固相多肽合成中Dmab保护基的脱除研究
|
摘要
在固相多肽合成中,Dmab作为羧基保护基具有脱保护条件温和、步骤简便、选择性高的特点,但有时脱保护效率并不稳定.为此,基于Fmoc/t Bu/Dmab三维正交保护策略,利用固相多肽合成技术设计并合成了4个肽树脂,对固相多肽合成中Glu和Asp主链和侧链羧基的Dmab保护基脱除规律进行了研究.结果显示,树脂上α-ODmab的脱保护快速、完全,β-ODmab和γ-ODmab脱保护反应较慢,可以检测到相应的中间产物(4-氨基苄酯肽),推测脱保护效率由快到慢依次为α-ODmab>β-ODmab>γ-ODmab.该结果表明Dmab作为α-COOH保护基具有较高的应用价值,但用于β-COOH和γ-COOH保护时,其脱保护条件尚不成熟.
Dmab was a protecting group of carboxyl with the advantages of rapid and chemoselective removal in solid phase peptide synthesis( SPPS),but the efficiency of deprotection of Dmab was not stable sometimes. Therefore, based on the Fmoc/t Bu/Dmab orthogonal protection strategy, four peptide resins were synthesized by SPPS,and the deprotection reaction condition of Dmab in SPPS was studied. The results showed that the α-ODmab of Glu and Asp could be removed quickly and completely on the peptide resin,but the intermediate product of 4-aminobenzyl ester peptide could be detected after the deprotective reaction of β-ODmab of Asp and γ-ODmab of Glu. The efficiency of deprotection of Dmab could be deduced as α-ODmab > β-ODmab > γ-ODmab. In conclusion,the Dmab protecting group held promise in SPPS,especially in the synthesis of head-to-tail cyclic peptides,but was not enough ideal in the synthesis of side-chain cyclic peptides or modified peptides.
Dmab was a protecting group of carboxyl with the advantages of rapid and chemoselective removal in solid phase peptide synthesis( SPPS),but the efficiency of deprotection of Dmab was not stable sometimes. Therefore, based on the Fmoc/t Bu/Dmab orthogonal protection strategy, four peptide resins were synthesized by SPPS,and the deprotection reaction condition of Dmab in SPPS was studied. The results showed that the α-ODmab of Glu and Asp could be removed quickly and completely on the peptide resin,but the intermediate product of 4-aminobenzyl ester peptide could be detected after the deprotective reaction of β-ODmab of Asp and γ-ODmab of Glu. The efficiency of deprotection of Dmab could be deduced as α-ODmab > β-ODmab > γ-ODmab. In conclusion,the Dmab protecting group held promise in SPPS,especially in the synthesis of head-to-tail cyclic peptides,but was not enough ideal in the synthesis of side-chain cyclic peptides or modified peptides.
引文
[1]BRIAND B,KOTZUR N,HAGEN V,et al.A new photolabile carboxyl protecting group for native chemical ligation[J].Tetrahedron Letters,2008,49(1):85-87.
[2]CONROY T,JOLLIFFE K A,PAYNE R J.Synthesis of N-linked glycopeptides via solid-phase aspartylation[J].Organic&Biomolecular Chemistry,2010,8(16):3723-33.
[3]XU Y,WANG T,GUAN C J,et al.Dmab/iv Dde protected diaminodiacids for solid-phase synthesis of peptide disulfide-bond mimics[J].Tetrahedron Letters,2017,58:1677-1680.
[4]WANG T,KONG Y F,XU Y,et al.Efficient synthesis of hydrocarbon-bridged diaminodiacids through nickel-catalyzed reductive cross-coupling[J].Tetrahedron Letters,2017,58:3970-3973
[5]CHAN W C,BYCROFT B W,EVANS D J,et al.A novel4-aminobenzyl ester-based carboxy-protecting group for synthesis of atypical peptides by Fmoc-Butsolid-phase chemistry[J].Journal of the Chemical Society,Chemical Communications,1995,21:2209-2210.
[6]JOHNSON T,LILEY M,CHEESERIGHT T J,et al.Problems in the synthesis of cyclic peptides through use of the Dmab protecting group[J].Journal of the Chemical Society,Perkin Transactions,2000,16:2811-2820.
[7]CONROY T,JOLLIFFE K A,PAYNE R J.Efficient use of the Dmab protecting group:applications for the solid-phase synthesis of N-linked glycopeptides[J].Organic&Biomolecular Chemistry,2009,7(11):2255-2258.
[8]CUDIC M,WADE J D,OTVOS L.Convenient synthesis of a head-to-tail cyclic peptide containing an expanded ring[J].Tetrahedron Letters,2000,41:4527-4531.
[9]GONCALVES M,ESTIEU-GIONNET K,LAIN G,et al.On-resin cyclization of a head-to-tail cyclopeptide using an allyldimethylsilyl polys resin[J].Tetrahedron,2005,61:7789-7795.
[10]BERTHELOT T,GONCALVES M,LAIN G,et al.New strategy towards the efficient solid phase synthesis of cyclopeptides[J].Tetrahedron,2006,62(6):1124-1130.
[2]CONROY T,JOLLIFFE K A,PAYNE R J.Synthesis of N-linked glycopeptides via solid-phase aspartylation[J].Organic&Biomolecular Chemistry,2010,8(16):3723-33.
[3]XU Y,WANG T,GUAN C J,et al.Dmab/iv Dde protected diaminodiacids for solid-phase synthesis of peptide disulfide-bond mimics[J].Tetrahedron Letters,2017,58:1677-1680.
[4]WANG T,KONG Y F,XU Y,et al.Efficient synthesis of hydrocarbon-bridged diaminodiacids through nickel-catalyzed reductive cross-coupling[J].Tetrahedron Letters,2017,58:3970-3973
[5]CHAN W C,BYCROFT B W,EVANS D J,et al.A novel4-aminobenzyl ester-based carboxy-protecting group for synthesis of atypical peptides by Fmoc-Butsolid-phase chemistry[J].Journal of the Chemical Society,Chemical Communications,1995,21:2209-2210.
[6]JOHNSON T,LILEY M,CHEESERIGHT T J,et al.Problems in the synthesis of cyclic peptides through use of the Dmab protecting group[J].Journal of the Chemical Society,Perkin Transactions,2000,16:2811-2820.
[7]CONROY T,JOLLIFFE K A,PAYNE R J.Efficient use of the Dmab protecting group:applications for the solid-phase synthesis of N-linked glycopeptides[J].Organic&Biomolecular Chemistry,2009,7(11):2255-2258.
[8]CUDIC M,WADE J D,OTVOS L.Convenient synthesis of a head-to-tail cyclic peptide containing an expanded ring[J].Tetrahedron Letters,2000,41:4527-4531.
[9]GONCALVES M,ESTIEU-GIONNET K,LAIN G,et al.On-resin cyclization of a head-to-tail cyclopeptide using an allyldimethylsilyl polys resin[J].Tetrahedron,2005,61:7789-7795.
[10]BERTHELOT T,GONCALVES M,LAIN G,et al.New strategy towards the efficient solid phase synthesis of cyclopeptides[J].Tetrahedron,2006,62(6):1124-1130.