【作者】 陈宏亮；

【导师】 冯亚青；

【作者基本信息】 天津大学 ， 应用化学， 2004， 博士

【摘要】 论文完成了海洋天然化合物Dragonamide的化学全合成,并纠正了文献中的构型错误。同时对海洋天然化合物Leucamide A的化学合成进行了研究。设计了Dragonamide的全合成路线,由四肽片段A.15和片段（R）-2-甲基-7-炔-辛酸,A.28组成。将片段A.15的氨基保护基脱去后,以BOPCl为偶合试剂,与A.28连接起来,得到A.30。将A.30的羧基保护基脱除后,以PyBOP为偶合试剂,与氨气反应,得到Dragonamide,收率为10.9%。四肽片段A.15的合成是以L-苯丙氨酸和L-撷氨酸为起始原料,利用邻硝基苯磺酰基作为氨基的保护基团,叔丁酯作为羧基的保护基团,碘甲烷作为烷基化试剂,酰氯作为偶合试剂而完成,收率为32.5%。（R）-2-甲基-7-炔-辛酸,A.28的合成是以1.5-戊二醇为起始原料,以苄基完成单保护后,经Swern氧化反应得到醛,再与wittig试剂反应,增长碳链。选择性加氢后,水解脱去酯基后与Evans手性助剂反应得到手性前体。以NaHMDSA为碱,在-78℃下,进行立体选择性烷基化反应,构造手性中心。脱去手性助剂,以重氮甲烷甲酯化,脱去苄基,得到醇。Swern氧化后,与Ohira-Bestmann试剂反应,在保持手性中心的前提下,得到炔基,脱去甲酯后,得到A.28,收率为17.1%,e.e.值大于99%。经过与标准谱图的比较,得出文献中分子构型错误的结论,即A.28中手性的构型应为S。合成相应的（S）-2-甲基-7-炔-辛酸后,重复前述步骤,得到构型正确的目标分子Dragonamide,构型为SSSSS（文献中构型为RSSSS）,总收率为1.86%。设计了Leucamide A的全合成路线,由中间体噁唑-亮氨酸-脯氨酸B.12,甲基噁唑衍生物B.20和苯并三唑衍生物B.24组成并完成了对它们的合成。片段B.12是由二肽片段B.10和噁唑衍生物B.6偶合得到。二肽片段B.10以L-亮氨酸和L-脯氨酸为起始原料,以叔丁氧羰基为氨基保护基团,甲酯为羧基保护基,以DCC为偶合试剂得到,收率为56.7%。噁唑衍生物B.6利用L-丝氨酸和L-丙氨酸为起始原料,得到二肽片段B.4后,经Burgess试剂关环,BrCCl₃和DBU脱氢得到,收率为46.8%。B.20以L-丝氨酸和L-苏氨酸为起始原料,得到二肽B.17,经过Dess-MartinPeriodinane氧化和三苯基膦与碘关环,生成甲基噁唑B.19,收率为36.5%。B.19脱去保护基后,得到B.20。硫代撷氨酸的活化中间体B.24以L-撷氨酸为起始原料,保护氨基后,利用氯甲酸异丁酯作为偶合试剂,与邻苯二胺反应,硫代后,利用亚硝酸关环得到。更多还原

【Abstract】 Dragonamide, an oceanic nature material, was total synthesized in the paper.And fragments of Leucamide A, an oceanic nature material too, were synthesized.Synthesis route to Dragonamide was designed. The molecule was made up withTetrapeptide A.15 and (R)-2-methyl-7-alkyl-octyl acid, A.28. They were coupledusing BOPCl as coupling reagent to give A.30. After cleavage of the t-butyl ester ofA.30, Dragonamide was achieved by activation with PyBOP and treatment withammonia in a yield of 10.9%.Tetrapeptide A.15 was prepared from L-Phe and L-Val in a yield of 32.5%, withO-nitrobenzenesulfonyl group and t-Butyl group as protecting groups.(R)-2-methyl-7-alkyl-octyl acid, A.28 was prepared from 1,5-pentanediol. Aftermonoprotection and Swern oxidation, aldehyde was got. Then it reacted with wittigreagent. After selective hydrogenation and hydrolyzation, the intermediate wascoupled with chiral auxiliary. Then alkylation of stereoselective was completed withNAHMDSA and MeI at -78 ℃ . Chiral auxiliary was removed, followed byesterification with diazomethane, hydrogenation and Swern oxidation to give anotheraldehyde. It was converted alkyne using the Ohira-Bestmann reagent.(R)-2-methyl-7-alkyl-octyl acid, A.28 was got after saponification in a yield of 17.1%and e.e. beyond 99%.Due to its NMR data and optical rotation data could not match them in reference,it was found that structure of dragonamide was wrong. Then(S)-2-methyl-7-alkyl-octyl acid was prepared using exactly the same procedure. Andcorrect Dragonamide was synthesized at finally in a total yield of 1.86%, andstructure was SSSSS not RSSSS.Synthesis route to Leucamide A was designed. The molecule was made up withB.12, B.20 and B.24 which were prepared in the paper.B.12 was given from coupling after removing protecting groups of B.10 and B.6.Dipeptide B.10 was obtained from L-Leu and L-Pro in a yield of 56.7%. In a similarway Dipeptide B.4 was got from L-Ser and L-Ala. After cyclodehydration withBurgess reagent and dehydrogenation with BrCCl3&DBU, the oxazole B.6 wasprepared in a yield of 46.8%.B.20 was obtained after removing protacting group of B.19. Dipeptide B.17 wasobtained from L-Ser and L-Thr through similar way, followed by oxidation withDess-Martin Periodinane and cyclodehydration with PPh3&I2 to givemethyloxazole B.19 in a yield of 36.5%.Activted intermediate B.24 was prepared from L-Val through coupling witho-diaminobenzene ,sulfuration and cyclodehydration.更多还原