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:Lithiation of 2,4-dibromothiazole (I) with n-BuLi at -78 C,followed by condensation with dimethylformamide gave aldehyde (II),which was reduced to alcohol (III) with NaBH4.After protection of the alcohol (III) as the tert-butyldimethylsilyl ether (IV),a second metalation with n-BuLi,and subsequent quenching with tri-n-butyltin chloride furnished stannane (V).Further desilylation of (V) by means of tetrabutylammonium fluoride yielded 2-(hydroxymethyl)-4-(tri-n-butylstannyl)thiazole (VI).
合成路线:Asymmetric allylation of 3-iodomethacrolein (VII) with (+)-allyldiisopinocampheyl borane at -100 C provided the enantiopure alcohol (IX).Subsequent coupling of (IX) with the diastereomeric mixture of (6R,7S) and (6S,7R)-acids (X) using DCC and DMAP afforded a mixture of diastereomeric esters from which the required (6R,7S)-isomer (XI) was isolated by flash chromatography.Ring closure by means of olefin methatesis in the presence of a ruthenium initiator gave a separable mixture of E (XII) and Z (XIII) macrolactones.Subsequent desilylation of the desired Z isomer (XIII) with HF.Pyr in THF provided the macrocyclic diol (XIV).Introduction of the thiazole unit in (XIV) was carried out by Stille coupling of vinyl iodide (XIV) with thiazolyl stannane (VI) in the presence of Pd catalyst to provide (XV).Finally,epoxidation of (XV) with methylperoxycarboximidic acid,generated in situ from hydrogen peroxide and acetonitrile,furnished the title compound.
参考文献标题:Total synthesis of epothilone E and related side-chain modified analogues via a stille coupling based strategy
文献作者:Nicolaou,K.C.; King,N.P.; Finlay,M.R.; He,Y.; Roschangar,F.; Vourloumis,D.; Vallberg,H.; Sarabia,F.; Ninkovic,S.; Hepworth,D.
参考来源:Bioorg Med Chem 1999,7(5),665
合成路线:Lithiation of 2,4-dibromothiazole (I) with n-BuLi at -78 C,followed by condensation with dimethylformamide gave aldehyde (II),which was reduced to alcohol (III) with NaBH4.After protection of the alcohol (III) as the tert-butyldimethylsilyl ether (IV),a second metalation with n-BuLi,and subsequent quenching with tri-n-butyltin chloride furnished stannane (V).Further desilylation of (V) by means of tetrabutylammonium fluoride yielded 2-(hydroxymethyl)-4-(tri-n-butylstannyl)thiazole (VI).
合成路线:Asymmetric allylation of 3-iodomethacrolein (VII) with (+)-allyldiisopinocampheyl borane at -100 C provided the enantiopure alcohol (IX).Subsequent coupling of (IX) with the diastereomeric mixture of (6R,7S) and (6S,7R)-acids (X) using DCC and DMAP afforded a mixture of diastereomeric esters from which the required (6R,7S)-isomer (XI) was isolated by flash chromatography.Ring closure by means of olefin methatesis in the presence of a ruthenium initiator gave a separable mixture of E (XII) and Z (XIII) macrolactones.Subsequent desilylation of the desired Z isomer (XIII) with HF.Pyr in THF provided the macrocyclic diol (XIV).Introduction of the thiazole unit in (XIV) was carried out by Stille coupling of vinyl iodide (XIV) with thiazolyl stannane (VI) in the presence of Pd catalyst to provide (XV).Finally,epoxidation of (XV) with methylperoxycarboximidic acid,generated in situ from hydrogen peroxide and acetonitrile,furnished the title compound.
