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WO2005054429A2 - Synthese du synthon ceto-acide en c1-c6 des epothilones - Google Patents

Synthese du synthon ceto-acide en c1-c6 des epothilones Download PDF

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WO2005054429A2
WO2005054429A2 PCT/US2004/038811 US2004038811W WO2005054429A2 WO 2005054429 A2 WO2005054429 A2 WO 2005054429A2 US 2004038811 W US2004038811 W US 2004038811W WO 2005054429 A2 WO2005054429 A2 WO 2005054429A2
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alkyl
formula
compound
intermediate compound
alkylamines
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WO2005054429A3 (fr
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Mitchell A. Avery
Yansong Zheng
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The University Of Mississippi
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    • 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
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
    • C07C45/66—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups by dehydration
    • 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
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/04—Saturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/17—Saturated compounds containing keto groups bound to acyclic carbon atoms containing hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/713—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups a keto group being part of a six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/26—Radicals substituted by doubly bound oxygen or sulfur atoms or by two such atoms singly bound to the same carbon atom

Definitions

  • the present invention relates to the synthesis of chemical compounds useful in the formation of epothilones. More specifically, the present invention is directed to methods for synthesizing chemical precursor compounds for use in epothilone synthesis. The present invention is also directed to chemical compounds and intermediates formed through the methods of the present invention.
  • epothilones A-D have evoked strong interest from the scientific community because of their anticancer activity.
  • paclitaxel taxol
  • MDR multiple drug resistance
  • one strategy for the total synthesis of epothilones includes construction of a C1-C6 synthon, such as a keto-acid of formula: which undergoes aldol condensation with an aldehyde to set important stereochemical features of the epothilone architecture.
  • a C1-C6 synthon such as a keto-acid of formula: which undergoes aldol condensation with an aldehyde to set important stereochemical features of the epothilone architecture.
  • One important stereochemical aspect of the C1-C6 synthon in particular is the 3S stereochemistry of the OX group, where X can be H or a protecting group, such as the tert- butyldimethylsilyl, t-BuMe 2 Si, or ether.
  • keto-acid synthons useful in the synthesis of epothilones and analogs and derivatives thereof.
  • the method of producing keto-acid synthons according to the present invention comprises performing an aldol condensation of a first aldehyde of this general formula:
  • R-i R2 with a carbonyl compound in the form of a ketone or a second aldehyde having a generalized formula:
  • the first aldehyde may have any of the following four formulas:
  • the carbonyl compound may be either a ketone or aldehyde.
  • the carbonyl compound is a ketone having the formula
  • the first compound Upon aldol condensation of the first aldehyde with the carbonyl compound, the first compound is formed.
  • the conversion of this first compound to the protected keto- acid synthon may be accomplished by forming at least one intermediate compound.
  • a first exemplary embodiment of the present invention contemplates aldol condensation of the first aldehyde with the carbonyl compound that is a ketone to ultimately form a protected keto-acid synthon through various routes. Additionally, the present invention contemplates a second alternative embodiment where aldol condensation of the first aldehyde occurs with an aldehyde to ultimately form a protected keto-acid synthon.
  • One route includes performing an aldol condensation of a first aldehyde of formula:
  • Catalyzed cyclization of the first compound may thereafter be performed to form a respective first intermediate compound having a formula:
  • the hydroxyl group of the first intermediate compound may then be protected with a protecting group, R 8 , to form a respective second intermediate having a formula:
  • oxidative cleavage of the second intermediate may then be performed to form the respective protected keto-acid synthon having a formula:
  • the respective diastereomers of the first compound formed by the aldol condensation of the first aldehyde and carbonyl compound may also be formed.
  • the respective diastereomers of the first compound have the formulas:
  • These diastereomers may similarly be converted to the protected keto-acid synthon by first performing catalyzed cyclization of these diastereomers to form a respective first intermediate compound having a formula:
  • the hydroxyl group of the respective first intermediate compounds may then be protected with a protecting group, R 8 , to form a respective second intermediate having a formula:
  • oxidative cleavage of the second intermediate may then be performed to form the respective protected keto-acid synthon having a formula:
  • a second route, with respect to the first exemplary embodiment of the present invention comprises performing an aldol condensation of a first aldehyde that is a ketal aldehyde of formula:
  • the hydroxyl group of the first compound may then be protected with a protecting group, Re, to form a respective first intermediate compound having the formula:
  • Oxidation and deketalization of the first intermediate compound may then be performed to form a respective protected keto-acid having the formula:
  • the step of oxidation and deketalization may include a first step of performing oxidation of the first intermediate compound thereby to form a resepctive second intermediate compound having the formula:
  • the respective diastereomers of the first compound may also be formed by the aldol condensation according to the second route.
