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WO1992020677A1 - Ligands chiraux heterocycliques et procede de dihydroxylation asymetrique et catalytique d'olefines - Google Patents

Ligands chiraux heterocycliques et procede de dihydroxylation asymetrique et catalytique d'olefines Download PDF

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Publication number
WO1992020677A1
WO1992020677A1 PCT/US1992/003940 US9203940W WO9220677A1 WO 1992020677 A1 WO1992020677 A1 WO 1992020677A1 US 9203940 W US9203940 W US 9203940W WO 9220677 A1 WO9220677 A1 WO 9220677A1
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Prior art keywords
derivative
dihydroquinidine
dihydroquinine
olefin
ether
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Inventor
K. Barry Sharpless
Matthias Beller
Brent Blackburn
Yasahiro Kawanami
Hoi-Lun Kwong
Yasukazu Ogino
Toinoyuki Shibata
Tatsuzo Ukita
Lisa Wang
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Massachusetts Institute of Technology
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Massachusetts Institute of Technology
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Priority to JP50013693A priority Critical patent/JP3550397B2/ja
Priority to CA002087035A priority patent/CA2087035C/fr
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    • 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
    • C07C29/48—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by oxidation reactions with formation of hydroxy groups
    • 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
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered

Definitions

  • Enantiomers are stereoisomers or chiral molecules whose configurations (arrangements of constituent atoms) are nonsuperimposed mirror images of each other; absolute configurations at chiral centers are determined by a set of rules by which a priority is assigned to each
  • R and S substituent and are designated R and S.
  • the physical properties of enantiomers are identical, except for the direction in which they rotate the plane of polarized light: one enantiomer rotates plane-polarized light to the right and the other enantiomer rotates it to the left. However, the magnitude of the rotation caused by each is the same.
  • enantiomers are also identical, with the exception of their interactions with optically active reagents.
  • Optically active reagents interact with enantiomers at different rates, resulting in reaction rates which may vary greatly and, in some cases, at such different rates that reaction with one enantiomer or isomer does not occur. This is particularly evident in biological systems, in which stereo- chemical specificity is the rule because enzymes (biological catalysts) and most of the substrates on which they act are optically active.
  • a mixture which includes equal quantities of both enantiomers is a racemate (or racemic modification).
  • a racemate is optically inactive, as a result of the fact that the rotation of polarized light caused by a molecule of one isomer is equal to and in the opposite direction from the rotation caused by a molecule of its enantiomer.
  • Racemates not optically active compounds, are the products of most synthetic procedures. Because of the identity of most physical characteristics of enantiomers, they cannot be separated by such commonly used methods as fractional distillation (because they have identical boiling points), fractional crystallization (because they are equally soluble in a solvent, unless it is optically active) and chromatography (because they are held equally tightly on a given adsorbent, unless it is optically active). As a result, resolution of a racemic mixture into enantiomers is not easily accomplished and can be costly and time consuming.
  • prostaglandins are a particularly critical consideration, for example, for drugs, because in living systems, it often happens that one enantiomer functions effectively and the other enantiomer has no biological activity and/or interferes with the biological function of the first enantiomer.
  • the enzyme catalyst involved in a given chemical reaction ensures that the reaction proceeds asymmetrically, producing only the correct enantiomer (i.e., the enantiomer which is biologically or physiologically functional). This is not the case in laboratory synthesis, however, and, despite the interest in and energy expended in developing methods by which asymmetric production of a desired chiral molecule (e.g., of a selected enantiomer) can be carried out, there has been only limited success.
  • Asymmetric homogeneous hydrogenation and asymmetric epoxidation have also been used to produce chiral molecules.
  • Asymmetric hydrogenation is seen as the first manmade reaction to mimic naturally-occurring asymmetric reactions.
  • heteroatom-containing functional groups are asymmetrically dihydroxylated, oxyaminated or diaminated using an osmium-catalyzed process which is the subject of the present invention.
  • Chiral ligands which are novel alkaloid derivatives, particularly dihydroquinidine derivatives or dihydroquinine derivatives or salts thereof, useful in the method of the present invention are also the subject of the present invention.
  • Derivatives of the parent alkaloids e.g. quinidine or quinine, or salts thereof can also be used, but the rate of catalysis is slightly slower.
  • the chiral ligand is immobilized to or incorporated within a polymer. Both monomeric and polymeric ligands can be immobilized to or incorporated into the polymer. The immobilized or incorporated ligands form a complex with the osmium catalyst during the reaction, resulting in efficient catalysis in which the complex can be preserved after the reaction, allowing repetitive use of the complex. Alternatively, a preformed osmium-ligand complex can be used in the reaction, and recovered.
  • an olefin, a selected chiral ligand, an organic solvent, water, an oxidant, an osmium source and, optionally, an additive which accelerates hydrolysis of the osmate intermediate are combined, under conditions appropriate for reaction to occur.
  • the method of ligand-accelerated catalysis of the present invention is useful to effect asymmetric dihydroxylation
  • Figure 1 is a schematic representation of asymmetric dihydroxylation via ligand-accelerated catalysis which is carried out by the method of the present invention.
  • Figure 2 is a schematic representation of asymmetric catalytic oxyamination of stilbene which is carried out by the method of the present invention.