合成路线:The condensation of 3-[2-(hydroxymethyl)thiazol-4-yl]-2-methylpropenal (I) with acetone (II) gives the racemic aldol derivative (III),which is submitted to a enantioselective retroaldol reaction catalyzed by antibodies 84G3,85H6 or 93F3,yielding the chiral aldol (IV) with 99% ee purity.The protection of the OH groups of (IV) with TbdmsCl and imidazole affords the bis silyl ether (V),which is oxidized with Tms-OTf,trifluoroacetone and oxone to provide the hydroxyketone (VI).The reduction of (VI) with NaBH4 in methanol gives the vicinal diol (VII),which is cleaved with Pb(OAc)4 to yield the aldehyde (VIII).The Wittig reaction of (VIII) with methyltriphenylphosphonium iodide (IX) and BuLi in THF affords the olefin (X),which is desilylated with TBAF in THF and selectively monosilylated at the primary alcohol with Tbdms-Cl and DIEA to give the secondary alcohol (XI).The esterification of (XI) with the known carboxylic acid (XII) (see later) by means of EDC in dichloromethane yields the ester (XIII),which is submitted to a ring-closing metathesis catalyzed by the Grubb's catalyst in dichloromethane to afford the protected macrolactone (XIV).The desilylation of (XIV) with HF and pyridine in THF gives the precursor (XV),which is finally epoxidated with H2O2 and KHCO3 in methanol to yield the target epothilone E.
参考文献标题:Total synthesis of epothilone E and analogs with modified side chains through the Stille coupling reaction
文献作者:Nicolaou,K.C.; et al.
参考来源:Angew Chem.Int Ed Engl 1998,37(1-2),84
合成路线:The synthesis of intermediate tridecenoic acid (VIII) has been performed as follows: The reaction of 2,2-dimethyl-3-oxopentanal (I) with (+)-diisopinocampheyl(allyl)borane (II) in ethyl ether gives the chiral beta-hydroxy ketone (III),which is protected with Tbdms-OTf,yielding the silyl ether (IV).The ozonolysis of the double bond of (IV) affords the aldehyde (V),which is oxidized with NaClO2 to the carboxylic acid (VI).Finally,this compound is condensed with 2(S)-methyl-6-heptenal (VII) by means of LDA in THF to provide the intermediate tridecenoic acid (VIII).
合成路线:The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (IX) with DIBAL in dichloromethane gives the corresponding aldehyde (X),which is condensed with the phosphorane (XI) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2-propenal (XII).The alkylation of (XII) with (+)-diisopinocampheyl(allyl)borane (II) in ethyl ether affords the chiral secondary alcohol (XIII) (1),which is esterified with the intermediate tridecenoic acid (VIII) by means of EDC and DMAP in dichloromethane to provide the ester (XIV).Ring-closing metathesis of (XIV) catalyzed by a Ru catalyst gives the macrolactone (XV),which is desilylated by means of TFA in dichloromethane,yielding the dihydroxymacrolactone (XVI).Finally,the double bond of (XVI) is epoxidized by means of dimethyldioxirane (DMDO) or MCPBA in chloroform.
合成路线:The reaction of 2,2-dimethyl-3-oxopentanal (XXXI) with (+)-diisopinocampheyl(allyl)borane (XXXII) in ethyl ether gives the chiral beta-hydroxy ketone (XXXIII),which is protected with Tbdms-OTf to yield the silyl ether (XXXIV).The ozonolysis of the double bond of (XXXIV) affords the aldehyde (XXXV),which is oxidized with NaClO2 to the carboxylic acid (XXXVI).Finally,this compound is condensed with 2(S)-methyl-6-heptenal (VII) by means of LDA in THF to provide the intermediate tridecenoic acid (XII).
合成路线:The synthesis of intermediate tridecenoic acid (VIII) has been performed as follows: The reaction of 2,2-dimethyl-3-oxopentanal (I) with (+)-diisopinocampheyl(allyl)borane (II) in ethyl ether gives the chiral beta-hydroxy ketone (III),which is protected with Tbdms-OTf,yielding the silyl ether (IV).The ozonolysis of the double bond of (IV) affords the aldehyde (V),which is oxidized with NaClO2 to the carboxylic acid (VI).Finally,this compound is condensed with 2(S)-methyl-6-heptenal (VII) by means of LDA in THF to provide the intermediate tridecenoic acid (VIII).
合成路线:The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (IX) with DIBAL in dichloromethane gives the corresponding aldehyde (X),which is condensed with the phosphorane (XI) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2-propenal (XII).The alkylation of (XII) with (+)-diisopinocampheyl(allyl)borane (II) in ethyl ether affords the chiral secondary alcohol (XIII) (1),which is esterified with the intermediate tridecenoic acid (VIII) by means of EDC and DMAP in dichloromethane to provide the ester (XIV).Ring-closing metathesis of (XIV) catalyzed by a Ru catalyst gives the macrolactone (XV),which is finally desilylated by means of TFA in dichloromethane,yielding the target epothilone C.
