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:The synthesis of intermediate tridecenoic acid (VII) has been performed as follows: The condensation of previously reported 1,3-dioxane intermediate (I) (see intermediate (X) in scheme no.22255601a) with 2(S)-methyl-6-heptenal (II) by means of LDA in THF gives the hydroxyundecenone (III),which is treated with pyridinium p-toluenesulfonate (PPTS) in methanol to cleave the 1,3-dioxane ring and yield the trihydroxy compound (IV).The silylation of (IV) with Tbdms-OTf and lutidine in dichloromethane affords the fully silylated compound (V),which is selectively monodesilylated with CSA to provide the primary alcohol (VI).Finally,this alcohol is oxidized by means of pyridinium dichromate (PDC) in DMF to furnish the desired tridecenoic acid intermediate (VII).
合成路线:The silylation of 2-methyl-5-(tert-butyldimethylsilyloxy)-1-penten-3(s)-ol (VIII) with Tbdms-Cl and imidazole in DMF gives the disilylated compound (IX),which is treated with ozone and PPh3 in dichloromethane to yield the 2-pentanone (X).The condensation of (X) with phosphonate (XI) by means of BuLi in THF yields the fully silylated diol (XII),which is selectively monodesilylated with HF in acetonitrile to afford the primary alcohol (XIII).The oxidation of (XIII) with DMP in dichloromethane affords the aldehyde (XIV),which is methylenated with the phosphonium salt (XV) and NaNH2 in THF to provide the silylated hexadienol (XVI).The reaction of (XVI) with TBAF in THF gives the free secondary alcohol (XVII),which is esterified with the intermediate tridecenoic acid (VII) by means of DCC and DMAP in dichloromethane,yielding the ester (XVIII).Ring-closing metathesis of (XVIII),catalyzed by a Ru catalyst,affords the macrolactone (XIX),which is desilylated by means of HF in acetonitrile to furnish the dihydroxymacrolactone (XX).Finally,the double bond of (XX) is epoxidated with dimethyldioxirane (DMDO) in dichloromethane to provide the target epothilone A.
合成路线:The reaction of 3-methyl-2-butenylmagnesium bromide (XVI) with propanal (XVII) gives racemic hexenol (XVIII),which is submitted to enzymatic resolution with ChiroCLEC-PC dry enzyme,yielding the R-enantiomer (XIX).The esterification of (XIX) with bromoacetyl bromide (XX) and dimethylaniline (DMA) affords the corresponding ester (XXI),which is oxidized with O3 and trimethyl phosphite and cyclized with SmI2 in THF to provide the chiral tetrahydropyranone (XXII).The reduction of (XXII) with Red-Al,followed by cyclization with 2-methoxypropene (XXIII) and PPTS,gives the acetonide (XXIV),which is oxidized with PPTS and NMO to provide the protected dihydroxyketone (XXV).The condensation of the ketone (XXV) with 2(S)-methyl-6-heptenal (XXVI) by means of LDA in THF gives the hydroxyundecenone (XXVII),which is treated with pyridinium p-toluenesulfonate (PPTS) in methanol to cleave the 1,3-dioxane ring and yield the trihydroxy compound (XXVIII).The silylation of (XXVIII) with Tbdms-OTf and lutidine in dichloromethane affords the fully silylated compound (XXIX),which is selectively monodesilylated with CSA to provide the primary alcohol (XXX).Finally,this alcohol is oxidized by means of pyridinium dichromate (PDC) in DMF to furnish the target tridecenoic acid intermediate (XII).
合成路线:The condensation of already reported 1,3-dioxane intermediate (I) (see intermediate (X) in scheme no.22255601a) with 2(S)-methyl-6-heptenal (II) by means of LDA in THF gives the hydroxyundecenone (III),which is treated with pyridinium p-toluenesulfonate (PPTS) in methanol to cleave the 1,3-dioxane ring and yield the trihydroxy compound (IV).The silylation of (IV) with Tbdms-OTf and lutidine in dichloromethane affords the fully silylated compound (V),which is selectively monodesilylated with CSA to provide the primary alcohol (VI).Finally,this alcohol is oxidized by means of pyridinium dichromate (PDC) in DMF to furnish the desired tridecenoic acid intermediate (VII).