  • Figure 3 is a plot of amine concentration vs second-order-rate constant k for the catalytic cis-dihydroxylation of styrene. At point a, no amine has been added. Point a thus represents the rate of the catalytic process in the absence of added amine ligands.
  • Line b represents the rate of the catalytic process in the presence of varying amounts of quinuclidine, a ligand which substantially retards catalysis.
  • Line c represents the rate of the catalytic process in the presence of the dihydroquinidine benzoate derivative 1 represented in
  • Figure 4 is a schematic representation of a proposed mechanism of catalytic olefin dihydroxylation. This scheme shows two diol-producing cycles believed to be involved in the ligand-accelerated catalysis of the present invention.
  • Formula 1 represents an alkaloidosmium complex
  • formula 2 represents a monoglycolate ester
  • formula 3 represents an osmium(VIII)trioxoglycolate complex
  • formula 4 represents a bisglycolate osmium ester
  • formula 5 represents a
  • Asymmetric epoxidation has been the subject of much research for more than ten years.
  • the titanium-tartrate epoxidation catalyst is actually a complex mixture of epoxidation catalysts in dynamic equilibrium with each other and that the main species present (i.e., the 2:2 structure) is the best catalyst (i.e., about six times more active than titanium isopropoxide bearing no tartrate).
  • This work also showed that this rate advantage is essential to the method's success because it ensures that the catalysis is channeled through a chiral ligand-bearing species.
  • the method of the present invention results in asymmetric induction and enhancement of reaction rate by binding of a selected ligand.
  • asymmetric dihydroxylation, asymmetric diamination or asymmetric oxyamination can be effected.
  • the new catalytic method of the present invention achieves substantially improved rates and turnover numbers (when compared with previously-available methods), as well as useful levels of asymmetric induction.
  • less osmium catalyst is needed in the method of the present invention than in previously-known methods.
  • the expense and the possible toxicity problem associated with previously-known methods are reduced.
  • the invention allows the recovery and reuse of osmium, which reduces the cost of the process.
  • the method of the present invention is exemplified below with particular reference to its use in the asymmetric dihydroxylation of E-stilbene (C 6 H 5 CH:CHC 6 H 5 ) and trans-3-hexene (CH 3 CH 2 CH: CHCH 2 CH 3 ).
  • the method can be generally described as presented below and that description and subsequent exemplification not only demonstrate the dramatic and unexpected results of ligand-accelerated catalysis, but also make evident the simplicity and effectiveness of the method.
  • asymmetric dihydroxylation method of the present invention is represented by the scheme illustrated in Figure 1.
  • asymmetric dihydroxylation of a selected olefin is effected as a result of ligand-accelerated catalysis. That is, according to the method, a selected olefin is combined, under appropriate conditions, with a selected chiral ligand (which in general will be a chiral substituted quinuclidine), an organic solvent, water, an oxidant and osmium tetroxide and, optionally, a compound which promotes hydrolysis of the products from the osmium. Acids or bases can be used for this purpose.
  • a selected olefin, a chiral ligand, an organic solvent, water and an oxidant are combined; after the olefin and other components are combined, OsO 4 is added.
  • the resulting combination is maintained under conditions (e.g., temperature, agitation, etc.) conducive for dihydroxylation of the olefin to occur.
  • the olefin, organic solvent, chiral ligand, water and OsO 4 are combined and the oxidant added to the resulting combination.
  • reaction mixture components of the reaction mixture are combined, to form an initial reaction combination, and olefin is added slowly to it, generally with frequent or constant agitation, such as stirring.
  • olefin is added slowly to it, generally with frequent or constant agitation, such as stirring.
  • organic solvent, chiral ligand, water, OsO 4 and the oxidant are combined.
  • the olefin can then be slowly added to the other reactants. It is important that agitation, preferably stirring, be applied during the olefin addition.
  • hydrocarbon olefins bearing no aromatic substituents, or other functional groups bearing no aromatic substituents, or other functional groups.
  • the olefin is added slowly (e.g., over time), as necessary to maximize ee. This method is particularly valuable because it results in higher ee's and faster reaction times.
  • the chiral ligands are immobilized or incorporated into a polymer, thereby immobilizing the ligands. Both monomers and polymers of alkaloid ligands can be immobilized.
  • the immobilized ligands form a complex with the osmium catalyst, which results in formation of an osmium catalyst complex which can be recovered after the reaction.
  • the OsO 4 -polymer complex is recoverable and can be used for iterative processes without washing or other treatment.
  • the complex can be recovered, for example, by filtration or centrifugation.
  • alkaloid polymers can be used as ligands.
  • Alkaloid polymers which can be used are described, for example, by Kobayashi and Iwai in Tetrahedron Letters, 21:2167-2170 (1980) and Polymer Journal,
  • polymeric as used herein is meant to include monomers or polymers of alkaloid ligands which are chemically bonded or attached to a polymer carrier, such that the ligand remains attached under the conditions of the reaction, or ligands which are copolymerized with one or more monomers (e.g., acrylonitrile) to form a co-polymer in which the alkaloid is incorporated into the polymer, or alkaloid polymers as described above, which are not immobilized or copolymerized with another polymer or other carrier.
