprises at least 3 free hydroxyl groups.
  • the pyrrolidine or piperidine intermediates are partially or fully protected during some of the synthesis and deprotected prior to the cyclisation step.
  • Such temporary protection may comprise, for example, the addition of temporary trimethyl silyl group(s).
  • the carbon skeleton precursors may be generated by any suitable techniques, including Kiliani chain extension(s) and/or Wittig reaction(s). Such techniques per se are known in the art and do not form part of the present invention. However, while the synthesis of acetonides of octonolactones (which are suitable carbon skeleton precursors for use according to the invention: see Example 9 below) by Kiliani chain extension is described in Bell et a/. (1996) Tetrahedron: Asymmetry 7(2): 595-606 and the products used in schemes for the production of four diastereoisomers of casuarine (Bell et al. (1997) Tetrahedron Letters 38(33): 5869-72), the use of the Wittig reaction to elaborate appropriate carbon skeleton precursors is not precedented and may provide short access to a wide variety of different stereoisomers (see Example 4, below).
  • the synthetic steps leading up to the formation of the pyrrolidine or piperidine intermediates may comprise an azide reduction step.
  • Any suitable reducing agent may be used to perform the reduction.
  • catalytic hydrogenation e.g. with a metal catalyst such as palladium
  • sodium hydrogen telluride reduction Sudzuki- Takaoka procedure
  • the latter procedure is particularly preferred in circumstances where steric hindrance from adjacent protected groups prevents efficient catalytic hydrogenation.
  • the azide reduction step may effect the formation of a first ring and may therefore elaborate, directly or indirectly (e.g. via a lactam), the pyrrolidine or piperidine intermediate.
  • the pyrrolidine or piperidine is conveniently derived therefrom by reduction. Any of a wide range of reducing agents may be employed for this step: preferred is borane reduction at elevated temperature.
  • the cyclisation of the pyrrolidine or piperidine intermediate may be effected by any suitable method.
  • Preferred is base-catalysed cyclisation.
  • any base may be used.
  • solid phase cyclisation may be achieved using polymer- bound bases (for example in conjunction with ion-exchange media).
  • the cyclisation step may terminate the synthesis.
  • the cyclisations are followed by further reactions and/or processing, particularly in embodiments where the alkaloid product is to be used in a pharmaceutical composition.
  • the product of the cyclisation may be subject to derivitization, crystallization, purification (e.g. by chromatography) and/or admixture with various pharmaceutical excipients.
  • Such complexing agents include metal ions (e.g. anions such as Na + or Mg ++ and Al +++ ), complex ions (such a borates) and zeolites.
  • metal ions e.g. anions such as Na + or Mg ++ and Al +++
  • complex ions such a borates
  • zeolites e.g. zeolites
  • Amberlite IR- 120, strongly acidic ion-exchange resin was prepared by soaking the resin in 2M hydrochloric acid for at least two hours followed by elution with distilled water until the eluant reached pH 5.
  • Dowex 50WX8-100 was prepared by soaking the resin with 2IW hydrochloric acid for at least two hours followed by elution with distilled water until neutral.
  • Infrared spectra were recorded on a Perkin-Elmer 1750 IR Fourier Transform spectrophotometer using thin films on sodium chloride plates. Only characteristic peaks are recorded. Optical rotations were measured on a Perkin-Elmer 241 polarimeter with a path length of 1dm. Concentrations are quoted in g/100mL.
  • Nuclear magnetic resonance spectra were recorded on a Bruker DQX 400 spectrometer in the stated deuterated solvent. All spectra were recorded at ambient temperature. Chemical shifts ( ⁇ ) are quoted in ppm and are relative to residual solvent as standard. Proton spectra (5H) were recorded at 400 MHz and carbon spectra ( ⁇ c) at 100 MHz.
  • the resulting foam was treated with acetone (500 ml) and sulphuric acid (5.4 ml) in the presence of anhydrous copper sulphate (10 g, 62 mmol) at room temperature for 48 h.
  • T.l.c analysis indicated the presence of two major products (ethyl acetate:cyclohexane, 1 :1; R f 0.72, 0.18).
  • the reaction mixture was filtered and the filtrate was treated with sodium bicarbonate (50 g) for 24 h at room temperature. Solid residues were removed by filtration and the filtrate was concentrated under reduced pressure.
  • the ring closure described above may be defined as a "1 , 4,7 ring closure”: the pyrrolidine intermediate (not shown) for cyclisation in the process of Example 1 is generated from a carbon skeleton precursor Qi having two electrophilic carbon atoms and an N function at positions 1 , 4 and 7, respectively.
