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WO1998035927A1 - Ligands alcaloides lies a du polyethyleneglycol et utilisation de ces derniers - Google Patents

Ligands alcaloides lies a du polyethyleneglycol et utilisation de ces derniers Download PDF

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Publication number
WO1998035927A1
WO1998035927A1 PCT/US1997/002442 US9702442W WO9835927A1 WO 1998035927 A1 WO1998035927 A1 WO 1998035927A1 US 9702442 W US9702442 W US 9702442W WO 9835927 A1 WO9835927 A1 WO 9835927A1
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Prior art keywords
reaction
dihydroquinidine
ligand
dihydroquinine
hydroxylation
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PCT/US1997/002442
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English (en)
Inventor
Kim D. Janda
Hyunsoo Han
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Scripps Research Institute
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Scripps Research Institute
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Priority to PCT/US1997/002442 priority Critical patent/WO1998035927A1/fr
Priority to AU22754/97A priority patent/AU2275497A/en
Publication of WO1998035927A1 publication Critical patent/WO1998035927A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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

Definitions

  • the present invention relates to ligand-accelerated catalytic (LAC) Sharpless asymmetric dihydroxylation reactions (AD) of olefins. More particularly, the present invention relates to polyethylene glycol (PEG) bound alkaloid ligands employable in the ligand- accelerated catalytic (LAC) Sharpless asymmetric dihydroxylation reaction (AD) of olefins and to their synthesis and use.
  • LAC ligand-accelerated catalytic
  • AD asymmetric dihydroxylation reaction
  • Insolubility can limit the range of substrates and/or the polymer-bound reagent/catalysts utility.
  • Insolubility can cause the reagent/catalyst reactivity to behave somewhat differently than its soluble (solution) counterpart.
  • LPCS polyethylene glycol monomethyl ether
  • LAC ligand-accelerated catalytic
  • AD asymmetric dihydroxylation
  • soluble polymer-bound ligand which provides all the advantages that an insoluble support can offer including ease of product separation and polymer-bound ligand recover/ reusability while also being as effective as a free ligand both in reactivity and selectivity. Furthermore, the new soluble polymer bound-ligand system should be applicable to other classes of AD ligands for improved enantioselectivity as well as other enantioselective catalytic processes.
  • the invention relates to polyethylene glycol monomethyl ether-bound alkaloid ligands (termed liquid phase ligands) which are constructed and employed in the ligand-accelerated catalytic (LAC) Sharpless asymmetric dihydroxylation reaction (AD) with a range of olefins.
  • LAC ligand-accelerated catalytic
  • AD Sharpless asymmetric dihydroxylation reaction
  • soluble polymer-bound ligands are much more efficient than the corresponding insoluble polymer-bound ligands both in reactivity and selectivity in AD reactions.
  • these chiral homopolymers provide the same enantioselectivity and reactivity as free ligands in solution.
  • the polymer serves as a scaffold allowing simple product separation, polymer-bound ligand recovery, and recycling of the chiral liquid phase support without a loss of catalytic activity.
  • PEG bound alkaloid ligand includes a polyethylene glycol which is soluble in aqueous medium and precipitable in aqueous/ether medium, and an alkaloid ligand coupled to the polyethylene glycol.
  • Preferred alkaloid ligands are selected from the following group, viz.:
  • the above alkaloid ligands are coupled to said polyethylene glycol by a linkage selected from the group consisting of ester linkage, amide linkage, thoester linkage, ester linkage, thiether linkage, and sulphone linkage.
  • a linkage selected from the group consisting of ester linkage, amide linkage, thoester linkage, ester linkage, thiether linkage, and sulphone linkage.
  • PEG bound alkaloid ligand are represented by the following structures:
  • the process is of the type which includes a step for admixing, within a reaction medium, an olefin, an oxidizing agent, a catalyst for catalyzing the hydroxylation reaction, and an alkaloid ligand for accelerating the catalysis of the hydroxylation reaction.
  • the process is improved by the use of a PEG bound alkaloid ligand.
  • the PEG bound alkaloid ligand is soluble in the reaction medium and precipitable in a precipitation medium.
  • the hydroxylation reactions are asymmetric dihydroxylation reaction and the PEG bound alkaloid ligand is chiral.
  • a preferred oxidizing agent is a mixture which includes V- CNK footassium ferricvanide III). CH,SO.NH. (methanesulfonamide) , 0s0 4 and K 2 C0 3 (potassium carbonate) .
  • Another preferred oxidizing agent is a mixture which includes methyl orpholine W-oxide (NMO) , tetraethylammonium acetate tetrahydrate, and 0s0 4 .
  • the preferred catalyst is 0s0 4 .
  • Preferred reaction media are acetone/water or butanol/water.
  • Preferred precipitation media include the addition of diethyl ether or cold ethanol to the reaction media.
  • Another aspect of the invention is directed to a process for catalyzing an hydroxylation reaction.
  • an olefin, an oxidizing agent, a catalyst for catalyzing the hydroxylation reaction, and an alkaloid ligand for accelerating the catalysis of the hydroxylation reaction are admixed in a reaction medium.
  • the admixture occurs in a reaction medium under reaction conditions for producing an hydroxylation product.
  • a precipitation medium is admixed with the reaction medium of the first step for precipitating the PEG bound alkaloid ligand.
  • the precipitated PEG bound alkaloid ligand of the second step is separated from the hydroxylation product so as to recover the PEG bound alkaloid ligand.
  • the hydroxylation reaction in the first step is an asymmetric dihydroxylation reaction and the PEG bound alkaloid ligand is chiral.
  • Another aspect of the invention is directed to a further process for catalyzing an hydroxylation reaction.
  • one or more reactants are admixed with a catalyst for catalyzing the hydroxylation reaction and with a PEG bound alkaloid ligand for accelerating the catalysis of the hydroxylation reaction.
  • the admixture occurs in a reaction medium under reaction conditions for producing an hydroxylation product.
  • a precipitation medium is admixed the reaction medium of of the first step for precipitating the PEG bound alkaloid ligand.
  • the hydroxylation product of the second step is separated B from the precipitated PEG bound alkaloid ligand for obtaing purified product.
  • the hydroxylation reaction is an asymmetric dihydroxylation reaction and the PEG bound alkaloid ligand is chiral.
  • Figure 1 illustrates a prior art alkaloid ligand, i.e. compound 1, a PEG radical, i.e., compound 4, alkaloid ligand coupled to a linkage unit, i.e. compound 3, and a PEG bound alkaloid ligand, i.e., compound 2.
  • Figure 2 illustrates the synthesis of ligands 2 and 3 with the following conditions: (a) TEA, DMAP, glutaric anhydride (60 %) ; (b) DCC, DMAP, ROH (95 %) .
  • Figure 3 illustrates the comparison of catalytic asymmetric hydroxylations using compound 1-4.
  • the indicated notations are as follows: (a) see Petri et al. Chirality 1995, 7, 580 for experimental details; (b) results from Petri et al. Chirality 1995, 7, 580; ligand 2 , which was recovered from entry 3 , was recycled a total of four times; (d) for the purpose of comparison, the reaction was stopped after 5 hours (e) slow addition time of olefin.
  • Figure 4 illustrates polymer-bound trajis-cinnamate esters 7-11 for the Sharpless AD reaction.
  • Figure 5 illustrates the reaction in which trans- cinnamic acid was immobilized to the four polymeric supports 7-11 (figure 4) and the reactivity of 7-11 was demonstrated by using the ligands 13 and 14 for the Sharpless AD reaction.
  • Figure 6 tabulates various AD reactions conducted upon various polymer bound trans-cinnamate esters using the ligands 13 and 14.
  • Figure 7 illustrates the chemical synthesis of ligands 20 and 14.
  • Figure 8 tabulates various catalytic Asymmetric Dihydroxylation Reactions using Ligand 14.
  • DHQD free ligand
  • the invention is directed to the synthesis and use of polyethylene glycol monomethyl ether-bound cinchona alkaloid ligands in the ligand-accelerated catalytic (LAC) Sharpless asymmetric dihydroxylation reaction (AD) with a range of olefins.
  • LAC ligand-accelerated catalytic
  • AD Sharpless asymmetric dihydroxylation reaction
  • Example 1 Synthesis and Exemplary use of Polyethylene glycol monomethyl ether-bound cinchona alkaloid ligands in the AD reaction
  • alkaloid ligands include the following:
  • 2-naphthoy1-dihydroquinidine 2-naphthoy1-dihydroquinidine; cyclohexanoyl dihydroquinidine; p-phenylbenzoyl dihydroquinidine; dimethylcarbamoyl dihydroquinidine; benzoyl dihydroquinine;
  • alkaloid ligands represented by the following structures:
  • Reaction conditions which cover temperature, substrate equivalents, reaction time(s) , work-up (s) and buffer solutions (pH levels) may vary, depending on the substrate used, however all proportions are annroximatelv the same.
  • a representative orocedure is provided in the synthetic protocals.
  • the chiral homopolymer 2 was the archetype used to examine and compare all of the AD reactions investigated.
  • we used the same conditions as reported for the ligand 1- AD catalytic reaction (Kim et. al. Tetrahedron Lett. 1990, 31, 3003).
  • the reaction is complete within the same time frame as that of its solution counterpart with no decrease of yields or enantioselectivity as tablutated in Figure 3.
  • product isolation, separation, and recovery of the polymer bound ligand must be straightforward and reliable.
  • the entire mixture was diluted with methylene chloride, dried (anhydrous sodium sulfate) and filtered.
  • MeO-PEG-bound ligand typically, the MeO- PEG-bound ligand was recovered in >98 % yield.
  • the filtrate contained the dihydroxylated product.
  • MeO-PEG-bound ligand 2 was as effective as free ligand 3 (compare entries 2 and 4, entries 6 and 7, entries 8 and 9, and entries 10 and 11) .
  • entries 2 and 4, entries 6 and 7, entries 8 and 9, and entries 10 and 11 were suggest that the MeO-PEG back-bone does not influence or affect the observed asymmetric induction (entry 5) .
  • these findings provide direct support for our notion that for successful polymer-bound LAC all components involved in the reaction must be able to interact freely with each other in solution.
  • a process has been invented which demonstrates how a chiral ligand can be integrated into a soluble polymeric species so that LAC can operate in an unhindered manner on a polymer support.
  • the soluble polymer-bound ligand provides all the advantages that an insoluble support can offer, while also being as effective as a free ligand both in reactivity and selectivity.
  • This new soluble polymer bound-ligand system should be applicable to other classes of AD ligands for improved enantioselectivity (Kolb et al. Chem. Rev. 1994, 116, 2483) as well as other enantioselective catalytic processes (Takaya et al. J. Am. Chem. Soc.
  • the MeO-PEG polymer will not only be useful to the research chemist but also for effecting the separation of catalyst from product in homogeneous industrial applications (Steckhan et al. Angew. Chem. Int. Ed.
  • Trans-cinnamic acid was immobilized to the four polymeric supports ( Figure 4) .
  • This format insured that all supports would have an olefin tethered as an ester with the composition of the polymer determining the overall reactivity.
  • ethyl trans-cinnamate (11) is a documented substrate for the AD reaction using the ligand 1,4-phthalazinediyldiether hydroquinidine [ (DHQD) 2 PHAL, 14, Figure 5] Sharpless et al. Org. Chem . 1992, 57, 2768-2771, a direct correlation could be made between solution and polymeric reactions.
  • Figure 6 shows that the resins structural make-up is the dominant factor influencing the AD reaction.
  • example 2 demonstrates that multipolymeric reactions should be applicable in the automation of organic synthesis.
  • Example 3 PEG Approach to the Sharpless Catalytic Asymmetric Dihydroxylation TAD) using a [ (DH0D)2PHAL-PEG-QMg] Ligand.
  • a homogeneous extention to the AD reaction using a soluble polymer, poly(ethylene glycol) monomethyl ether (MeO-PEG) , bound cinchona alkaloid ligand (Han et al. J . Am . Chem . Soc . 1996, 118 , 7633).
  • This liquid-phase methodology (Han et al. J . Am . Chem . Soc .
  • Figure 7 In the first step, a mixture of dihydroquinidine, 1, 4-dichlorophthalazine, KOH, and K 2 C0 3 in dry toluene are refluxed, with a concurrent azeotropic removal of water, to give the mono- substituted chlorophthalazine 17 which upon similar transformation with quinidine provided the di- substituted phthalazine 18 (Amberg et al. J. Org . Chem . 1993, 58 , 844; Lohray et al. Tet . Lett . 1994, 35 , 6559).