参考文献标题:The olefin metathesis approach to epothilone A and its analogues
文献作者:Nicolaou,K.C.; et al.
参考来源:J Am Chem Soc 1997,119(34),7960
合成路线:The synthesis of intermediate tridecenoic acid (VIII) has been performed as follows: The reaction of 2,2-dimethyl-3-oxopentanal (I) with (+)-diisopinocampheyl(allyl)borane (II) in ethyl ether gives the chiral beta-hydroxy ketone (III),which is protected with Tbdms-OTf,yielding the silyl ether (IV).The ozonolysis of the double bond of (IV) affords the aldehyde (V),which is oxidized with NaClO2 to the carboxylic acid (VI).Finally,this compound is condensed with 2(S)-methyl-6-heptenal (VII) by means of LDA in THF to provide the intermediate tridecenoic acid (VIII).
合成路线:The oxoacid intermediate (VI) has been obtained as follows: The condensation of 2,2-dimethyl-3-oxopentanal (I) with (+)-diisopinocampheyl(allyl)borane (II) gives the chiral 5(S)-hydroxy-4,4-dimethyl-7-octen-3-one (III),which is protected with Tbdms-OTf,yielding the silyl ether (IV).The ozonolysis of (IV) in dichloromethane affords the aldehyde (V),which is finally oxidized with NaClO2 in tert-butanol/water to provide the target oxoacid intermediate (VI).
合成路线:The intermediate phosphonium salt (XVI) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (VII) with DIBAL in dichloromethane gives the corresponding aldehyde (VIII),which is condensed with the phosphorane (IX) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (X).The allylation of (X) with (+)-diisopinocampheyl(allyl)borane (II) affords the chiral secondary alcohol (XI),which is protected with Tbdms-Cl and imidazole in DMF,providing the silyl ether (XII).The oxidation of the terminal double bond of (XII) with OsO4 and Pb(OAc)4 in THF/tert-butanol/water gives rise to the aldehyde (XIII),which is reduced with NaBH4 in methanol to give the corresponding primary alcohol (XIV).The reaction of (XIV) with I2,PPh3 and imidazole in ethyl ether/acetonitrile yields the expected iodo derivative (XV),which is finally condensed with PPh3 at 100 C to afford the desired intermediate phosphonium salt (XVI).
合成路线:Assembly of the final product: The condensation of SAMP hydrazone (XVII) with 4-(benzyloxy)butyl iodide (XVIII) by means of LDA in THF gives the chiral 2-methylhexanal hydrazone (XIX),which is ozonolyzed in dichloromethane,yielding the free aldehyde (XX).The reduction of (XX) with NaBH4 in methanol affords the corresponding alcohol (XXI),which is protected with Tbdms-Cl and TEA in dichloromethane,providing the silyl ether (XXII).The hydrogenolysis of (XXII) with H2 over Pd/C in THF furnishes the alcohol (XXIII),which is oxidized to the aldehyde (XXIV) with oxalyl chloride,DMSO and TEA in dichloromethane.The condensation of aldehyde (XXIV) with the intermediate phosphonium salt (XVI) by means of NaHMDS in THF gives the silylated diol (XXV),which is selectively monodesilylated with CSA in dichloromethane/methanol to yield the primary alcohol (XXVI).The oxidation of (XXVI) with SO3/pyridine,DMSO and TEA in dichloromethane affords the corresponding aldehyde (XXVII),which is condensed with the oxoacid intermediate (VI) by means of LDA in THF to provide the linear heptadecadienoic acid (XXVIII) as a diastereomeric mixture.
