合成路线:The reaction of 4-methyl-4-penten-1-ol (I) with PBr3 gives the corresponding alkyl bromide (II),which is condensed with epoxide (III) and propyne (IV) by means of Mg,CuI and pentynyl lithium to yield,after silylation with Tbdms-Cl,the protected diol (V).The selective deprotection of (V) with DDQ gives the secondary alcohol (VI),which is oxidized by the Swern reagent to afford the ketone (VII).Alternatively,ketone (VII) can also be obtained by direct oxidation of the protected diol (V) with the Jones reagent.The Horner Emmons condensation of ketone (VII) with phosphonate (VIII) provides the unsaturated alkyl thiazole (IX),which is treated with (Ipc)2BH and sodium formate in THF to give the secondary alcohol (X).The oxidation of (X) with the complex SO3/Pyr yields the carbaldehyde (XI).Alternatively,(XI) can also be obtained by direct oxidation of the terminal double bond of (IX) with (Ipc)2BH and pyridinium chlorochromate (PCC).The condensation of aldehyde (XI) with ketoacid (XII) by means of LDA in THF affords the heptadecadienoic acid (XIII),which is silylated with Tbdms-OTf to provide the protected linear precursor (XIV).The cyclization of (XIV) by means of 2,4,6-trichlorobenzoyl chloride and DMAP in pyridine gives the protected cyclic precursor (XV),which is desilylated by means of TBAF in THF to yield the unprotected precursor (XVI).Finally,this compound is epoxidated by means of dimethyldioxirane (DMDO) in acetone to afford the target epothilone B.
合成路线:The condensation of 3-buten-2-one (I) with the phosphonate (II) by means of LDA gives the alkylated thiazole (III),which is enantioselectively epoxidated to the chiral oxirane (V) by means of oxone and the chiral ketone (IV).Alternatively,the oxidation of the chiral epoxybutanol (VI) with CrO3 or SO3 /pyridine yields the epoxybutanone (VII),which is condensed with phosphorane (II) by means of LDA to afford the already reported chiral oxirane (V).The condensation of (V) with alkyl bromide (VIII) and propyne (IX) by means of Mg,CuBr and pentynyl lithium provides the undecatrienyl thiazole (X),which is treated with Tms-OTf in order to protect its OH group,yielding the silyl ether (XI).The oxidation of the terminal double bond of (XI) by means of (Ipc)2BH and CrO3 affords the carbaldehyde (XII),which is condensed with ketoacid (XIII) by means of LDA in THF to provide the undecadienoic acid (XIV).The cyclization of (XIV) by means of benzenesulfonyl chloride and pyridine gives the macrocyclic intermediate (XV),which is finally epoxidated by means of DMDO in acetone to furnish the target epothilone B.
合成路线:The condensation of alkyl bromide (I) with epoxide (II) and propyne (III) by means of Mg,CuI and pentynyl lithium gives the secondary alcohol (IV),which is silylated with Sem-Cl to yield the protected diol (V).The selective deprotection of (V) with DDQ gives the secondary alcohol (VI),which is oxidized by means of SO3 /pyridine to afford the ketone (VII).The condensation of ketone (VII) with phosphonate (VIII) by means of BuLi in THF provides the unsaturated alkyl thiazole (IX),which is treated with (Ipc)2BH and sodium formate in THF to give the secondary alcohol (X).The oxidation of (X) with oxalyl chloride yields the carbaldehyde (XI),which is condensed with ketoacid (XII) by means of LDA in THF to afford the heptadecadienoic acid (XIII).The protection of the free OH group of (XIII) with Troc-Cl and DMAP in dichloromethane provides the protected linear precursor (XIV),which is selectively monodeprotected with TFA in dichloromethane to furnish the linear hydroxyacid (XV).The macrocyclization of (XV) by means of 2,4,6-trichlorobenzoyl chloride and DMAP in pyridine gives the protected cyclic precursor (XVI),which is deprotected first with HF and pyridine (desilylation),and then with Zn and HOAc (elimination of the Troc protecting group),to yield the unprotected precursor (XVII).Finally,this compound is epoxidated by means of dimethyldioxirane (DMDO) in acetone to afford the target epothilone B.