  • monomers e.g., acrylonitrile
  • Polymeric cinchona alkaloids which are useful in the present method can be prepared by art-recognized techniques. See, for example, Grubhofer and Schleith,
  • These polymers include: (a) co-polymers of cinchona alkaloid derivatives with co-polymerizing reagents, such as vinyl chloride, styrene, acrylamide, acrylonitrile, or acrylic or methacrylic acid esters; (b) cross-linked polymers of cinchona alkaloid derivatives with cross-linking reagents, such as 1,4-divinylbenzene, ethylene glycol bismethacrylate; and (c) cinchona
  • alkaloid derivatives covalently linked to polysiloxanes.
  • the connecting point of the polymer backbone to the alkaloid derivative can be at C(10), C(11), C(9)-O,N(1'), or C(6')-O as shown below for both quinidine and quinine derivatives.
  • Table 3 shows the examples of the monomeric alkaloid derivatives which can be incorporated in the polymer system.
  • a polymer binding dihydroquinidine was prepared by copolymerizing 9-(10-undecenoyl)dihydroquinidine in the presence of acrylonitrile (5 eq); a 13% yield was obtained exhibiting 4% alkaloid incorporation.
  • This polymer an acrylonitrile co-polymer of 9-(10-undecenoyl)-10,11-dihydroquinidine, is shown as polymer 4 in Table 1, below.
  • polymer 3, Table 1 (polymer 3, Table 1) were prepared according to the procedures of Inaguki et al., or slightly modified versions of this procedure. See Inaguki et al., Bull.
  • reaction with polymer 2 exhibited the highest degree of asymmetric induction.
  • the activity of the OsO 4 -polymer complex is preserved after the reaction, thus allowing repetitive use of the complex.
  • This reaction can be carried out with terminal and aliphatically substituted olefins to show good yields and enantioselectivities (for example, styrene with polymer 2, 60% ee , 68% yield, and ethyltrans-2-octenoate with polymer 3, 60% ee, 85% yield) and the same process can be applied to a variety of different olefins.
  • an additive which accelerates hydrolysis of the osmate ester intermediates can, optionally, be added to the reaction combination.
  • These additives can be acids or bases, for example. Bases are preferred for this purpose.
  • soluble, carboxylic acid salts with organic- solubilizing counter-ions e.g., tetraalkyl ammonium ions
  • Carboxylate salts which are preferred in the present reaction are soluble in organic media and in organic/aqueous co-solvent systems.
  • tetraethyl ammonium acetate has been shown to enhance the reaction rate and ee of some olefins (Table 5).
  • the additive does not replace the alkaloid in the reaction.
  • Compounds which can be used include benzyltrimethyl- ammoniumacetate, tetramethylammonium acetate and
  • oxyanion compounds e.g., sulfonates, carbonates, borates or phosphates
  • the compound can be added to the reaction combination of organic solvent, chiral ligand, water and OsO 4 in a reaction vessel, before olefin addition. It is important to agitate (e.g., by stirring) the reaction combination during olefin addition.
  • the additive can also be added to the reaction combination, described above, wherein all of the olefin is added at the beginning of the reaction. In one embodiment, the amount of additive is generally approximately 2 equivalents; in general from about 1 to about 4 equivalents will be used.
  • the process can be run in an organic non-polar solvent such as toluene.
  • an organic non-polar solvent such as toluene.
  • a carboxylate compound which accelerates hydrolysis of the osmate ester intermediates e.g., tetraethyl- or tetramethyl ammonium acetate
  • This embodiment is designated the "phase transfer" method.
  • olefins which are not soluble, or have limited solubility, in mixtures of acetone/water or acetonitrile/water are dissolved in toluene and then added slowly a mixture of organic solvent, chiral ligand, water and OsO 4 .
  • the carboxylate salt serves the dual function of solubilizing the acetate ion in the organic phase where it can promote hydrolysis of the osmate ester, and carrying water associated with it into the organic phase, which is essential for hydrolysis. Higher ee's are obtained with many substrates using this method.
  • boric acid itself i.e., B(OH) 2
  • phenylboric acid i.e., Ph-B(OH) 2
  • the boric acid is added to the ligand - organic solvent - OsO 4 mixture prior to the addition of the olefin.
  • the amount of boric acid added is an amount sufficient to form the borate ester of the diol produced in the reaction.
  • the boric acid hydrolyzes the osmium ester and captures the diols which are generated in the reaction. Neither water nor a soluble carboxylate such as tetraalkyl ammonium carboxylate, is required to hydrolyze the osmium ester in the present reactions. Because the presence of water can make the isolation and recovery of water-soluble diols difficult, the addition of a boric acid makes isolation of these diols easier. Especially, in the case of an aryl or alkyl boric acid, it is easy because, in place of the diol, the product is the cyclic borate ester which can be subsequently hydrolyzed to the diol. Iwasawa et al., Chemistry Letters, pp. 1721-1724 (1988). The addition of a boric acid is particularly useful in the slow addition method.
  • oxidants such as potassium hexacyanoferrate (III)
  • K 3 Fe(CN) 6 potassium ferricyanide, K 3 Fe(CN) 6
  • K 2 CO 3 potassium carbonate
  • NMO N-methylmorpholine-N-oxide
  • the ferricyanide reactions can be run at a range of temperatures, however, depending upon the substrate.
  • the amount of water added to the reaction mixture is an important factor in the present method.