  • the respective diasteromers of the first compound have the formulas:
  • Oxidation and deketalization of the first intermediate compound may then be performed to form the respective protected keto-acid synthon having the formula :
  • the oxidation and deketalization may include a first step of performing oxidation of the first intermediate compound thereby to form a respective second intermediate compound having the formula:
  • the first and second intermediate compounds formed during the method according to route 2 can be generally represented by the following respective formulas:
  • the respective hydroxyl groups of the first compound may then be protected with a protecting group, R 8 , to form a respective first intermediate compound having a formula:
  • the first intermediate compound may then be converted to a respective second intermediate compound having a formula:
  • deketalization of the second intermediate compound may be performed to form the respective protected keto-acid having a formula:
  • the diastereomers of the first compound formed according to the third route may be used to ultimately provide the protected keto-acid synthon.
  • the respective diastereomers of the first compound have the formulas:
  • the first intermediate compound may then be converted to a respective second intermediate compound having a formula:
  • first intermediate compound and the second intermediate compound which are formed according to the scheme of route three, can be represented with the following generalized formulas, respectively:
  • a fourth route provides a further method for producing a keto-acid synthon useful in the synthesis of epothilones and analogs and derivatives thereof, comprising performing an aldol condensation of an olefinic-aldehyde of formula:
  • the respective hydroxyl groups of the first compound may then be protected with a protecting group, R 8 to form a respective intermediate compound having a formula:
  • Dual oxidative cleavage of the double bonds of the intermediate compound may then be performed to form the respective protected keto-acid having a formula:
  • the diastereomers of the first compound formed according to the fourth route may be used to ultimately provide the protected keto-acid synthon.
  • the respective diastereomers the first compound have the formulas
  • Dual oxidative cleavage of the double bonds of the first intermediate compound may then be performed to form the respective protected keto-acid having a formula:
  • a fifth route, with respect to the first exemplary embodiment of the present invention, for producing a keto-acid synthon according to the present invention comprises performing an aldol condensation of a protected alcohol-aldehyde synthon of formula:
  • the respective hydroxyl groups of the first compound may then be protected with a protecting group, R 8 to form a respective first intermediate compound having a formula:
  • the first intermediate compound may then be converted to a respective second intermediate compound having a formula:
  • the second intermediate compound may then be deprotected and oxidized to form the respective protected keto-acid synthon of formula:
  • the diastereomers of the first compound formed according to the fifth route may also be used to ultimately provide the protected keto-acid synthon.
  • the respective diastereomers of the first compound formed by the fifth route have the formulas
  • the first intermediate compound may then be converted to a respective second intermediate compound having a formula:
  • the second intermediate compound may then be deprotected and oxidized to form the respected protected keto-acid synthon of formula:
  • the various compounds can be summarized with respective general formulas that serve as a representative for each compound and its diastereomer.
  • the first compound can be represented with the general formula:
  • first and second intermediate compounds can be represented by the following respective general formulas: first intermediate compound second intermediate compound
  • the conversion of the first intermediate compound to the second intermediate compound may be accomplished by haloform reaction, enol ether oxidation, or benzylidene ketone oxidation.
  • the step of enol ether oxidation may include enolization of the first intermediate compound to form an oxidizable silyl enol ether intermediate of formula:
  • the step of benzylidene ketone oxidation may include aldol condensation with benzaldehyde to form a respective benzylidene ketone of formula:
  • the diastereomers of the first compound formed according to the second exemplary embodiment of the present invention may also be used to ultimately provide the protected keto-acid synthon.
  • the respective diastereomers have the formulas
  • the various compounds associated with the scheme according to the second exemplary embodiment can be summarized with respective generalized formulas that serve as a representative for each compound and its diastereomer for the sake of clarity and simplicity. Accordingly, the step of crossed aldol condensation provides a first compound having the general formula:
  • the first compound may have a formula:
  • the aldol condensations may be performed in the presence of a catalyst, such as a chiral amine base, which may be D-proline or L-proline, or racemic proline, for example.
  • a catalyst such as a chiral amine base, which may be D-proline or L-proline, or racemic proline, for example.
  • the aldehydes may be reacted with the ketones in the presence of a solvent such as DMSO.
  • the ketone may specifically be 4-aryl but-3-ene-2-one, methyl ketone or acetone.
  • the catalyzed cyclization may be performed with a secondary amine, such as pyrrolidine, piperidene, or morpholine, in THF, benzene or other solvents.
  • the steps of protecting the hydroxyl group may be accomplished by reacting the second compound with R 8 X, imidazole and DMF at room temperature for a time period such as 72 hours.
  • the hydroxyl may be specifically protected with a tert-butyldimethylsilyl (TBS) protecting group, such that R 8 is t-BuMe 2 Si, or with other protecting groups as known in the art.
