Epoxomicin, BU-4061T

环氧酶素Chemical Name: 2-[Acetyl-(N-methyl)isoleucyl-isoleucyl-threonyl-leucyl]-2(R)-methyloxyrane
CAS No. 134381-21-8
项目整合开发状态: Preclinical
项目研究机构: Bristol-Myers Squibb (Originator), Yale University (Originator)
合成路线:Coupling of threonine benzyl ester (I) to Fmoc-Ile-OH (A) with HBTU,HOBt and DIEA in dichloromethane followed by protection of the hydroxyl group with TBDPS-Cl and imidazole in THF affords protected dipeptide (II).Removal of the Fmoc group of (II) with piperidine/DMF followed by coupling of Fmoc-N-Me-Ile-OH (B) with HBTU,HOBt and DIEA gives fully protected tripeptide (III),which is treated with piperidine/DMF for Fmoc removal and acetylated by means of Ac2O,DIEA in dichloromethane to furnish (IV).Debenzylation of (IV) by hydrogenolysis over Pd/C provides intermediate (V).Addition of 2-bromopropene (VII) and t-BuLi to the Boc-leucine Weinreb amide (VI) in Et2O yields alpha',beta'-unsaturated ketone (VIII),which is oxidized by treatment with H2O2 and DIEA in H2O/benzonitrile/MeOH to afford a mixture of epoxides from which (IX) is separated by column chromatography.Boc deprotection and coupling of peptide (V) with intermediate (IX) by means of TFA,HATU,HOAt,DIEA in dichloromethane,furnishes TBDPS-protected derivative (X),which is finally deprotected by treatment with TBAF in THF.

合成路线:Alternatively,a solid phase procedure can be followed: Fmoc-Thr(O-TBDMS)-OH (XI) is anchored on 2-chlorotrityl chloride resin by means of DIEA in CH2Cl2 to yield (XII),which then follows a standard solid-phase peptide synthesis (SPPS) protocol to be converted into (XIII).Peptide (XIV) is obtained by treatment of resin (XIII) with HOAc,trifluoroethanol/dichloromethane and is then coupled with intermediate (IX) to afford (XV) in the conditions described above.Finally,the TBDMS group is removed by means of TBAF in THF.