  • the optimum amount of water to be added can be determined empirically and, in general, should be that amount which results in maximum ee. Generally, approximately 10 to 16
  • An olefin of interest can undergo asymmetric dihydroxylation according to the present invention.
  • any hydrocarbon containing at least one carbon-carbon double bond as a functional group can be asymmetrically dihydroxylated according to the subject method.
  • the method is applicable to any olefin of interest and is particularly well suited to effecting asymmetric dihydroxylation of prochiral olefins (i.e., olefins which can be converted to products exhibiting chirality or handedness).
  • prochiral olefins i.e., olefins which can be converted to products exhibiting chirality or handedness.
  • the method of the present invention is used to asymmetrically dihydroxylate a chiral olefin, one enantiomer will be more reactive than the other.
  • the chiral ligand used in the asymmetric dihydroxylation method will generally be an alkaloid, or a basic nitrogenous organic compound, which is generally
  • the chiral ligand can be a naturally occurring compound, a purely synthetic compound or a salt thereof, such as a hydrochloride salt.
  • the optimum derivative which is used can be determined based upon the process conditions for each reaction.
  • alkaloids which can be used as the chiral ligand in the asymmetric dihydroxylation method include cinchona alkaloids, such as quinine, quinidine, cinchonine, and cinchonidine.
  • Examples of alkaloid derivatives useful in the method of the present invention are shown in Table 3. As described in detail below, the two cinchona alkaloids quinine and quinidine act more like enantiomers than like dias tereomers in the scheme represented in Figure 1.
  • dihydroquinidine derivatives represented as DHQD
  • dihydroquinine derivatives represented as DHQ
  • DHQD and DHQ have a pseudo-enantiomeric relationship in the present method (DHQD and DHQ are actually diastereomers). That is, they exhibit opposite enantiofacial selection.
  • Such derivatives can be, for example, esters or ethers, although other forms can be used. The choice of derivative depends upon the process. When dihydroquinidine is used as the ligand, delivery of the two hydroxyl groups takes place from the top or upper face
  • aromatic ethers of various cinchona alkaloids are used as ligands.
  • aromatic ethers includes aryl ethers and heterocyclic ethers.
  • a high level of asymmetric induction can be obtained using aromatic ethers of dihydroquinidine or dihydroquinine as ligands.
  • aromatic ethers having the following formula are particularly useful:
  • R is phenyl, naphthyl, or o-methoxyphenyl.
  • the stoichiometric asymmetric dihydroxylation of various dialkyl substituted olefins was performed using the phenyl ether derivative of dihydroquinidine. The results are shown in Table 6.
  • reaction was performed by adding 1 eq of olefin to a 1:1 mixture of OsO 4 and the ligand in dry toluene (0.1M) followed by a reductive work-up using lithium aluminum hydride (LiAlH 4 ) to yield the (R,R)-diol in 60-95% yield with good to excellent enantiomeric excess.
  • Reactions with ⁇ , ⁇ -unsaturated esters also proceeded with much improved enantio- and diastereoselectivities (>90%, as shown in entries 7 and 8, Table 6) using this ligand.
  • aromatic ether ligands were used in the catalytic asymmetric dihydroxylation of (E)-3-hexene.
  • the results are summarized in Table 8. The catalytic
  • Enantioselectivities in the dihydroxylation of dialkyl substituted olefins which were previously only po s s ible through the use of stoichiometric reagents at low temperature, can now be obtained in the catalytic asymmetric dihydroxylation using these aromatic ether ligands at room temperature.
  • the R group can include other benzenoid hydrocarbons.
  • the aromatic moieties also can be modified by
  • Additional effective heterocyclic aromatic ligands include:
  • ligands 1a and 1b also deliver a significant ee enhancement for trans-substituted olefins, especially those lacking aromatic substituents (entries 8 and 9).
  • a further advantage is that the most expensive component, the ligand, can be easily recovered in >80% yield.
  • Another olefin class can be asymmetrically
  • DHQD dihydroxylated when O-carbamoyl-, p-chlorobenzoate- or O-phenanthrolene- substitutions of DHQD or DHQ ligands are used in the method of the present invention.
  • This class is the cis-disubstituted type of olefin.
  • Table 10 shows the ee's and % yields for a variety of substrates when these ligands were used. Procedures for producing these ligands and for carrying out the ADH are illustrated in Examples 23 and 24. where the ligands are ether linked substituents of DHQD designated as dimethyl carbamoyl (DMC), methyl phenyl carbomoyl (MPC), diphenylcarbamoyl (DPC),
  • PCB p-chlorobenzoate
  • PPN phenanthryl
  • PhC phenyl carbomoyl
  • the concentration of the chiral ligand used will range from approximately 0.001 M or less to 2.0 M. In one embodiment, exemplified below, the solution is 0.261M in alkaloid 1 (the dihydroquinidine derivative). In one embodiment of the method, carried out at room temperature, the concentrations of each alkaloid
  • the amount of chiral ligand necessary for the method of the present invention can be varied as the temperature at which the reaction occurs varies. For example, it is possible to reduce the amount of alkaloid (or other chiral ligand) used as the temperature at which the reaction is carried out is changed. For example, if it is carried out, using the dihydroquinidine derivative, at 0oC, the alkaloid concentration can be 0.15M. In another embodiment, carried out at 0oC, the alkaloid concentration was 0.0625M.
