Spontaneous butenolide ring formation of pregnane-21-O-malonyl hemiesters under mild reaction conditions is facilitated by the 14β-hydroxy group present in all natural cardenolides. Issue 30 (28th July 2016)

• Record Type: Journal Article
• Authors: Pádua, R.M.; Meitinger, N.; Hennemann, M.; Schebitz, P.; Waibel, R.; Löber, S.; Gmeiner, P.; Clark, T.; Kreis, W.
• Is Part Of: Tetrahedron. Volume 72:Issue 30(2016)
• Page Start: 4556
• Page End: 4563
• Publication Date: 2016-07-28
• Subjects: Cardenolide biosynthesis -- Butenolide ring formation -- 21-O-Malonyl hemiester -- Intramolecular hydrogen bond -- Lactonization; APCI Atmosphere pressure chemical ionization -- PPB Potassium phosphate buffer -- SCRF Self-Consistent Reaction Field -- DTF Density functional theory; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tet.2016.06.024
• Languages: English
• ISSNs: 0040-4020

Abstract

Abstract: Cardenolides are composed of a steroid nucleus and a five-membered unsaturated lactone (butenolide) ring at C-17β. It is assumed that the butenolide ring is formed from a pregnane 21- O -malonyl hemiester after a condensation reaction between the methylenic group of the malonic acid residue and the C-20 carbonyl of the pregnane scaffold. Here, the formation of the butenolide ring was studied starting from pregnane 21- O -malonyl hemiesters with and without a hydroxyl group in position C-14β. Efficient lactonization was only achieved in the case of the 14β-hydroxylated derivative. The reaction involves: 1) formation of an intramolecular hydrogen bond between the C-20 carbonyl group and the 14β-hydroxyl group which stabilizes a negatively charged intermediate and/or increases the positive character of the C-20 carbonyl carbon, 2) nucleophilic attack that enables efficient lactonization by release of water, and 3) subsequent decarboxylation. We provide chemical and mechanistic evidence that 14β-hydroxylation would precede lactonization in cardenolide biosynthesis. Graphical abstract: