Synthesis and in vitro cytotoxic evaluation of spiro-β-lactone-γ-lactam scaffolds

• Published in: Tetrahedron Vol. 76; no. 18; p. 131144
• Main Authors: Fábian, Martin, Gonda, Jozef, Jacková, Dominika, Martinková, Miroslava, Pilátová, Martina Bago, Jáger, Dávid
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01-05-2020
• Subjects: [3,3]-Sigmatropic rearrangement; Antiproliferative activity; Oxazolomycins; Spiro-β-lactone-γ-lactam framework; Antiproliferative activity; [3,3]-Sigmatropic rearrangement; Oxazolomycins; Spiro-β-lactone-γ-lactam framework
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2020.131144

A successful approach to the construction of spiro-β-lactone-γ-lactam synthons 5 and ent-5 as a similar structural motif present in natural products such as oxazolomycins was developed. Two chirons, the protected 3-isothiocyanato-3-C-vinyl-α-d-xylofuranose and its antipode, were employed as the starting material. In order to obtain a lactone-pyrrolidine cyclic framework, a ring-closing metathesis, a highly diastereoselective reduction of a double bond and the formation of a β-lactone skeleton were involved as the key transformations. The final enantiomeric pharmacophores were screened for their capacity to alter the viability of cancer cells.
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•Synthesis of spiro-β-lactone-γ-lactam scaffolds was accomplished.•Developed strategy relied on a RCM reaction and highly diastereoselective catalytic hydrogenation.•A single crystal X-ray analysis of the key substructure was performed.•The target lactone-pyrrolidine cyclic systems demonstrate the interesting cytotoxic activity.