合成路线:The condensation of 3-buten-2-one (I) with the phosphonate (II) by means of LDA gives the alkylated thiazole (III),which is enantioselectively epoxidated to the chiral oxirane (V) by means of oxone and the chiral ketone (IV).Alternatively,the oxidation of the chiral epoxybutanol (VI) with CrO3 or SO3 /pyridine yields the epoxybutanone (VII),which is condensed with phosphorane (II) by means of LDA to afford the already reported chiral oxirane (V).The condensation of (V) with alkyl bromide (VIII) and propyne (IX) by means of Mg,CuBr and pentynyl lithium provides the undecatrienyl thiazole (X),which is treated with Tms-OTf in order to protect its OH group,yielding the silyl ether (XI).The oxidation of the terminal double bond of (XI) by means of (Ipc)2BH and CrO3 affords the carbaldehyde (XII),which is condensed with ketoacid (XIII) by means of LDA in THF to provide the undecadienoic acid (XIV).Finally,the cyclization of (XIV) by means of benzenesulfonyl chloride and pyridine gives the target epothilone D.
合成路线:The reaction of 4-methyl-4-penten-1-ol (I) with PBr3 gives the corresponding alkyl bromide (II),which is condensed with epoxide (III) and propyne (IV) by means of Mg,CuI and pentynyl lithium to yield,after silylation with Tbdms-Cl,the protected diol (V).The selective deprotection of (V) with DDQ gives the secondary alcohol (VI),which is oxidized by the Swern reagent to afford the ketone (VII).Alternatively,ketone (VII) can also be obtained by direct oxidation of the protected diol (V) with the Jones reagent.The Horner Emmons condensation of ketone (VII) with phosphonate (VIII) provides the unsaturated alkyl thiazole (IX),which is treated with (Ipc)2BH and sodium formate in THF to give the secondary alcohol (X).The oxidation of (X) with the complex SO3/Pyr yields the carbaldehyde (XI).Alternatively,(XI) can also be obtained by direct oxidation of the terminal double bond of (IX) with (Ipc)2BH and pyridinium chlorochromate (PCC).The condensation of aldehyde (XI) with ketoacid (XII) by means of LDA in THF affords the heptadecadienoic acid (XIII),which is silylated with Tbdms-OTf to provide the protected linear precursor (XIV).The cyclization of (XIV) by means of 2,4,6-trichlorobenzoyl chloride and DMAP in pyridine gives the protected cyclic precursor (XV),which is finally desilylated by means of TBAF in THF to yield the target epothilone D.
合成路线:The condensation of alkyl bromide (I) with epoxide (II) and propyne (III) by means of Mg,CuI and pentynyl lithium gives the secondary alcohol (IV),which is silylated with Sem-Cl to yield the protected diol (V).The selective deprotection of (V) with DDQ gives the secondary alcohol (VI),which is oxidized by means of SO3 /pyridine to afford the ketone (VII).The condensation of ketone (VII) with phosphonate (VIII) by means of BuLi in THF provides the unsaturated alkyl thiazole (IX),which is treated with (Ipc)2BH and sodium formate in THF to give the secondary alcohol (X).The oxidation of (X) with oxalyl chloride yields the carbaldehyde (XI),which is condensed with ketoacid (XII) by means of LDA in THF to afford the heptadecadienoic acid (XIII).The protection of the free OH group of (XIII) with Troc-Cl and DMAP in dichloromethane provides the protected linear precursor (XIV),which is selectively monodeprotected with TFA in dichloromethane to furnish the linear hydroxyacid (XV).The macrocyclization of (XV) by means of 2,4,6-trichlorobenzoyl chloride and DMAP in pyridine gives the protected cyclic precursor (XVI),which is deprotected first with HF and pyridine (desilylation),and then with Zn and HOAc (elimination of the Troc protecting group),to finally yield the target epothilone D.
