合成路线:Activation of Boc-allo-isoleucine acid (I) with CDI in THF followed by reaction with ethyl lithioacetate (II) in THF,affords beta-keto ester (III) (alternatively,(III) can be obtained as follows: formation of the corresponding methyl ester of (I) by reaction with MeI and KHCO3 in DMF,followed by reduction with NaBH4 and LiCl in THF/EtOH and subsequent Swern oxidation with pyr:SO3,Et3N and DMSO provides aldehyde (IV),which is then condensed to ethyl lithioacetate (II) in THF and finally oxidized with PDC in CH2Cl2/HOAc).Stereospecific reduction of beta-keto ester (III) with NaBH4 in EtOH affords beta-hydroxy ester (V) (1-3),which is first saponified with NaOH in EtOH and then esterified with trichloroethanol (VI) by means of DCC and DMAP in CH2Cl2,furnishing ester (VII).Removal of the Boc group of (VII) by means of HCl/dioxane yields amine derivative (VIII),which is then coupled to Boc-Thr(Bzl)-OH (IX) by means of diethyl phosphorocyanidate (DEPC) and DIEA in DMF and treated with HCl for Boc removal,allowing isolation of dipeptide (X).Coupling of (X) with Boc-MeLeu-OH (XI) -- obtained in turn by methylation of Boc-Leu-OH (XII) with MeI and NaH in THF -- with DEPC and Et3N in DMF,followed by O-protection with TBDMSCl and imidazole in DMF,provides tripeptide (XIII).Removal of the benzyl group of (XIII) by hydrogenation over Pd/C in THF affords Boc-Me-Leu-Thr-Ist(TBDMS)-OTce (XIV),which is then coupled with Z-Me-Tyr(Me)-OH (XV) by means of DMAP and DCC in CH2Cl2 to furnish depsipeptide (XVII) (protected amino acid Z-Me-Tyr(Me)-OH (XV) can be obtained in turn by methylation of Z-Tyr-OH (XVI) with MeI and NaH in THF).Deprotection of (XVII) by first treatment with Zn in THF in the presence of NH4OAc yields fragment (XVIII).
合成路线:Protection of 2-hydroxyisovaleric acid (XIX) with tert-butyldimethylsilyl chloride and imidazole in DMF,followed by condensation with Meldrum's acid (XX) by use of diethyl phosphorocyanidate (DEPC) and Et3N in THF,furnishes derivative (XXI),which is then subjected to reaction with benzyl alcohol (XXII) in refluxing benzene to afford beta-keto ester (XXIII).Next,derivative (XXIII) is methylated with MeI and NaH and its benzyl group is removed by hydrogenation over Pd/C in THF to yield carboxylic acid (XXIV).Coupling between H-Pro-OBzl.HCl (XXV) and Boc-Leu-OH (XXVI) by means of DEPC and Et3N in DMF affords dipeptide (XXVII),which is then converted into fragment (XXVIII) by first condensation with carboxylic acid (XXIV) by means of DCC,HOBt and NMM in THF/DMF and treatment with tetrabutylammonium fluoride for TBDMS protecting group removal.Coupling of fragment (XXVIII) with fragment (XVIII) by means of DCC and DMAP in CH2Cl2 furnishes linear peptide (XXIX),which is hydrogenated over Pd/C in THF and then subjected to cyclization by means of BOPCl and Et3N in CH2Cl2 to give macrolide (XXX).Next,deprotection of (XXX) with TMSOTf affords intermediate (XXXI) (didemnin A).
合成路线:Treatment of ethyl lactate (XXXII) with benzyl bromide and silver oxide in DMF gives Bzl-Lac-OH (XXXIII),which is then coupled with H-Pro-OMe (XXXIV) by means of DEPC and then saponified with NaOH in MeOH to yield derivative (XXXV).Finally,didemnin B is obtained by coupling of intermediate (XXXI) with (XXXV) by means of BOPCl and Et3N,followed by debenzylation with HCO2H and Pd in MeOH.
参考文献标题:Efficient total synthesis of didemnins A and B
文献作者:Hamada,Y.; et al.