  • TBS tert-butyldimethylsilyl
  • the steps of oxidation/oxidative cleavage may be accomplished with RuCl 3 Nal0 ; or 03/Jones oxidation; or O 3 , low temperature, Me 2 S workup; or Ru0 .
  • the haloform reaction may be accomplished, for example, by Br 2 or l 2 /NaOH/Dioxane/H 2 0, 0°C.
  • the deketalization reactions may be performed, for example, by reaction with aqueous mineral acid in a suitable organic solvent such as tetrahydrofuran, or through other methods such as sequestering the alcohol corresponding to the ketalizing reagent.
  • the present invention is also directed to chemical compounds useful in the synthesis of epothilones and analogs and derivatives thereof and to methods for forming each of these chemical compounds, as illustrated in the individual steps of the above-described methods.
  • the chemical compounds of the present invention comprise compounds having formulas selected from:
  • the present invention provides a method for use in producing epothilones and analogs and derivatives thereof.
  • the method comprises performing an aldol condensation of a first compound having the formula:
  • Z is selected from and stereoisomers thereof, wherein R 1 -R 3 , R 5 and R 8 are as above and Rn-Ri ⁇ and R 18 are each individually selected from H, methyl, or optionally substituted n-alkyl, s- alkyl, t-alkyl, E or Z alkenyl, terminal alkenyl, alkynyl, aryl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, alkynylheteroaryl, cycloalkyl, alkylheterocyclic, alkenylheterocyclic, alkynylheterocyclic, heteroalkyl, heteroalkenyl, heteroalkynyl, primary alkylamines, secondary alkylamines, tertiary alkylamines, alkyl sulfides, alkylethers, hydroxyalkyls, alkylthi
  • R 1 R 2 , R 3 , Rn, R 13 , and R 4 may each specifically be methyl; R 5 and R 12 may each specifically be H; R 8 and R ⁇ 8 may each specifically be a TBS protecting group; and R 15 and R 16 may each specifically be a TBS or TMS protecting group.
  • Figure 1 is a diagram of an exemplary synthetic route for forming epothilones
  • Figure 2 is a diagram of a generalized reaction according to the present invention to produce a protected keto-acid synthon
  • Figure 3(a) is a diagram of chemical reaction Scheme l- ⁇ according to the present invention.
  • Figure 3(b) is a diagram of chemical reaction Scheme l- ⁇ according to the present invention.
  • Figure 4(a) is a diagram of chemical reaction Scheme ll- ⁇ according to the present invention.
  • Figure 4(b) is a diagram of chemical reaction Scheme I l- ⁇ according to the present invention.
  • Figure 5(a) is a diagram of chemical reaction Scheme lll- ⁇ according to the present invention.
  • Figure 5(b) is a diagram of chemical reaction Scheme 11 l- ⁇ according to the present invention.
  • Figure 6(a) is a diagram of chemical reaction Scheme IV- ⁇ according to the present invention.
  • Figure 6(b) is a diagram of chemical reaction Scheme IV- ⁇ according to the present invention.
  • Figure 7 is a diagram of an exemplary aldol condensation reaction according to the present invention.
  • Figure 8 is a diagram of an exemplary cyclization reaction according to the present invention.
  • Figure 9 is a diagram of an exemplary hydroxyl protection reaction according to the present invention.
  • Figure 10 is a diagram of an exemplary oxidative cleavage reaction according to the present invention.
  • Figure 11 (a) is a diagram showing an exemplary selective formation of enantiomers using D-Proline or L-Proline, and optional formation of diastereomers thereof;
  • Figure 11 (b) is a diagram showing an exemplary selective formation of the reverse enantiomers of Figure 10(a), and optional formation of diastereomers thereof;
  • Figure 11 (c) is a diagram showing an exemplary formation of a racemic mixture of the enantiomers of Figures 10(a) and 10(b) using racemic proline, and optional formation of diastereomers thereof;
  • Figure 12(a) is a diagram showing an exemplary synthesis of epothilones using a syn- ⁇ compound formed according to the methods of the present invention
  • Figure 12(b) is a diagram showing an exemplary synthesis of epothilones using an anti- ⁇ compound formed according to the methods of the present invention.
  • Figure 12(c) is a diagram showing an exemplary synthesis of epothilones using a syn- ⁇ compound formed according to the methods of the present invention
  • Figure 12(d) is a diagram showing an exemplary synthesis of epothilones using an anti- ⁇ compound formed according to the methods of the present invention.
  • Figure 13(a) is a diagram showing an alternative exemplary synthesis of epothilones using a syn- ⁇ compound formed according to the methods of the present invention
  • Figure 13(b) is a diagram showing an alternative exemplary synthesis of epothilones using an anti- ⁇ compound formed according to the methods of the present invention.
