+

WO2006002470A1 - Ligands chiraux pour catalyse asymétrique - Google Patents

Ligands chiraux pour catalyse asymétrique Download PDF

Info

Publication number
WO2006002470A1
WO2006002470A1 PCT/AU2005/000963 AU2005000963W WO2006002470A1 WO 2006002470 A1 WO2006002470 A1 WO 2006002470A1 AU 2005000963 W AU2005000963 W AU 2005000963W WO 2006002470 A1 WO2006002470 A1 WO 2006002470A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
group
aryl
alkyl
asymmetric
Prior art date
Application number
PCT/AU2005/000963
Other languages
English (en)
Inventor
Patrick Perlmutter
Neeranat Thienthong
Original Assignee
Monash University
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 claimed from AU2004903601A external-priority patent/AU2004903601A0/en
Application filed by Monash University filed Critical Monash University
Publication of WO2006002470A1 publication Critical patent/WO2006002470A1/fr

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
    • B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
    • B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
    • C07C29/40—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing carbon-to-metal bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/49—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with carbon monoxide
    • C07C45/50—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with carbon monoxide by oxo-reactions
    • C07C45/505—Asymmetric hydroformylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/32—Addition reactions to C=C or C-C triple bonds
    • B01J2231/324—Cyclisations via conversion of C-C multiple to single or less multiple bonds, e.g. cycloadditions
    • B01J2231/326—Diels-Alder or other [4+2] cycloadditions, e.g. hetero-analogues
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/34—Other additions, e.g. Monsanto-type carbonylations, addition to 1,2-C=X or 1,2-C-X triplebonds, additions to 1,4-C=C-C=X or 1,4-C=-C-X triple bonds with X, e.g. O, S, NH/N
    • B01J2231/341—1,2-additions, e.g. aldol or Knoevenagel condensations
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
    • B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
    • B01J2231/4261—Heck-type, i.e. RY + C=C, in which R is aryl
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/44—Allylic alkylation, amination, alkoxylation or analogues
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
    • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
    • B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
    • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
    • B01J2231/645—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of C=C or C-C triple bonds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/20—Complexes comprising metals of Group II (IIA or IIB) as the central metal
    • B01J2531/26—Zinc
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/824—Palladium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/828—Platinum
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention relates to asymmetric organic synthesis, and in particular to chiral ligands and organometallic catalysts derived from these chiral ligands, and to synthetic processes which use such catalysts in asymmetric transformations.
  • the asymmetric induction afforded by an organometallic catalyst is largely dependent on the chiral ligands that bind the intrinsically achiral metal atom.
  • the properties of a chiral catalyst (structure and electronic nature) can induce discrimination between enantiotopic atoms, groups, or faces in prochiral and enantiomeric molecules.
  • phosphine ligands include DIPAMP (prepared using resolution techniques), BINAP (derived from binapthyl), DEGUPHOS (derived from tartaric acid), BPPM (derived from L-proline), SKEWPHOS (derived from R,R-pentane-2,4-diol) and DUPHOS (derived from enantiomerically pure phospholane).
  • Chiral nitrogen based ligands have also demonstrated utility in asymmetric transformations.
  • catalysts incorporating chiral oxazolidines as a ligand framework have shown promise in various asymmetric reactions including the hydride- transfer reduction of ketones.
  • the most popular representation of this class is the tridentate PYBOX ligand (bis(oxazolinylmethyl)pyridine) and its amine derivative, AMBOX.
  • the two chiral groups which are positioned on the 4-carbon position of the oxazolidine rings enable better differentiation of the Re and Si faces of incoming substrates.
  • P,N-bidentate ligands from chiral oxazolidines and triphenyl phosphine are also known.
  • dihydro(phosphinophenyl)oxazole has been successfully applied to a range to enantioselective transition metal catalysed reactions.
  • Pfaltz et ah Helvetica Chimica Acta, Vol. 84 (2001) 3233, recently investigated the benzofused six-membered equivalents, particularly 1,3-benzoxazines.
  • These ligands are similar to the PYBOX ligand framework wherein the stereogenic centre is positioned at the 4-carbon position of the benzoxazine moiety.
  • the present invention provides a transition metal complex of an enantiomerically enriched compound of the general formula (I)
  • R and R 1 which cannot be the same, independently represent hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aryloxy, optionally substituted alkaryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or R and R 1 are linked together to form a substituted asymmetric cycloalkyl or cycloalkenyl group,