参考来源:J Am Chem Soc 1989,111(2),669
合成路线:Activation of Boc-allo-isoleucine acid (I) with CDI in THF followed by reaction with ethyl lithioacetate (II) in THF,affords beta-keto ester (III) (alternatively,(III) can be obtained as follows: formation of the corresponding methyl ester of (I) by reaction with MeI and KHCO3 in DMF,followed by reduction with NaBH4 and LiCl in THF/EtOH and subsequent Swern oxidation with pyr:SO3,Et3N and DMSO provides aldehyde (IV),which is then condensed to ethyl lithioacetate (II) in THF and finally oxidized with PDC in CH2Cl2/HOAc).Stereospecific reduction of beta-keto ester (III) with NaBH4 in EtOH affords beta-hydroxy ester (V) (1-3),which is first saponified with NaOH in EtOH and then esterified with trichloroethanol (VI) by means of DCC and DMAP in CH2Cl2,furnishing ester (VII).Removal of the Boc group of (VII) by means of HCl/dioxane yields amine derivative (VIII),which is then coupled to Boc-Thr(Bzl)-OH (IX) by means of diethyl phosphorocyanidate (DEPC) and DIEA in DMF and treated with HCl for Boc removal,allowing isolation of dipeptide (X).Coupling of (X) with Boc-MeLeu-OH (XI) -- obtained in turn by methylation of Boc-Leu-OH (XII) with MeI and NaH in THF -- with DEPC and Et3N in DMF,followed by O-protection with TBDMSCl and imidazole in DMF,provides tripeptide (XIII).Removal of the benzyl group of (XIII) by hydrogenation over Pd/C in THF affords Boc-Me-Leu-Thr-Ist(TBDMS)-OTce (XIV),which is then coupled with Z-Me-Tyr(Me)-OH (XV) by means of DMAP and DCC in CH2Cl2 to furnish depsipeptide (XVII) (protected amino acid Z-Me-Tyr(Me)-OH (XV) can be obtained in turn by methylation of Z-Tyr-OH (XVI) with MeI and NaH in THF).Deprotection of (XVII) by first treatment with Zn in THF in the presence of NH4OAc yields fragment (XVIII).
合成路线:Protection of 2-hydroxyisovaleric acid (XIX) with tert-butyldimethylsilyl chloride and imidazole in DMF,followed by condensation with Meldrum's acid (XX) by use of diethyl phosphorocyanidate (DEPC) and Et3N in THF,furnishes derivative (XXI),which is then subjected to reaction with benzyl alcohol (XXII) in refluxing benzene to afford beta-keto ester (XXIII).Next,derivative (XXIII) is methylated with MeI and NaH and its benzyl group is removed by hydrogenation over Pd/C in THF to yield carboxylic acid (XXIV).Coupling between H-Pro-OBzl.HCl (XXV) and Boc-Leu-OH (XXVI) by means of DEPC and Et3N in DMF affords dipeptide (XXVII),which is then converted into fragment (XXVIII) by first condensation with carboxylic acid (XXIV) by means of DCC,HOBt and NMM in THF/DMF and treatment with tetrabutylammonium fluoride for TBDMS protecting group removal.Coupling of fragment (XXVIII) with fragment (XVIII) by means of DCC and DMAP in CH2Cl2 furnishes linear peptide (XXIX),which is hydrogenated over Pd/C in THF and then subjected to cyclization by means of BOPCl and Et3N in CH2Cl2 to give macrolide (XXX).Next,deprotection of (XXX) with TMSOTf affords intermediate (XXXI) (didemnin A).
合成路线:Treatment of ethyl lactate (XXXII) with benzyl bromide and silver oxide in DMF gives Bzl-Lac-OH (XXXIII),which is then coupled with H-Pro-OMe (XXXIV) by means of DEPC and then saponified with NaOH in MeOH to yield derivative (XXXV).Finally,didemnin B is obtained by coupling of intermediate (XXXI) with (XXXV) by means of BOPCl and Et3N,followed by debenzylation with HCO2H and Pd in MeOH.
参考文献标题:Synthetic studies of didemnins.II.Approaches to statine diastereomers
文献作者:Harris,B.D.; et al.
参考来源:Tetrahedron Lett 1987,28(25),2837
合成路线:Coupling of benzyloxy isovalery propionic acid (Bzl-Hip-OH) (I) with leucine trimethylsilylethyl ester (II) by means of HOBt and DCC followed by hydrogenation over Pd/C in isopropanol for benzyl protecting group removal provides dipeptide (III),which is then converted into compound (V) by first coupling to Boc-Sta(TBDMS)-OH (IV) by means of DMAP and DCC followed by removal of the TMSe group by means of TBAF.Coupling between Z-D-N-MeLeu-OH (VI) and H-Thr-OTMSe (VII) by means of N-hydroxysuccinimide (NHS) and EDC yields protected dipeptide (VIII),which is then condensed with dipeptide (IX) by means of DMAP and DCC and then treated with HCl in EtOAc for Boc removal to afford tetrapeptide (X) (in turn,dipeptide (IX) can be obtained by coupling between Boc-Pro-OH (XI) and Me2Tyr-ONb (XII) by means of EDC followed by p-nitrobenzyl removal by hydrogenation over Pd/C in HOAc).Coupling of tetrapeptide (X) with compound (V) by means of EDC,HOBt leads to formation of linear peptide (XIII),which is partially deprotected by treatment with TBAF and TFA and then cyclized by means of HOBt,EDC and NMM,providing macrolide (XIV).
