合成路线:The cyclization of 3-(benzyloxy)-2(S)-methylpropenal (X) with the diene (XI) by means of TiCl4 in dichloromethane gives the dihydropyranone (XII),which is reduced with LiAlH4 in ethyl ether to yield the alcohol (XIII).The cyclopropanation of (XIII) by means of diiodomethane and Et2Zn in ethyl ether affords the cyclopropano derivative (XIV),which is cleaved by means of N-iodosuccinimide (NIS) in methanol,affording the iodomethyl derivative (XV).The dehalogenation of (XV) by means of Bu3SnH and AIBN in refluxing benzene provide the gem-dimethyltetrahydropyran (XVI),which is treated with triphenylchlorosilane and imidazole in DMF to give the silyl ether (XVII).Opening of the tetrahydropyran ring of (XVII) by means of propane-1,2-dithiol and TiCl4 in dichloromethane yields the 1,3-dithiolane derivative (XVIII),which is treated with Tbdms-OTf and lutidine to afford the disilylated compound (XIX).The debenzylation of (XIX) with DDQ in dichloromethane/water provides the primary alcohol (XX),which is oxidized with oxalyl chloride in DMSO/dichloromethane,furnishing the corresponding aldehyde (XXI).The condensation of (XXI) with the phosphonium salt (XXII) by means of KOtBu in THF gives the enol ether (XXIII),which is hydrolyzed to the corresponding aldehyde (XXIV) by means of TsOH in dioxane/water.The condensation of (XXIV) with phosphonium salt (XXV) by means of NaHMDS in toluene yields the terminal olefin (XXVI),which is treated with phenyliodonium trifluoroacetate in methanol/THF to afford the aldehyde dimethylacetal (XXVII).The condensation of (XXVII) with thiazole intermediate (IX) by means of 9-BBN,a Pd catalyst and Cs2CO3 in DMF/water gives the adduct (XXVIII).
合成路线:Hydrolysis of the dimethylacetal group of (XXVIII) with Ts-OH in dioxane/water yields the corresponding aldehyde (XXIX),which is submitted to an intramolecular aldolization by means of KHMDS in THF to afford a mixture of diastereomeric macrolactones (XXX) and (XXXI).The undesired isomer (XXX) was recovered,oxidized with DMP to the ketone (XXXII) and reduced again with NaBH4 to provide high yields of the desired isomer (XXXI).Selective desilylation of (XXXI) with HF/pyridine in THF gives the diol (XXXIII),which is selectively monosilylated with Tbdms-OTf and lutidine in dichloromethane,yielding the bis-silylated triol (XXXIV).The oxidation of the free OH group of (XXXIV) with DMP in dichloromethane affords the corresponding ketonic derivative (XXXV),which is deprotected with HF/pyridine in THF,providing the free dihydroxy compound (XXXVI).Finally,this compound is epoxidized by means of dimethyldioxirane (DMDO) in dichloromethane.
合成路线:The reaction of (R)-glycidol (XLVI) with dihydropyran (DHP) and PPTS in dichloromethane gives the protected glycidol (XLVII),which is treated with the lithium acetylide (XLVIII) and BF3/Et2O in THF to yield the acetylenic alcohol (IL).The protection of the OH group of (IL) with Mem-Cl and DIEA in hot dichloroethane affords compound (L),which is treated with PPTS in methanol to provide the primary alcohol (LI).The oxidation of (LI) with oxalyl chloride in DMSO/dichloromethane gives the corresponding aldehyde (LII),which is treated with Me-MgBr in ethyl ether to yield the secondary alcohol (LIII).The oxidation of (LIII) with TPAP and NMO in dichloromethane affords the methyl ketone (LIV),which is condensed with the phosphine oxide (LV) by means of BuLi in THF,providing the adduct (LVI).The reaction of (LVI) with N-iodosuccinimide (NIS) and Cy2BH in ethyl ether gives the iodovinyl compound (LVII),which is treated with acetic anhydride,yielding the intermediate (IX).
合成路线:Synthesis of thiazole intermediate (IX): The reaction of 2-methylthiazole-4-carbaldehyde (I) with triphenylphosphorane (II) in refluxing benzene gives 2-methyl-3-(2-methyl-4-thiazolyl)-2-propenal (III),which is enantioselectively allylated with ally(tributyl)stannane (IV) and catalyzed by (S)-(-)-BINOL and Ti(O-iPr)4 in dichloromethane to yield the chiral homoallyl alcohol (V).The reaction of (V) with acetic anhydride TEA and DMAP in dichloromethane affords the acetate (VI),which is oxidized at its terminal double bond with OsO4 and NaIO4 to provide the aldehyde (VII).Finally,this compound is condensed with triphenylphosphorane (VIII) to gives the desired thiazole intermediate (IX).