  • R 2 , R 3 , R 4 and R 5 each independently represent hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted oxyacylamino, optionally substituted oxyacyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted acyloxy, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, nitro, cyano, trihalomethyl, hydroxyl, carboxyl, optionally substituted mono- and di-alkylamino, optionally substituted acylamino, optionally substituted aminoacyl, or an amino group, or one of R 2 , R 3 , R 4 and R 5 is a divalent linker group bound to a polymer solid support ; and
  • R 6 is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted acyl, optionally substituted oxyacylamino, optionally substituted oxyacyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted acyloxy, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted acylamino, optionally substituted aminoacyl, optionally substituted mono- and di- alkylamino; or
  • R, R 1 , R 2 and R 6 is a group -Y-Z, where Y is a direct bond or a divalent linker group having a length equivalent to 0 to 6 single C-C bonds, and Z is a group of the formulae (II), (III), or (IV),
  • R, R > 1 1 , ⁇ R> 5 5 are independently selected and are as described above.
  • catalysts are useful as catalysts to facilitate catalytic asymmetric transformations.
  • Any reference to "catalyst” or “catalysts” or “metal catalyst” in the context of the present invention refers to the complexation product of a metal with the enantiomerically enriched compound of formula (I).
  • the present invention also provides the use of a transition metal complex of an enantiomerically enriched compound of formula (I) as a catalyst in a catalytic asymmetric transformation.
  • the transition metal complex should be present in a catalytically effect amount.
  • the present invention also provides a class of enantiomerically enriched (as well as enantiomerically pure) chiral ligands of the general formula (I), for use in the preparation of catalysts for asymmetric transformations.
  • One of the aims of the present invention is to provide a metal catalyst comprising an enantiomerically enriched compound of general formula (I) which provides high enantioselectivities and efficient substrate conversions.
  • a catalytically effective amount refers to the amount of the transition metal complex of an enantiomerically enriched compound of general formula (I) which is required to generate desirable reactivity and selectivity in a method to which the catalyst is applied.
  • the amount is substantially less than the mole amount of the reactive substrate, for instance
  • the catalytic effect of the catalyst of the present invention is observed with an amount most preferably in the range of 5-0.01 mol%.
  • enantiomerically enriched means that the compound is in a form such that there is more of the enantiomer of general formula (I) than its enantiomeric pair.
  • Such enantiomerically enriched chiral compounds display optical activity with respect to plane polarised light.
  • enantiomerically pure means that the enantiomer of formula (I) is substantially free of its enantiomeric pair. Enantiomeric purity is generally expressed in terms of enantiomeric excess or % e.e. For a pair of enantiomers [(+) and (-)] wherein the mixture of the two is given as the mole or weight fractions F (+) and FQ (wherein F (+) + F ( . )
  • the enantiomeric excess is defined as F (+ ) - F(.). Accordingly, the percentage e.e is expressed by 100 x (F( + ) - F(.)).
  • the term "enantiomerically pure” refers to an enantiomer having a % e.e. of greater than 70%.
  • the enantiomerically pure enantiomer has a % e.e. of greater than 85%, more preferably greater than 95%, and most preferably greater than 98%.
  • the compounds of formula (I) in respect of the present invention are utilised in enantiomerically pure form.
  • the benzoxazine compounds of general formula (I) are chiral by virtue of the non- equivalent substitution at the C-2 position (ie. R ⁇ R 1 ). Yet the present invention also includes such compounds which have more than one chiral or "asymmetric centre". In this regard, depending upon the substituents R-R 6 the compounds of general formula (I) may possess multiple asymmetric centres. Where the compounds of the present invention possess asymmetric centres additional to that at C-2 it is preferred that these additional asymmetric centres are enantiomerically pure. It is also preferred that the compounds of general formula (I) are substantially free of diastereomers.
  • Alkyl refers to monovalent alkyl groups which may be straight chained or branched and preferably have from 1 to 10 carbon atoms or more preferably 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, ⁇ -propyl, /so-propyl, n-butyl, iso- butyl, «-hexyl, and the like.
  • Alkylene refers to divalent alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. Examples of such alkylene groups include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), and the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and -CHCH 3 )CH 2 -), and the like.
  • Aryl refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), preferably having from 6 to 14 carbon atoms.
  • aryl groups include phenyl, naphthyl and the like.
  • Arylene refers to a divalent aryl group wherein the aryl group is as described above.
  • Aryloxy refers to the group aryl-O- wherein the aryl group is as described above.
  • Alkaryl refers to -alkylene-aryl groups preferably having from 1 to 10 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.
  • Alkaryloxy refers to the group alkylaryl-O- wherein the alkylaryl group is as described above. Such alkaryloxy groups are exemplified by benzyloxy and the like.
  • Alkoxy refers to the group alkyl-O- where the alkyl group is as described above. Examples include, methoxy, ethoxy, ⁇ -propoxy, zsopropoxy, «-butoxy, tert-butoxy, sec- butoxy, n-pentoxy, w-hexoxy, 1,2-dimethylbutoxy, and the like.