  • oxidants i.e., essentially any source of oxygen
  • amine oxides e.g., trimethyl amine oxides
  • tert-butyl hydroperoxide hydrogen peroxide
  • oxygen plus metal catalysts e.g., copper (Cu + -Cu ++ /O 2 ), platinum (Pt/O 2 ), palladium (Pd/O 2 )
  • metal catalysts e.g., copper (Cu + -Cu ++ /O 2 )
  • platinum Pt/O 2
  • palladium Pd/O 2
  • NaOCl NaOCl
  • KIO 4 KBrO 3 or KClO 3 can be used.
  • N-methylmorpholine N-oxide NMO is used as the oxidant.
  • NMO is available commercially (e.g., Aldrich Chemicals, 97% NMO anhydrous, or as a 60% solution in water).
  • potassium ferricyanide can be used in lieu of the amine oxide. Potassium ferricyanide is an efficient oxidant in the present method.
  • Osmium will generally be provided in the method of the present invention in the form of osmium tetroxide (OsO 4 ) or potassium osmate VI dihydrate, although other sources (e.g., osmium trichloride anhydrous, osmium trichloride hydrate) can be used. OsO 4 can be added as a solid or in solution.
  • OsO 4 can be added as a solid or in solution.
  • the osmium catalyst used in the method of the present invention can be recycled, for re-use in subsequent reactions. This makes it possible not only to reduce the expense of the procedure, but also to recover the toxic osmium catalyst.
  • the osmium catalyst can be recycled as follows: Using reduction catalysts (e.g., Pd-C), the osmium VIII species is reduced and adsorbed onto the reduction catalyst. The resulting solid is filtered and resuspended.
  • NMO or an oxidant
  • the alkaloid and the substrate (olefin) are added, with the result that the osmium which is bound to the Pd/C solid is reoxidized to OsO 4 and re-enters solution and plays its usual catalytic role in formation of the desired diol.
  • This procedure (represented below) can be carried out through several cycles, thus re-using the osmium species.
  • the palladium or carbon can be immobilized, for example, in a fixed bed or in a cartridge.
  • an olefin such as recrystallised trans-stilbene (C 6 H 5 CH: HC 6 H 5 ) is combined with a chiral ligand (e.g., p-chlorobenzoyl hydroquinidine), acetone, water and NMO.
  • a chiral ligand e.g., p-chlorobenzoyl hydroquinidine
  • acetone e.g., p-chlorobenzoyl hydroquinidine
  • acetone e.g., p-chlorobenzoyl hydroquinidine
  • NMO chiral ligand
  • cooling can be carried out using an ice-water bath.
  • OsO 4 is then added (e.g., by injection), in the form of a solution of OsO 4 in an organic solvent (e.g., in
  • the components can be added sequentially or simultaneously and the order in which they are combined can vary.
  • the resulting combination is cooled (e.g., to approximately 0oC); cooling can be carried out using an ice-water bath. It is particularly preferred that the combination is agitated (e.g., stirred).
  • an olefin e.g., trans-3-hexene
  • is added slowly e.g., by injection.
  • the optimum rate of addition (i.e., giving maximum ee), will vary depending on the nature of the olefinic substrate.
  • the olefin was added over a period of about 16-20 hours.
  • the mixture can be stirred for an additional period of time at the low temperature (1 hour in the case of trans-3-hexene).
  • the slow-addition method is preferred as it results in better ee and faster reaction times.
  • a compound which accelerates hydrolysis of the osmate ester intermediates e.g., a soluble carboxylate salt, such as tetraethylammonium acetate
  • a compound which accelerates hydrolysis of the osmate ester intermediates e.g., a soluble carboxylate salt, such as tetraethylammonium acetate
  • the compound (approximately 1-4 equiv.) can be added to the mixture of chiral ligand, water, solvent, oxidant and osmium
  • the diol-producing mechanistic scheme which is thought to operate when the slow-addition of olefin method is used is represented in Figure 4. According to the proposed mechanism, at least two diol-producing cycles exist. As shown in Figure 4, only the first cycle appears to result in high ee.
  • the key intermediate is the osmium (VIII) trioxoglycolate complex, shown as formula 3 in Figure 4, which has the following general formula:
  • L is a chiral ligand and wherein R 1 , R 2 , R 3 and R 4 are organic functional groups corresponding to the olefin.
  • R 1 , R 2 R 3 and R 4 could be alkyl, aryl, alkoxy aryloxy or other organic functional groups compatible with the reaction process. Examples of olefins which can be used, and their functional groups, are shown on Table 4 hereinabove.
  • This complex occupies the pivotal position at the junction between the two cycles, and determines how diol production is divided between the cycles.
  • Reduced ee is just part of the counterproductivity of turning on the second cycle; reduced turnover is the other liability.
  • the bisosmate esters (formula 4, Figure 4) are usually slow to reoxidize and hydrolyze, and therefore tend to tie up the catalyst. For example, 1-phenylcyclohexene took 7 days to reach completion under the original conditions (the 8% ee cited above). With slow addition of the olefin, the oxidation was complete in one day and gave the diol in 95% yield and 78% ee (entry 3, Table 5).
  • the maximum ee obtainable in the catalytic process is determined by the addition of the alkaloid osmium complex (formula 1, Figure 4) to the olefin (i.e., the first column in Table 5).
