衍生于手性双二茂铁乙胺的单齿亚磷酰胺配体在不对称催化氢化中的应用

研究了衍生于手性双二茂铁乙胺的手性单齿亚磷酰胺配体的铑络合物催化剂在烯酰胺、β-脱氢氨基酸酯、衣康酸酯以及α-脱氢氨基酸酯的不对称氢化中的应用,结果显示该催化剂具有较好的催化性能,对烯酰胺类底物最高获得了96%的ee值,对β-脱氢氨基酸酯类底物最高获得了86%的ee值,对衣康酸酯最高获得了75%的ee值,对α-脱氢氨基酸酯类底物最高获得了95%的ee值.     

β-模拟肽的构象限制在药物设计中的应用

传统肽类药物在体内环境下易水解,具有不稳定性,以β-氨基酸为基本单位的β-肽相比传统的α-肽,药代动力学参数更加良好,因此蕴藏更大的药物开发价值。β-氨基酸构象限制后,可发展为β-模拟肽。构象限制的目的是使β-模拟肽链趋向于形成固定的二级结构,按特定方式折叠,最终具备理想的三维空间结构,嵌合于特定的酶和受体,从而提高目标肽的生物活性和代谢稳定性。本文主要综述β-模拟肽局部修饰和肽链整体环化的构象限制方法以及限制后生物活性或物理化学参数的变化,以此为β-肽类药物的设计原则和方法提供指导,减少设计盲目性。     

海藻糖抑制淀粉质多肽42构象转变的分子动力学模拟

应用分子动力学模拟方法研究了海藻糖抑制淀粉质多肽42(Aβ42)构象转变的分子机理.结果表明,海藻糖溶液浓度对Aβ42构象转变具有非常重要的影响.在水和低浓度海藻糖溶液(0.18mol·L-1)中,Aβ42可由初始的α-螺旋结构转变成β-折叠的二级结构;但海藻糖浓度为0.37mol·L-1时即可有效抑制Aβ42的构象转变.这是因为海藻糖利用其优先排阻作用使水分子在多肽周围0.2nm内富集,而其自身却在距离多肽0.4nm的位置附近团聚.另外,海藻糖还可通过降低多肽间的疏水相互作用,减少多肽分子内远距离的接触,有效抑制多肽的疏水塌缩和构象转变.上述分子模拟的结果对于进一步合理设计阿尔茨海默病的高效抑制剂具有非常重要的理论指导意义.     

2-(N-三氟乙酰-N-三甲基硅烷基)氨基-3-三甲基硅烷氧基-羧酸三甲基硅烷酯和2-(N-三氟乙酰)-2,3-脱氢氨基酸的合成

利用三氟甲基磺酸三甲基硅烷酯, 我们合成了一种新的、化学活性很高的合成中间产物2-(N-三氟乙酰-N-三甲基硅烷基)氨基-1, 1-二(三甲基硅烷氧基)乙烯。脂肪醛或芳香醛发生碳碳成键的加成反应, 生成β碳原子上带有易离去基团三甲基硅烷氧基、N原子上带有保护基团三氟乙酰基的α氨基酸三甲基硅烷酯。消除反应得到了一个合成α、β脱氢氨基酸的可行途径。这类化合物是合成复杂多肽和肽生物碱的基元物。     

α-氟-β-氨基酸酯的合成

采用简易方法从取代苯乙酮出发制得α-氟-β-脱氢氨基酸酯;在N,N-二甲基甲酰胺存在下用三氯硅烷将其还原,高收率和非对映选择性地合成了α-氟-β-氨基酸酯,其结构经1H NMR,13C NMR和MS确证。     

手性辅基诱导β-脱氢氨基酸酯的非均相不对称氢化（英文）

研究了手性辅基诱导Pt/Al_2O_3催化的β-脱氢氨基酸酯的非均相不对称氢化,成功地氢化了一系列β-脱氢氨基酸酯的底物,得到了很好的转化率和dr值(dr值可高达5.2∶94.8).提供了一种非常高效、便捷的关于β-脱氢氨基酸酯的不对称氢化方法,产物可以作为西他列汀药物重要中间体.     

多肽与朊蛋白相互作用研究

朊病毒病是一类累及多种动物和人类中枢神经系统退行性疾病,但至今针对这类疾病尚无有效的治疗方法.考虑到在180位的缬氨酸突变为异亮氨酸的180I突变蛋白的突变位点与朊蛋白181位的糖基化位点非常接近,其生物化学性质对朊病毒病的影响非常重要.本文针对180I突变蛋白的182-190段序列设计了KNFTK、KTDVE、EMMKE和EVVKK等四种αxyzβ型多肽.研究发现,四种多肽中只有EVVKK能稳定蛋白的构象,同时诱导β-折叠向α-螺旋的转变,而其他三种蛋白对180I的结构基本没有影响.该结论对于开发多肽药物并进一步用于临床治疗具有一定的借鉴作用.     