  • Alkenyloxy refers to the group alkenyl-O- wherein the alkenyl group is as described above.
  • Alkynyl refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1, and preferably from 1-2, carbon to carbon, triple bonds.
  • alkynyl groups include ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH) and the like.
  • Alkynyloxy refers to the group alkynyl-O- wherein the alkynyl groups is as described above.
  • Alkynylene refers to the divalent alkynyl groups preferably having from 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms. Examples include ethynylene (-C ⁇ C-) , propynylene (-CH 2 -C ⁇ C-) , and the like.
  • Acyl refers to groups H-C(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl- C(O)- and heterocyclyl-C(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Oxyacyl refers to groups alkyl-OC(O)-, cycloalkyl-OC(O)-, aryl-OC(O)-, heteroaryl- OC(O)-, and heterocyclyl-OC(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Aminoacyl refers to the group -C(O)NRR where each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Acylamino refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
  • Acyloxy refers to the groups -OC(O)-alkyl, -OC(O)-aryl, -C(O)O-heteroaryl, and -C(O)O-heterocyclyl where alkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Aminoacyloxy refers to the groups -OC(O)NR-alkyl, -OC(O)NR-aryl, -OC(O)NR- heteroaryl, and -OC(O)NR-heterocyclyl where R is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Oxyacylamino refers to the groups -NRC(O)O-alkyl, -NRC(O)O-aryl, -NRC(O)O- heteroaryl, and NRC(O)O-heterocyclyl where R is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Cycloalkyl refers to cyclic alkyl groups having a single cyclic ring or multiple condensed rings, preferably incorporating 3 to 8 carbon atoms.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
  • Cycloalkenyl refers to cyclic alkenyl groups having a single cyclic ring and at least one point of internal unsaturation, preferably incorporating 4 to 8 carbon atoms.
  • suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclohex-4-enyl, cyclooct-3-enyl and the like.
  • Halo or halogen refers to fluoro, chloro, bromo and iodo.
  • Heteroaryl refers to a monovalent aromatic carbocyclic group, preferably of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring. Preferably the heteroatom is nitrogen.
  • Such heteroaryl groups can have a single ring (e.g., pyridyl, pyrrolyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl).
  • Heterocyclyl refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, preferably from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur, oxygen, selenium or phosphorous within the ring. The most preferred heteroatom is nitrogen.
  • heterocyclyl and heteroaryl groups include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7- tetrahydrobenzo[b]
  • Heteroarylene refers to a divalent heteroaryl group wherein the heteroaryl group is as described above.
  • Heterocyclylene refers to a divalent heterocyclyl group wherein the heterocyclyl group is as described above.
  • a group may or may not be further substituted or fused (so as to form a condensed polycyclic group) with one or more groups selected from hydroxyl, acyl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, acylamino, cyano, halogen, nitro, sulphate, phosphate, phosphine, heteroaryl, heterocyclyl, oxyacyl, oxyacylamino, aminoacyloxy, trihalomethyl, mono- and di-alkylamino, mono-and di- (substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclyl amino, and unsymmetric di-substituted amine
  • an optionally substituted alkylene group could be represented by a group such as -CH 2 CH 2 OCH 2 -, -CH 2 CH 2 NH-CH 2 -, -CH 2 NHCH 2 -, CH 2 CHOCH 2 and the like.
  • Divalent linker group is taken to mean a divalent group capable of forming a stable bridge between the core structure of formula (I) and a group of formulae (II), (III), or (IV).
  • divalent linker groups include alkylene, alkenylene, alkynylene, arylene, heteroarylene, heterocyclylene, alkylenearylene, alkylenearylenealkylene, alkyleneheteroarylenealkylene, alkyleneheterocyclylenealkylene, and the like.
  • the substituents R and R 1 to R 6 are groups that may be selected for their chemical stability under the reaction conditions selected for either preparing the ligand framework, or catalyst thereof, or under the conditions for carrying out a catalytic asymmetric transformation.
  • R and R 1 substituents are groups which enable chiral induction while at the same time do not interfere with co-ordination of a metal atom.
  • R and R 1 are independently a hydrogen atom, optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocyclyl or together represent a substituted chiral cycloalkyl group. More
  • R and R 1 are independently selected from a hydrogen atom and an optionally substituted alkyl group or together represent a substituted asymmetric cycloalkyl group.
  • the benzoxazine nitrogen is capable of coordinating with a metal atom to form a metal complex with the ligand framework, and as such, the ligand framework of general formula (I) encompasses ligands capable of mono-, bi-, tri-, quaternary-, and penta-dentate metal coordination.
  • R, R 1 , R 2 , and R 6 may be a group which provides extra ligand denticity and as such may be a group which contains suitably placed heteroatom(s) like nitrogen and/or phosphorus, which can co-ordinate with a metal atom.
  • Such groups which provide sites for added co-ordination to a metal are referred to herein as "co-ordination groups".
