Progress Towards The Formal Enantioselective Total Synthesis Of Clavosolide A

Author : Bob Lui
Publisher : Open Dissertation Press
ISBN 13 : 9781361418536
Total Pages : pages
Book Rating : 4.4/5 (185 download)

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Download or read book Enantioselective Total Synthesis of (-)-16-Hydroxytriptolide written by Bob Lui and published by Open Dissertation Press. This book was released on 2017-01-27 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: This dissertation, "Enantioselective Total Synthesis of (-)-16-hydroxytriptolide" by Bob, Lui, 呂思奇, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled ENANTIOSELECTIVE TOTAL SYNTHESIS OF (-)-16-HYDROXYTRIPTOLIDE Submitted by Lui Bob for the degree of Doctor of Philosophy at The University of Hong Kong in August 2005 (-)-16-Hydroxytriptolide, a natural product isolated from the Chinese medicinal plant Tripterygium wilfordii Hook F (Lei Gong Teng), shows potent immunosuppressive, antileukemic, and antineuropathic activities. The goal of this project is to develop an enantioselective total synthesis of (-)-16-hydroxytriptolide. The results are summarized as follows. (1) A convergent and efficient synthetic scheme towards ()-16-hydroxytriptolide ()-3.19a has been developed using 2-methylanisole as the starting material. This route involves 21 steps in a 1.8% total yield. The key steps include (i) radical cyclization of ()-3.1 mediated by Mn(OAc) -2HO, (ii) 3 2 α,β-unsaturated γ-lactone construction of ()-3.3, (iii) side-chain installation by Sonogashira coupling from ()-Q5, and (iv) triepoxide construction from ()-3.12. (2) Following a similar synthetic scheme as that of ()-16-hydroxytriptolide, the enantioselective synthesis of (-)-16-hydroxytriptolide has been accomplished. This route involves 21 steps in a 2.4% total yield. The chirality of the trans-ring juncture of the tricyclic core was established by diastereoselective radical cyclization using (+)-8-phenylmenthol as the chiral auxiliary (73% yield, 34:1 dr). The chiral induction of side chain at C-15 was achieved by asymmetric hydrogenation (90% yield, 5.3:1 dr). (3) α-Halogenation reactions of 1,3-dicarbonyl compounds have been investigated to improve the synthetic efficiency of ()-16-hydroxytriptolide. The effect of Lewis acids was examined. In the absence of Lewis acid, the α-bromination of 1,3-dicarbonyl compounds 4.1f afforded both di-brominated 4.4f and mono-brominated products 4.3f in poor yield and selectivity (45%, 4.3f:4.4f = 1.5:1). However, when the α-bromination reaction was carried out in the presence of 0.3 equiv of Mg(ClO ) at room temperature, both the yield and the selectivity of 4 2 α-monobromination improved significantly (85%, 4.3f:4.4f = 14.8:1). (4) In connection to the asymmetric radical cyclization of 5.1 using (+)-8-phenylmenthol as the chiral auxiliary, a one-pot synthesis of its precursor, (S)-(-)-pulegone, has been developed. The reaction of LiClO (0.1 equiv), IBX (3 equiv), and (S)-(-)-citronellol in EtOAc under reflux for 17 h followed by basic treatment, led to a high chemical yield (90%) of (S)-(-)-pulegone. This provides an efficient and economical means to afford (+)-8-phenylmenthol for our (-)-16-hydroxytriptolide synthesis. OMe OMe O OMe H H Cl CO Me CO Me 2 (-)-3.3 (-)-Q5 O (-)-3.1 OH OMe O HO HO C H O O H O O (-)-3.19a (-)-3.12 O O O O O O Ph OEt Ph OEt Ph OEt Br Br Br 4.3f 4.4f 4.1f DOI: 10.5353/th_b3636945 Subjects: Terpenes Organic compounds - Synthesis Medicinal plants - Analysis