Synthetic studies towards isaindigotidione

Abstract

(Uncorrected OCR) Abstract of thesis entitled SYNTHETIC STUDIES TOWARDS ISAINDIGOTIDIONE Submitted by Poon Ch Yan for the degree of Doctor of Philosophy at The University of Hong Kong in October 2004 Banlangen (WlWMi), more commonly known in the West as baphicacanthus, is a well-reputed traditional Chinese medicinal herbal drug commonly used to treat ailments such as influenza. It was even prescribed recently in Hong Kong for bolstering immunity against the Severe Acute Respiratory Syndrome (SARS) virus. It is the root of Isatis indigotica Fort. (Cruciferae), a biennial plant found along the valley of the Yangtze River (Changjiang) in central China. Isaindigotidione (I) is an alkaloid isolated from the root of I. indigotica. The organic extracts of this root were found to be active in antiendotoxic tests, indicating that isaindigotidione, like other alkaloids from the root, may possess interesting biological activity. As isaindigotidione is found naturally only in small quantities in I. indigotica, further investigation will only be possible when sufficient quantities are synthesized. Chemically, the structure of isaindigotidione is a novel derivative of indolizino[7,6- cjquinoline (II) found in natural and synthetic products for the first time. To our knowledge, no synthetic studies of this compound or its derivatives have yet been reported, and this thesis describes our efforts to synthesize isaindigotidione and its analogues. The main building blocks of the tetracyclic framework II were L-proline (V) and isatin (VI). The acylation of L-proline derivative VII by BOC-protected isatin was achieved under basic conditions to give phenylglyoxylic amide VIII. It was found that, in the presence of base under reflux, VIII underwent bis-cyclization to afford II. It was noted that four transformations (aldol cyclization, dehydration, acylation, and BOC-deprotection) occurred in a one-pot operation very efficiently to produce excellent yields of II. The isaindigotidione analogues III and IV were also synthesized by the same strategy. Substituents at C-7 were introduced by cuprate addition and a Heck reaction to intermediate IX. Epimerization at the C-7 centre was found to occur under the bis-cyclization conditions, and analogues III and IV were obtained as epimeric mixtures. Unfortunately, it was discovered upon extensive investigation that these organometallic conjugate addition reactions did not lend themselves to the addition of the 2,6-dimethoxy-l-phenol moiety to IX and its derivatives, which this retroanalysis indicates is required for the synthesis of isaindigotidione. Several factors were found to deter the addition of the desired substituent, including the steric demands of IX, and the low reactivity of phenyl and aryl organometallic reagents. O. ^N�''/ i H ^O OMe OH OMe II ,NL !""'H ^CH3 i H ^O III IV COOH "N H O^N H VI H .0 OMe OMe � ^ BOC f OMe VII VIII IX