  • Such preferred groups include substituted alkyl, substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl or the group -Y-Z, where Y is a direct bond or a divalent linker group having a length equivalent to 1 to 6 single C-C bonds, and may represent an optionally substituted alkenylene, optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene, optionally substituted alkylenearylene, optionally substituted alkylenearylenealkylene, optionally substituted alkyleneheteroarylenealkylene, optionally substituted alkyleneheterocyclylenealkylene, and Z a group of formulae (II), (III), or (IV).
  • one of R, R 1 , R 2 , and R 6 is the group -Y-Z where Y represents a direct bond, an optionally substituted alkenylene, optionally substituted alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, and Z is a group of formulae (II), (III), or (IV).
  • R, R 1 , R 2 , and R 6 moieties which may be representative of the -Y-Z group include those of formulae (a) to (f);
  • R 7 and R 8 are independently selected from, hydrogen, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted alkaryl, or together represent an optionally substituted cycloalkyl or cycloalkenyl group.
  • R 6 is an optionally substituted aryl, optionally substituted alkyl or optionally substituted heteroaryl group.
  • R substituents which are representative of optionally substituted aryl, optionally substituted alkyl, and optionally substituted heteroaryl groups are those of formulae (g), (h), (i), and (j).
  • the benzoxazine nitrogen is capable of coordinating with a metal atom to form a metal complex with the ligand framework
  • the ligand framework of general formula (I) encompasses ligands capable of mono-, bi-, tri-, quaternary- and penta-dentate metal coordination.
  • the below structures illustrate some of possible ligand frameworks which are encompassed by the present invention.
  • the elements in the highlighted circles ( @ and @ ) are illu- strative of potential co-ordination groups, which provide for ligand denticity.
  • Q may represent -NH, -NH 2 , -N-, -NR 2 , -NR'-, -PR 2 , in which each R is an optionally substituted alkyl or optionally substituted aryl group, or a heterocyclic group, for example a pyridine, oxazole, pyrrole or the like.
  • R is an optionally substituted alkyl or optionally substituted aryl group, or a heterocyclic group, for example a pyridine, oxazole, pyrrole or the like.
  • R 2 to R 5 substituents are hydrogen.
  • substituents may be a substituent which affects the basicity of the co-ordinating groups through its ability to either donate or withdraw electron density from the benzoxazine nitrogen or other co-ordinating atoms which may be present on the ligand framework, for instance at C-2 (R or R 1 ) or at C-4 (R 6 ).
  • Preferred electron withdrawing groups include halogen atoms, nitro, cyano, carboxylic acid or esters thereof, formyl, sulphate, acetyl, or quaternary ammonium salts.
  • Preferred electron donating groups include alkyl, alkoxyl, amino, hydroxyl and amide groups.
  • an advantage of the ligand framework of the general formula (I) is that it can be electronically “tuned” depending upon the electronic nature of the selected R 2 -R 5 substituents. Varying the electronic nature of the ligand is extremely advantageous as it offers a convenient way to manipulate the affinity of a particular ligand to a particular metal. This tuning also offers an avenue to better control the kinetics and selectivities of the catalysed asymmetric transformations which utilise the metal catalysts of the present invention. Substituents R 2 -R 5 may also be used as sites for attachment to solid polymeric supports for applications in many technologies, including solution phase, solid phase and microreactors.
  • Typical polymeric solid supports include the commercially available resins, which are currently being used in solid phase organic synthesis. Examples include, alkenyl resins: eg. REM resins; BHA resins: eg. benzhydrylamine (polymer-bound hydrochloride, 2% crosslinked), benzhydryl chloride (polymer bound); Br- functionalised resins: eg.
  • brominated PPOA resin brominated Wang resin
  • Chloromethyl resins eg. 4-methoxybenzhydryl chloride (polymer bound); CHO- functionalised resins: eg. indole resin, formylpolystyrene; Cl-functionalised resins: eg. Merrifields' resin, chloroacetyl (polymer bound); CO 2 H-functionalised resins: eg. carboxypolystyrene; I-functionalised resins: eg. 4-iodophenol (polymer bound); Janda JelsTM; MBHA resins: eg.
  • polymer supported reagents for instance, polymer bound bases like piperidine, dimethylaminopyridine, morpholine, diethylamine as well polymer bound coupling reagents like l-(3-dimethylaminopropyl)-3-ethyl carbodiimide, diethylazodicarboxylate, and N-benzyl-N'-cyclohexylcarbodiimide.
  • the compound of formula (I) is prepared bound to the polymer support resin prior to being used in an asymmetric reaction. Accordingly, another advantage of the present invention is that it enable asymmetric transformation to be conducted under solid-phase conditions.
  • a further advantage of the compounds of the general formula (I) is that benzofusion causes the ligand framework to be conformationally stable and relatively flat. It is proposed that such framework will enhance chiral recognition of the corresponding catalyst, and as such, aid the catalyst in chiral induction.
  • ligands of general formula (I) can be achieved using modified strategies based upon existing methodologies for the synthesis of 2/f-l,3-benzoxazines.
  • Scheme 1 depicts a general protocol which involves reacting a salicylamide with an aldehyde or ketone (or equivalent, for example, a dimethyl acetal) in the presence of an acid catalyst to prepare the ring closed 2H-l,3-benzoxazine-4-one.