  • CDCI 3 1.36, 1.40, 1.41 (12H, 3 x s, C(CH 3 ) 2 ), 3.87 (1H, dd, H-6', J 7.2 Hz, 8.6 Hz), 3.90 (1 H, m, H-4), 3.91 (3H, s, OCH 3 ), 4.08 (1 H, m, H-5), 4.20 (1H, dd, H-6, J 6.2 Hz, 8.6 Hz), 4.55 (1H, dd, H-3, J 1.9 Hz, 7.6 Hz), 5.33 (1 H, d, H-2, J 1.9 Hz); ⁇ c (100 MHz, CDCI 3 ) 25.0, 26.1 , 27.2 (C(CHs) 2 ), 54.5 (OCH 3 ), 68.1 (C-6), 76.9, 77.0, 79.3, 80.5 (C-2, C-3, C-4, C-5), 110.2, 111.4 (C(CH 3 ) 2 ), 115.2 (CF 3 , q, J C ,F
  • Methyl 3,4:5,6-di-O-isopropylidene-2-O-trifluoromethanesulphonyl-D-gluconate 3 (15.1 g, 35.7 mmol) was dissolved in DMF (30 ml) and NaNe (2.55 g, 39.2 mmol) was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere. Then, the solvent was evaporated in vacuo and the residue was redissolved in EtOAc (100 ml).
  • methyl (triphenylphosphoranylidene)acetate 5 (12.8 g, 38.3 mmol) was added in one portion and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The solvents were evaporated in vacuo, after which Et 2 O (100 ml) and 2M NaOH (100 ml) were added. The layers were separated, and the organic phase was dried on Na 2 SO 4 . After filtration and evaporation of the volatiles, the resulting white solid was triturated with petroleum ether 40-60 and the solids were removed by filtration. Column chromatography (EtOAc/cyclohexane 1/6 v/v) afforded the product as a white solid (8.95 g, 75%).
  • Methyl 4-azido-2,3,4-trideoxy-5,6:7,8-di-0-isopropylidene-D-eAyfftro-L-manno-oct-2-enoate 6 (6.85 g, 20.0 mmol) was dissolved in a mixture of acetone (50 ml) and water (10 ml), after which N-methylmorpholi ⁇ e oxide (4.69 g, 40.0 mmol) and OSO 4 (50 mg) were added. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. Subsequently, EtOAc (100 ml) and 5% NaHCO 3 (100 ml) were added and the layers were separated.
  • a 4/1 mixture of methyl 4-azido-4-deoxy-5,6:7,8-di-Q-isopropylidene-D-e/yf/7ro-L-a/fro-octonate 7a and methyl 4-azido-4-deoxy-5,6:7,8-di-0-isopropylidene-D-e/yf/7ro-L-g/uco-octonate 7b (5.28 g, 14.07 mmol) was dissolved in THF (50 ml) and 20% Pd(OH) 2 on carbon (150 mg) was added. The resulting mixture was stirred for 48 hours at room temperature under a hydrogen atmosphere.
  • the opening stages of the synthesis of 3-epicasuarine are outlined in Scheme 1.
  • the first step was the ring opening and concomitant acetonide protection of D-glucono- ⁇ -lactone 1 according to a known procedure 1 .
  • treatment of 1 with 2,2-dimethoxypropane in a mixture of acetone and methanol in the presence of a catalytic amount of para-toluenesulphonic acid afforded ester 2 in 79% yield.
  • the required nitrogen centre was introduced by nucleophilic displacement of triflate ester 3 which was formed by reaction of 2 with trifluoromethanesulphonic anhydride in the presence of pyridine.
  • the substitution reaction with sodium azide in DMF to yield azide 4 proceeded with near quantitative yield.
  • the hydroxyl group at the 7-position had to be furnished with a good leaving group (Scheme 4).
  • the terminal acetonide was selectively removed with 60% acetic acid, affording mono-acetonide 9 in 69%.
  • the primary hydroxyl group of 9 was protected using TBMDS-Cl and pyridine as the base.
  • a mesylate leaving group could be introduced using mesyl chloride and triethylamine. This yielded mesylate 10 in 66% yield over two steps.
  • direct cyclisation or indirect via the epoxides may be selectively driven by optimisation of reaction parameters, including pH, metal ion content and/or reactant concentrations.
  • reaction parameters including pH, metal ion content and/or reactant concentrations.
  • ring formation on displacement of the tosylate is either direct formation of the six-membered ring (to give the indolizidine) or the formation of an epoxide in competition - in the latter the epoxide is later opened by the nitrogen to yield the pyrrolizidine.