参考文献标题:Synthesis of epothilones and related analogs
文献作者:Avery,M.A.(University of Mississippi)
参考来源:WO 0230356
合成路线:Treatment of diketoester (I) with trimethylsilyl diazomethane and diisopropyl ethylamine produced enol ether (II).This was condensed with (S)-2-methyl-4-pentenal (III) in the presence of LDA at -120 C to afford the aldol condensation product (IV) as the major isomer.Protection of the 7-hydroxyl group of (IV) with trichloroethoxycarbonyl chloride gave carbonate (V).Enol ether of (V) was then hydrolyzed with p-TsOH in acetone to provide diketoester (VI).Hydroboration of the terminal olefin of (VI) with 9-borabicyclo[3.3.1]nonane gave organoborane (VII).Then,Suzuki coupling of (VII) with vinyl iodide (VIII),followed by acid hydrolysis of the silyl protecting group,provided the thiazolyl heptadecadienoate (IX).Asymmetric hydrogenation of 3-keto group of (IX) in the presence of the modified Noyori's catalyst [RuCl2(R)-BINAP)]2[Et3N] furnished the desired 3-(S) alcohol (X).
合成路线:Further treatment of (X) with Et3SiOTf and 2,6-lutidine protected both 3- and 15-hydroxyl groups as the triethylsilyl ethers and cleaved the tert-butyl ester to yield carboxylic acid (XI).The bis(triethylsilyl)-protected diol (XI) was selectively hydrolyzed to the required 15-hydroxy acid (XII) upon treatment with cold 0.12 M HCl in MeOH.Macrolactonization of (XII) was then performed by means of 2,4,6-trichlorobenzoyl chloride,Et3N and DMAP yielding (XIII).Removal of the trichloroethoxycarbonyl protecting group from the resulting lactone (XIII) employing SmI2 and a catalytic amount of NiI2 in THF at -78 C yielded (XIV).Finally,desilylation of (XIV) with HF-pyridine afforded the target compound.
合成路线:The treatment of diketoester (XII) with trimethylsilyl diazomethane and DIEA gives enol ether (XIII),which is condensed with 2(S)-methyl-4-pentenal (XIV) by means of LDA to yield the aldol condensation product (XV) as the major isomer.The protection of the OH group of (XV) with Troc-Cl and pyridine affords the trichloroethyl carbonate (XVI),whose enol ether group is hydrolyzed with TsOH in acetone to provide the diketoester (XVII).The condensation of (XVII) with iodovinyl intermediate (XI) by means of BBN,(dppf)2PdCl2,AsPh3 and Cs2CO3 in THF/DMF/water gives adduct (XVIII),which is desilylated by means of HCl in methanol to yield the secondary alcohol (XIX).The asymmetric hydrogenation of (XIX) with H2 over a chiral Ru catalyst in acidic methanol affords the secondary diol (XX),which is silylated with Tes-OTf and lutidine to provide the bis-silyl ether (XXI).The selective desilylation of (XXI) with simultaneous hydrolysis of its tert-butyl ester by means of HCl in methanol gives the hydroxyacid (XXII) suitable for cyclization.
参考文献标题:New chemical synthesis of the promising cancer chemotherapeutic agent 12,13-desoxyepothilone B: Discovery of a surprising long-range effect on the diastereoselectivity of an aldol condensation
文献作者:Harris,C.R.; et al.
参考来源:J Am Chem Soc 1999,121(30),7050
合成路线:Synthesis of undecenoic ester intermediate (XXI): The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde,TsOH and DIBAL gives the monobenzyl ether (II),which is oxidized with SO3/pyridine in dichloromethane,yielding the propionaldehyde (III).The condensation of (III) with butanone (IV) by means of LDA and TFAA affords the heptenone (V),which is epoxidated with H2O2 and NaOH in aq.methanol to provide the racemic epoxide (rac)-(VI).The reaction of ketone (VI) with O-methylhydroxylamine and NaOAc in methanol gives the corresponding oxime (rac)-(VII),which is treated with CuCN and Me-Li in ethyl ether to yield the beta-hydroxy oxime (rac)-(VIII).The treatment of (VIII) with H2 and Raney-Ni in acetone/THF affords the corresponding beta-hydroxy ketone (rac)-(IX),which is allylated with allyl bromide (X) and LHMDS in the presence of 1,3-dimethylperhydropyrimidin-2-one to give the beta-hydroxynonen-5-one (rac)-(XI).The reduction of (XI) with Me4NBH(OAc)3 and HOAc in acetonitrile yields the diol (rac)-(XII),which is protected with 2-methoxypropene (XIII) and TsOH,affording the 1,3-dioxane (rac)-(XIV).The reaction of (XIV) with Li in liquid ammonia,tert-butanol and THF provides the debenzylated primary alcohol (rac)-(XV),which is oxidized with tetrapropylammonium perrhuthenate in dichloromethane,giving the corresponding aldehyde (rac)-(XVI).