  • Figure 13(c) is a diagram showing an alternative exemplary synthesis of epothilones using a syn- ⁇ compound formed according to the methods of the present invention
  • Figure 13(d) is a diagram showing an alternative exemplary synthesis of epothilones using an anti- ⁇ compound formed according to the methods of the present invention.
  • Figure 14 is a diagram showing a generalized reaction scheme for forming the ketal starting compounds of Schemes ll- ⁇ and I l- ⁇ and Schemes lll- ⁇ and 11 l- ⁇ ;
  • Figure 15 is a diagram showing an exemplary synthesis of a ketal starting compound for use in Schemes ll- ⁇ and ll- ⁇ and Schemes lll- ⁇ and lll- ⁇ ;
  • Figure 16(a) is a diagram of chemical reaction Scheme V- ⁇ according to the present invention
  • Figure 16(b) is a diagram of chemical reaction Scheme V- ⁇ according to the present invention
  • Figure 17(a) is a diagram of chemical reaction Scheme Vl- ⁇ according to the present invention.
  • Figure 17(b) is a diagram of chemical reaction Scheme Vl- ⁇ according to the present invention.
  • Figure 18 is a diagram showing the stereoisomers resulting from the aldol condensation reactions of Figures 16(a) and (b) utilizing an enantiomerically pure protected alcohol aldehyde;
  • Figure 19 is a diagram of exemplary enol ether oxidations for use with Schemes lll- ⁇ and lll- ⁇ ;
  • Figure 20 is a diagram of exemplary benzylidene ketone oxidations for use with Schemes lll- ⁇ and lll- ⁇ ;
  • Figure 21 is a diagram of exemplary enol ether oxidations for use with Schemes Vl- ⁇ and Vl- ⁇ ;
  • Figure 22 is a diagram of exemplary benzylidene ketone oxidations for use with Schemes Vl- ⁇ and Vl- ⁇ .
  • the present invention provides new compounds useful in forming a C1-C6 keto-acid synthon for use in synthesizing epothilones and methods for forming these synthons.
  • epothilone compounds such as Epothilone A or Epothilone B may be synthesized by, in part, reacting a C1-C6 keto-acid synthon of the epothilone, or analogs or derivatives thereof, with another compound .
  • Such methods for synthesizing epothilones and related analogs and derivatives are described more thoroughly, for example, in U.S. Patent Application No. 09 981 ,312 entitled "Synthesis of Epothilones and Related Analogs" (U.S.
  • the present invention provides a method for constructing the key C-3 chiral center of such a keto-acid synthon.
  • Figure 2 shows a generalized method for forming the C1 -C6 keto-acid compound.
  • the method includes performing an aldol condensation of a first aldehyde with either a ketone or a second aldehyde, and further transformations of the product thereof so as to arrive at a keto-acid useful in the synthesis of epothilones.
  • the ordinarily skilled artisan will appreciate that the carbons numbered 2, 3 and 4 in Figure 2 are stereocenters such that numerous stereoisomers may be formed by the method of the present invention.
  • the 5 carbon is also a stereocenter, further increasing the number of possible stereoisomers.
  • Figures 3(a) and (b) through 6(a) and (b), and 17(a) and (b) provide several generalized reaction schemes (Schemes l- ⁇ through IV- ⁇ ; l- ⁇ through IV- ⁇ ; and Vl- ⁇ and Vl- ⁇ ) for forming the C1-C6 keto-acid synthon of the epothilones according to the present invention involving the aldol condensation of a ketone.
  • Figure 16(a) and (b) provide a generalized reaction scheme (Schemes V- ⁇ and V- ⁇ ) for forming the C1-C6 keto-acid synthon of the epothilones according to the present invention involving the aldol condensation of an aldehyde.
  • R- ⁇ through Rio in Figures 2, 3(a) and (b) through 6(a) and (b), 16(a) and (b) and 17(a) and (b) (Schemes l- ⁇ through Vl- ⁇ and l- ⁇ through Vl- ⁇ ) are each individually selected from H or optionally substituted n-alkyl, s-alkyl, t-alkyl, E ox Z alkenyl, terminal alkenyl, alkynyl, aryl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, alkynylheteroaryl, cycloalkyl, alkylheterocyclic, alkenylheterocyclic, alkynylheterocyclic, heteroalkyl, heteroalkenyl, heteroalkynyl, primary alkylamines, secondary alkylamines, tertiary alkylamines
  • acetals exist when R 9 and Rio are not connected to one another. Common acetals for a hindered system such as these would be a dimethylacetal. However, R g and Rio may be optionally connected to form cyclic ketals. For example, R g and R 10 may both be -CH 2 - and be connected through a single bond to specify a 1 ,3-dioxolane. This ketal, prepared from ethylene glycol, acid and the ketone, is commonly referred to as an ethylene ketal. In a number of embodiments, various ones of Ri through R 10 may each be H, methyl or protecting groups such as TBS or TMS.