  • the linking of the R 6 group can be carried out by converting the benzoxazin-4-one to the corresponding imide where the L' group represents an appropriate leaving group.
  • the R 6 group can be introduced by an appropriate substitution reaction.
  • palladium catalysed cross coupling with an R 6 -halogen compound.
  • Scheme 2 depicts an alternate route which commences from a benzonitrile and essentially involves a one pot synthesis.
  • a lithiating agent eg. 2- lithiopyridine
  • the versatility of the various synthetic strategies for preparing racemic compounds of formula (I) means that the R 2 to R 6 groups can be introduced either before or after the formation of the 1,3-benzoxazine ring.
  • Enantiomerically enriched and pure compounds of the general formula (I) can be prepared from their racemic counterparts through existing techniques available for resolving pairs of enantiomers, including chemical, kinetic, physical (eg. using chiral chromotography), or through enzymatic processes.
  • the enantiomers may be separated through initial conversation to diastereomers.
  • the treatment of racemic mixtures of a compound of formula (I) with chiral auxiliaries, like (+)-O-Methylmandelyl chloride affords chromatographically separable diastereomeric mixtures, for example, mixtures of diastereomeric mandelyl imides.
  • Physical separation of each of the pure diastereomers and removal of the auxiliary provides enantiomerically pure compounds of formula (I).
  • resolution is performed on the racemic 2H-l,3-benzoxazine-4-one (see scheme 1) prior to the addition of the R 6 group.
  • Enzymatic techniques may also be employed to resolve a racemic mixture of benzoxazines.
  • the exocyclic carbonyl of a N-acylbenzoxazine can be hydrolysed selectively.
  • hydrolases, amidases and esterases which have been reported to selectively hydrolyse acyl derivatives can be used to resolve the enantiomers after a racemic synthesis of the compounds of the present invention.
  • a convenient alternative to resolving racemic compounds of formula (I) is to employ enantiomerically pure ketones in the synthetic strategies already described.
  • Preferred enantiomerically pure ketones are cyclic ketones.
  • R 1 and R 2 together form substituted asymmetric cycloalkyl or cycloalkenyl group.
  • Preferred substituted cycloalkyl are enantiomerically pure cyclic ketones including [-] or [+]- menthone, 8-substituted [+] or [-]-menthone, [+] or [-] carvone and the like.
  • the ligand framework of compounds of formula (I) has been found to complex with reactive transition metals.
  • Preferred metal complexes include those which contain Ru, Ir, Rh, Zn, Re, Au, Ag, Ni, Pt, Cu and Pd.
  • transition metal or "metal” as referred to in the present invention includes either a metal in-isolation or a metal bound as a complex with stabilising ligands, eg. chloride, acetate, cyclooacta-1, 5-diene (COD), methylcyano, alkyl, benzonitrile, triaryl stibine, etc.
  • the catalysts of the present invention are produced by complexing the ligands of formula (I) with a reactive transitional metal or transition metal complex. This is preferably achieved by an exchange reaction between the ligand of formula (I) and a stabilising complex of the metal wherein the bond between the metal and stabilising ligand is more labile than the bond that is formed between the metal and ligand of formula (I).
  • the stabilised metal complex will be dissolved in a suitable solvent followed by the addition of the ligand of formula (I).
  • the addition of the ligand of the present invention can be done either directly as a solid or as a solution in a suitable solvent which may or may not be the same solvent used to dissolve the metal complex.
  • the solvents are matched so as to avoid precipitation of the reactants from the reaction solvent mixture.
  • Preferred solvents include polar solvents like alcohols, dimethylformamide, or chlorinated solvents like dichloromethane, chloroform, and carbontetrachloride, or aromatic hydrocarbons like benzene and toluene, or ethers like diethylether and tertrahydrofuran.
  • the formation of the catalyst can usually be followed by observing colour changes in the reaction mixture or through spectroscopic means, such as for instance, 31 P-NMR and/or G.C.
  • the catalyst can be recovered by simply removing the reaction solvent in vacuo.
  • the catalyst may be subjected to further purification according to known techniques or used without additional purification. Accordingly, the present invention also provides for transition metal complexes of the compounds of general formula (I) which are in an isolated form.
  • the catalysts are preferably prepared immediately prior to their use in an asymmetric catalytic transformation. More preferably however, the catalysts of the present invention are prepared in situ. That is, the complexation of the metal or metal complex with the ligand (of formula I) is carried out in the presence of the reactants of the particular asymmetric reaction which requires the catalyst of the present invention.
  • the catalyst of the present invention may be used in any chemical reaction requiring an asymmetric catalyst.
  • examples of such reactions include asymmetric hydride-transfer reactions, hydrosilylations, alkene hydrogenation, allylic substitution, cycloaddition reactions, Heck reactions, hydroformylations, conjugate addition reactions, nucleophilic additions to carbonyl compounds, expoxidations, dihydroxlations, aminohydroxylations, etc.