  • the insoluble urea side-product was removed by filtration and the pegylated ligand 20 was isolated from the reaction mixture by precipitation following a slow addition of diethyl ether.
  • the sulfide 20 was oxidized to the desired sulfone 14 by a mixture of Os04/W-methylmorpholine-W- oxide (NMO) [in acetone/water (v/v, 2/1)] (Kaldor et al. Tetrahedron . Lett . 1991, 32 , 5043).
  • NMO Os04/W-methylmorpholine-W- oxide
  • Ligand 14 was completely soluble either in t- butanol/water or acetone/water solvent systems allowing the study of homogeneous AD reactions.
  • the AD reaction results of 14 with various olefins are shown in Figure 8 and a number of features are noteworthy. First, it is evident that the t-Butanol/water solvent produces considerably higher ees for all olefins tested consistent with previous reports (Pini et al.
  • Dihydroquinidine hydrochloride 5 (0.500 g, 1.38 mmol; Aldrich) dissolved in methylene chloride was neutralized by the slow addition of triethylamine (0.140 g, 1.38 mmol) at 4 °C. This was followed by the addition of 4-(W,W- dimethyl) aminopyridine (0.170 g, 1.39 mmol) in methylene chloride. To this reaction mixture was slowly added glutaric anhydride (0.315 g, 2.76 mmol). The reaction temperature was raised to room temperature, and the reaction mixture was stirred for an additional 2 h.
  • the olefin (4 eq. relative to the polymer ligand) was added either in one portion or by a slow addition.
  • the reaction mixture was stirred at 4 °C until the olefin disappeared as judged by TLC.
  • solid sodium metabisulfate (0.500 g) was added, and the mixture was stirred for an additional 5 min, then diluted with methylene chloride (10 ml) and dried over Na 2 S0 4 . All solids were removed by filtration and washed three times with methylene chloride (3 x 5 ml) .
  • the combined filtrates were evaporated to half volume and diethyl ether was slowly added to the mixture under vigorous stirring conditions.
  • 2-naphthoy1-dihydroquinidine 2-naphthoy1-dihydroquinidine; cyclohexanoyl dihydroquinidine; p-phenylbenzoyl dihydroquinidine; dimethylcarbamoyl dihydroquinidine; benzoyl dihydroquinine; 4-methoxybenzoyl dihydroquinine;
  • acetone/water solvent and methylmorpholine W-oxide were used.
  • the reaction mixture contained a small aliquot of 0s0 ⁇ in t-butanol (0s0 4 2.5 wt % solution, 13 ⁇ l, 0.01 eq. relative to the olefin), the ligand (0.0025 g, 0.025 eq.), 4-methylmorpholine W-oxide (0.022 g, 1.5 eq.), and tetraethylammonium acetate tetrahydrate (0.033 g, 1.0 eq.) in acetone-water (10/1, v/v, 4 ml) at 4 °C.
  • ligand acids may be obtained for the following alkaloids:
  • ligand acids may be obtained for the following alkaloids: dimethylcarbamoyl dihydroquinidine; benzoyl dihydroquinidine;
  • 3-methoxybenzoyl dihydroquinidine 2-naphthoy1-dihydroquinidine; cyclohexanoyl dihydroquinidine; p-phenylbenzoyl dihydroquinidine; dimethylcarbamoyl dihydroquinidine; benzoyl dihydroquinine; 4-methoxybenzoyl dihydroquinine;
  • ligand acids may be obtained for the following alkaloids: acrylonitrile co-polymer of 9- (4- chlorobenoyloxy) -quinidine; acrylonitrile co-polymer of 11- ( (2- acryloyloxy) ethyl-sulfinyl) -9- (4- chlorobenoyloxy) -10, 11-dihydroquinidine; acrylonitrile co-polymer of 11- [2- acryloyloxy)ethylsulfonyl]-9-(N,N- dimethylcarbamoyl) -10, 11-dihydroquinidine; and acrylonitrile co-polymer of 9-
  • K 3 Fe(CN) 6 (0.250 g, 6 eq. relative to the olefin), K 2 C0 3 (0.052 g, 3 eq.), methanesulfonamide (0.012 g, 1 eq.), and the PEG-bound alkaloid ligand 14 (0.025-0.25 eq.) or any of the PEG-bound alkaloid ligands described above, in t-butanol-water (1/1, v/v, 4 ml) at room temperature. After stirring for 10 min, the olefin substrate (0.125 mmol, 1 eq.was added in one portion.
  • Permissible substrates include all classes of primary, secondary, tertiary and quaternary substituted olefins described in the prior art for the AD reaction.
  • the reaction mixture was stirred for 24 hours.
  • the reaction mixture was stirred at 4°C or room temperature until the olefin disappeared as judged by TLC.
  • solid sodium metabisulfate (0.500 g) was added, and the mixture was stirred for an additional 5 min, then diluted with methylene chloride (10 ml) and dried over Na 2 S0 4 . All solids were removed by filtration and washed three times with methylene chloride (3 x 5 ml) .
  • the combined filtrates were evaporated to half volume and diethyl ether was slowly added to the mixture under vigorous stirring conditions.