合成路线:Hydrolysis of the dimethylacetal group of (XXVIII) with Ts-OH in dioxane/water yields the corresponding aldehyde (XXIX),which is submitted to an intramolecular aldolization by means of KHMDS in THF to afford a mixture of diastereomeric macrolactones (XXX) and (XXXI).The undesired isomer (XXX) was recovered,oxidized with DMP to the ketone (XXXII) and reduced again with NaBH4 to provide high yields of the desired isomer (XXXI).Selective desilylation of (XXXI) with HF/pyridine in THF gives the diol (XXXIII),which is selectively monosilylated with Tbdms-OTf and lutidine in dichloromethane,yielding the bis-silylated triol (XXXIV).The oxidation of the free OH group of (XXXIV) with DMP in dichloromethane affords the corresponding ketonic derivative (XXXV),which is deprotected with HF/pyridine in THF,providing the free dihydroxy compound (XXXVI).Finally,this compound is epoxidized by means of dimethyldioxirane (DMDO) in dichloromethane to afford the target epothilone B.
参考文献标题:Synthesis of epothilones,intermediates thereto,analogues and uses thereof
文献作者:Bertinato,P.; Danishefsky,S.J.; Su,D.-S.; Kamenecka,T.; Meng,D.F.; Sorensen,E.J.; Savin,K.A.; Chou,T.-C.; Balog,A.(Sloan-Kettering Institute)
参考来源:JP 2001507716; US 6242469; WO 9901124
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:Butane-1,4-diol (II) is anchored to chloromethyl-RESIN (I) by means of tetrabutylammonium iodide and NaH in DMF,and without isolation is treated with PPh3 I2 and imidazole to yield the phosphonium salt (III),which is treated with NaHMDS in THF/DMSO,affording the phosphorane (IV).The condensation of (IV) with the chiral aldehyde (V) in THF provides the anchored olefin (VI),which is desilylated with HF in pyridine/THF.The resulting alcohol is submitted to a Swern oxidation to give the anchored aldehyde (VII).The condensation of (VII) with the ketoacid (VIII) by means of LDA and ZnCl2 in THF yields the adduct (IX) as a diastereomeric mixture.The esterification of carboxylic acid (IX) with the alcohol (X) by means of DCC and DMAP affords the corresponding ester (XI),which is submitted to a macrocyclic ring-closing metathesis catalyzed by a ruthenium catalyst providing,after chromatographic separation of isomers,the macrocyclic lactone (XII).The desilylation of (XII) by means of TFA in dichloromethane gives the precursor (XIII),which is finally epoxidated with methyl(trifluoromethyl)dioxirane (XI) to yield the target epothilone A.
合成路线:The condensation of the phosphonium salt (I) with the ketone (II) by means of NaHMDS in THF gives the diene (III),which is selectively monodeprotected with CSA in methanol/dichloromethane to yield the primary alcohol (IV).The oxidation of (IV) with SO3/pyridine affords the corresponding aldehyde (V),which is condensed with the ketoacid (VI) by means of LDA in THF to provide the heptadienoic acid (VII).The protection of the OH group of (VII) y means of Tbdms-OTf and lutidine in dichloromethane gives the fully silylated compound (VIII),which is selectively monodeprotected with TBAF in THF to yield the hydroxyacid (IX).The macrolactonization of (IX) by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF affords the macrolactone (X),which is deprotected with TFA in dichloromethane to provide the precursor (XI).Finally,this compound is epoxidized by means of methyl(trifluoromethyl)dioxirane in acetonitrile to furnish the target epothilone B.
合成路线:Butane-1,4-diol (II) is anchored to chloromethyl-RESIN (I) by means of tetrabutylammonium iodide and NaH in DMF,and without isolation is treated with PPh3 I2 and imidazole to yield the phosphonium salt (III),which is treated with NaHMDS in THF/DMSO,affording the phosphorane (IV).The condensation of (IV) with the chiral aldehyde (V) in THF provides the anchored olefin (VI),which is desilylated with HF in pyridine/THF.The resulting alcohol is submitted to a Swern oxidation to give the anchored aldehyde (VII).The condensation of (VII) with the ketoacid (VIII) by means of LDA and ZnCl2 in THF yields the adduct (IX) as a diastereomeric mixture.The esterification of carboxylic acid (IX) with the alcohol (X) by means of DCC and DMAP affords the corresponding ester (XI),which is submitted to a macrocyclic ring-closing metathesis catalyzed by a ruthenium catalyst providing,after chromatographic separation of isomers,the macrocyclic lactone (XII).Compound (XII) is finally desilylated by means of TFA in dichloromethane to give the target epothilone C.