合成路线:The asymmetric catalytic aldol reaction of aldehyde (XVI) with acetophenone by means of a chiral lanthane catalyst yields a diastereomeric mixture of hydroxyketones from which the desired isomer (XVII) is isolated.The Baeyer-Villiger oxidation of (XVII) with trimethylsilyl peroxide and SnCl4 affords the phenyl ester (XVIII),which is deprotected with BCl3 in dichloromethane,giving the trihydroxyester (XIX).The selective protection of (XIX) with Tbdms-OTf and DIEA in dichloromethane yields the bis silylated compound (XX),which is finally oxidized with DMP in dichloromethane to furnish the target undecenoic ester intermediate (XXI).
合成路线:Synthesis of the thiazole intermediate (XXXIV): The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII),which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water.The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV),which is reduced with DIBAL in toluene,affording the aldehyde (XXVI).The reaction of (XXVI) with lithium trimethylsilylacetylide (A) in THF provides the adduct (XXVII),which is esterified with methyl chloroformate (XXVIII),furnishing the carbonate (XXIX).The reduction of (XXIX) by means of Pd(OAc)2,Bu3P and ammonium formate gives the protected acetylenic compound (XXX).The selective reduction of the triple bond of (XXX) by means of Ti(OiPr)4 and iPr-MgBr in ethyl ether yields the cis-silylated vinyl compound (XXXI),which is iodinated with I2 in dichloromethane to afford the cis-iodovinyl compound (XXXII).The desilylation of (XXXII) with HF and pyridine in THF gives the secondary alcohol (XXXIII),which is finally acetylated with Ac2O,TEA and DMAP in CH2Cl2 to yield the target thiazole intermediate (XXXIV).
合成路线:Assembly of the target compound: The condensation of intermediates (XXI) and (XXXIV) by means of 9-BBN,a PdCl2 catalyst and K3PO4 in hot DMF/water gives the adduct (XXXV),which is hydrolyzed with NaOH in methanol/water to yield the hydroxyacid (XXXVI).The macrolactonization of (XXXVI) by the Yamaguchi procedure using 2,4,6-trichlorobenzoyl chloride,TEA and DMAP in THF affords the macrolactone (XXXVII),which is desilylated with HF and pyridine in THF,furnishing the dihydroxylactone (XXXVIII).Finally,this compound is epoxidated by means of dimethyldioxirane (XXXIX) in dichloromethane.
合成路线:The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde,Ts-OH and DIBAL gives the monobenzyl ether (II),which is oxidized with SO3/pyridine in dichloromethane,yielding the propionaldehyde (III).The condensation of (III) with butanone (IV) by means of LDA and TFAA affords the heptenone (V),which is epoxidated with H2O2 and NaOH in aq.methanol to provide the racemic epoxide (rac)-(VI).The reaction of ketone (VI) with O-methylhydroxylamine and NaOAc in methanol gives the corresponding oxime (rac)-(VII),which is treated with CuCN and MeLi in ethyl ether to yield the beta-hydroxy oxime (rac)-(VIII).The treatment of (VIII) with H2 and Raney-Ni in acetone/THF affords the corresponding beta-hydroxy ketone (rac)-(IX),which is allylated with allyl bromide (X) and LHMDS in the presence of 1,3-dimethylperhydropyrimidin-2-one to give the beta-hydroxynonen-5-one (rac)-(XI).The reduction of (XI) with Me4NBH(OAc)3 and HOAc in acetonitrile yields the diol (rac)-(XII),which is protected with 2-methoxypropene (XIII) and Ts-OH,affording the 1,3-dioxane (rac)-(XIV).The reaction of (XIV) with Li in liquid ammonia,tert-butanol and THF provides the debenzylated primary alcohol (rac)-(XV),which is oxidized with tetrapropylammonium perrhuthenate in dichloromethane,giving the corresponding aldehyde (rac)-(XVI).