  • stoichiometric additions can be used to enable one to determine the ee-ceiling which can be reached or approached in the catalytic process if the hydrolysis of 3 ( Figure 4) can be made to dominate the alternative reaction with a second molecule of olefin to give 4 ( Figure 4).
  • the effect of temperature on the ee is opposite the effect when NMO is the secondary oxidant. That is, lowering the temperature can often increase the ee when potassium ferricyanide is the secondary oxidant. Also, the olefin need not be slowly added to the mixture but can, instead, be added all at once when potassium ferricyanide is the secondary oxidant.
  • the reaction mixture When the olefin addition rate is slow enough, the reaction mixture remains yellow-orange (color of 1, Figure 4); when the rate is too fast, the solution takes on a blackish tint, indicating that the dark-brown-to-black bisglycolate complex (4, Figure 4) is being generated; 3) If the ceiling ee is not reached after steps 1 and 2, slow addition plus tetraalkyl ammonium acetate (or other compound which assists hydrolysis of the osmate ester intermediate) at 0°C can be used; 4) slow addition plus a soluble carboxylate salt, such as tetraalkyl ammonium acetate at room temperature can also be used. For all these variations, it is preferable that the mixtures is agitated (e.g., stirred) for the entire reaction period.
  • agitated e.g., stirred
  • the method of the present invention can be carried out over a wide temperature range and the limits of that range will be determined, for example, by the limit of the organic solvent used.
  • the method can be carried out, for example, in a temperature range from about 40°C to about -30°C.
  • Concentrations of individual reactants e.g., chiral ligand, oxidant, etc.
  • concentration of individual reactants can be varied as the temperature at which the method of the present invention is carried out.
  • the saturation point e.g., the concentration of chiral ligand at which results are maximized
  • the organic solvent used in the present method can be, for example, acetone, acetonitrile, THF, DME ,
  • solvents are particularly suitable when NMO is the secondary oxidant.
  • potassium ferricyanide K 3 Fe(CN 6 ) is the secondary oxidant, it is advantageous to use a
  • Tables 11-12 The yields and ee's for a variety of organic solvents, mixed with water and a variety of substrates are shown in Tables 11-12.
  • Table 11 shows yields and ee's for several organic solvents (with water) for a specific substrate.
  • the ligand is either
  • DHQD-p-chlorobenzoate PCB
  • DHQD - napthyl ether DHQD-p-chlorobenzoate
  • Table 12 shows the ee's for a veriety of substrates for either t-butanol or cyclohexane as the organic phase. It is apparent from these Tables that preferred organic phase solvents include cyclohexane, hexane, ethyl ether and t-butyl methyl ether.
  • the preferred aqueous solvent is water.
  • styrene was combined with a chiral ligand (DHQD), acetone, water and NMO and OsO 4 .
  • DHQD chiral ligand
  • the plot of amine concentration vs second-order-rate-constant K for the catalytic cis-dihydroxylation of styrene is represented in Figure 2.
  • the kinetic data of Figure 2 clearly shows the dramatic effect of ligand-accelerated catalysis achieved by use of the method of the present invention.
  • Line b shows the rates of the process in the presence of varying amounts of quinuclidine, a ligand which substantially retards catalysis (at greater than 0.1M quinuclidine, t1/2 is greater than 30 hours).
  • acceleration by added ligand 1 is due to formation of an osmium tetroxide-alkaloid complex which, in the case of styrene, is 23 times more reactive than free osmium tetroxide.
  • the rate reaches a maximal and constant value beyond an (approximate) 0.25 M concentration of ligand 1.
  • the rate acceleration in the presence of the alkaloid is accounted for by facilitation of the initial osmylation step.
  • the strikingly opposite effects of quinuclidine and DHQD on the catalysis can be related to the fact that although quinuclidine also accelerates the addition of osmium tetroxide to olefins, it binds too strongly to the resulting osmi-um(VI) ester intermediate and inhibits catalyst turnover by retarding the hydrolvsis/reoxidation steps of the cycle.
  • the alkaloid appears to achieve a balancing act which renders it near perfect for its role as an accelerator of the dihydroxylation
  • the method of the present invention has been applied to a variety of olefins.
  • the face selection rule described above has been shown to apply (with reference to the orientation of the olefin as represented in Figure 1). That is, in the case of the asymmetric dihydroxylation reaction in which the dihydroquinidine derivative is the chiral ligand, attack occurs on the re- or re, re- face) and in the case in which the dihydroquinine derivative is the chiral ligand, attack occurs on the si- or si, si- face.
  • the method of the present invention is effective in bringing about catalytic asymmetric dihydroxylation; in all cases, the yield of the diol was 80-95%, and with the slow-addition modification, most olefins give ee's in the rage of 40-90%.
  • the present method can be used to synthesize chiral intermediates which are important building blocks for biologically active chiral molecules, such as drugs.
  • the present method was used to produce an optically pure intermediate used in synthesizing the drug diltiazem (also known as cardizem). The reaction is shown in the following scheme:
  • the method of the present invention is also useful to effect asymmetric vicinal oxyamination of an olefin, and may be useful for asymmetric vicinal diamination.
  • an amino derivative is used as an amino transfer agent and as an oxidant.