  • Asymmetric amplification involves asymmetric catalysis where the product of the reaction being studied is itself acting as a catalyst. Thus the desired reaction is assisted or an undesired reaction suppressed by the product of the reaction.
  • Such reactions are said to be “autocatalytic” and are generally observed in metal catalysed systems where the catalyst comprises 2 or more metal co-ordinating sites.
  • Emperical models have been formulated by Kagan (Angew. Chem. Int.
  • acetophenone is generally used as a standard test substrate.
  • the reaction is often carried out with diphenylsilane in the presence of the catalyst at room temperature with a suitable aprotic solvent such as tetrahydrofuran. After hydrolysis the reaction affords (R) and/or (S)-l-phenylethanol.
  • the determination of the chiral efficiency (% e.e) of a particular catalyst can be determined by gas chromatography through comparison with commercially available standard samples of (R) and (S)-l-phenylethanol.
  • Acetophenone can also be used as a test substrate for studying the efficacy of a particular catalyst for the asymmetric hydrogenation of ketones.
  • catalytic asymmetric hydrogenations of ketones were carried out using rhodium complexes of phosphine-based ligands with unsatisfactory enantioselectivity.
  • chiral nitrogen-based ligands like AMBOX in ruthenium based catalysts improves the efficiency of these processes. Accordingly, the present catalysts are also predicted to find utility in such transformations.
  • acetophenone can be used as a test substrate in the determination of the chiral efficiency and reactivity of the catalysts of the present invention the reaction is amenable to a wide range of functionalised ketones.
  • the reaction is also amenable to the reaction of selected imines to their corresponding amines.
  • a typical test system for such a reaction is represent below:
  • a catalytic amount of the desired catalyst these reactions are performed in the presence of a hydrogen donor.
  • Preferred hydrogen donors include alcohols, like iso-propanol and acids, such as formic acid.
  • the typical test reaction medium is an iso-propanol/alkaline base system.
  • a formic acid/triethylamine mixture also serves to effect reduction and is the preferred reaction medium for the test system illustrated for assessing the catalysts efficiency in reducing imines.
  • the reaction is usually performed at room temperature, in a suitable chlorinated solvent, preferably dichloromethane, in the presence of potassium acetate and bis(trimethylsilyl)acetamide.
  • the palladium catalyst can be generated in situ, preferably prior to the generation of the malonate nucleophile.
  • the reaction yields, time and enantioselectivities can be determined using standard methods.
  • [dihydro(phosphinophenyl)oxazole] iridium catalysts are effective in reducing alkenes which are tetra or tri-substituted by groups lacking heteroatoms in close proximity with the
  • the catalysts of the present invention are predicted to show general applicability in these processes.
  • a general procedure for a test system would involve mixing a catalytic amount of the desired catalyst with a substrate in a chlorinated solvent, for example dichloromethane.
  • the reaction container is pressurised with hydrogen ( ⁇ 30 ⁇ 80 bar) at room temperature.
  • the reaction products (alkanes) can be analysed and the reaction enantioselectivies assessed by conventional means, for instance by chiral GC and chiral HPLC/GC.
  • Test systems for such reactions may involve the coupling of either cyclohex-1-en-lyl trifluoromethanesulfonate or phenyl trifluoromethanesulfonate with 2,3-dihydrofuran.
  • the test alkyl triflate coupling can be performed at room temperature, with the catalyst, in the presence of a sterically hindered base like N,N-diisopropylethylamine (Hunigs base), in an aprotic solvent like, for instance benzene or toluene.
  • the test aryl triflate coupling is preferably performed at elevated temperatures, (ie. ⁇ > 50°C) in an appropriate solvent, like, for instance, tetrahydrofuran. Substrate conversion and enantiomeric excess can be determined using known techniques as mentioned previously.
  • a suitable test system to assess the present inventions ability to induce desirable reaction stereoselectivites is a reaction between cyclopentadiene and an acryloyl-oxazolidinone.
  • the reactions are preferably catalysed by Cu(II) catalysts and the test system can be performed at temperatures between 5O 0 C and -78 0 C in a suitable solvent, for instance dichloromethane. Higher enantioselectivies are generally observed at lower reaction temperatures.
  • diastereoslectivities ratio of endo:exo products
  • enantioselectivities can be carried out using known techniques.
  • the diastereomeric cycloadducts can be separated via column chromatography.
  • Trifluoromethanesulfonic anhydride (185 ⁇ L, 1.1 mmol) was added dropwise to a solution of 1 (200 mg, 0.73 mmol) in dry dichloromethane (8 mL) under a nitrogen atmosphere at -78 0 C and the mixture was stirred for 40 min. Then fresh distilled 2,6- lutidine (128 ⁇ L, 1.1 mmol) was added dropwise and stirred for 30 min. The reaction was quenched with saturated NaHCO 3 solution (10 mL) and extracted with dichloromethane (20 mL).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne des complexes métalliques de transition de composés enrichis pour un usage en tant que catalyseur dans des transformations asymétriques.
PCT/AU2005/000963 2004-06-30 2005-06-30 Ligands chiraux pour catalyse asymétrique WO2006002470A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU2004903601A AU2004903601A0 (en) 2004-06-30 Chiral Ligands for Asymmetric Catalysis
AU2004903601 2004-06-30

