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  Total Synthesis of Belizentrin Methyl Ester: The Polyhydroxylated Sidechain

Größl, S. (2018). Total Synthesis of Belizentrin Methyl Ester: The Polyhydroxylated Sidechain. PhD Thesis, Technische Universität, Dortmund.

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 Creators:
Größl, Sylvester1, Author              
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1Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1445584              

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 Abstract: Belizentrin (A) was isolated in 2014 from the marine dinoflagellate Prorocentrum belizeanum as the first member of a group of odd-numbered macrolactamic toxins (Scheme 1). This toxin of marine origin contains a 27-membered macrocycle which bears a high degree of unsaturation. Furthermore, the polyhydroxylated side chain embodies eleven of the 16 stereocentres decorating the core structure of this secondary metabolite. Belizentrin (A) shows significant neurotoxicity when administered to cerebellar cells with an extrapolated EC50 value of 193 nM. Experimentally, belizentrin (A) was found to be unstable, undergoing observable decomposition during the biological assay. Therefore, we aimed for the total synthesis of both belizentrin methyl ester (B) and its congener, belizentrin TMS-ethyl ester (C) (Scheme 1). The synthesis of the latter was proposed for the planned release of the natural product A by global fluoride-based deprotection. We sought to synthesize belizentrin (A) in a highly convergent manner, with the central E-configured C-C double bond of the natural product A disconnected via a Julia-Kocienski olefination (Scheme 1). This resulted in a western side chain D, bearing a tetrazolylsulfone, and an eastern macrocycle E, bearing the required aldehyde. The eastern belizentrin fragment E was prepared in 13 steps (LLS) with an overall yield of ca. 2.5% by Ph.D. student F. Anderl, starting from different commercially available C3 to C5 building blocks (for further details, see projected Ph.D. thesis by F. Anderl). The western belizentrin fragment D was accessed in 17 steps (LLS) with an overall yield of 3-5% (regarding both esters) from the commercially available amino acid L-glutamic acid ((S)-I) and the per-O-acetyl derivative L of α-D-glucose (K) (Scheme 2). Based on the literature known synthesis of the enantiomer of 2,5-trans-disubstituted ether H, tetrazolylsulfone G was obtained in 13 steps with an overall yield of 12% (Scheme 2). Key steps included a cyclizing 1,4-addition towards ether H and a Mitsunobu reaction to introduce a tetrazolylsulfide. Further functional group modifications led to sulfone G. Phosphorus ylide J was obtained via an anomeric allylation, an alkene oxidation, and an α-bromination at the C1’ terminus of per-O-acetyl-α-D-glucopyranose (L) (Scheme 2). Selective silyl ether deprotection and oxidation followed by Wittig olefination introduced the ester functionality to the C6’ terminus of J. Overall, phosphorus ylide J was synthesized in eleven steps with an overall yield in the range of 17-18% (regarding both esters). Wittig olefination of aldehyde G with phosphorus ylide J furnished enone F, which was subsequently reduced to the corresponding allylic alcohol by a CBS reduction (Scheme 2). The key step of the synthetic route was a Sharpless dihydoxylation of the allylic alcohol, installing the central triol motif of the western belizentrin fragment D. After exhaustive protection with TESOTf, fragment D was obtained. The absolute configuration was confirmed by a combination of Mosher ester analyses, derivatization into five-membered carbonate derivatives and NMR comparison of constitutionally isomeric triols, obtained via different synthetic routes. The final steps towards belizentrin methyl ester (B) were carried out by Ph.D. student F. Anderl. The proposed Julia olefination of aldehyde E with tetrazolylsulfone D proved difficult due to significant base sensitivity of the skipped polyene motif (Scheme 1). This transformation was achieved by transmetallation of deprotonated tetrazolylsulfone D from lithium to zinc. Global deprotection with aqueous hydrofluoric acid in acetonitrile finally yielded belizentrin methyl ester (B) (in comparison to 3.1 mg of belizentrin (A) obtained by the isolation team).

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Language(s): eng - English
 Dates: 2018-08-222018-10-242018-10-24
 Publication Status: Published in print
 Pages: 360
 Publishing info: Dortmund : Technische Universität
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.17877/DE290R-19805
 Degree: PhD

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