TY - BOOK

T1 - Synthese neuer Tetracyclin-Abkömmlinge und weiterer bioaktiver, naturstoff-basierter Derivate

AU - Sara, Alexandru-Adrian

PY - 2023

Y1 - 2023

N2 - Ever since the isolation of its first members in the late 1940s, the tetracycline class of natural products has been greatly enriched, with the production of chemically modified or semisynthetic compounds contributing significantly to the total number. With his 1953 preparation of (−)-tetracycline by hydrogenolysis of chlortetracycline, Lloyd Conover was not only the first to ever describe a chemically modified tetracycline, but his unprecedented discovery also proved that synthetically modified natural product-derived compounds could exhibit biological activity. Since this breakthrough in the field, several semisynthetic tetracyclines have entered the market, and the practice of elaborating older compounds into novel active derivatives has gained increased popularity. Following this motivation, this work aimed at the total synthetic preparation of five atypical tetracycline-related natural products: demethylpremithramycinone and premithra-mycinone, both identified in 1998 as precursors of the biosynthesis of aureolic acids; chromocyclin, the aglycon of the 1968 isolated streptomyces metabolite chromocylclomycin along with its C4-empimer epi-chromocyclin; and carbamidochelocardin, a potent chelocardin-derived antibiotic compound prepared in 2015 through biosynthetic engineering. Following a convergent approach, the construction of the naphthacene core of the proposed targets was envisioned to proceed via an unprecedented Diels−Alder reaction with furan key step between variously decorated decalin-enones (eastern fragments) and in-situ generated isobenzofurans (western fragments). The chosen strategy would allow for high tunability of the two fragments, fulfilling the premise of synthesizing the targeted tetracyclines via a common pathway. An additional asset of the proposed protocol is represented by the quick and facile installation of the (S)-configured C12a-positioned alcohol via a late-stage hydroxylation, followed by an ketol rearrangement. At first, the required western and eastern fragments for accessing demethylpremithramycinone, premithramycinone, chromocyclin, and epi-chromocyclin, as well as the western fragment of carbamidochelocardin, were successfully prepared, and the total synthesis of demethylpremithra-mycinone was pursuit. By employing a Diels−Alder reaction with furan, the naphthacene core of the target was successfully constructed from a C8a-deoxy eastern fragment. The installation of the C12a-positioned tertiary alcohol with the desired configuration in the previously prepared product resulted in the formation of an advanced precursor, which was finally subjected to the global deprotection strategy. The targeted natural product was ultimately isolated as a dimedone enamine (14 steps; 2,2%-yield), with the conversion of the functionality towards the desired methyl ketone repeatedly failing to set in. Nevertheless, the viability of the global approach was confirmed, with the proposed strategy allowing for the preparation of novel tetracycline-derived compounds, three of which were subjected to biological evaluation. With respect to carbamidochelocardin, since the preparation of a suitable eastern fragment couldn’t be completed, the route leading to its preparation was ultimately abandoned. Despite the uncompleted preparation of the originally envisioned targets, the strategy elaborated for their synthesis managed to prove its potential on account of three fulfilled premises: I) by providing convenient access to structurally diverse eastern fragments via a divergent approach; II) by a facile construction of the naphthacene core along with the required decorations; and III) by the ability to generate both (R)- and (S)- configured tertiary alcohols at the C12a-position starting from deoxy-precursors.

AB - Ever since the isolation of its first members in the late 1940s, the tetracycline class of natural products has been greatly enriched, with the production of chemically modified or semisynthetic compounds contributing significantly to the total number. With his 1953 preparation of (−)-tetracycline by hydrogenolysis of chlortetracycline, Lloyd Conover was not only the first to ever describe a chemically modified tetracycline, but his unprecedented discovery also proved that synthetically modified natural product-derived compounds could exhibit biological activity. Since this breakthrough in the field, several semisynthetic tetracyclines have entered the market, and the practice of elaborating older compounds into novel active derivatives has gained increased popularity. Following this motivation, this work aimed at the total synthetic preparation of five atypical tetracycline-related natural products: demethylpremithramycinone and premithra-mycinone, both identified in 1998 as precursors of the biosynthesis of aureolic acids; chromocyclin, the aglycon of the 1968 isolated streptomyces metabolite chromocylclomycin along with its C4-empimer epi-chromocyclin; and carbamidochelocardin, a potent chelocardin-derived antibiotic compound prepared in 2015 through biosynthetic engineering. Following a convergent approach, the construction of the naphthacene core of the proposed targets was envisioned to proceed via an unprecedented Diels−Alder reaction with furan key step between variously decorated decalin-enones (eastern fragments) and in-situ generated isobenzofurans (western fragments). The chosen strategy would allow for high tunability of the two fragments, fulfilling the premise of synthesizing the targeted tetracyclines via a common pathway. An additional asset of the proposed protocol is represented by the quick and facile installation of the (S)-configured C12a-positioned alcohol via a late-stage hydroxylation, followed by an ketol rearrangement. At first, the required western and eastern fragments for accessing demethylpremithramycinone, premithramycinone, chromocyclin, and epi-chromocyclin, as well as the western fragment of carbamidochelocardin, were successfully prepared, and the total synthesis of demethylpremithra-mycinone was pursuit. By employing a Diels−Alder reaction with furan, the naphthacene core of the target was successfully constructed from a C8a-deoxy eastern fragment. The installation of the C12a-positioned tertiary alcohol with the desired configuration in the previously prepared product resulted in the formation of an advanced precursor, which was finally subjected to the global deprotection strategy. The targeted natural product was ultimately isolated as a dimedone enamine (14 steps; 2,2%-yield), with the conversion of the functionality towards the desired methyl ketone repeatedly failing to set in. Nevertheless, the viability of the global approach was confirmed, with the proposed strategy allowing for the preparation of novel tetracycline-derived compounds, three of which were subjected to biological evaluation. With respect to carbamidochelocardin, since the preparation of a suitable eastern fragment couldn’t be completed, the route leading to its preparation was ultimately abandoned. Despite the uncompleted preparation of the originally envisioned targets, the strategy elaborated for their synthesis managed to prove its potential on account of three fulfilled premises: I) by providing convenient access to structurally diverse eastern fragments via a divergent approach; II) by a facile construction of the naphthacene core along with the required decorations; and III) by the ability to generate both (R)- and (S)- configured tertiary alcohols at the C12a-position starting from deoxy-precursors.

U2 - 10.15488/15735

DO - 10.15488/15735

M3 - Doctoral thesis

CY - Hannover

ER -