Publications (1)

Publication Number Publication Date
WO2006002470A1 true WO2006002470A1 (fr) 2006-01-12

Family

ID=35782411

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU2005/000963 WO2006002470A1 (fr) 2004-06-30 2005-06-30 Ligands chiraux pour catalyse asymétrique

Country Status (1)

Country Link
WO (1) WO2006002470A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012131313A1 (fr) * 2011-03-31 2012-10-04 The University Of Sussex Complexes d'organo-or et leurs procédés de préparation
US8586732B2 (en) 2011-07-01 2013-11-19 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8703759B2 (en) 2010-07-02 2014-04-22 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8952034B2 (en) 2009-07-27 2015-02-10 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8962610B2 (en) 2011-07-01 2015-02-24 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9115096B2 (en) 2011-05-10 2015-08-25 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57130979A (en) * 1981-02-09 1982-08-13 Sankyo Co Ltd 4-amino-1,3-benzoxazine derivative and its preparation
EP0477789A1 (fr) * 1990-09-25 1992-04-01 Takeda Chemical Industries, Ltd. Dérivés de benzoxazine-1,3, leur préparation et leur utilisation
WO1994004521A1 (fr) * 1992-08-17 1994-03-03 Chugai Seiyaku Kabushiki Kaisha Derives de benzopyranne et de benzoxazine
JPH07196635A (ja) * 1993-12-28 1995-08-01 Chugai Pharmaceut Co Ltd ベンゾオキサジン誘導体

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57130979A (en) * 1981-02-09 1982-08-13 Sankyo Co Ltd 4-amino-1,3-benzoxazine derivative and its preparation
EP0477789A1 (fr) * 1990-09-25 1992-04-01 Takeda Chemical Industries, Ltd. Dérivés de benzoxazine-1,3, leur préparation et leur utilisation
WO1994004521A1 (fr) * 1992-08-17 1994-03-03 Chugai Seiyaku Kabushiki Kaisha Derives de benzopyranne et de benzoxazine
JPH07196635A (ja) * 1993-12-28 1995-08-01 Chugai Pharmaceut Co Ltd ベンゾオキサジン誘導体