  • the olefin to be modified, an organic solvent, water, a chiral ligand, an amino derivative and an osmium-containing compound are combined and the combination maintained under conditions appropriate for the reaction to occur.
  • the amino derivative can be, for example, an N-chlorocarbamate or chloroamine T.
  • Asymmetric catalytic oxyamination of recrys tallized trans stilbene, according to the method of the present invention, is represented in Figure 2.
  • the present method was used to produce intermediates for the synthesis of homo- brassinolide and 24-epibrassinolide, which are known to exhibit the same biological activities as brassinolide.
  • These brass inosteroids show very potent plant-growth activity at hormonal level and access to these compounds in a large quantity can only be achieved by synthetic means.
  • h i ghly optically active diol was produced from the asymmetric dihydroxylation of ethyl trans-2-octenoate. This diol has been converted to optically pure ⁇ -lactam structure, which are well-known for their antibiotic activities:
  • N-Methylmorpholine N-Oxide (NMO, Aldrich 97%).
  • the bottle was capped, shaken for 30 seconds, cooled to 0-4oC using an ice-water bath.
  • OsO 4 (4.25 mL of a solution prepared using 0.120g OsO 4 /mL toluene; 0.002 Mol%; 0.002 eq.) was injected.
  • the bottle was shaken and placed in a refrigerator at ca. 4oC with occasional shaking. A dark purple color developed and was slowly replaced by a deep orange one; the heterogeneous reaction mixture gradually became homogeneous and at the end of the reaction, a clear orange solution was obtained.
  • the reaction can be conveniently monitored by TLC (silica gel; CH 2 Cl 2 ; disappearance of the starting material at a defined Rf).
  • the crude oil was dissolved in ethyl acetate (750 mL), extracted thiee times with 500 ml. portions of 2.0 M HCl, once with 2.0 M NaOH, dried over Na 2 SO 4 and concentrated in vacuo to leave 190 g (89%) of the crude diol as a pale yellow solid.
  • the aqueous layer was cooled to 0oC and treated with
  • the salt was suspended in 500mL of ethyl acetate, cooled to 0°C and treated with 28% NH 4 OH until pH-11 was reached. After separation, the aqueous layer was
  • the enantiomeric excess of the diol was determined by GLC analysis (5% phenyl-methylsilicone, 0.25 m film, 0317 mm diameter, 29 m long) of the derived bis-Mosher ester to be 70%.
  • Example 1 The procedure set out in Example 1 was followed, except that 1-phenylcyclohexene (1.0M) was substituted for trans-stilbene. The reaction was allowed to proceed for three days, after which only 40% conversion to the diol was obtained (8% ee).
  • Example 13 Asymmetric Dihydroxylation of trans- ⁇ - Methylstyrene in the presence of Boric Acid
  • the solvent was evaported under reduced pressure, and the residual oil was subjected to column chromatography on silica gel (5g, elution with hexaneethyl acetate, 2:1 v/v, R f 0.10) to afford 48.6 mg (70%) of the diol.
  • the enantiomeric excess of the diol was determined by HPLC analysis of the derived bis-acetate (Pirkle 1A column using 0.5% isopropanol/hexane mixture as eluant.
  • This example describes the enantioselectivity-ligand structure relationship of the 9-O-aryl DHQD ligands which explains the advantages of these new ligands.
  • 9-O-phenyl DHQD 2 is obviously a better ligand for aliphatic olefins, but not for aromatic olefins.
  • DHQD 4 exhibit much higher enantioselectivities for both aromatic and aliphatic olefins.
  • DHQD derivatives were next examined.
  • the structures of the 9-O-substituents of these DHQD derivatives and their enantioselectivities for the typical aliphatic and aromatic olefins, trans-5-decene and trans-stilbene are shown in Table 14.
  • Each structure in Table 14 is drawn with its expected spatial orientation in the reaction intermediate, osmate ester such that the more sterically hindering 6-methoxyquinoline moiety is on the left side of the structure
  • ⁇ -positions need to be C-H or larger for high ee's with aliphatic olefins.
  • DHQD dihydroquinidine
  • phenanthryl ether derivative 4a is greatly superior to 1a for a wide range of substrates. The improvement is especially dramatic for transdisubs tituted aliphatic olefins such as 5-decene (entry 1) as well as for
  • the reaction can be successfully carried out at 0°C with a significant improvement of enantioselectivity especially for terminal olefins (entries 1,3 and 7).
  • N-methyl-N-phenylcarbamoyl chloride (1.6 g, 9.4 mmol, 2.2 eq) was dissolved in 6 ml CH 2 Cl 2 and added to the
  • reaction mixture dropwise via an addition funnel.
  • the reaction mixture was stirred under N 2 for three days before reaching reaction completion.
  • 50 ml of 2N NaOH were added, and the phases were separated.
  • the CH 2 Cl 2 layer was saved, and the aqueous phase was extracted with 50 ml of CH 2 Cl 2 .