合成路线:The silylation of 2-methyl-5-(tert-butyldimethylsilyloxy)-1-penten-3(s)-ol (VIII) with Tbdms-Cl and imidazole in DMF gives the disilylated compound (IX),which is treated with ozone and PPh3 in dichloromethane to yield the 2-pentanone (X).The condensation of (X) with phosphonate (XI) by means of BuLi in THF yields the fully silylated diol (XII),which is selectively monodesilylated with HF in acetonitrile to afford the primary alcohol (XIII).The oxidation of (XIII) with DMP in dichloromethane affords the aldehyde (XIV),which is methylenated with the phosphonium salt (XV) and Na-NH2 in THF to provide the silylated hexadienol (XVI).The reaction of (XVI) with TBAF in THF gives the free secondary alcohol (XVII),which is esterified with the intermediate tridecenoic acid (VII) by means of DCC and DMAP in dichloromethane yielding the ester (XVIII).Ring-closing metathesis of (XVIII),catalyzed by a Ru catalyst,affords the macrolactone (XIX),which is finally desilylated by means of HF in acetonitrile to furnish the target epothilone C.
参考文献标题:Total synthesis of (-)-epothilone A
文献作者:Schinzer,D.; et al.
参考来源:Angew Chem.Int Ed Engl 1997,36(5),523
合成路线:C1-C6 fragment.- The reaction of 3-methyl-2-butenylmagnesium chloride (I) with propanal (II) gives racemic 4,4-dimethyl-5-hexen-3-ol (III),which was submitted to enzymatic resolution with ChiroCLEC-PC dry enzyme yielding the (R) enantiomer (IV).The esterification of (IV) with bromoacetyl bromide (V) and dimethylaniline yields the corresponding ester (VI),which is oxidized with O3 and trimethyl phosphite and cyclized with SmI2 in THF to afford chiral tetrahydropyran-2-one (VII).The reduction of (VII) with Red-Al,followed by cyclization with 2-methoxypropene (VIII) and PPTS yields the acetonide (IX),which is finally oxidized with N-methylmorpholine-N-oxide and PPTS in dichloromethane giving the target intermediate (X).
合成路线:C7-C12 fragment.- The selective monoepoxidation of 1,7-octadiene (I) with m-chloroperbenzoic acid (MCPBA) gives the epoxide (II),which is oxidized with periodic acid to the aldehyde (III).Further oxidation of (III) by means of NaClO2 yields 6-heptenoic acid (IV),which is condensed with the lithium salt of the chiral oxazolidinone (V) by means of pivaloyl chloride affording the chiral imide (VI).The methylation of (VI) with methyl iodide and sodium hexamethyldisylazide (NaHMDS) in THF provides the methylated chiral imide (VII) as a single enantiomer.The hydrolysis of (VII) with H2O2 and LiOH gives the corresponding free acid (VIII),which is reduced with LiAlH4 to the primery alcohol (IX).Finally,(IX) is treated with Swern oxidant to afford the desired taret aldehyde (X).
合成路线:The reaction of 3-methyl-2-butenylmagnesium bromide (XVI) with propanal (XVII) gives racemic hexenol (XVIII),which is submitted to enzymatic resolution with ChiroCLEC-PC dry enzyme,yielding the R-enantiomer (XIX).The esterification of (XIX) with bromoacetyl bromide (XX) and dimethylaniline (DMA) affords the corresponding ester (XXI),which is oxidized with O3 and trimethyl phosphite and cyclized with SmI2 in THF to provide the chiral tetrahydropyranone (XXII).The reduction of (XXII) with Red-Al,followed by cyclization with 2-methoxypropene (XXIII) and PPTS,gives the acetonide (XXIV),which is oxidized with PPTS and NMO to provide the protected dihydroxyketone (XXV).The condensation of the ketone (XXV) with 2(S)-methyl-6-heptenal (XXVI) by means of LDA in THF gives the hydroxyundecenone (XXVII),which is treated with pyridinium p-toluenesulfonate (PPTS) in methanol to cleave the 1,3-dioxane ring and yield the trihydroxy compound (XXVIII).The silylation of (XXVIII) with Tbdms-OTf and lutidine in dichloromethane affords the fully silylated compound (XXIX),which is selectively monodesilylated with CSA to provide the primary alcohol (XXX).Finally,this alcohol is oxidized by means of pyridinium dichromate (PDC) in DMF to furnish the target tridecenoic acid intermediate (XII).
参考文献标题:A formal total synthesis of epothiolone A: Enantioselective preparation of the C1-C6 and C7-C12 fragments
文献作者:Taylor,R.E.; et al.
