26-Fluoroepothilone, CGP-85715

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).

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


合成路线:The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (I) with DIBAL in dichloromethane gives the corresponding carbaldehyde (II),which is condensed with phosphorane (III) in refluxing benzene to yield the propionaldehyde (IV).The diastereocontrolled condensation of (IV) with (+)-allyl-di(isopinocampheyl)borane (V) in ethyl ether affords the chiral homoallyl alcohol (VI),which is silylated with Tbdms-Cl and imidazole to provide the silyl ether (VII).The oxidation of the terminal double bond of (VII) by means of OsO4,NaIO4 and 4-methylmorpholine N-oxide gives the 4-pentenal derivative (VIII),which is condensed with the phosphorane (IX) in refluxing benzene to yield the methyl heptadienoate (X).The reduction of (X) with DIBAL in THF affords the carbinol (XI),which is protected with trityl chloride and DMAP to provide the trityl ether (XII).The Hydroxylation of the terminal double bond of (XII) with 8-BBN and H2O2 gives the primary alcohol (XIII),which is treated with I2 and PPh3 to yield the iodo compound (XIV).The condensation of (XIV) with the hydrazone (XV) by means of LDA affords the chiral undecadienylhydrazone (XVI),which is treated with monoperoxyphthalic magnesium salt (MMPP) to provide the undecadienenitrile (XVII).The reduction of (XVII) with DIBAL in toluene gives the corresponding aldehyde (XVIII).

合成路线:The condensation of aldehyde (XVIII) with the chiral 3-heptanone derivative (XIX) by means of LDA in THF gives the heptadecadien-7-ol derivative (XX),which is silylated with Tbdms-OTf to yield the fully silylated compound (XXI).The selective desilylation of the primary OH group with HF and pyridine in THF affords the heptadecadien-1-ol derivative (XXII),which is submitted to a Swern oxidation followed by a treatment with NaClO2 to provide the carboxylic acid (XXIII).The selective desilylation of the 15-hydroxyl of (XXII) by means of TBAF in THF gives the hydroxyacid (XXIV),which is submitted to macrolactonization by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF to yield the macrolactone (XXV).The fully deprotection of (XXV) with HF and pyridine affords the hydroxymethyl macrolactone (XXVI),which is epoxidated with Ti(O-iPr)4,diethyl-L-tartrate and tBu-OOH to provide the epoxidated precursor (XXVII).Finally,this compound is treated with diethylaminosulfurtrifluoride (DAST) in dichloromethane to furnish the target fluorinated epothilone.
参考文献标题:Total synthesis of 26-hydroxy-epothilone B and related analogs via a macrolactonization based strategy
文献作者:Nicolaou,K.C.; et al.
参考来源:Tetrahedron 1998,54(25),7127