五氯化磷辅助下氨基酸的自组装成肽反应研究

L-α-氨基酸和D-α-氨基酸可与五氯化磷直接发生磷酰化反应，随后自组装成多肽，但β-氨基酸不能成肽，DL-α-氨基酸成肽困难；在SOCl2存在下，α-氨基酸也不能成肽，用电喷雾质谱研究了氨基酸的自组装反应，反应过程中有五元环状的氨基酸五配位磷中间体生成，使用硅烷基保护的氨基酸，在^31PNMR中可观察到五配位磷中间体。     

五氯化磷辅助下氨基酸的自组装成肽反应研究

L-α-氨基酸和D-α-氨基酸可与五氯化磷直接发生磷酰化反应，随后自组装成多肽，但β-氨基酸不能成肽，DL-α-氨基酸成肽困难；在SOCl2存在下，α-氨基酸也不能成肽，用电喷雾质谱研究了氨基酸的自组装反应，反应过程中有五元环状的氨基酸五配位磷中间体生成，使用硅烷基保护的氨基酸，在^31PNMR中可观察到五配位磷中间体。     

含氨基酸和多肽的树枝状化合物的合成与分子动力学模拟研究

合成了一系列以氨基酸和多肽为外周功能基团的醚-酰胺型树枝状化合物, 化合物结构经NMR, ESI-MS确证. 并对该系列化合物在水溶液中的状态进行了分子动力学模拟. 结果显示: 化合物的构象与原子数相关, 随原子数的增加有逐渐接近球形的趋势; 氨基酸α碳原子径向分布显示, 随着外周功能基团的增大, 分子可能存在部分卷曲构象.     

Transformations of N-heteroarylformamidines into derivatives of β-heteroarylamino-α,β-dehydro-α-amino acids, β-heteroarylamino-α-amino acids,and dipeptides

Transformations of N'-heteroaryl-N,N-dimethylformamidines 1 as a general method for the preparation of β-heteroarylamino-α,β-dehydro-α-amino acids, β-heteroarylamino-α-amino acid derivatives 5–9 , and dipeptides 10 , are described.     

The synthesis of β-heteroarylamino-α,β-dehydro-α-amino acid and β-heteroarylamino-α-amino acid derivatives

From heteroarylaminomethyleneoxazolones 4 , obtained from N-heteroarylformamidines 2 and 2-phenyl-5-oxo-4,5-dihydro-1,3-oxazole ( 3 ), the following β-heteroarylamino-α,β-dehydro-α-amino acid derivatives were prepared: methyl 8 and ethyl esters 9 , amides 10 and 11 , hydrazides 12 , and azides 15 . By catalytic hydrogenation the compounds 4 were converted into β-heteroarylamino substituted amides 18 and β-heteroarylamino-α-amino acids 20 .     

The Michael Addition of Sulfur Anions to β,β-Substituted Nα-Formyl-α, β-Dehydroamino Acid Esters

The addition of lithium benzylthiolates to N^α,-formyl-α,β-dehydro-α-amino acid esters gave protected N^α-formyl-β-S-benzyl-β,β-dialkylcysteine esters. Hydrolysis and N^α-protection produced β,β-dialkyl-cysteines which can be used for peptide synthesis.     

A new convenient synthesis of N-acyl-2-(dimethoxyphosphoryl)glycinates

Easily accessible N-acyl-2-triphenylphosphonioglycinate tetrafluoroborates react smoothly with trimethylphosphite in the presence of methyltriphenylphosphonium iodide to give N-acyl-2-(dimethoxyphosphoryl)glycinates in good or very good yields. The dimethoxyphosphorylglycinates may be isolated by column chromatography, or used directly for the Wadsworth-Emmons synthesis of α,β-dehydro-α-amino acids in a one-pot procedure without purification.     

Preparation of α,β-dehydro-β-amino acid derivatives by tin-promoted addition of malonates to simple nitriles

Simple aliphatic and aromatic nitriles undergo reaction with malonate esters in the presence of tin(IV) chloride to give derivatives of α,β-dehydro-β-amino acids. The same products are obtained through use of bromomalonate esters.     