合成路线:Removal of the Z protecting group of (XIV) by hydrogenation over Pd/C gives secondary amine (XV),which is then condensed with carboxylic acid derivative (XVI) by means of EDC to furnish benzyl-protected didemnin B (XX) (in turn,synthesis of (XVI) can be performed by coupling of O-benzyl lactyl azide (obtained from ethyl O-benzyl lactate (XVII)) with Pro-OMe (XVIII) to afford methyl ester (XIX),followed by saponification of the methyl ester with NaOH).Finally,didemnin B is obtained by hydrogenation of (XX) over Pd/C for benzyl group removal.
参考文献标题:Total synthesis of didemnins A,B,and C
文献作者:Rinehart,K.L.; et al.
参考来源:J Am Chem Soc 1987,109(22),6846
合成路线:Activation of Boc-allo-isoleucine acid (I) with CDI in THF followed by reaction with ethyl lithioacetate (II) in THF,affords beta-keto ester (III) (alternatively,(III) can be obtained as follows: formation of the corresponding methyl ester of (I) by reaction with MeI and KHCO3 in DMF,followed by reduction with NaBH4 and LiCl in THF/EtOH and subsequent Swern oxidation with pyr:SO3,Et3N and DMSO provides aldehyde (IV),which is then condensed to ethyl lithioacetate (II) in THF and finally oxidized with PDC in CH2Cl2/HOAc).Stereospecific reduction of beta-keto ester (III) with NaBH4 in EtOH affords beta-hydroxy ester (V) (1-3),which is first saponified with NaOH in EtOH and then esterified with trichloroethanol (VI) by means of DCC and DMAP in CH2Cl2,furnishing ester (VII).Removal of the Boc group of (VII) by means of HCl/dioxane yields amine derivative (VIII),which is then coupled to Boc-Thr(Bzl)-OH (IX) by means of diethyl phosphorocyanidate (DEPC) and DIEA in DMF and treated with HCl for Boc removal,allowing isolation of dipeptide (X).Coupling of (X) with Boc-MeLeu-OH (XI) -- obtained in turn by methylation of Boc-Leu-OH (XII) with MeI and NaH in THF -- with DEPC and Et3N in DMF,followed by O-protection with TBDMSCl and imidazole in DMF,provides tripeptide (XIII).Removal of the benzyl group of (XIII) by hydrogenation over Pd/C in THF affords Boc-Me-Leu-Thr-Ist(TBDMS)-OTce (XIV),which is then coupled with Z-Me-Tyr(Me)-OH (XV) by means of DMAP and DCC in CH2Cl2 to furnish depsipeptide (XVII) (protected amino acid Z-Me-Tyr(Me)-OH (XV) can be obtained in turn by methylation of Z-Tyr-OH (XVI) with MeI and NaH in THF).Deprotection of (XVII) by first treatment with Zn in THF in the presence of NH4OAc yields fragment (XVIII).
合成路线:Protection of 2-hydroxyisovaleric acid (XIX) with tert-butyldimethylsilyl chloride and imidazole in DMF,followed by condensation with Meldrum's acid (XX) by use of diethyl phosphorocyanidate (DEPC) and Et3N in THF,furnishes derivative (XXI),which is then subjected to reaction with benzyl alcohol (XXII) in refluxing benzene to afford beta-keto ester (XXIII).Next,derivative (XXIII) is methylated with MeI and NaH and its benzyl group is removed by hydrogenation over Pd/C in THF to yield carboxylic acid (XXIV).Coupling between H-Pro-OBzl.HCl (XXV) and Boc-Leu-OH (XXVI) by means of DEPC and Et3N in DMF affords dipeptide (XXVII),which is then converted into fragment (XXVIII) by first condensation with carboxylic acid (XXIV) by means of DCC,HOBt and NMM in THF/DMF and treatment with tetrabutylammonium fluoride for TBDMS protecting group removal.Coupling of fragment (XXVIII) with fragment (XVIII) by means of DCC and DMAP in CH2Cl2 furnishes linear peptide (XXIX),which is hydrogenated over Pd/C in THF and then subjected to cyclization by means of BOPCl and Et3N in CH2Cl2 to give macrolide (XXX).Next,deprotection of (XXX) with TMSOTf affords intermediate (XXXI) (didemnin A).
合成路线:Treatment of ethyl lactate (XXXII) with benzyl bromide and silver oxide in DMF gives Bzl-Lac-OH (XXXIII),which is then coupled with H-Pro-OMe (XXXIV) by means of DEPC and then saponified with NaOH in MeOH to yield derivative (XXXV).Finally,didemnin B is obtained by coupling of intermediate (XXXI) with (XXXV) by means of BOPCl and Et3N,followed by debenzylation with HCO2H and Pd in MeOH.
参考文献标题:Anti-tumor active cyclic peptide derived from marine organism: Synthesis,conformation and bioactivity
文献作者:Hamada,Y.; Shioiri,T.
参考来源:Kagaku Zokan 1990,(118),31
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