  • the methods of the present invention involve the selective resolution of diastereomers through the use of either D-proline or L-proline to provide high enantiomeric excesses, as illustrated for example in Figures 11 (a) and (b).
  • the present invention provides either the syn-a or syn- ⁇ adducts having the desired 3S or 3R stereochemistry of the epothilones.
  • experimental observation is used to determine which stereoisomer is produced by each form of proline.
  • D-proline may produce the syn- product and L-proline the syn- ⁇ product for a given set of reactants of Formulas A and B.
  • L-proline may produce the syn- product and D-proline the syn- ⁇ product for a given set of reactants of Formulas A and B, depending upon the substituents thereof.
  • the enantiomers may be converted to their respective anti- ⁇ and anti- ⁇ diastereomers in the presence of LDA at room temperature.
  • use of racemic proline provides a racemic mixture of the enantiomers, which may each be further converted to their diastereomers in the presence of LDA at room temperature, as shown.
  • R 5 is H in the formulas of the present invention
  • the 2-carbon is not a stereocenter, such that the possible stereoisomers are then limited.
  • the formulas: are equivalent structures when R 5 is H, and both could be represented as formula:
  • keto-aldehyde A an ⁇ -substituted or unsubstituted aldehyde may be converted to its enamine by routine chemistry (See, Carey and Sundberg, Advanced Organic Chemistry, Book B, 3 rd Edition, 2001), and then trapped by an electrophilic acid chloride. Both aldehyde and acid chlorides are commercially available or made by routine methods known in the art. For the component ketone B, again, routine chemistry may be employed to prepare those that are not commercially available.
  • the present invention provides a generalized method for synthesizing a keto-acid for use in synthesizing epothilones, as follows.
  • acetone by direct aldol reaction under catalysis by a specific enantiomer of proline (either D-proline or L-proline) to form a first compound shown here as a diketoalcohol of formula:
  • the C syn- ⁇ enantiomer may be further converted to the C ant i- ⁇ diastereomer, if desired, in the presence of LDA at room temperature.
  • the other enantiomer of proline may be used to provide the C syn - ⁇ enantiomer or C an ti- ⁇ diastereomer, if desired.
  • the formation of the C an ti diastereomer may provide either a mixture of syn and anti aldol adducts, or syn adducts can be epimerized to anti by- warming, as addressed for example in "The Aldol Addition Reaction", Heathcock, Clayton H., Dep. Chem., Univ. California, Berkeley, CA, USA. Editor(s): Morrison, James D. Asymmetric Synth. (1984), 3, 111-212. Publisher: Academic, Orlando, Fla., which provides a general reference to syn-anti aldols, mixtures, interconversions, predictions and so on.
  • the various formulas for the diketoalcohol shown in Figures 3(a) and 3(b) can be collectively represented with the following general formula:
  • the Mosher ester was synthesized as follows: Into a flask, 2 (37.2 mmg, 0.2 mmol), R-(+)- ⁇ -methoxy- ⁇ -trifluromethylphenylacetic acid (MPTA, 56.2 mg, 0.24 mmol), DCC (53.6 mg, 0.26 mmol), DMAP (6.1 mg, 0.05 mmol) and dichloromethane (5 mL) were added in order. The mixture was stirred at room temperature for 24 hours and directly subjected to flash chromatography (silica gel, 40 % ethyl acetate in hexanes) to give the Mosher ester, which was analyzed by nmr for its enantiomeric purity.
  • MPTA R-(+)- ⁇ -methoxy- ⁇ -trifluromethylphenylacetic acid
  • DCC 53.6 mg, 0.26 mmol
  • DMAP 6.1 mg, 0.05 mmol
  • dichloromethane 5 mL
  • the first intermediate compound can be collectively represented with the general formula:
  • the second intermediate compounds can be collectively represented with the general formula:
  • the oxidative cleavage of the ether can be accomplished in a number of ways, such as RuCl3/Nal0 4 ; Os/Jones oxidation; 0 3 , low temperature, Me 2 S workup; or Ru0 4 , affording the target keto-acid synthon (a common C1-C6 synthon for total synthesis of the epothilones) of formula:
  • keto-acid synthon can be collectively represented with the general formula:
  • Exemplary starting compounds for use in the present invention further include compounds of Formula B in schemes l- ⁇ and l- ⁇ wherein R 5 is a thiomethyl, methyl or ether functionality (such as O-methyl, O-ethyl or the like). R may further be a vinyl group.
  • Formula B may be mesitylene oxide (4-methylpent-3-ene- 2-one).