  • Example 6 Alternative schemes for the synthesis of indolizidines and/or pyrrolidines
  • i Ph 3 P CO 2 'Bu, ⁇ ; ii 1mol% OsO 4 , NMO; iii TFA / H 2 O 9/1 v/v; iv acetone, cat. H 2 SO 4 ; v TBDMS-CI, imidazole, ⁇ ; vi HOAc / H 2 O 1/1 v/v, ⁇ ; vii TBDMS-CI, pyridine; viii cone, ammonia, dioxane; ix Ms-Cl, Et 3 N; x BH 3 -DMS, THF, ⁇ ; xi TFA / H 2 O 9/1 v/v; xii NaOAc, H 2 O.
  • Example 8 Synthesis of 3,7a-diepi-(+Vcasuarine
  • i Ph 3 P CO 2 ⁇ Bu, ⁇ ; ii 1mol% OsO 4 , NMO; iii TFA / H 2 O 9/1 v/v; iv acetone, cat. H 2 SO 4 ; v TBDMS-CI, imidazole, ⁇ ; vi HOAc / H 2 O 1/1 v/v, ⁇ ; vii TBDMS-CI, pyridine; viii cone, ammonia, dioxane; ix Ms-Cl, Et 3 N; x BH 3 -DMS, THF, ⁇ ; xi TFA / H 2 O 9/1 v/v; xii NaOAc, H 2 O.
  • the lactol 2 is used directly in the Kiliani homologation to the eight-carbon lactone.
  • the Kiliani reaction is routinely carried out on ⁇ 360g batches of the crude lactol 2.
  • Treatment with sodium cyanide affords the octonolactone which when treated with acetone under acidic conditions generates approximately a 1 :1 mixture of di- and triacetonides, 4 and 3 respectively (Scheme 2).
  • T ⁇ acetonide 3 can be brought through the synthesis in 5Og batches Deprotection with 40% aqueous acetic acid affords the 7,8-d ⁇ ol 5 in 77-94% yield This compound can be selectively silylated in 86-93 % yield on up to 8Og scale It was found that conducting the reaction at twice the concentration with less silylating reagent and at lower temperature gave an increased yield for this transformation
  • the silyl compound 6 is treated with triflic anhydride to afford the triflate, which after aqueous workup is washed through a small 'plug' of silica to remove polar residues
  • the t ⁇ flate is then stirred with sodium azide to give the fully protected derivative 7 in 66-81% yield over the two steps (Scheme 3)
  • the silyl compound 6 is routinely brought through these two steps in 30- 4Og batches
  • the crude Kiliani product is essentially insoluble in acetone Yields can be improved by stirring the reaction with an overhead motor this significantly increases the mixing of both the crude Kiliani product and the cupric sulfate and also decreases the reaction time Further improvement in yield can be achieved by concentrating the crude Kiliani product with toluene to form a 'crispy foam' This foam can then be ground up in a pestle and mortar to a fine solid thereby increasing the surface area of lactone in the reaction This also significantly decreases reaction times Heating the reaction to reflux (75-8O 0 C) not only speeds up the reaction but also allows a smaller volume of acetone to be employed (typically 1-2L for each 10Og of starting lactone)
  • step v selective silylation of the primary alcohol
  • step ⁇ x (mesylation of the diol 8)
  • mesyl chloride 6 equivalents of mesyl chloride are sufficient if the reaction concentration is kept to less than 5ml solvent (pyridine) per gram of starting material
  • a 0 5M HCI wash helps to remove any traces of pyridine and stirring the organic phase with sodium bicarbonate for -1 hour removes excess mesyl chloride any unremoved mesyl chloride will be converted to methanesufonic acid and may interfere with the cyclisation (step x ⁇ )
  • the product, 3,7-d ⁇ ep/-casua ⁇ ne 12, can be further purified by crystallization (if desired) Alternatively, anion exchange chromatography (e g using Dowex 1 in hydroxide form) may be employed
  • Potassium ferricyanide (6.38 g, 19.38 mmol), potassium carbonate (2.68 g, 19.38 mmol), methane sulphonamide (614 mg, 6.46 mmol), potassium osmate dihydrate (24 mg, 0.0646 mmol) and (DHQ) 2 PHAL (57 mg, 0.0646 mmol) were dissolved in a mixture of fert-butanol (30 ml) and water (30 ml).
  • reaction mixture was neutralised by addition of NaHCCb (s), and after filtration and evaporation, column chromatography (EtOAc/cyclohexane, 1/3 v/v) afforded the product (1.36 g, 63%) as a clear, colourless oil.
  • Methyl 4-azido-4-deoxy-2,3:5,6:7,8-tri-0-isopropylidene-L-a/fro-L-fftreo-octonate 1.8 (921 mg, 2.22 mmol) was dissolved in a mixture of acetic acid (10 ml), H 2 O (5 ml) and dioxane (5 ml), which was stirred for 6 hours at 5O 0 C. The solvents were evaporated and the residue was redissolved EtOAc (10 ml), washed with satd. NaHCO 3 (10 ml) and dried on Na 2 S ⁇ 4 .
