The Total Synthesis Of 2-amino Quinazolinone Guanidine Derivatives And Natural Product Licochalcone E

Guanidine functionalities play a key role in many biologically active natural products and heterocyclic derivatives of guanidine because of their strong basicity and high stability.4(3H)-Quinazolinone guanidine derivatives have attracted much attention because of their various biological and medicinal properties, such as anticancer, diuretic, anti-inflammatory and so on. However, the simple skeleton of 2-amino-3-substituted-quinazolin-4(3H)-ones which with a free amino group at position 2, up to date, only a limited number of synthesis strategy have been disclosed. Therefore, the development of efficient methods to access these compounds is still desirable.Licochalcone E was firstly isolated in 2005 by Cheon's group. The initial biological activity study showed that this compound exhibited a higher cytotoxicity compared to the analogous licochalcone A. Furthermore, licochalcone E has also been reported to modulate the nuclear factor (NF)-KB and Bc1-2 families to induce endothelial cell apoptosis. Due to the demand of large amount of licochalcone further biological activity studies and the low isolated yield from natural p(?)duct (yield:0.0005% from 1 kg of G. inflate), chemical synthesis of licochalcone(?)is highly desirable.This thesis is divided into three parts. The first part introduces the application and synthesis of guanidine, and summarizes the synthesis of quinazolinone, especially 2-amino quinazolinone derivatives including guanidine functionalities.In the second part of this paper, we based on the previous research in our laboratory, explore a new method to synthesize 2-amino-quinazolinone guanidine. First, we synthesize the key intermediate Pbf-NCS (2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl isothiocyanate) during five-step reactions with 2,3,5-trimethylphenol as the initiative material, then Pbf-activated thiourea derived from Pbf-NCS and methyl anthranilate. The guanidine transformation of thiourea upon treatment with primary amines underwent intramolecular cyclization reaction via iodine-mediated guanidinylation to construct the quinazolinone heterocycle skeleton. The desired compounds are obtained easily after Pbf cleavage by TFA. Each structure of these compounds are identified by1H NMR,13C NMR. MS. and elemental analysis. We can synthesize various 3-substituted products via diversified primary amines in this method which emphasizes the application of Pbf-activated thiourea in the synthesis of heterocyclic guanidine.The third part of this paper firstly introduces the biological properties of licorice. And then describes the total synthesis of licochalcone E. Considering the literatures' reported in recent years, we present a shorter and more efficient protocol for synthesis of licochalcone E.4-hydroxy-2-methoxybenzaldehyde reacts with prenyl bromide to give 2-methoxy-4-(3-methylbut-2-enyloxy)benzaldehyde. And the key intermediate (4-hydroxy-2-methoxu-5-(3-methylbut-3-en-2-yl)benzaldehyde is obtained via abnormal Claisen rearrangement, then reacted with 4-hydroxyacetophenone during Claisen-Schmidt condensation reaction to give licochalcone E. In this new route to synthesis licochalone E, we firstly applied abnormal Claisen rearrangement reaction in the total synthesis of natural products, compared with the previous methods.we develop an efficient and short access to licochalcone E. and make the synthesis of licochalcone E in large scale possible.