  • ketone group of the aldehyde is protected as a ketal or acetal of some variety, of formula:
  • compounds of formula G can be formed indirectly by oxidative cleavage (for example, by 0 3 or catalytic Os0 4 , Nal0 4 , aqueous ethanol) of the terminal double bond of a ketalized ⁇ , ⁇ -disubstituted- ⁇ , ⁇ -unsaturated ketone, such as of formula:
  • Ketal formation normally can be done using ethylene glycol, benzene, and catalytic p-TSA with a Dean-Stark apparatus, as known in the art.
  • Various appropriate ketal protecting groups and their protection/deprotection procedures are described, for example, in Green et al., Protecting Groups in Organic Synthesis, cited above.
  • the first compound may optionally be converted to its respective diastereomer l an ti- a or l ant i- ⁇ in the presence of LDA at room temperature, as illustrated in Figures 4(a) and 3(b) and as described above with respect to Schemes l- ⁇ and l- ⁇ .
  • This aldol condensation may be performed under the same reaction conditions and utilizing the same reagents as given above for the aldol condensation step of Schemes l- ⁇ and l- ⁇ (for example, D-proline/DMSO/rt, 24hours).
  • the first compound shown illustrated in Figures 4(a) and 4(b) can be collectively represented with the general formula:'
  • the enone starting material H is again either easily prepared by those skilled in the art, or commercially available. Many low molecular weight enones are used as polymer monomers and a large industry exists in the synthesis of compounds such as methyl vinyl ketone, methyl acrylate, acrylic acid, acrylonitrile, and so on.
  • This hydroxyl protection may be performed under the same reaction conditions and utilizing the same reagents as given above for the hydroxyl protection step of Schemes l- ⁇ and l- ⁇ (for example, R 8 X/lmidazole/DMF/rt, 72 hours).
  • the first intermediate compound can be collectively represented with the general formula:
  • the second intermediate compound can be collectively represented with the general formula:
  • the oxidation of the second compound may be performed under the same reaction conditions and utilizing the same reagents as given above for the oxidative cleavage step of Schemes l- ⁇ and l- ⁇ (for example, RuCl 3 /Nal ⁇ 4 or Os/Jones oxidation, or RUO4).
  • Enones such as J S yn- ⁇ , Jsyn- ⁇ , Janti- ⁇ and/or Janti- ⁇ overoxidize upon ozonolysis or other oxidation conditions/reagents, leading to loss of the entire double bond and its substituents, and replacing the bond to the enone carbonyl with a hydroxyl group, thereby leaving a carboxylic acid at the position of the enone.
  • the deketalization step may be performed under conditions known in the art, such as using dilute aqueous mineral acid (such as 1 N HCI) in solvent such as THF and water, stirring at room temperature, or through other methods known in the art such as sequestering the alcohol corresponding to the ketalizing reagent (such as ethylene glycol in many cases shown herein).
  • dilute aqueous mineral acid such as 1 N HCI
  • solvent such as THF and water
  • sequestering the alcohol corresponding to the ketalizing reagent such as ethylene glycol in many cases shown herein.
  • the oxidation can be combined with the deketalization step to go directly from the second compound to the keto-acid in a one pot procedure.
  • This aldol condensation may be performed under the same reaction conditions and utilizing the same reagents as given above for the aldol condensation step of Schemes l- ⁇ and l- ⁇ (for example, D- proline/DMSO/rt, 24hours).
  • the diastereomers N an ti- ⁇ and Nanti- ⁇ may be formed in the presence of LDA at room temperature.
  • the first compound shown in Figures 5(a) and (b) can be collectively represented with the general formula:
  • This hydroxyl protection may be performed under the same reaction conditions and utilizing the same reagents as given above for the hydroxyl protection step of Scheme I (for example, R 8 X/lmidazole/DMF/rt, 72 hours).
  • the first intermediate compound can be collectively represented with the formula:
  • the first intermediate compound may be subjected to a haloform reaction to convert the methyl ketone to a carboxylic acid.
  • a haloform reaction to convert the methyl ketone to a carboxylic acid.
  • the first intermediate compound undergoes the haloform reaction cleanly providing a second intermediate compound of formula K S y n- ⁇ or K an ti- ⁇ ; or for the other enantiomer of proline, K syn - ⁇ or K anti-P :
  • the haloform reaction may be performed under conditions known in the art, such as a bromoform reaction (for example, Br 2 /NaOH/Dioxane/H 2 0, 0°C) or an iodoform reaction (for example, l 2 /NaOH/Dioxane/H 2 0, 0°C).
  • a bromoform reaction for example, Br 2 /NaOH/Dioxane/H 2 0, 0°C
  • an iodoform reaction for example, l 2 /NaOH/Dioxane/H 2 0, 0°C.
  • the second intermediate compound can be collectively represented with the general formula:
  • FIGS 19 and 20 Two alternatives to the haloform reaction are shown in Figures 19 and 20.