  • 3,5-O-Benzylidene-D-gulonolactone 2.2 (6.92 g, 25.99 mmol), imidazole (5.31 g, 77.97 mmol) and DMAP (64 mg, 0.52 mmol) were dissolved in DMF (150 ml). After cooling to -20 0 C, a solution of TBS-Cl (3.92 g, 25.99 mmol) in DMF (100 ml) was added dropwise. The resulting mixture was stirred overnight at -20 0 C up to room temperature. The solvent was evaporated and the residue redissolved in EtOAc (150 ml). After washing with 1M HCI (150 ml), satd.
  • Methyl 4-azido-5,7-O-benzylidene-6-O-terf-butyIdimethylsilyl-2,3,4-trideoxy-D-gu/o-oct-2-enoate 2.5 (2.32 g, 5.00 mmol) was dissolved in a mixture of tert-butanol (25 ml) and water (25 ml) and potassium ferricyanide (4.94, 15.0 mmol), potassium carbonate (2.07 g, 15.0 mmol), methanesulfonamide (476 mg, 5.00 mmol) and (DHQ) 2 PHAL (39 mg, 0.050 mmol) were added.
  • Methyl 4-azido-4-deoxy-2,3:5,6:7,8-tri-0-isopropylidene-D-g/uco-D-tf7reo-octonate 2.7 (222 mg, 0.53 mmol) was dissolved in a mixture of acetic acid (5.0 ml), dioxane (2.5 ml) and water (2.5 ml). The resulting solution was stirred overnight at 50 0 C after which the solvents were evaporated. The residue was redissolved in EtOAc (20 ml), washed with water (20 ml) and dried on Na 2 SO 4 .
  • Methyl 4-azido-5,7-0-be ⁇ zylidene-8-0-terf-butyldimethylsilyl-4-deoxy-D-fftreo-D-a#ro-octo ⁇ ate 3.1 (2.21 g, 4.44 mmol) was dissolved in a mixture of TFA (4.5 ml) and water (0.5 ml) and stirred for three hours at room temperature. Then, the solvents were evaporated and the residue was dried in vacuo and redissolved in a mixture of 2,2-DMP (16 ml), acetone (5.6 ml) and methanol (3.6 ml). After addition of camphor sulfonic acid (100 mg), the mixture was stirred for 48 hours at 50 0 C.
  • Methyl 4-azido-4-deoxy-2,3:5,6:7,8-tri-0-isopropylidene-D-a/fr ⁇ -D-fftreo-octonate 3.2 (1.05 mg, 2.52 mmol) was dissolved in a mixture of acetic acid (5.0 ml), H 2 O (2.5 ml) and dioxane (2.5 ml), which was stirred overnight at 5O 0 C. The solvents were evaporated and the residue was redissolved EtOAc (10 ml), washed with satd. NaHCO 3 (10 ml) and dried on Na 2 S ⁇ 4 .

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Abstract

Procédé de fabrication d’un alcaloïde bicyclique polyhydroxylé (par exemple une pyrrolizidine telle que la casuarine (10), l’indolizidine ou la quinolizidine) qui comprend la cyclisation d’un composé intermédiaire de la pyrrolidine ou de la pipéridine comportant trois groupes hydroxy libres ou plus.
PCT/GB2005/002800 2004-07-23 2005-07-18 Synthèse des alcaloïdes polyhydroxylés WO2006008493A1 (fr)

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US10111456B2 (en) 2005-02-28 2018-10-30 22Nd Century Limited, Llc Methods and compositions for identifying NBB1 mutations
US8987555B2 (en) 2005-02-28 2015-03-24 22Nd Century Limited, Llc Reducing levels of nicotinic alkaloids in plants
US9029656B2 (en) 2005-02-28 2015-05-12 22Nd Century Limited, Llc Reducing levels of nicotinic alkaloids in plants
US11839231B2 (en) 2005-02-28 2023-12-12 22Nd Century Limited, Llc Reducing levels of nicotinic alkaloids in plants
US11109617B2 (en) 2005-02-28 2021-09-07 22Nd Century Limited, Llc Reducing levels of nicotine in plants
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US10085478B2 (en) 2005-02-28 2018-10-02 22Nd Century Limited, Llc Reducing levels of nicotinic alkaloids in plants
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US9834780B2 (en) 2005-02-28 2017-12-05 22Nd Century Limited, Llc Reducing levels of nicotinic alkaloids in plants
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