合成路线:The asymmetric catalytic aldol reaction of aldehyde (XVI) with acetophenone by means of a chiral lanthane catalyst yields a diastereomeric mixture of hydroxyketones from which the desired isomer (XVII) is isolated.The Baeyer-Villiger oxidation of (XVII) with trimethylsilyl peroxide and SnCl4 affords the phenyl ester (XVIII),which is deprotected with BCl3 in dichloromethane,giving the trihydroxyester (XIX).The selective protection of (XIX) with Tbdms-OTf and DIEA in dichloromethane yields the bis-silylated compound (XX),which is finally oxidized with DMP in dichloromethane to furnish the target undecenoic ester intermediate (XXI)
合成路线:Synthesis of the thiazole intermediate (XXXIII):The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII),which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water.The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV),which is reduced with DIBAL in toluene,affording the aldehyde (XXVI).The reaction of (XXVI) with phosphonium salt (XXVII),LHMDS,Hg(OAc)2 and tetrabutylammonium iodine (TBAI) in THF provides the olefin (XXX),which is iodinated with I2 and NaHMDS in THF to give the iodinated olefin (XXXI).The desilylation of (XXXI) with HF and pyridine in THF yields the secondary alcohol (XXXII),which is acylated with Ac2O,TEA and DMAP in dichloromethane to afford the target thiazole intermediate (XXXIII).
合成路线:Assembly of the target compound:The condensation of intermediates (XXI) and (XXXIII) by means of 9-BBN,a PdCl2 catalyst and K3PO4 in hot DMF/water gives the adduct (XXXIV),which is hydrolyzed with NaOH in methanol/water to yield the hydroxyacid (XXXV).The macrolactonization of (XXXV) by the Yamaguchi procedure using 2,4,6-trichlorobenzoyl chloride,TEA and DMAP in THF affords the macrolactone (XXXVI),which is desilylated with HF and pyridine in THF,furnishing the dihydroxylactone (XXXVII).Finally,this compound is epoxidated by means of dimethyldioxirane (XXXVIII) in dichloromethane to give the target epothilone B.
合成路线:The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde,Ts-OH and DIBAL gives the monobenzyl ether (II),which is oxidized with SO3/pyridine in dichloromethane,yielding the propionaldehyde (III).The condensation of (III) with butanone (IV) by means of LDA and TFAA affords the heptenone (V),which is epoxidated with H2O2 and NaOH in aq.methanol to provide the racemic epoxide (rac)-(VI).The reaction of ketone (VI) with O-methylhydroxylamine and NaOAc in methanol gives the corresponding oxime (rac)-(VII),which is treated with CuCN and MeLi in ethyl ether to yield the beta-hydroxy oxime (rac)-(VIII).The treatment of (VIII) with H2 and Raney-Ni in acetone/THF affords the corresponding beta-hydroxy ketone (rac)-(IX),which is allylated with allyl bromide (X) and LHMDS in the presence of 1,3-dimethylperhydropyrimidin-2-one to give the beta-hydroxynonen-5-one (rac)-(XI).The reduction of (XI) with Me4NBH(OAc)3 and HOAc in acetonitrile yields the diol (rac)-(XII),which is protected with 2-methoxypropene (XIII) and Ts-OH,affording the 1,3-dioxane (rac)-(XIV).The reaction of (XIV) with Li in liquid ammonia,tert-butanol and THF provides the debenzylated primary alcohol (rac)-(XV),which is oxidized with tetrapropylammonium perrhuthenate in dichloromethane,giving the corresponding aldehyde (rac)-(XVI).
合成路线:The asymmetric catalytic aldol reaction of aldehyde (XVI) with acetophenone by means of a chiral lanthane catalyst yields a diastereomeric mixture of hydroxyketones from which the desired isomer (XVII) is isolated.The Baeyer-Villiger oxidation of (XVII) with trimethylsilyl peroxide and SnCl4 affords the phenyl ester (XVIII),which is deprotected with BCl3 in dichloromethane,giving the trihydroxyester (XIX).The selective protection of (XIX) with Tbdms-OTf and DIEA in dichloromethane yields the bis-silylated compound (XX),which is finally oxidized with DMP in dichloromethane to furnish the target undecenoic ester intermediate (XXI).
合成路线:Synthesis of the thiazole intermediate (XXXIII):The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII),which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water.The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV),which is reduced with DIBAL in toluene,affording the aldehyde (XXVI).The reaction of (XXVI) with phosphonium salt (XXVII),LHMDS,Hg(OAc)2 and tetrabutylammonium iodine (TBAI) in THF provides the olefin (XXX),which is iodinated with I2 and NaHMDS in THF to give the iodinated olefin (XXXI).The desilylation of (XXXI) with HF and pyridine in THF yields the secondary alcohol (XXXII),which is acylated with Ac2O,TEA and DMAP in dichloromethane to afford the target thiazole intermediate (XXXIII).
合成路线:Assembly of the target compound :The condensation of intermediates (XXI) and (XXXIII) by means of 9-BBN,a PdCl2 catalyst and K3PO4 in hot DMF/water gives the adduct (XXXIV),which is hydrolyzed with NaOH in methanol/water to yield the hydroxyacid (XXXV).The macrolactonization of (XXXV) by the Yamaguchi procedure using 2,4,6-trichlorobenzoyl chloride,TEA and DMAP in THF affords the macrolactone (XXXVI),which is finally desilylated with HF and pyridine in THF,furnishing the target epothilone D.
合成路线:Synthesis of undecenoic ester intermediate (XXI): The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde,Ts-OH and DIBAL gives the monobenzyl ether (II),which is oxidized with SO3/pyridine in dichloromethane,yielding the propionaldehyde (III).The condensation of (III) with butanone (IV) by means of LDA and TFAA affords the heptenone (V),which is epoxidated with H2O2 and NaOH in aq.methanol to provide the racemic epoxide (rac)-(VI).The reaction of ketone (VI) with O-methylhydroxylamine and NaOAc in methanol gives the corresponding oxime (rac)-(VII),which is treated with CuCN and Me-Li in ethyl ether to yield the beta-hydroxy oxime (rac)-(VIII).The treatment of (VIII) with H2 and RaNi in acetone/THF affords the corresponding beta-hydroxy ketone (rac)-(IX),which is allylated with allyl bromide (X) and LHMDS in the presence of 1,3-dimethylperhydropyrimidin-2-one to give the beta-hydroxynonen-5-one (rac)-(XI).The reduction of (XI) with Me4NBH(OAc)3 and HOAc in acetonitrile yields the diol (rac)-(XII),which is protected with 2-methoxypropene (XIII) and Ts-OH,affording the 1,3-dioxane (rac)-(XIV).The reaction of (XIV) with Li in liquid ammonia,tert-butanol and THF provides the debenzylated primary alcohol (rac)-(XV),which is oxidized with tetrapropylammonium perrhuthenate in dichloromethane,giving the corresponding aldehyde (rac)-(XVI).
合成路线:The asymmetric catalytic aldol reaction of aldehyde (XVI) with acetophenone by means of a chiral lanthane catalyst yields a diastereomeric mixture of hydroxyketones from which the desired isomer (XVII) is isolated.The Baeyer-Villiger oxidation of (XVII) with trimethylsilyl peroxide and SnCl4 affords the phenyl ester (XVIII),which is deprotected with BCl3 in dichloromethane,giving the trihydroxyester (XIX).The selective protection of (XIX) with Tbdms-OTf and DIEA in dichloromethane yields the bis-silylated compound (XX),which is finally oxidized with DMP in dichloromethane to furnish the target undecenoic ester intermediate (XXI).