参考来源:J Org Chem 1998,63(25),9580
合成路线:Synthesis of intermediate (XVI): The condensation of 3(S)-(phenyldimethylsilyl)-4(E)-hexenoic acid methyl ester (I) with 2-(tert-butyldimethylsilyloxy)acetaldehyde (II) by means of Tms-OBn,Tms-OTf and BF3/Et2O in dichloromethane gives the 3(E)-heptenoic ester (III),which is ozonolyzed with O3 and pyridine in methanol/dichloromethane to yield the aldehyde (IV).The condensation of (IV) with the silyl ketal (V) by means of TiCl4 in dichloromethane affords the partially protected trihydroxyester (VI),which is silylated with Tbdms-OTf and lutidine in dichloromethane to provide the fully protected ester (VII).Regioselective monodesilylation of (VII) by means of TBAF/HOAc in THF gives the primary alcohol (VIII),which is oxidized with oxalyl chloride to the corresponding aldehyde (IX).The condensation of (IX) with phosphorane (X) in refluxing benzene yields the octenedioic diester (XI),which is methylated with Me2CuLi and Tms-Cl in THF,affording the tetramethyl diester (XII).The two ester groups of (XII) were easily differentiated by a reduction with DIBAL in dichloromethane,providing the 8-hydroxyoctanal derivative (XIII),which was silylated with TBdms-Cl and imidazole in DMF to give the fully protected aldehyde (XIV).Finally,this compound was subjected to a Wittig olefination reaction with methyltriphenylphosphonium bromide (XV) and NaHMDS in THF to yield the desired intermediate (XVI).
合成路线:Synthesis of the thiazole intermediate (XXVI): The Grignard reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XVII) with vinylmagnesium bromide (XVIII) in THF gives the racemic secondary alcohol (XIX),which is submitted to enzymatic optical resolution with Pseudomonas AK lipase and vinyl acetate to yield the desired (S)-secondary alcohol (XX) along with the (R)-acetate,which is easily separated by chromatography.The silylation of (XX) with Tbdms-Cl and imidazole in DMF affords the silyl ether (XXI).The selective hydroboration of the terminal double bond of (XXI) with dicyclohexylborane followed by oxidation with H2O2 provided the primary alcohol (XXII),which is oxidized with DMP in dichloromethane to give the corresponding aldehyde (XXIII).The reaction of (XXIII) with the iodomethyl phosphonium salt (XXIV) by means of NaHMDS in THF yields the cis-iodovinyl compound (XXV),which is desilylated with aqueous HF in acetonitrile,affording the corresponding alcohol (XXVI).Finally,this alcohol is treated with acetic anhydride,TEA and DMAP to provide the desired thiazole intermediate (XXVII).
合成路线:Assembly of the target compound: The condensation of intermediates (XVI) and (XXVII) by means of 9-BBN,a Pd catalyst and Cs2CO3 in THF/DMF gives the adduct (XXVIII),which is selectively deprotected with HF/pyridine in THF,yielding the primary alcohol (XXIX).The oxidation of (XXIX) with DMP in dichloromethane affords the aldehyde (XXX),which is condensed with the silyl enol ether (XXXI) by means of TiCl4 in dichloromethane to provide the isopropyl carboxylate (XXXII).The desilylation of (XXXII) with TBAF in THF gives the dihydroxyester (XXXIII),which is selectively monosilylated with Tbdms-Cl and imidazole,yielding the hydroxyester (XXXIV).The oxidation of (XXXIV) with DMP in dichloromethane affords the ketoester (XXXV),which was submitted to a basic hydrolysis of its acetoxy and isopropyl ester groups with NaOH in refluxing methanol to furnish the hydroxyacid (XXXVI).
合成路线:The Yamaguchi macrolactonization of (XXXVI) by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF gives the macrolactone (XXXVII),which is debenzylated with DDQ,yielding (XXXVIII) and desilylated with TFA to afford the dihydroxylactone (XXXIX).Finally,this compound is epoxidated by means of H2O2 and acetonitrile in methanol/water.
