【作者】 孟凡华；

【导师】 许家喜；

【作者基本信息】 北京化工大学 ， 化学， 2012， 博士

【摘要】 膦酰肽和次膦酰肽及其衍生物作为天然肽的结构类似物，由于具有四面体结构的P-X（X=N，O）键，可以用来模拟酯和酰胺类化合物水解的过渡态，因此被广泛用作蛋白质水解酶的抑制剂，抗体酶的半抗原、以及抗菌剂、除草剂、植物生长调节剂，抗高血压药物等。该类化合物在农业和医药领域具有非常广阔的应用前景。此外，磺酰肽类化合物作为另一类重要的天然肽结构类似物，也具有重要的生物活性。目前已报道的合成次膦酰肽的方法大致分为以下几类：次膦酰氯合成法、缩合试剂合成法，混合酸酐合成法，固相合成法，酶促合成法、及改进的类Mannich合成法。前几种方法均要先合成氨基烷基次膦酸或其酯，相对合成路线较长，中间产物处理麻烦，累积产率往往并不理想。除此之外，固相合成法还存在着中间体不能进行提纯，合成的量受限制，并且传统的分析方法无法评价反应等缺点。采用酶促反应合成次膦酰肽化合物虽然能够得到较好的产率，但该方法受催化剂酶的限制，所以应用范围较小。前人采用改进的类Mannich方法合成次膦酰肽，底物的适用性不好，在酰胺的使用上多数使用氨基甲酸苄酯，限制了生成物膦酰肽结构的多样性，并且该酰胺的反应活性比普通酰胺高许多，所以反应比较容易进行。而且，氨基甲酸酯的使用也使肽链的延伸只能向氨基酸酯或羟基酸酯一侧进行，氨基膦酸只能在肽链的氨基端或羟基酸酯衍生物的羟基端，如果想从氨基次膦酸的氨基端进行延伸，还必须采用前面几种传统的方法。以上传统合成方法的不足已严重影响了对次膦酰肽类化合物生物活性的研究。因此，本文开发了一种简便、高效、直接合成次膦酰肽类化合物的方法。首先，采用该方法一锅直接合成了C末端具有α‐氨基烷基次膦酸结构的次膦酰二肽及三肽。主要以苄氧羰基（Cbz）保护的氨基酸酰胺、二肽酰胺，与不同的醛（包括脂肪醛和芳香醛）和芳基二氯化膦进行类Mannich反应，随即直接水解制得具有结构多样性的次膦酰肽类化合物，产率较高，得到的次膦酰肽均为新化合物。此外，还研究了该反应机理，通过机理确定了产物的最终构型，并对该反应过程中的立体选择性进行了合理的解释。其次，采用准四组分缩合的方法设计合成了一系列C‐次膦酰酯肽，均为新化合物。主要是以Cbz保护的氨基酸酰胺，醛、芳基二氯化膦为起始原料合成相应的次膦酰氯后，让其与不同结构的羟基酸酯进行醇解反应原位合成了具有不同结构的C‐次膦酰酯肽。并对其反应机理进行了研究，合理地解释了反应过程中副产物的形成原因以及产物立体选择性的控制机理。再者，首次合成了一系列C末端具有α‐氨基烷基次膦酸结构的杂交的磺酰次膦酰二肽。主要以Cbz保护的2‐氨基烷基磺酰胺为原料，与不同的醛及芳基二氯化膦发生类Mannich反应，反应结束后无需任何处理直接进行水解反应制得杂交的磺酰次膦酰二肽，该二肽同时具有氨基烷基次膦酸结构及氨基烷基磺酰胺结构，且产率较高。采用该方法还成功地制得了杂交的磺酰次膦酰酯肽，说明该方法也适用于该类磺酰次膦酰酯肽的合成。以上合成法均采用多组分汇聚式的合成法，直接原位合成了一系列次膦酰肽类化合物，具有原料易得，反应路线短，操作简便，产率高等优点，并且实现了产物的肽链同时向氨基次膦酸的两端分别延伸。从绿色化学的角度讲还具有原子经济性的特点。该反应对产物还具有一定的立体选择性。本文工作的研究对膦酰肽种类的开发具有重要的意义，填补了C末端具有α‐氨基烷基次膦酸结构的杂交的磺酰次膦酰二肽及磺酰次膦酰酯肽的合成空白。为科学家对该类化合物生物活性的研究奠定了丰富的物质基础。最后，本文还开发了一种高效简便地制备N-苄氧羰基‐2‐氨基烷基磺酰胺的合成方法。以邻氨基醇为原料，先后经过苄氧羰基保护、光延反应（Mitsunobu）、N-氯代丁二酰亚胺（NCS）氧化反应及氨解反应制得N-苄氧羰基2‐氨基烷基磺酰胺，采用该方法共合成出7种N-苄氧羰基-2-氨基烷基磺酰胺，其中5种为新化合物。该方法与传统合成具有类似结构的磺酰胺方法相比，不但原料无毒易得，操作简便，重现性好，而且产率较高，是目前合成氨基烷基磺酰胺的最有效方法。更多还原