合成路线:Synthesis of the thiazole intermediate (XXXIV): The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII),which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water.The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV),which is reduced with DIBAL in toluene,affording the aldehyde (XXVI).The reaction of (XXVI) with lithium trimethylsilylacetylide (A) in THF provides the adduct (XXVII),which is esterified with methyl chloroformate (XXVIII),furnishing the carbonate (XXIX).The reduction of (XXIX) by means of Pd(OAc)2,Bu3P and ammonium formate gives the protected acetylenic compound (XXX).The selective reduction of the triple bond of (XXX) by means of Ti(OiPr)4 and iPr-MgBr in ethyl ether yields the cis-silylated vinyl compound (XXXI),which is iodinated with I2 in dichloromethane to afford the cis-iodovinyl compound (XXXII).The desilylation of (XXXII) with FH and pyridine in THF gives the secondary alcohol (XXXIII),which is finally acetylated with Ac2O,TEA and DMAP in dichloromethane to yield the target thiazole intermediate (XXXIV).
合成路线:Assembly of the target compound: The condensation of intermediates (XXI) and (XXXIV) by means of 9-BBN,a PdCl2 catalyst and K3PO4 in hot DMF/water gives the adduct (XXXV),which is hydrolyzed with NaOH in methanol/water to yield the hydroxyacid (XXXVI).The macrolactonization of (XXXVI) by the Yamaguchi procedure using 2,4,6-trichlorobenzoyl chloride,TEA and DMAP in THF affords the macrolactone (XXXVII),which is finally desilylated with HF and pyridine in THF to provide the target epothilone C.
参考文献标题:Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis
文献作者:Sawada,D.; et al.
参考来源:J Am Chem Soc 2000,122(43),10521
合成路线:The reaction of (S)-malic acid (I) with dimethoxypropane (II) and Ts-OH gives the carboxymethyldioxolanone (III),which is reduced with BH3/DMS and Ts-OH in toluene,yielding the chiral 2-hydroxybutyrolactone (IV).The silylation of (IV) with Tbdms-Cl and imidazole affords the silyl ether (V),which is methylated to the lactol (Via) by means of methyl lithium in THF.The condensation of the partially silylated dihydroxypentanone (VIb) (tautomer of (VIa)) with thiazolylphosphonium salt (VII) by means of LiHMDS in THF provides the unsaturated primary alcohol (VIII),which by Swern oxidation is converted into the corresponding aldehyde (IX).The condensation of (IX) with phosphonate (X) by means of KHMDS in THF furnishes the heptadienoic ester (XI),which is reduced with DIBAL in THF to give the primary alcohol (XII).The reaction of (XII) with I2 and PPh3 in acetonitrile/Et2O gives the allylic iodide (XIII),which is condensed with sulfone (XIV) by means of KHMDS and Na/Hg in MeOH/THF,yielding the protected diol (XVII).The sulfone (XIV) has been obtained by condensation of the chiral propanol (XV) with methylphenylsulfone (XVI) by means of Ts-Cl and BuLi.The selective deprotection of the primary silyl ether of (XVIII) with CSA in methanol/dichloromethane affords the primary alcohol (XVIII),which is finally oxidized with DMP in dichloromethane to afford the target intermediate carbaldehyde (XIX).
合成路线:The enantioselective condensation of 3-(tert-butyldimethylsilyloxy)propanal (XX) with ketene acetal (XXI) catalyzed by N-tosyl-D-valine and BH3/THF gives the beta-hydroxyester (XXII),which is silylated with Tbdms-OTf,yielding the bis-silyl ether (XXIII).The reduction of (XXIII) with DIBAL in toluene affords the carbinol (XXIV),which is oxidized to the corresponding aldehyde (XXV) with DMP in dichloromethane.The Grignard condensation of (XXV) with Et-MgBr in ethyl ether gives the secondary alcohol (XXVI),which is oxidized with DMP as before to yield the ketone (XXVII).Alternatively,the silylated ester (XXIII) can be treated with Tms-CH2-Li in pentane/methanol to give the methyl ketone (XXVIII),which is methylated again with MeI and LDA in THF to afford the ketone (XXVII).The condensation of ketone (XXVII) with the intermediate carbaldehyde (XIX) by means of BuLi in THF gives the adduct (XXIX),which is silylated with Tbdms-OTf,yielding the fully silylated compound (XXX).The selective monodesilylation of (XXX) with CSA in MeOH/dichloromethane affords the primary alcohol (XXXI),which is oxidized with DMP and NaClO2 to provide the carboxylic acid (XXXII).