合成路线:Synthesis of intermediate (XVI): The condensation of 3(S)-(phenyldimethylsilyl)-4(E)-hexenoic acid methyl ester (I) with 2-(tert-butyldimethylsilyloxy)acetaldehyde (II) by means of Tms-OBn,Tms-OTf and BF3/Et2O in dichloromethane gives the 3(E)-heptenoic ester (III),which is ozonolyzed with O3 and pyridine in methanol/dichloromethane to yield the aldehyde (IV).The condensation of (IV) with the silyl ketal (V) by means of TiCl4 in dichloromethane affords the partially protected trihydroxyester (VI),which is silylated with Tbdms-OTf and lutidine in dichloromethane to provide the fully protected ester (VII).Regioselective monodesilylation of (VII) by means of TBAF/AcOH in THF gives the primary alcohol (VIII),which is oxidized with oxalyl chloride to the corresponding aldehyde (IX).The condensation of (IX) with phosphorane (X) in refluxing benzene yields the octenedioic diester (XI),which is methylated with Me2CuLi and Tms-Cl in THF,affording the tetramethyl diester (XII).The two ester groups of (XII) were easily differentiated by a reduction with DIBAL in dichloromethane,providing the 8-hydroxyoctanal derivative (XIII),which was silylated with TBdms-Cl and imidazole in DMF to give the fully protected aldehyde (XIV).Finally,this compound was subjected to a Wittig olefination reaction with methyltriphenylphosphonium bromide (XV) and NaHMDS in THF to yield the desired intermediate (XVI).
合成路线:Synthesis of the thiazole intermediate (XXVI): The Grignard reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XVII) with vinylmagnesium bromide (XVIII) in THF gives the racemic secondary alcohol (XIX),which is submitted to enzymatic optical resolution with Pseudomonas AK lipase and vinyl acetate to yield the desired (S)-secondary alcohol (XX) along with the (R)-acetate,which is easily separated by chromatography.The silylation of (XX) with Tbdms-Cl and imidazole in DMF affords the silyl ether (XXI).The selective hydroboration of the terminal double bond of (XXI) with dichlohexylborane followed by oxidation with H2O2 provides the primary alcohol (XXII),which is oxidized with DMP in dichloromethane to give the corresponding aldehyde (XXIII).The reaction of (XXIII) with the iodomethyl phosphonium salt (XXIV) by means of NaHMDS in THF yields the cis-iodovinyl compound (XXV),which is desilylated with aqueous HF in acetonitrile affording the corresponding alcohol (XXVI).Finally,this alcohol is treated with acetic anhydride,TEA and DMAP to provide the desired thiazole intermediate (XXVII).
合成路线:Assembly of the target compound: The condensation of intermediates (XVI) and (XXVII) by means of 9-BBN,a Pd catalyst and Cs2CO3 in THF/DMF gives the adduct (XXVIII),which is selectively deprotected with HF/pyridine in THF,yielding the primary alcohol (XXIX).The oxidation of (XXIX) with DMP in dichloromethane affords the aldehyde (XXX),which is condensed with the silyl enol ether (XXXI) by means of TiCl4 in dichloromethane to provide the isopropyl carboxylate (XXXII).The desilylation of (XXXII) with TBAF in THF gives the dihydroxyester (XXXIII),which is selectively monosilylated with Tbdms-Cl and imidazole,yielding the hydroxyester (XXXIV).The oxidation of (XXXIV) with DMP in dichloromethane affords the ketoester (XXXV),which was submitted to a basic hydrolysis of its acetoxy and isopropyl ester groups with NaOH in refluxing methanol to furnish the hydroxyacid (XXXVI).
合成路线:The Yamauchi macrolactonization of (XXXVI) by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF gives the macrolactone (XXXVII),which is debenzylated with DDQ,yielding (XXXVIII),finally desilylated with TFA to afford the target epothilone C.
参考文献标题:Total synthesis of apothilone A
文献作者:Zhu,B.; Panek,J.S.
参考来源:Org Lett 2000,2(17),2575
合成路线:The intermediate carboxylic acid (VI) has been obtained as follows: The condensation of the chiral oxazolidinone (I) with the aldehyde (II) gives the chiral ketone (III) as the major product.The cleavage of the chiral auxiliary with LiOOH in THF yields the carboxylic acid (IV),which is deprotected with HCl in THF to afford the oxoacid (V).Finally,the OH group of (V) is silylated with Tbdms-Cl to furnish the target intermediate carboxylic acid (VI).
参考文献标题:An unusual reversal of stereoselectivity in a boron mediated aldol reaction: Enantioselective synthesis of the C1-C6 segment of the epothilones
文献作者:Panicker,B.; et al.
参考来源:Tetrahedron 2000,56(40),7859
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).
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. 152044-53-6››