合成路线:Intermediate (XXVIII) separated at the carboxylic acid (XXX) step.The full silylation of (XXVIII) with Tbdms-OTf and lutidine in dichloromethane gives the tetrasilyloxy compound (XXIX),which is stepwise desilylated first with K2CO3 in methanol to yield the carboxylic acid (XXX),and then with TBAF in THF to afford the hydroxyacid (XXXI).The macrolactonization of (XXXI) was carried out with the Yamaguchi method using 2,4,6-trichlorobenzoyl chloride,TEA and DMAP in THF to yield the silylated macrolactone (XXXII),which is deprotected with TFA in dichloromethane to afford the dihydroxymacrolactone (XXXIII).Finally,the double bond of (XXXIII) is epoxidated with methyl(trifluoromethyl)dioxirane (A) in acetonitrile.
合成路线:The synthesis of the intermediate chiral aldehyde (XVIII) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid methyl ester (I) with DIBAL in dichloromethane gives the aldehyde (II),which by condensation with phosphorane (III) in refluxing benzene yields the unsaturated aldehyde (IV).The condensation of (IV) with the chiral borane (V) in ethyl ether affords the chiral unsaturated alcohol (VI),which is treated with Tbdms-Cl and imidazole to provide the sill ether (VII).The oxidation of the terminal double bond of (VIII) with OsO4 and Pb(OAc)4 in THF/tBuOH/water gives the aldehyde (VIII),which is condensed with the phosphorane (IX) in refluxing benzene to yield the carboxylic acid (X).The reduction of (X) with DIBAL in THF affords the carbinol (XI),which is reduced by reaction with CCl4 and PPh3,followed by a reductive dechlorination with LiBHEt3,to furnish the dimethylated olefin (XII).Hydroxylation of the terminal double bond of (XII) with 9-BBN in THF gives the primary alcohol (XIII),which is treated with I2 and PPh3 in ethyl ether/CH3CN to yield the iodo derivative (XIV).The condensation of (XIV) with the chiral 1-(propylideneamino)pyrrolidine (XV) by means of LDA in THF affords intermediate (XVI),which is converted into the nitrile (XVII) by reaction with monoperoxyphthalic acid magnesium salt (MMPP) in MeOH.Finally this compound is reduced with DIBAL in toluene to afford the target aldehyde intermediate (XVIII).
合成路线:The condensation of 2,2-dimethyl-3-oxopentanal (XIX) with the chiral borane (V) in ethyl ether gives the chiral hydroxyketone (XX),which is treated with Tbdms-OTf and lutidine in dichloromethane to yield the silyl ether (XXI).Ozonolysis of the terminal double bond of (XXI) affords the aldehyde (XXII),which is oxidized to the carboxylic acid (XXIII) with NaClO2.The condensation of (XXIII) with the reported intermediate aldehyde (XVIII) by means of LDA in THF provides the hydroxyacid (XXIV),which is silylated with Tbdms-OTf and lutidine in dichloromethane to furnish the fully silylated compound (XXV).The hydrolysis of the silyl ester of (XXV) with K2CO3 in methanol gives the carboxylic acid (XXVI),which is selectively desilylated with TBAF in THF to yield the hydroxyacid (XXVII).The macrolactonization of (XXVII) by treatment with 2,4,6-trichlorobenzoyl chloride and TEA in THF,followed by a treatment with DMAP in toluene,affords the silylated macrolactone (XXVIII).
合成路线:Compound (XXVIII) is deprotected with TFA in CH2Cl2 to provide the dihydroxymacrolactone (XXIX).Finally,this compound is epoxidated with methyl(trifluoromethyl)dioxirane (XXX) or MCPBA to furnish the target epothilone B.
合成路线:The oxoacid intermediate (VI) has been obtained as follows: The condensation of 2,2-dimethyl-3-oxopentanal (I) with (+)-diisopinocampheyl(allyl)borane (II) gives the chiral 5(S)-hydroxy-4,4-dimethyl-7-octen-3-one (III),which is protected with Tbdms-OTf,yielding the silyl ether (IV).The ozonolysis of (IV) in dichloromethane affords the aldehyde (V),which is finally oxidized with NaClO2 in tert-butanol/water to provide the target oxoacid intermediate (VI).