  • enolization of the first intermediate compound to form an oxidizable silyl enol ether intermediate for example, TBSOTf/Et 3 N/CH 2 CI 2 , -78 °C to room temperature, see Tetrahedron. Lett., 1984, 5953
  • oxidizable silyl enol ether intermediate for example, TBSOTf/Et 3 N/CH 2 CI 2 , -78 °C to room temperature, see Tetrahedron. Lett., 1984, 5953
  • aldol condensation of the first intermediate compound with benzaldehyde to form a benzylidene ketone for example, DBU/THF, room temperature
  • oxidation also forms the second intermediate compound.
  • the third compound only requires deketalization to arrive at the keto-acid products of formula F sy n- ⁇ , F an ti- ⁇ > F syn - ⁇ , or Fan t i- ⁇ , respectively.
  • the deketalization step may be performed as described above with respect to Schemes ll- ⁇ and I l- ⁇ (for example, 1 N HCI/THF/H 2 0, r.t.). IV. Schemes IV- ⁇ and IV- ⁇
  • This hydroxyl protection may be performed under the same reaction conditions and utilizing the same reagents as given above for the hydroxyl protection step of Schemes l- ⁇ and l- ⁇ (for example, R 8 X/lmidazole/DMF/rt, 72 hours).
  • the intermediate compound can be collectively represented with the general formula:
  • the oxidative cleavage may be performed under the same reaction conditions and utilizing the same reagents as given above for the oxidative cleavage step of Scheme I (for example, RuCl3/Nal0 4 or Os/Jones oxidation, or Ru0 4 ) or for oxidation of the complex enone in Scheme II.
  • Schemes V- ⁇ and V- ⁇ are examples of the same reagents as given above for the oxidative cleavage step of Scheme I (for example, RuCl3/Nal0 4 or Os/Jones oxidation, or Ru0 4 ) or for oxidation of the complex enone in Scheme II.
  • This method comprises performing a crossed aldol condensation of an aldehyde of formula:
  • the aldehyde of formula DD may be a compound such as acetaldehyde, propionaldehyde or other appropriate compound.
  • the use of propionaldehyde, for example, works well to provide final acids having R 5 Me.
  • Other R 5 groups may be substituted by using other aldehydes of formula DD, as would be appreciated by the ordinarily skilled artisan.
  • the first compound shown in Figures 16(a) and (b) can be collectively represented with the general formula:
  • the hydroxyl group of the first compound or its diastereomer may be protected with a protecting group to form an intermediate compound having a formula selected from:
  • This hydroxyl protection may be performed under the same reaction conditions and utilizing the same reagents as given above for the hydroxyl protection step of Scheme I (for example, R 8 X/lmidazole/DMF/rt, 72 hours).
  • the intermediate compound can be collectively represented with the general formula:
  • keto-acid having a formula:
  • the oxidation may be performed under the same reaction conditions and utilizing the same reagents as given above for the oxidative cleavage step of Scheme I (for example, RuCl 3 /Nal0 4 or OsJones oxidation, or Ru0 4 ) or for oxidation of the complex enone in Scheme II.
  • the first compound may have a formula:
  • the hydroxyl group of the first compound or its diastereomer may be protected with a protecting group to form a first intermediate compound having a formula: Rs
  • This hydroxyl protection may be performed under the same reaction conditions and utilizing the same reagents as given above for the hydroxyl protection step of Scheme I (for example, R 8 X/lmidazole/DMF/rt, 72 hours).
  • the first intermediate compound may be collectively represented with the general formula:
  • the first intermediate compound may be subjected to a haloform reaction to convert the methyl ketone to a carboxylic acid.
  • a haloform reaction to convert the methyl ketone to a carboxylic acid.
  • the first intermediate compound undergoes the haloform reaction cleanly providing a second intermediate compound of formula KK sy n- or KK ant i - ⁇ ; or for the other enantiomer of proline, KK S y n - ⁇ or KK ant i- ⁇ :
  • the haloform reaction may be performed under conditions known in the art, such as a bromoform reaction (for example, Br 2 /NaOH/Dioxane/H 2 0, 0°C) or an iodoform reaction (for example, l 2 /NaOH/Dioxane/H 2 0, 0°C).
  • a bromoform reaction for example, Br 2 /NaOH/Dioxane/H 2 0, 0°C
  • an iodoform reaction for example, l 2 /NaOH/Dioxane/H 2 0, 0°C.
  • the third compound may then be deprotected and oxidized to form the keto- acid of formula:
  • the deprotection step may be performed as described above with respect to the deketalization step of Schemes ll- ⁇ and ll- ⁇ (for example, 1 N HCI/THF/H 2 0, r.t.).
  • the oxidation may be performed under the same reaction conditions and utilizing the same reagents as given above for the oxidative cleavage step of Scheme I (for example, RuCls/Nal ⁇ 4 or Os/Jones oxidation, or Ru0 4 ) or for oxidation of the complex enone in Scheme II.
