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  Unified Total Synthesis of the Antibiotic Macrolides Aldgamycin N and Mycinamicin IV & De novo Syntheses of their Carbohydrate Units

Späth, G. (2022). Unified Total Synthesis of the Antibiotic Macrolides Aldgamycin N and Mycinamicin IV & De novo Syntheses of their Carbohydrate Units. PhD Thesis, Technische Universität, Dortmund.

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 Creators:
Späth, Georg1, Author           
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1Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1445584              

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 Abstract: The present thesis provides a unified total synthesis approach to the 16-membered macrolide antibiotics aldgamycin N and mycinamicin IV. Both natural products represent two distinct series of macrolide targets, which are characterized by a highly conserved “eastern” acid half but subtle variations within their macrocyclic frameworks, as well as their specific glycosides. The unified total syntheses are enabled by the swift assembly of the macrocyclic frameworks by merging individual carbonyl and alkyne modules as the two main synthetic fragments and the subsequent ruthenium-catalyzed transformation of the C–C triple bonds into the key functionalities distinguishing the individual targets. The eastern carbonyl fragments are reached from a single common terminal alkene building block formed on multi-gram scale by an asymmetric vinylogous Mukaiyama-type aldol reaction. Wacker oxidation of the common alkene terminus provides a ketone as the anchor point towards aldgamycin N, while an unprecedented stereo- and branch-selective hydroformylation at this site controlled by a literature-reported rhodium complex furnishes an aldehyde to serve as the handle for the preparation of mycinamicin IV. After combination of these fragments with their respective alkyne counterparts by carbonyl addition and closure of the macrolactone rings by an unusual stannoxane-mediated transesterification, the individual target moieties are forged using ruthenium- catalyzed transformations of the propargylic alcohols obtained from the carbonyl additions. Specifically, these late-stage key steps comprise a regioselective hydrostannation/Chan-Lam-type oxygenative coupling sequence to unveil the acyloin of aldgamycin N, and a rare example of a rearrangement of a secondary propargylic alcohol into the unsaturated ketone of mycinamicin IV. Completion of the target syntheses by attachment of the carbohydrates proved challenging and required close attention to both the timing of the glycosidation events and the exact glycosylation conditions employed. Systematic screening of the glycosylation conditions showcases the crucial distinction in reactivity between different silyl triflates for the activation of trichloroacetimidate donors. The rare branched-chain octose D-aldgarose and the basic amino sugar D-desosamine, required as the 4,6-dideoxy carbohydrates at the C5 position of both natural products, are also reached by a unified approach. The employed common building block is synthesized using an enantioselective hetero-Diels-Alder reaction, and intermediates of both de novo syntheses may serve the practical preparation of other naturally occurring 4,6-dideoxy sugars as well as derivatives thereof.

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Language(s): eng - English
 Dates: 2022-04-062022-04-06
 Publication Status: Published in print
 Pages: 185
 Publishing info: Dortmund : Technische Universität
 Table of Contents: -
 Rev. Type: -
 Identifiers: -
 Degree: PhD

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