Trading N and O. Part 4: Asymmetric synthesis of syn-β-substituted-α-amino acids

A total of nine enantiopure syn-β-substituted-α-amino acids have been synthesised, comprising both syn-β-hydroxy-α-amino acids and syn-β-fluoro-α-amino acids. The key step in the synthetic strategy towards these syn-β-substituted-α-amino acids involves a stereospecific rearrangement, which proceeds via the intermediacy of the corresponding aziridinium ions. The requisite enantiopure syn-α-hydroxy-β-amino esters were prepared via asymmetric aminohydroxylation of the corresponding α,β-unsaturated esters followed by epimerisation of the resultant anti-α-hydroxy-β-amino esters at the C(2)-position. Subsequent activation of the α-hydroxy moiety as a leaving group followed by displacement by the β-amino substituent gave the corresponding aziridinium species. Regioselective in situ ring-opening of the aziridinium intermediates with either water or fluoride gave the corresponding syn-β-hydroxy-α-amino ester or syn-β-fluoro-α-amino ester, respectively, and N-deprotection and ester hydrolysis afforded the target syn-β-substituted-α-amino acids as single diastereoisomers in good overall yield.     

The structure of β-heteroaryl-α,β-dehydro-α-amino acid derivatives,intermediates in the synthesis of fused pyran-2-ones. Substituted methyl (Z)-2-benzoylamino-3-(5-oxopyrazolinyl-4)propenoates

It was shown by some chemical transformations that β-heteroaryl-α,β-dehydro-α-amino acid derivatives 3 and 7 , obtained from pyrazolone derivatives 1 or 6 and 2 , exist in Z-forms. The structure of 7 was confirmed by X-ray analysis.     

Über einen neuartigen synthetischen Zugang zu β,γ-ungesättigten α-Aminocarbonsäuren

A New Synthetic Route to β,α-Unsaturated α-Amino Acids A versatile new synthetic pathway for the preparation of βγ-unsaturated α-amino acids ( 1 ) is presented. Cu(I)-catalyzed addition of ethyl isocyanoacetate ( 2 ) to α-chloro carbonyl compounds ( 3 ) gives 5-chloroalkyl-2-oxazolin-4-carboxylates ( 4 ) in high yields. A reductive elimination on 4 by means of zinc yields the N-formyl derivatives of βγ-unsaturated α-amino carboxylates ( 5 ), which on acid hydrolysis lead to the free amino acids 1 . The five different βγ-dehydro-α-amono acids 1b-1f have been prepared by this method.     

Asymmetric syntheses of the N-terminal α-hydroxy-β-amino acid components of microginins 612, 646 and 680

The asymmetric syntheses of the N-terminal α-hydroxy-β-amino acid components of microginins 612, 646 and 680 are reported. Conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to the requisite (E)-α,β-unsaturated ester followed by in situ enolate oxidation with (?)-(camphorsulfonyl)oxaziridne (CSO) gave the corresponding anti-α-hydroxy-β-amino esters. Sequential Swern oxidation followed by diastereoselective reduction gave the corresponding syn-α-hydroxy-β-amino esters. Subsequent N-debenzylation (i.e., hydrogenolysis for microginin 612, and NaBrO₃-mediated oxidative N-debenzylation for microginins 646 and 680) followed by acid catalysed ester hydrolysis gave the corresponding syn-α-hydroxy-β-amino acids, the N-terminal components of microginins 612, 646 and 680, in good yield. An analogous strategy for elaboration of the enantiopure anti-α-hydroxy-β-amino esters facilitated the asymmetric synthesis of the corresponding C(2)-epimeric α-hydroxy-β-amino acids.     

Trading N and O. Part 2: Exploiting aziridinium intermediates for the synthesis of β-hydroxy-α-amino acids

The β-hydroxy-α-amino acids (S,S)-allo-threonine, (S,S)-β-hydroxyleucine and a range of aryl substituted (S,S)-β-hydroxyphenylalanines were prepared from the corresponding enantiopure anti-α-hydroxy-β-amino esters via a rearrangement protocol, which proceeds via the intermediacy of the corresponding aziridinium ions. The starting anti-α-hydroxy-β-amino esters were prepared in >99:1 dr using our diastereoselective aminohydroxylation procedure, whereby conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to an α,β-unsaturated ester is followed by oxidation of the resultant enolate with (−)-camphorsulfonyloxaziridine. Subsequent activation of the hydroxyl group within the anti-α-hydroxy-β-amino esters promoted aziridinium ion formation [which proceeds with inversion of configuration at C(2)], and regioselective ring-opening of the intermediate aziridinium ions with H₂O [which proceeds with inversion of configuration at C(3)] gave the corresponding anti-β-hydroxy-α-amino esters as single diastereoisomers (>99:1 dr). Deprotection of these substrates via sequential hydrogenolysis and ester hydrolysis gave the corresponding β-hydroxy-α-amino acids in good yield and high diastereoisomeric and enantiomeric purity.