【Abstract】 Phosphonopeptides and phosphinopeptides are importantphosphorus analogues of naturally occurring peptides. They have beenwidely used as enzyme inhibitors and as haptens for production ofcatalytic antibodies because they can be considered as stable mimeticsof tetrahedral transition states in ester and amide hydrolysis andformation. Several phosphonopeptides and phosphinopeptides alsoshowed antibacterial, herbicidal, plant growth regulative andantihypertensive activities. Thus, phosphonopeptides andphosphinopeptides have widely potential application prospects. Besides,sulfonopeptides, as another sulfur analogues of naturally occurringpeptides, have also important biological activities.Nowadays, there were some methods for synthesis ofphosphinopeptides, such as phosphinochloridate method, couplingreagent condensation method, mixed anhydride method, solid phasemethod, enzyme-catalyzed coupling method and Mannich-type reactionmethod and so on. Most of them utilized aminoalkylphosphinic acids ortheir derivatives as starting materials, which were generally synthesized in multi-step procedure, resulting in some disadvantages, such ascomplicated multi-step procedure of preparation, isolation andpurification of products. The overall yields from the desired peptideproducts are seldom satisfactory. In solid phase method, conventionalanalytical tools for assessing the reaction could not be used, intermediatepurifications in a multi-step synthesis were not possible and the synthesisscale was limited. Although the enzyme-catalyzed coupling ofaminoalkylphosphinate and amino ester in satisfactory yields, the methodcould not be widely used due to the restriction by the sort of catalyticalenzymes.The Mannich-type reaction using benzyl carbamate with highlyreactive activities as amide component not only reduced the variety ofphosphinopeptides but also could only extend peptide chain fromN-terminal. The conventional methods can not be applied to giveproducts with peptide chain extending from both sides. Thus, it isnecessary to develop an efficient and facile method to synthesizephosphinopeptides. Recently, we reported the Mannich-type condensationof N-Cbz protected amino amides/peptide amides, aldehydes,aryldichlorophosphines, and subsequent aminolysis with amino acidesters/peptide esters to synthesize phosphinopeptides, in which theaminoalkylphosphinic acid was located in the middle position of thepeptides. We herein present the facile synthesis of phosphinopeptides containing different structures via the multicomponent condensationreactions.Firstly, a series of phosphinopeptides containing C-terminalα-aminoalkylphosphinic acids were prepared directly in one-pot reactionsof2-(N-benzoxycarbonylamino)alkanamides/peptide amides, aldehydes,and aryldichlorophosphines in acetonitrile, followed by hydrolysis. In thecurrent method, the peptide bond was formed in a Mannich-type reaction.Through this approach, phosphinopeptides containing C-terminalα-aminoalkylphosphinic acids which have never been reported can beconveniently prepared in good yields directly from simple chemicals. Wesystematically studied the reaction mechanism through which the ultimatestructure of the product was determined.Secondly, a series of new depsiphosphinopeptides, theaminoalkylphosphinic acids were located in the middle position of thepeptides, were synthesized in satisfactory yields viapseudo-four-component condensation reaction of2-(N-benzoxy-carbonyl-amino)alkanamides/peptide amides, aldehydes, andaryldichlorophosphines, followed by in situ alcoholysis with hydroxylesters. The formation of byproducts was explained and the absoluteconfiguration of the desired products was determined via the mechanismstudies.Thirdly, we synthesized hybrid sulfonophosphinodipeptides composing of taurines and1-aminoalkylphosphinic acids for the first timein satisfactory to good yields via a convenient Mannich-type reaction ofN-benzyloxycarbonylaminoalkanesulfonamides, aldehydes, andaryldichlorophosphines, and subsequent hydrolysis. Hybriddepsisulfonophosphinopeptides were also successfully synthesized via thesimilar preparation method, indicating that the method was alsoapplicable for the synthesis of sulfonophosphinopeptides.The multicomponent convergent methods were utilized to synthesizevarious phosphinopeptides in good yields directly from simple chemicals.The method has several advantages over the traditional preparationmethod, such as short procedure, facile operation, high overall yields,atom-economic strategy. And the peptide chain extending from both sidesof the aminophosphonic acids was achieved. Stereoselectivity in theproducts was also observed. Our work was supplementary to thesynthesis of hybrid sulfonophosphinodipeptides anddepsisulfonophosphinopeptides with C-terminal α-aminoalkyl-phosphinates and offered excellent foundation for the research on thebiological activities of these compounds.Finally, we have developed a highly efficient and convenientmethod for the synthesis of N-Cbz-β-aminoalkanesulfonamides fromvicinal amino alcohols via the N-Cbz protection, the Mitsunobuesterification, N-chlorosuccinimide oxidation, and ammonolysis process. The current method is an efficient, nontoxic, simple, and reproducibleroute to synthesize N-Cbz-β-aminoalkanesulfonamides. And most ofthese sulfonamides are new products.更多还原