Studien zur Totalsynthese von Pristinamycin IIA und Synthese biologischer Synthons

Im Rahmen der vorliegenden Arbeit wurden zwei Makrozyklisierungsvorläufer CAB und ABC zum totalsynthetischen Aufbau des Streptogramins Pristinamycin IIA in Betracht gezogen. Als gemeinsamer Vorläufer diente Amid AB, welches in einer neuartigen Reaktionssequenz in hoher Ausbeute stereoselektiv über n...

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Bibliographic Details
Main Author: Susnik, Peter
Contributors: Koert, Ulrich (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2020
Online Access:PDF Full Text
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In this work two possible precursors CAB and ABC towards the total synthesis of Pristinamycin IIA via macrocyclization were considered. As unified precursor the AB-building block could be synthesized in a nine-step procedure (longest linear sequence, LLS) in high yield and stereoselectivity from building blocks A and B. Although the esterification of AB with novel dehydroproline-building block C was not possible, the sequential construction of CAB was achieved in excellent yields (LLS: 16, 18%). The synthesis of ABC via SmI2-mediated BARBIER- or NHTK-reaction on the other hand was not possible. Macrocyclization of the CAB precursor was also unsuccessful under similar conditions. Although having high similarity to the precursor reported by PANEK et al., dehydroproline-CAB seems to be unsuitable for a macrocyclization via reductive addition towards the 23-membered backbone. The theoretical conformational analysis suggests that the chance for cyclization seems to be decreased severely, possibly through the lack of hydrogen-bonds. Nevertheless, new synthetic strategies towards advanced intermediates in high yield and stereoselectivity could be established and the understanding of streptogramin chemistry expanded. In a collaborative enterprise with the AG ERB of the Max-Plank-Institute Marburg, the incorporation of extender units in the Phoslactomycin (Pn) PKS and 6-deoxyerythronolid-B-synthase (DEBS) was studied. Therefore, different biological synthons were synthesized, which served as substrates for downstream-processing and reference probes. In the course of studying the promiscuity and selectivity of the dehydratase domain of Pn PKS, (Z,Z)- and (E,Z)-diene esters and β-hydroxy esters could be synthesized. In the second sub-project, methyl-, butyl- and hexyl-substituted lactones as reference probes could be provided. In summary all synthons could be synthesized stereoselectively and in good yields. The following implementation by the AG ERB in Pn PKS- and DEBS-essays was successful, whereas parts of these results led to a joint publication by the groups of KOERT and ERB.