参考文献标题:Synthesis of epothilones A and B in solid and solution phase
文献作者:Nicolaou,K.C.; Winssinger,N.; Pastor,J.; Ninkovic,S.; Sarabia,F.; He,Y.; Vourloumis,D.; Yang,Z.; Li,T.; Giannakakou,P.; Hamel,E.
参考来源:Nature 1997,387(6630),268
合成路线:Synthesis of intermediate triphenylphosphonium salt (VII): The condensation of the chiral oxazolidinone (I) with cinnamyl bromide (II) by means of NaHMDS in THF gives the adduct (III),which is treated with LiBH4 in Et2O/water to yield the alcohol (IV).The protection of (IV) with Tbdms-Cl and imidazole in DMF affords the silyl ether (V),which is treated with ozone and reduced with NaBH4 to provide the alcohol (VI).The reaction of (VI) with I2 and PPh3 gives the desired triphenylphosphonium iodide (VII).
合成路线:Synthesis of intermediate aldehyde (XV): The oxidation of 4-(benzyloxy)butanol (VIII) with oxalyl chloride gives the aldehyde (IX),which is condensed with 2-(triphenylphosphoranylidene)propionic acid ethyl ester (X) in hot THF to yield the unsaturated ester (XI).The enantioselective dihydroxylation of (XI) by means of AD-mix beta and methanesulfonamide in butanol/water affords the chiral dihydroxyester (XII),which is protected with 2,2-dimethoxypropane and CSA to provide the acetonide (XIII).The reduction of the ester group of (XIII) with DIBAL in THF gives the alcohol (XIV),which is finally oxidized with DMP to yield the desired intermediate aldehyde (XV).
合成路线:Assembly of the target compound: The condensation of the phosphonium salt (VII) with the aldehyde (XV) by means of NaHMDS in THF gives the adduct (XIX),which is debenzylated and hydrogenated with H2 over Pd/Al2O3 in ethanol and oxidized with NaIO4 and RuCl3 to yield the carboxylic acid (XX).The activation of (XX) with pivaloyl chloride affords the anhydride (XXI),which is condensed with the lithium oxazolidinone (XXII) to provide the cyclic amide (XXIII).The enantioselective hydroxylation of (XXIII) by means of the Davis oxaziridine and NaHMDS gives the alpha-hydroxyamide (XXIV),which is treated with N,O-dimethylhydroxylamine (XXV) to yield the methoxyamide (XXVI).The protection of the OH group of (XXVI) with Tbdms-OTf and lutidine affords the silyl ether (XXVII),which is treated with MeLi in THF,affording the methyl ketone (XXVIII).The condensation of (XXVIII) with tributyl(2-methylthiazol-4-ylmethyl)phosphonium chloride (XXIX) by means of KHMDS in THF provides the adduct (XXX).
合成路线:The selective deprotection of (XXX) with CSA in dichloromethane gives the primary alcohol (XXXI),which is oxidized with DMP in dichloromethane to yield the aldehyde (XXXII).The condensation of (XXXII) with methyltriphenylphosphonium iodide (XXXIII) by means of BuLi in hexane/THF,followed by treatment with HCl in ethanol,affords the diunsaturated vicinal diol (XXXIV),which is selectively silylated to provide the vicinal diol (XXXV).The monosulfonation of (XXXV) with Ms-Cl and TEA furnishes the mesylate (XXXVI),which is cyclized to the epoxide (XXXVII) by means of K2CO3 in methanol.The oxidation of the terminal double bond of (XXXVII) with OsO4 and NaIO4 gives the aldehyde (XXXVIII),which is condensed with the intermediate ketone (XVIII) by means of LDA in THF to provide the adduct (XXXIX).
合成路线:The treatment of (XXXIX) with Tbdms-OTf as before gives the silyl ether (XL),which is oxidized at its terminal double bond with OsO4 and NaIO4 to give the aldehyde (XLI).The oxidation of (XLI) with NaClO2 yields the carboxylic acid (XLII),which is selectively deprotected with TBAF in THF affording the hydroxyacid (XLIII).The macrolactonization of (XLIII) by means of 2,3,6-trichlorobenzoyl chloride and TEA in toluene provides the protected macrolactone (XLIV),which is finally desilylated by means of TFA in dichloromethane to yield the target epothilone B.
参考文献标题:A novel highly stereoselective total synthesis of epothilone B and of its (12R,13R) acetonide
文献作者:Mulzer,J.; et al.
参考来源:Tetrahedron Lett 2000,41(40),7635
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.
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
产品链接: CAS No. 152044-54-7››