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des ligands alcaloïdes liés à de l'éther mono-méthylique de polyéthylèneglycol (ligands alcaloïdes liés à du polyéthylèneglycol). Ces ligands sont construits et utilisés dans la réaction de dihydroxylation asymétrique catalytique accélérée par des ligands de Sharpless. Le polyéthylèneglycol sert de structure pour permettre la séparation de produits simple, la récupération de ligands liés à des polymères, et le recyclage du support de phase liquide chiral sans perte de l'activité catalytique ou de l'accélération par les ligands.
PCT/US1997/002442 1997-02-14 1997-02-14 Ligands alcaloides lies a du polyethyleneglycol et utilisation de ces derniers Ceased WO1998035927A1 (fr)

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PCT/US1997/002442 WO1998035927A1 (fr) 1997-02-14 1997-02-14 Ligands alcaloides lies a du polyethyleneglycol et utilisation de ces derniers
AU22754/97A AU2275497A (en) 1997-02-14 1997-02-14 Peg-bound alkaloid ligands and use thereof

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6646102B2 (en) 2001-07-05 2003-11-11 Dow Global Technologies Inc. Process for manufacturing an alpha-dihydroxy derivative and epoxy resins prepared therefrom
US7531662B2 (en) * 2003-06-11 2009-05-12 Brandeis University Cinchona-alkaloid-based catalysts, and asymmetric alcoholysis of cyclic anhydrides using them

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992020677A1 (fr) * 1991-05-13 1992-11-26 Massachusetts Institute Of Technology Ligands chiraux heterocycliques et procede de dihydroxylation asymetrique et catalytique d'olefines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992020677A1 (fr) * 1991-05-13 1992-11-26 Massachusetts Institute Of Technology Ligands chiraux heterocycliques et procede de dihydroxylation asymetrique et catalytique d'olefines

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
J. AM. CHEM. SOC., January 1996, Vol. 118, No. 2, COREY et al., "Kinetic Investigations Provide Additional Evidence that an Enzyme-Like Binding Pocket is Crucial for High Enantioselectivity in the Bis-Cinchona Alkaloid Catalyzed Asymmetric Dihydroxylation of Olefins", pages 319-329. *
SONG et al., "Polymeric Cinchona Alkaloids for the Heterogeneous Catalytic Asymmetric Dihydroxylation of Olefins: The Influence of the Polymer Backbone Polarity on the Compatibility Between Polymer Support and Reaction Medium", November 1995, Vol. 6, No. 11, pages 2687-2694. *
TETRAHEDRON: ASYMMETRY, November 1995, Vol. 6, No. 11, ZHANG et al., "Nonlinear Effects Involving Two Competing Pseudo-Enantiomeric Catalysts: Example in Asymmetric Dihydroxylation of Olefins", pages 2637-2640. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6646102B2 (en) 2001-07-05 2003-11-11 Dow Global Technologies Inc. Process for manufacturing an alpha-dihydroxy derivative and epoxy resins prepared therefrom
US7049388B2 (en) 2001-07-05 2006-05-23 Dow Global Technologies Inc. Process for manufacturing an α-dihydroxy derivative and epoxy resins prepared therefrom
US7531662B2 (en) * 2003-06-11 2009-05-12 Brandeis University Cinchona-alkaloid-based catalysts, and asymmetric alcoholysis of cyclic anhydrides using them

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