【作者】 杨绍波；

【导师】 许鹏飞；

【作者基本信息】 兰州大学 ， 有机化学， 2008， 博士

【摘要】 天然产物鞘氨酸抗菌素(Sphingofungin)类化合物是烟曲酶产生的抗菌代谢物的一种新科,首先在1992年由Merck公司的Van Middlesworth与他的合作者从海洋生物Aspergillus和Paecilomyces中分离得到。这些化合物表达其生物活性有独特的机制,即对丝氨酸十六(烷)酰转移酶(SPT,生物合成鞘酯类的一种很重要的酶)具有很有效的抑制活性。由于其独特的生物活性,有许多化学家对其进行了全和成工作。尽管如此,发展一种更为高效简洁的路线来合成天然产物Sphingofungin类化合物对其研究及应用仍然有很大的化学和生物学意义。本文就Sphingofungin家族化合物的发现、结构确定及化学合成进行了全面的总结。结合本实验室应用以樟脑为原料合成的三环亚胺内酯在不对称合成α-氨基酸方面的经验,特别是利用Aldol反应合成β-羟基α-氨基酸方面的经验,设计了两条合成路线对天然产物Sphingofungin F经行了全合成的探索并取得了较大的进展。在对天然产物Sphingofungin F的全合成过程中,发展了由内酯一锅法合成末端羟基酮的方法学并应用于全和成工作,有效的提高了全合成的效率。另外,还发展了利用格氏试剂异丙基溴化镁为试剂,以甲醇钠为催化剂一锅法高产率的由内酯合成末端羟基酰胺的方法,为酰胺的合成以及Weinreb酰胺的合成提供了另外一条高效的途径。本文的主要内容有:1.在实验室对三环亚胺内酯合成路线的基础上进行了条件优化,提高了手性氨基酸辅助基的合成效率,并合成了天然产物中的重要片段甲基化的三环亚胺内酯。2.发展了由内酯为原料,以甲醇钠为催化剂,一锅法合成末端羟基酮的方法。以不同的内酯与不同的格氏试剂反应,研究了这个反应的适用性,并均得到了很好的结果。在由核糖衍生的内酯的反应中发现了开环又重新关环的反应,探索了其反应机理,以单晶衍射确定了其产物构型,发展了一种合成与文献中构型相反的化合物的新方法。3.发展了以内酯为原料、以异丙基溴化镁为试剂、甲醇钠为催化剂一锅法合成Weinreb酰胺或其他酰胺的方法学,为末端羟基酰胺的合成提供了一条有效的途经。4.利用我们发展的一锅法制备内酯的方法合成了天然产物中的一个重要片段砜,并以L-(+)酒石酸为起始原料合成了另外一个重要片段不同保护的烯丙基溴。尝试了偶联反应并均取得了成功。成功将所得的偶联产物转化为全和成中所需要的重要片段醛。5.研究了醛与甲基化三环亚胺内酯的Aldol反应条件,并将其应用于天然产物的全和成中成功得到了目标产物,将其进一步水解除去手性辅助基并脱掉保护基即可完成对天然产物Sphingofungin F的全和成工作。更多还原

【Abstract】 Sphingofungins are a new class of antifungal agents isolated from Aspergillus and Paecilomyces and are reported to be potent and specific inhibitors of serine palmitoyl transferase（SPT）.These naturally occurring SPT inhibitors also have attractive pharmacological potential since they possess fungicidal and immunosuppressive activity,although the latter activity is apparently not a consequence of inhibition of SPT.The structure elucidation study revealed that sphingofungins are novel polyhydroxy amino acid derivatives bearing a C₂₀ straight carbon chain with E-olefin and four contiguous asymmetric centers.Therefore,numerous methods to synthesize these compounds have been reported. In this thesis,the development for the chemical synthesis of Sphingofungin was reviewed.In our laboratory,we have reported two novel chiral tricyclic iminolactones, prepared from（1R）-（+）-camphor as glycine equivalents,which have been successfully applied to the asymmetric synthesis of or-substitutedα-amino acids andβ-hydroxyα-amino acid.Two synthesis stragies toward Sphingofungin F using Aldol reaction of aldehyde and methyl tricyclic iminolactone were researched in this thesis and one of them was found effectively.We have developed a convenient one-pot methodology for the synthesis ofω-hydroxyketones from commercially available lactones and Grignard regents in good yields.The one-pot reaction that Grignard regents added to lactones to affordω-hydroxyketones using NaOCH₃ as catalyst is first reported.We found some new cyclic compounds via hydroxyketone.The reaction mechanism was researched and the configuration was charactered by X-ray.We have developed an efficient,generally high-yields（up to 98%） method to generate amides.The reaction is most easily executed when THF was used as solvent, and isopropyl magnesium bromide as base.NaOCH₃ can promote the reaction rate and yield.The present method constitutes an important modification to the well known Weinreb methodology.This method can be used to synthesize other amides with hydroxyl group in good yield.The necessary key compound sulfone was synthesized using our strategy of one-pot reaction fromε-Caprolactone.Two deferent protected allylic bromides were obtained from L-（+）-tartaric acid.The coupling reactions were explerored and the desire target compounds was obtained.The key compound adehyde was got by chemical transform the coupling product.The Aldol reaction of aldehyde and the methyl tricyclic iminolactone was detected and the good result was observed.Hydroxylation of the Aodol product could complete the syntheses of the natural product Sphingofungin F.更多还原