合成路线:The selective monodesilylation of (XXXII) with TBAF in THF gives the hydroxyacid (XXXIII),which is submitted to a macrolactonization by means of EDC and DMAP in chloroform to yield the macrolactone (XXXIV).The desilylation of (XXXIV) with HF in pyridine/THF affords the dihydroxy macrolactone (XXXV),which is finally epoxidized by means of MCPBA in chloroform to furnish the target epothilone B.
合成路线:The reaction of (S)-malic acid (I) with dimethoxypropane (II) and Ts-OH gives the carboxymethyldioxolanone (III),which is reduced with BH3/DMS and Ts-OH in toluene,yielding the chiral 2-hydroxybutyrolactone (IV).The silylation of (IV) with Tbdms-Cl and imidazole affords the silyl ether (V),which is methylated to the lactol (VIa) by means of methyl lithium in THF.The condensation of the partially silylated dihydroxypentanone (VIb) (tautomer of (VIa)) with thiazolylphosphonium salt (VII) by means of LiHMDS in THF provides the unsaturated primary alcohol (VIII),which by Swern oxidation is converted into the corresponding aldehyde (IX).The condensation of (IX) with phosphonate (X) by means of KHMDS in THF furnishes the heptadienoic ester (XI),which is reduced with DIBAL in THF to give the primary alcohol (XII).The reaction of (XII) with I2 and PPh3 in acetonitrile/Et2O gives the allylic iodide (XIII),which is condensed with sulfone (XIV) by means of KHMDS and Na/Hg in MeOH/THF,yielding the protected diol (XVII).The sulfone (XIV) has been obtained by condensation of the chiral propanol (XV) with methylphenylsulfone (XVI) by means of Ts-Cl and BuLi .The selective deprotection of the primary silyl ether of (XVIII) with CSA in methanol/dichloromethane affords the primary alcohol (XVIII),which is finally oxidized with DMP in dichloromethane to afford the target intermediate carbaldehyde (XIX).
合成路线:Assembly of the target compound: The enantioselective condensation of 3-(tert-butyldimethylsilyloxy)propanal (XX) with ketene acetal (XXI) catalyzed by N-tosyl-D-valine and BH3/THF gives the beta-hydroxyester (XXII),which is silylated with Tbdms-OTf,yielding the bis-silyl ether (XXIII).The reduction of (XXIII) with DIBAL in toluene affords the carbinol (XXIV),which is oxidized to the corresponding aldehyde (XXV) with DMP in dichloromethane.The Grignard condensation of (XXV) with Et-MgBr in ethyl ether gives the secondary alcohol (XXVI),which is oxidized with DMP as before to yield the ketone (XXVII).Alternatively,the silylated ester (XXIII) can be treated with Tms-CH2-Li in pentane/methanol to give the methyl ketone (XXVIII),which is methylated again with MeI and LDA in THF to afford the ketone (XXVII).The condensation of ketone (XXVII) with the intermediate carbaldehyde (XIX) by means of BuLi in THF gives the adduct (XXIX),which is silylated with Tbdms-OTf,yielding the fully silylated compound (XXX).The selective monodesilylation of (XXX) with CSA in MeOH/dichloromethane affords the primary alcohol (XXXI),which is oxidized with DMP and NaClO2 to provide the carboxylic acid (XXXII).
合成路线:The selective monodesilylation of (XXXII) with TBAF in THF gives the hydroxyacid (XXXIII),which is submitted to a macrolactonization by means of EDC and DMAP in chloroform to yield the macrolactone (XXXIV).Finally,the desilylation of (XXXIV) with HF in pyridine/THF affords the target epothilone D
参考文献标题:Total synthesis of epothilones B and D
文献作者:Mulzer,J.; Mantoulidis,A.; Ohler,E.
参考来源:J Org Chem 2000,65(22),7456
参考文献标题:Total syntheses of epothilones A and B via a macrolactonization-based strategy
文献作者:Nicolaou,K.C.; et al.
参考来源:J Am Chem Soc 1997,119(34),7974
参考文献标题:Total syntheses of epothilones A and B via a macrolactonization-based strategy
文献作者:Nicolaou,K.C.; et al.
参考来源:J Am Chem Soc 1997,119(34),7974
产品链接: CAS No. 189453-10-9››