Conversion of leucomycin-A3 antibiotic into novel triazole analogues via regio- and diastereoselective SN1′ substitution with allylic rearrangement and 1,3-dipolar cycloaddition of CuAAC type

• Published in: Tetrahedron letters Vol. 57; no. 15; pp. 1661 - 1666
• Main Authors: Domagalska, Joanna, Pyta, Krystian, Przybylski, Piotr
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 13.04.2016
• Subjects: 16-Membered unsaturated lactones; 1D and 2D NMR spectroscopy; Dipolar cycloaddition; Reaction mechanism; Regio- and diastereoselective SN1′ nucleophilic substitution; Reaction mechanism; Regio- and diastereoselective SN1′ nucleophilic substitution; 1D and 2D NMR spectroscopy; 16-Membered unsaturated lactones; Dipolar cycloaddition
• ISSN: 0040-4039; 1873-3581
• DOI: 10.1016/j.tetlet.2016.02.113

[Display omitted] •New derivatives of leucomycins have been obtained via combined SN and ‘click’ chemistry approach.•Complicated chemistry of leucomycins’ acetals has been presented.•2D NMR and DFT revealed the C(13S) configuration of the triazole-functionalized leucomycins.•Analysis of the rate of nucleophilic substitution versus concentration indicated SN1′ mechanism.•DFT and 1H–1H NOESY indicated arrangement of triazole moieties relative to the aglycone. In view of the complicated chemistry of josamycin’s (leucomycin-A3) acetal functional groups, reduction of the aldehyde followed by nucleophilic substitution of josamycin’s dienol system in the aglycone yielded novel products having an alkyne group attached at the C(13) carbon atom. Detailed 1H–1H NOESY and 1H–13C HMBC investigations together with DFT calculations indicated the C(13S) configuration within the structures of alkyne-functionalized leucomycins. Analysis of the relationship between the rate of nucleophilic substitution and concentration revealed the unimolecular mechanism of the substitution with protonation of the leaving group as the rate determining step. Further conversion of the alkyne substituent on the aglycone using the CuAAC reaction provided access to novel heterocyclic leucomycin analogues bearing substituted 1,2,3-triazole rings.