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Synthesis of cyclic depsipeptides under direct amide cyclization conditions


Iliev, Boyan Iliev. Synthesis of cyclic depsipeptides under direct amide cyclization conditions. 2005, University of Zurich, Faculty of Science.

Abstract

This work describes the use of the "direct amide cyclization" (DAC) of dipeptides which contain β-, γ-, or δ-hydroxy acids, obtained by the reaction of the corresponding hydroxy acids with 3-amino-2H-azirines, the so-called "azirine/oxazolone" method. The goal of this work was to synthesize cyclic depsipeptides with potential biological activities and to establish the limits of the DAC. Several attempts to prepare a 7-membered cyclodepsipeptide via DAC are described, based on analogies with syntheses of 6- and 9-membered depsipeptides. Instead of the desired 7-membered ring, only its dimer was obtained. Variation of the concentration, temperature, reaction time, solvents and substituents led to the dimeric product exclusively, and no monomeric product was found in any of the reaction mixtures. Molecular modeling shows that the formation of the dimeric depsipeptide is indeed energetically favored over the formation of the monomer. Extending the use of the DAC on depsipeptides containing γ-hydroxy acids, which could potentially yield 8-membered cyclic depsipeptides, did not lead to the desired products, but instead to 5-membered imino lactones or chlorinated acids. A mechanism for the formation of both products has been proposed. When the DAC conditions were applied to a linear precursor, containing a δ-hydroxy acid, again none of the expected products was formed. The linear ω-chloro acid was the only product isolated. Thus, the dependence of the result of the DAC reaction on whether an α-, β-, γ-, or δ- hydroxy acid diamide is used has been confirmed and it may be concluded that the direct amide cyclization is an appropriate method for the synthesis of cyclic depsipeptides only if the terminal OH group is in α- or β-position of the hydroxy acid.

Abstract

This work describes the use of the "direct amide cyclization" (DAC) of dipeptides which contain β-, γ-, or δ-hydroxy acids, obtained by the reaction of the corresponding hydroxy acids with 3-amino-2H-azirines, the so-called "azirine/oxazolone" method. The goal of this work was to synthesize cyclic depsipeptides with potential biological activities and to establish the limits of the DAC. Several attempts to prepare a 7-membered cyclodepsipeptide via DAC are described, based on analogies with syntheses of 6- and 9-membered depsipeptides. Instead of the desired 7-membered ring, only its dimer was obtained. Variation of the concentration, temperature, reaction time, solvents and substituents led to the dimeric product exclusively, and no monomeric product was found in any of the reaction mixtures. Molecular modeling shows that the formation of the dimeric depsipeptide is indeed energetically favored over the formation of the monomer. Extending the use of the DAC on depsipeptides containing γ-hydroxy acids, which could potentially yield 8-membered cyclic depsipeptides, did not lead to the desired products, but instead to 5-membered imino lactones or chlorinated acids. A mechanism for the formation of both products has been proposed. When the DAC conditions were applied to a linear precursor, containing a δ-hydroxy acid, again none of the expected products was formed. The linear ω-chloro acid was the only product isolated. Thus, the dependence of the result of the DAC reaction on whether an α-, β-, γ-, or δ- hydroxy acid diamide is used has been confirmed and it may be concluded that the direct amide cyclization is an appropriate method for the synthesis of cyclic depsipeptides only if the terminal OH group is in α- or β-position of the hydroxy acid.

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Additional indexing

Item Type:Dissertation (monographical)
Referees:Heimgartner Heinz, Robinson John
Communities & Collections:UZH Dissertations
Dewey Decimal Classification:Unspecified
Language:English
Place of Publication:Zürich
Date:2005
Deposited On:05 Jun 2019 14:42
Last Modified:15 Apr 2021 14:58
Number of Pages:157
Additional Information:Enthält Sonderdrucke
OA Status:Green

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