  • the CH 2 Cl 2 phases were combined and dried over MgSO 4 before being concentrated down to afford a gummy pink material. Purification via flash
  • DHQD-MPC dihydroquinidine methylphenylcarbamate
  • K 3 Fe(CN) 6 200 mg, 0.6 mmol, 3 equiv
  • K 2 CO 3 85 mg, 0.6 mmol, 3 equiv
  • osmium tetroxide was added in acetonitrile solution (0.5 M, 4 ⁇ l, 0.01 equiv) at room temperature.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

On décrit des procédés d'addition sur une oléfine, consistant à effectuer une catalyse par osmium. Selon le procédé de dihydroxylation asymétrique de la présente invention, une oléfine, un ligand chiral, un solvant organique, de l'eau, un oxydant et un composé contenant de l'osmium sont combinés. Selon le procédé d'oxyamination asymétrique de l'invention, une oléfine, un ligand chiral, un solvant organique, de l'eau, un dérivé de métallo-chloramine, un composé contenant de l'osmium et, éventuellement, un composé d'ammonium tétra-alkyle sont combinés. Selon un troisième procédé de diamination asymétrique, une oléfine, un ligand chiral, un solvant organique, un dérivé de métallo-chloramine, une amine et un composé contenant de l'osmium sont combinés. Selon un mode de réalisation, une oléfine, un ligand chiral composé d'un dérivé de dihydroquinidine polymère ou un dérivé de dihydroquinine, de l'acétone, de l'eau, une base, un oxydant, et un tétroxyde d'osmium sont combinés afin d'effectuer la dihydroxylation asymétrique de l'oléfine.
PCT/US1992/003940 1991-05-13 1992-05-08 Ligands chiraux heterocycliques et procede de dihydroxylation asymetrique et catalytique d'olefines Ceased WO1992020677A1 (fr)

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US5491237A (en) * 1994-05-03 1996-02-13 Glaxo Wellcome Inc. Intermediates in pharmaceutical camptothecin preparation
WO1997046557A1 (fr) * 1996-06-05 1997-12-11 Wolfgang Lindner Selecteurs chiraux a base de cinchonane, destines a la separation de stereo-isomeres
WO1998035927A1 (fr) * 1997-02-14 1998-08-20 The Scripps Research Institute Ligands alcaloides lies a du polyethyleneglycol et utilisation de ces derniers
US6559309B2 (en) 1996-11-01 2003-05-06 Osi Pharmaceuticals, Inc. Preparation of a camptothecin derivative by intramolecular cyclisation
US6646102B2 (en) 2001-07-05 2003-11-11 Dow Global Technologies Inc. Process for manufacturing an alpha-dihydroxy derivative and epoxy resins prepared therefrom
WO2012116945A2 (fr) 2011-02-28 2012-09-07 Boehringer Ingelheim Rcv Gmbh & Co Kg Séparation en phase liquide d'isoformes et de topoisomères d'un adn plasmidique
US8987504B2 (en) 2010-06-18 2015-03-24 Victoria Link Limited Aminohydroxylation of alkenes
CN110642856A (zh) * 2019-10-21 2020-01-03 河南科技大学 二氢奎尼丁类化合物及其制备方法和应用、植物源杀虫剂

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WO2014148591A1 (fr) * 2013-03-21 2014-09-25 国立大学法人名古屋大学 Procédé de production d'un composé de 1,2-diol

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6462196B1 (en) 1994-05-03 2002-10-08 Osi Pharmaceuticals, Inc. Preparation of a camptothecin derivative by intramolecular cyclization
US5840898A (en) * 1994-05-03 1998-11-24 Glaxo Wellcome, Inc. Method of removing heavy metal contaminants from organic compounds
US6063923A (en) * 1994-05-03 2000-05-16 Glaxo Wellcome Inc. Preparation of a camptothecin derivative by intramolecular cyclisation
US5491237A (en) * 1994-05-03 1996-02-13 Glaxo Wellcome Inc. Intermediates in pharmaceutical camptothecin preparation
US6313247B1 (en) 1996-06-05 2001-11-06 Wolfgang Lindner Cinchonan based chiral selectors for separation of stereoisomers
WO1997046557A1 (fr) * 1996-06-05 1997-12-11 Wolfgang Lindner Selecteurs chiraux a base de cinchonane, destines a la separation de stereo-isomeres
US6821982B2 (en) 1996-11-01 2004-11-23 Osi Pharmaceuticals, Inc. Preparation of a camptothecin derivative by intramolecular cyclisation
US6559309B2 (en) 1996-11-01 2003-05-06 Osi Pharmaceuticals, Inc. Preparation of a camptothecin derivative by intramolecular cyclisation
WO1998035927A1 (fr) * 1997-02-14 1998-08-20 The Scripps Research Institute Ligands alcaloides lies a du polyethyleneglycol et utilisation de ces derniers
US7049388B2 (en) 2001-07-05 2006-05-23 Dow Global Technologies Inc. Process for manufacturing an α-dihydroxy derivative and epoxy resins prepared therefrom
US6646102B2 (en) 2001-07-05 2003-11-11 Dow Global Technologies Inc. Process for manufacturing an alpha-dihydroxy derivative and epoxy resins prepared therefrom
US8987504B2 (en) 2010-06-18 2015-03-24 Victoria Link Limited Aminohydroxylation of alkenes
WO2012116945A2 (fr) 2011-02-28 2012-09-07 Boehringer Ingelheim Rcv Gmbh & Co Kg Séparation en phase liquide d'isoformes et de topoisomères d'un adn plasmidique
CN110642856A (zh) * 2019-10-21 2020-01-03 河南科技大学 二氢奎尼丁类化合物及其制备方法和应用、植物源杀虫剂

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