  • the oxidative cleavage step of Scheme I for example, RuCls/Nal ⁇ 4 or Os/Jones oxidation, or Ru0 4
  • keto-acid synthons formed according to the methods of the present invention may be incorporated into various routes for epothilone synthesis.
  • F. ant ⁇ - ⁇ or analogs, derivatives or stereoisomers thereof may undergo aldol condensation with a second compound selected from the formulas:
  • the aldol condensation may be performed, for example, under conditions a) 2LDA / -40°C; b) TBSOTf; c) silica gel, as reported in U.S. Patent Application No. 09/981 ,312 entitled “Synthesis of Epothilones and Related Analogs" (U.S. Publication No. US 2002/0091269 A1) and in PCT Application No. PCT/US01/32225 of the same title (PCT Publication No. WO 02/30356 A2).
  • This second compound can be collectively represented with the formula:
  • the resulting product in the form of a third compound has a formula selected from:
  • the macrolactonization may be performed, for example, under conditions of CI 3 PhCOCI/pyridine/DMAP, again as reported in U.S. Patent Application No. 09/981 ,312 entitled "Synthesis of Epothilones and Related Analogs" (U.S. Publication No. US 2002/0091269 A1) and in PCT Application No. PCT/US01/32225 of the same title (PCT Publication No. WO 02/30356 A2).
  • the third compound can be collectively represented as:
  • the macrolactonization step forms an epothilone compound, or analogs or derivatives thereof, having a formula selected from:
  • R1-R3, R5 and R 8 are as above and R 11 -R16 and R ⁇ s are each individually selected from H or optionally substituted n-alkyl, s-alkyl, t- alkyl, E or Z alkenyl, terminal alkenyl, alkynyl, aryl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, alkynylheteroaryl, cycloalkyl, alkylheterocyclic, alkenylheterocyclic, alkynylheterocyclic, heteroalkyl, heteroalkenyl, heteroalkynyl, primary alkylamines, secondary alkylamines, tertiary alkylamines, alkyl sulfides, alkylethers, hydroxyalkyls, alkylthiols and other functional groups known in the art.
  • R-i, R 2 , R 3 , Rn, R ⁇ 3 , and R 14 may each specifically be methyl; R 5 and R 12 may each specifically be H; R 8 and R ⁇ 8 may each specifically be a TBS protecting group; and R 15 and R 16 may each specifically be a TBS or TMS protecting group.
  • the epothilone compound can be collectively represented as:
  • keto-acid synthons of formula F syn - a , F syn . ⁇ and Fanti- ⁇ may be substituted for the keto-acid synthon F ant i- ⁇ in the above-described exemplary epothilone synthesis to provide epothilones of formula W, Z, W", Z", W" and Z'", and stereoisomers thereof, as shown in Figures 12(a) and 13(a), 12(c) and 13(c), and 12(d) and 13(d), respectively.
  • the present invention is also directed to novel chemical compounds disclosed herein that are useful in the synthesis of epothilones and analogs and derivatives thereof.
  • the present invention provides compounds having the following formulas:
  • the present invention provides methods for forming each of these chemical compounds, as illustrated in the individual steps of the above-described methods.

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Abstract

L'invention concerne des procédés alternatifs de production de synthons céto-acides utiles dans la synthèse d'épothilones et des analogues et des dérivés de ceux-ci. Un procédé général selon l'invention consiste à effectuer une condensation d'aldol d'un premier aldéhyde de formule générale (I), avec un composé carbonyle sous la forme d'une cétone ou un second aldéhyde de formule généralisée (II), de manière à former un premier composé de formule généralisée (III), puis à convertir le premier composé en un synthon céto-acide protégé de formule généralisée (IV). L'invention concerne également des composés chimiques utiles dans la synthèse d'épothilones et des analogues et des dérivés de ceux-ci, ainsi que des procédés de formation de ces composés chimiques.
PCT/US2004/038811 2003-11-19 2004-11-19 Synthese du synthon ceto-acide en c1-c6 des epothilones WO2005054429A2 (fr)

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CN111960935A (zh) * 2020-09-21 2020-11-20 济南悟通生物科技有限公司 一种甲基环戊烯醇酮的绿色合成方法

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US6605599B1 (en) * 1997-07-08 2003-08-12 Bristol-Myers Squibb Company Epothilone derivatives

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CN111960935A (zh) * 2020-09-21 2020-11-20 济南悟通生物科技有限公司 一种甲基环戊烯醇酮的绿色合成方法
CN111960935B (zh) * 2020-09-21 2023-07-25 济南悟通生物科技有限公司 一种甲基环戊烯醇酮的绿色合成方法

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