Studies Toward the Total Synthesis of Pseudolaric Acid B Via an Improved Carbene Cyclization Cycloaddition Cascade Strategy PDF Download

Author: Baojian Li
Publisher: Open Dissertation Press
ISBN: 9781361345825
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Languages : en
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This dissertation, "Studies Toward the Total Synthesis of Pseudolaric Acid B via an Improved Carbene Cyclization Cycloaddition Cascade Strategy" by Baojian, Li, 李保健, 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 STUDIES TOWARD THE TOTAL SYNTHESIS OF PSEUDOLARIC ACID B VIA AN IMPROVED CARBENE CYCLIZATION CYCLOADDITION CASCADE STRATEGY submitted by LI Baojian for the Degree of Doctor of Philosophy at The University of Hong Kong in April 2014 Pseudolaric B is a major active constituent of tujingpi, a traditional Chinese medicinal herb for the treatment of dermatological fungal infections (Figure 1). Recent investigations showed that it possesses diverse biological activities, including cytotoxicity towards cancer cell lines and inhibition of tubulin polymerization. Our group has reported the first total synthesis of its congener, pseudolaric acid A, via a carbene cyclization cycloaddition cascade (CCCC) strategy to construct the [5,7] fused ring system. The synthesis of the CCCC precursor required 14 steps, and the limitations of the method employed to cleave the oxygen bridge permitted only the synthesis of the less active pseudolaric acid A. Moreover, the diastereoselectivity of the key CCCC reaction was low, only 1.6:1. In the present work, we have successfully synthesized the CCCC precursor 4.32 in 11 steps. This route featured several transformations accomplished with improved yields, and is also highlighted by a cyclopropanone acetal-derived zinc homoenolate alkylation to give 4.11, a direct trans-esterification of 4.11 to give 4.20, and bis-reduction of 4.21 without the need for protection and deprotection (Scheme 1). We carried out model CCCC studies on diazo ketoesters 3.37 and 3.39, and found that they reacted under catalysis by Hashimoto's Rh (S-TFPTTL) complex 2 4 with the highest yields and enantioselectivities, achieving 63% yield with 70% ee, and 70% yield with 69% ee, respectively, using PhCF /PhH as solvent at 0 C (Scheme 2). Using the same catalyst, the CCCC reaction of 4.32 proceeded in 84% yield and a significantly improved 6.0:1 diastereoselectivity for the desired cycloadduct 4.54 compared with a 1.6:1 diastereoselectivity in the previous route. Models have been proposed to account for these diastereoselectivities. Finally, treatment of ketone 4.54 with benzyloxymethyllithium, then chlorination yielded 4.60. Removal of protecting groups in one step to give diol 4.65, then a reductive elimination with concomitant deprotection using LiDBB successfully provided triol 4.66. This advanced intermediate 4.66 synthesized in 16 steps from 4.3 could be carried forward towards a more concise asymmetric total synthesis of pseudolaric acid B. In the course of preparing substituted BNPH ligands for obtaining chiral rhodium complexes, we designed a protecting group-free, two-step route to synthesize 3,3'- and 6,6'-substituted BNPHs. We found that direct Suzuki coupling of boronic acids with the brominated BNPH could successfully generate substituted BNPHs 3.11 and 3.18. Racemization under the reaction conditions was suppressed by the BINOL being tethered by the phosphoric acid moiety. Our studies revealed Pd(OAc) /CataCXium A as the most active catalyst system for these Suzuki reactions, which led to good yields of substituted BNPH over relatively short reaction times (Scheme 4). DOI: 10.5353/th_b5295521 Subjects: Antifungal agents Diterpenes - Synthesis