"第一部分：Friedelin之分離及含氮衍生物之製備;第二部分：6a,7-Didehydroglaucine衍生物之製備"

Abstract

天然物於藥物發展中扮演相當重要的角色，研究報導三萜類化合物具有許多生物活性，其中friedelin於過去研究中發現其含有抗發炎、抗氧化、抗微生物及降血糖等活性。近年研究中更發現許多三萜類化合物，經化學修飾成含氮衍生物，不僅增加其水溶性，更具有多種細胞抗癌活性。因此本研究擬藉分離之friedelin，以之為起始物製備一系列含氮衍生物，進一步供生物活性之研究。 於過去研究發現，殼斗科植物含有許多三萜類化合物成分，其中殼斗科柯屬植物-大葉石櫟(Pasania kawakamii (Hayata) Schottky)為一台灣特有種植物。本研究自大葉石櫟葉部之乙醇萃取物，經極性分割得正己烷、乙氰、正丁醇及水可溶部分，其中正己烷可溶部分經初步分離得到friedelin (2)、squalene (1)、β-sitosterol (3)及epifriedelanol (4)。以2為起始物，形成酮肟化合物，經鉑催化還原反應及還原性胺化作用共得14個含氮及含氮苄基衍生物，供未來生物活性之研究。

阿朴芬型生物鹼-海罌粟鹼(glaucine)具有多種生物活性，本實驗室亦有許多其化學結構修飾之研究。文獻報導此類化合物於氮上作取代反應時，易行Hofmann elimination而得到開環之產物。以去氫化反應得6a,7-didehydroglaucine，避免開環反應之產生。本研究利用6a,7-didehydroglaucine與酸酐進行反應，以吡啶作為溶劑及催化劑，可得到氮上去甲基之醯胺化產物，透過SN2'之作用機轉，進而產生去甲基醯胺化反應。然而產率並不理想，未來需進一步提升其產率。

Natural products play an important role in drug development, and it has reported triterpenoids have many bioactivities. Friedelin, a triterpene, has been demonstrated possess anti-inflammatory, antioxidant, antimicrobial, and hypoglycemic activities. Recent studies indicate some amino-triterpenes, prepared from chemical modification, not only increase water solubility but also enhance cytotoxicity. Therefore, this study was aimed to use friedelin as the starting material to prepare a series of aminofriedelans for further biological evaluation. Past chemical investigations revealed that Fagaceaus plants contain triterpenoids such as friedelin (2). In this study, friedelin was isolated from Pasania kawakamii (Hayata) Schottky. The ethanol extract of its leaves was divided into the n-hexane, acetonitrile, n-butanol, and water soluble fractions via liquid-liquid partition. Friedelin (2), along with squalene (1), β-sitosterol (3) and epifriedelanol (4) was isolated from the n-hexane soluble fraction. Starting from 2, 14 aminofriedelans were prepared via three step reaction, i.e. reaction with hydroxylamine to form oximinofriedelan, catalytic hydrogenation to give 3β-aminofriedelan, and reductive amination. Glaucine is an aporphine alkaloid with a variety of biological activity. Some chemical modifications have been undertaken in our lab. Of these, N-demethylation by general methods will accompany with Hofmann elimination. 6a,7-Didehydroglaucine (20) might avoid the ring-opening reaction during N-demethylation. Thus this study, 6a,7-didehydroglaucine was used as key intermediate. Reaction of 6a,7-didehydroglaucine (20) with anhydrides in pyridine yields the corresponding N-acyl products through SN2' mechanism. The yields, however, are poor. Optimization of reaction conditions is required.