Wołczański Grzegorz, Lisowski Marek
Faculty of Chemistry, University of Wrocław, F. Joliot-Curie 14, 50-383, Wrocław, Poland.
J Pept Sci. 2018 Aug;24(8-9):e3091. doi: 10.1002/psc.3091. Epub 2018 Jun 3.
N-(tert-butyloxycarbonyl) or N-(9-fluorenylmethoxycarbonyl) dipeptides with C-terminal (Z)-α,β-didehydrophenylalanine (∆ Phe), (Z)-α,β-didehydrotyrosine (∆ Tyr), (Z)-α,β-didehydrotryptophan (∆ Trp), (Z)-α,β-didehydromethionine (∆ Met), (Z)-α,β-didehydroleucine (∆ Leu), and (Z/E)-α,β-didehydroisoleucine (∆ Ile) were synthesised from their saturated analogues via oxidation of intermediate 2,5-disubstituted-oxazol-5-(4H)-ones (also known as azlactones) with pyridinium tribromide followed by opening of the produced unsaturated oxazol-5-(4H)-one derivatives in organic-aqueous solution with a catalytic amount of trifluoroacetic acid or by a basic hydrolysis. In all cases, a very strong preference for Z isomers of α,β-didehydro-α-amino acid residues was observed except of the ΔIle, which was obtained as the equimolar mixture of Z and E isomers. Reasons for the (Z)-stereoselectivity and the increased stability of the aromatic α,β-didehydro-α-amino acid residue oxazol-5-(4H)-ones over the corresponding aliphatic ones are also discussed. It is the first use of such a procedure to synthesise peptides with the C-terminal unsaturated residues and a peptide with 2 consecutive ΔPhe residues. This approach is very effective especially in the synthesis of peptides with aliphatic α,β-didehydro-α-amino acid residues that are difficult to obtain by other methods. It allowed the first synthesis of the ∆Met residue. It is also more cost-effective and less laborious than other synthesis protocols. The dipeptide building blocks obtained were used in the solid-phase synthesis of model peptides on a polystyrene-based solid support. Peptides containing aromatic α,β-didehydro-α-amino acid residues were obtained with PyBOP or TBTU as a coupling agent with good yields and purities. In the case of aliphatic α,β-didehydro-α-amino acid residues, a good efficiency was achieved only with DPPA as a coupling agent.
N-（叔丁氧羰基）或N-（9-芴甲氧羰基）二肽，其C端为（Z）-α，β-二脱氢苯丙氨酸（∆Phe）、（Z）-α，β-二脱氢酪氨酸（∆Tyr）、（Z）-α，β-二脱氢色氨酸（∆Trp）、（Z）-α，β-二脱氢甲硫氨酸（∆Met）、（Z）-α，β-二脱氢亮氨酸（∆Leu）以及（Z/E）-α，β-二脱氢异亮氨酸（∆Ile），是通过用三溴化吡啶氧化中间体2,5-二取代-恶唑-5-（4H）-酮（也称为氮杂内酯），然后在有机水溶液中用催化量的三氟乙酸或通过碱性水解使生成的不饱和恶唑-5-（4H）-酮衍生物开环，从它们的饱和类似物合成得到的。在所有情况下，除了∆Ile是以Z和E异构体的等摩尔混合物形式获得外，均观察到对α，β-二脱氢-α-氨基酸残基的Z异构体有非常强烈的偏好。还讨论了（Z）-立体选择性以及芳香族α，β-二脱氢-α-氨基酸残基恶唑-5-（4H）-酮比相应脂肪族恶唑-5-（4H）-酮稳定性增加的原因。这是首次使用这种方法合成具有C端不饱和残基的肽以及具有2个连续∆Phe残基的肽。这种方法非常有效，特别是在合成用其他方法难以获得的具有脂肪族α，β-二脱氢-α-氨基酸残基的肽时。它实现了∆Met残基的首次合成。与其他合成方案相比，它还更具成本效益且更省力。所得到的二肽构建块用于在聚苯乙烯基固相载体上固相合成模型肽。以PyBOP或TBTU作为偶联剂可获得含有芳香族α，β-二脱氢-α-氨基酸残基的肽，产率和纯度良好。对于脂肪族α，β-二脱氢-α-氨基酸残基，仅以DPPA作为偶联剂时才能获得良好的效率。