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
CHEM BERICHTE, vol. 103, no. 9, 1970, pages 2760 - 2767 *
DATABASE CA [online] MIZUFUNE H ET AL: "Process development of potassium channel opener,TCV-295 based on convenient ring information of 2H-1,3 benzoxazine and selective N oxidation of the pyridyl moiety", accession no. stn Database accession no. 135:371695 *
DATABASE CA [online] SCHMIDT R R ET AL: "3-azapyrylium salts VI alkyliden-1,3 oxazines and alkylidenepyrimides", accession no. stn Database accession no. 73:109753 *
DATABASE CA [online] THIENTHONG N ET AL: "Anew class of nitrogen based chiral ligands: 2H-1,3 benzoxazines.Ligand synthesis X ray strutural studies and asymmetric catalysis", accession no. stn Database accession no. 143:26548 *
DATABASE WPI Week 198238, 13 August 1982 Derwent World Patents Index; Class B02, AN 1982-80042 *
DATABASE WPI Week 199214, 1 April 1992 Derwent World Patents Index; Class B02, AN 1992-106200 *
DATABASE WPI Week 199410, 3 March 1994 Derwent World Patents Index; Class B02, AN 1994-083073 *
DATABASE WPI Week 199542, 1 August 1995 Derwent World Patents Index; Class B02, AN 1995-322961 *
JOURNAL OF ORGANOMETALLIC CHEMISTRY, vol. 690, no. 8, 2005, pages 2027 - 2034 *
TETRADRON, vol. 57, no. 35, 2001, pages 7501 - 7506 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9371329B2 (en) 2009-07-27 2016-06-21 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8952034B2 (en) 2009-07-27 2015-02-10 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9079901B2 (en) 2010-07-02 2015-07-14 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8703759B2 (en) 2010-07-02 2014-04-22 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
CN103534261A (zh) * 2011-03-31 2014-01-22 苏塞克斯大学 有机金络合物及其制备方法
US9260460B2 (en) 2011-03-31 2016-02-16 The University Of Sussex Organogold complexes and methods for making the same
WO2012131313A1 (fr) * 2011-03-31 2012-10-04 The University Of Sussex Complexes d'organo-or et leurs procédés de préparation
US9115096B2 (en) 2011-05-10 2015-08-25 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9403782B2 (en) 2011-05-10 2016-08-02 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9682998B2 (en) 2011-05-10 2017-06-20 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8962610B2 (en) 2011-07-01 2015-02-24 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9193694B2 (en) 2011-07-01 2015-11-24 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8697863B2 (en) 2011-07-01 2014-04-15 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8586732B2 (en) 2011-07-01 2013-11-19 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9598435B2 (en) 2011-07-01 2017-03-21 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9676760B2 (en) 2011-07-01 2017-06-13 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9695192B2 (en) 2011-07-01 2017-07-04 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators

Similar Documents

Publication Publication Date Title
Kasak et al. A chiral phosphepine–olefin rhodium complex as an efficient catalyst for the asymmetric conjugate addition
JP2002513376A (ja) 環式キラルホスフィン配位子を有する遷移金属錯体を触媒とする不斉合成
US6486337B2 (en) Ruthenium-disphosphine complexes and their use as catalysts
JP4837857B2 (ja) キラル配位子、その遷移金属錯体および不斉反応におけるその使用
Hayashi et al. New chiral chelating phosphine complexes containing tricarbonyl (η6-arene) chromium for highly enantioselective allylic alkylation
EP0941231B1 (fr) Diphosphines du type hétéroarylique-arylique en tant que ligands chiraux
EP0582668B1 (fr) Ligands de bis(phospholanes) tridentes chiraux
JP2006508161A (ja) 炭素−ヘテロ原子二重結合の接触水素化
JPH0853480A (ja) ハロゲン化ビフェニル−２，２′−ジイルビスジフェニルホスフィンおよびそれらの製法
CN110494439B (zh) 手性联苯二膦配体及其制备方法
WO2006002470A1 (fr) Ligands chiraux pour catalyse asymétrique
Ferrand et al. Hydrophilic diamine ligands for catalytic asymmetric hydrogenation of C O bonds
Gladiali et al. Binaphthalene-templated N, S-and N, P-heterobidentate ligands with an achiral oxazoline pendant: Synthesis and assessment in asymmetric catalysis
EP0732337B1 (fr) Diphosphines asymmétriques optiquement actives et procédé pour préparer des substances optiquement actives en leur présence
JP2005523939A (ja) フェロセニル配位子及び前記配位子の製造方法
JP2004091488A (ja) ホスファイトおよび遷移金属錯体の製造方法
Šebesta et al. Influence of structural changes in ferrocene phosphane aminophosphane ligands on their catalytic activity
JP4682141B2 (ja) イリジウム錯体
US20090227805A1 (en) Axially Asymmetric Phosphorus Compound and Production Method Thereof
Kinting et al. Asymmetric hydrogenation catalyzed by rhodium complexes of 2, 3-bis (dimenthylphosphino) maleic anhydride and 2, 3-bis (dimenthylphosphino)-N-phenylmaleimide
DE102004022900A1 (de) Chirale Diphosphorverbindungen und deren Übergangsmetallkomplexe
Fan et al. Rhodium catalyzed asymmetric Pauson-Khand reaction using SDP ligands
JP4490211B2 (ja) 光学活性３−キヌクリジノール類の製造方法
US20080227978A1 (en) Method for the Preparation of Enantiomerically Enriched Secondary Alcohols by the Addition of Organoaluminium Reagents to Carbonyl Compounds
JP5232374B2 (ja) ２位に置換基を有する光学活性キヌクリジノール類の製造方法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载