合成路线:The intermediate phosphonium salt (XVI) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (VII) with DIBAL in dichloromethane gives the corresponding aldehyde (VIII),which is condensed with the phosphorane (IX) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (X).The allylation of (X) with (+)-diisopinocampheyl(allyl)borane (II) affords the chiral secondary alcohol (XI),which is protected with Tbdms-Cl and imidazole in DMF,providing the silyl ether (XII).The oxidation of the terminal double bond of (XII) with OsO4 and Pb(OAc)4 in THF/tert-butanol/water gives rise to the aldehyde (XIII),which is reduced with NaBH4 in methanol to give the corresponding primary alcohol (XIV).The reaction of (XIV) with I2,PPh3 and imidazole in ethyl ether/acetonitrile yields the expected iodo derivative (XV),which is finally condensed with PPh3 at 100 C to afford the desired intermediate phosphonium salt (XVI).
合成路线:Assembly of the final product: The condensation of SAMP hydrazone (XVII) with 4-(benzyloxy)butyl iodide (XVIII) by means of LDA in THF gives the chiral 2-methylhexanal hydrazone (XIX),which is ozonolyzed in dichloromethane,yielding the free aldehyde (XX).The reduction of (XX) with NaBH4 in methanol affords the corresponding alcohol (XXI),which is protected with Tbdms-Cl and TEA in dichloromethane,providing the silyl ether (XXII).The hydrogenolysis of (XXII) with H2 over Pd/C in THF furnishes the alcohol (XXIII),which is oxidized to the aldehyde (XXIV) with oxalyl chloride,DMSO and TEA in dichloromethane.The methylation of aldehyde (XXIV) with Me-MgBr in THF gives the secondary alcohol (XXV),which is oxidized with tetrapropylammonium perruthenate (TPAP) in dichloromethane,yielding the methyl ketone (XXVI).The condensation of ketone (XXVI) with the intermediate phosphonium salt (XVI) by means of NaHMDS in THF gives the silylated diol (XXVII),which is selectively monodesilylated with CSA in dichloromethane/methanol to yield the primary alcohol (XXVIII).The oxidation of (XXVIII) with SO3/pyridine,DMSO and TEA in dichloromethane affords the corresponding aldehyde (XXIX),which is condensed with the oxoacid intermediate (VI) by means of LDA in THF to provide the linear heptadecadienoic acid (XXX) as a diastereomeric mixture that is separated at the carboxylic acid (XXXII) step.
合成路线:The fully silylation of (XXX) with Tbdms-OTf and lutidine in dichloromethane gives the tetrasilyloxy compound (XXXI).The stepwise desilylation first with K2CO3 in methanol to yield the carboxylic acid (XXXII),and then with TBAF in THF,affords the hydroxyacid (XXXIII).The macrolactonization of (XXXIII) was carried out with the Yamaguchi method using 2,4,6-trichlorobenzoyl chloride,TEA and DMAP in THF to yield the silylated macrolactone (XXXIV),which is deprotected with TFA in dichloromethane to afford the dihydroxymacrolactone (XXXV).Finally,the double bond of (XXXV) is epoxidated with methyl(trifluoromethyl)dioxirane (XXXVI) in acetonitrile to provide the target epothilone B.
合成路线:The condensation of the known ketone (XVII) with aldehyde (XVIII) by means of LDA in THF gives the hydroxyketone (XIX),which is silylated with Tbdms-OTf and TEA in dichloromethane,yielding the silyl ether (XX).The terminal vinyl group of (XX) is cleaved oxidatively by means of OsO4 and NaIO4 in THF/water,affording the aldehyde (XXI),which is oxidized to acid (XXII) by means of NaClO2 in t-butanol/water.Acid (XXII) is esterified to methyl ester (XXIII),which is selectively deprotected at the Pmb group by hydrogenation with H2 over Pd/C in ethanol to provide the primary alcohol (XXIV).The oxidation of (XXIV) with tetrapropylammonium perruthenate (TPAP) furnishes the aldehyde (XXV),which is submitted to a Wittig condensation with the intermediate phosphonium salt (XVI) by means of LiHMDS in THF to give the adduct (XXVI).The hydrolysis of the ester group of (XXVI) with NaOH in warm isopropanol yields the carboxylic acid (XXVII),which is selectively deprotected by means of TBAF in THF to afford the hydroxyacid (XXVIII).
合成路线:Synthesis of intermediate ketone (XVIII): The reaction of 2,2-dimethyl-3-oxopentanal (XVI) with (+)-allyldi(isopinocampheyl)borane in ethyl ether gives the chiral beta-hydroxyketone (XVII),which is silylated with Tbdms-OTf and lutidine in dichloromethane to afford the desired intermediate ketone (XVIII).
合成路线:The aldol condensation of 2,2-dimethyl-3-oxopentanal (I) with acetylsultam (II) by means of Et3B/OTf and DIEA gives the aldol adduct (III),which is treated with Tbdms-OTf to yield the silyl ether (IV).The TiCl4 catalyzed aldol reaction between ketone (IV) with the intermediate aldehyde (V) affords the aldol adduct (VI),which is treated with Tbdms-OTf to provide the silylated adduct (VII).Finally the cleavage of the sultam group of (VII) by means of LiO2H furnishes the already known carboxylic acid intermediate (VIII)
合成路线:The synthesis of the intermediate chiral aldehyde (XVIII) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid methyl ester (I) with DIBAL in dichloromethane gives the aldehyde (II),which by condensation with phosphorane (III) in refluxing benzene yields the unsaturated aldehyde (IV).The condensation of (IV) with the chiral borane (V) in ethyl ether affords the chiral unsaturated alcohol (VI),which is treated with Tbdms-Cl and imidazole to provide the sill ether (VII).The oxidation of the terminal double bond of (VIII) with OsO4 and Pb(OAc)4 in THF/tBuOH/water gives the aldehyde (VIII),which is condensed with the phosphorane (IX) in refluxing benzene to yield the carboxylic acid (X).The reduction of (X) with DIBAL in THF affords the carbinol (XI),which is reduced by reaction with CCl4 and PPh3,followed by a reductive dechlorination with LiBHEt3,to furnish the dimethylated olefin (XII).Hydroxylation of the terminal double bond of (XII) with 9-BBN in THF gives the primary alcohol (XIII),which is treated with I2 and PPh3 in ethyl ether/acetonitrile to yield the iodo derivative (XIV).The condensation of (XIV) with the chiral 1-(propylideneamino)pyrrolidine (XV) by means of LDA in THF affords intermediate (XVI),which is converted into the nitrile (XVII) by reaction with monoperoxyphthalic acid magnesium salt (MMPP) in methanol.Finally,this compound is reduced with DIBAL in toluene to afford the target aldehyde intermediate (XVIII).
合成路线:The condensation of 2,2-dimethyl-3-oxopentanal (XIX) with the chiral borane (V) in ethyl ether gives the chiral hydroxyketone (XX),which is treated with Tbdms-OTf and lutidine in dichloromethane to yield the silyl ether (XXI).Ozonolysis of the terminal double bond of (XXI) affords the aldehyde (XXII),which is oxidized to the carboxylic acid (XXIII) with NaClO2.The condensation of (XXIII) with the reported intermediate aldehyde (XVIII) by means of LDA in THF provides the hydroxyacid (XXIV),which is silylated with Tbdms-OTf and lutidine in dichloromethane to furnish the fully silylated compound (XXV).The hydrolysis of the silyl ester of (XXV) with K2CO3 in methanol gives the carboxylic acid (XXVI),which is selectively desilylated with TBAF in THF to yield the hydroxyacid (XXVII).The macrolactonization of (XXVII) by treatment with 2,4,6-trichlorobenzoyl chloride and TEA in THF,followed by a treatment with DMAP in toluene,affords the silylated macrolactone (XXVIII),which is finally deprotected with TFA in dichloromethane to provide the target epothilone D.
合成路线:The oxoacid intermediate (VI) has been obtained as follows: The condensation of 2,2-dimethyl-3-oxopentanal (I) with (+)-diisopinocampheyl(allyl)borane (II) gives the chiral 5(S)-hydroxy-4,4-dimethyl-7-octen-3-one (III),which is protected with Tbdms-OTf,yielding the silyl ether (IV).The ozonolysis of (IV) in dichloromethane affords the aldehyde (V),which is finally oxidized with NaClO2 in tert-butanol/water to provide the target oxoacid intermediate (VI).
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. 201049-37-8››