Biomimetic Total Synthesis of Mbandakamine A and Further Antiplasmodial Naphthylisoquinoline Dimers

Abstract

The first total synthesis of mbandakamine A, an unsymmetrically coupled dimeric naphthylisoquinoline alkaloid with a high steric hindrance, is described. Key step was the phenol‐oxidative cross‐coupling of its two 5,8’‐linked monomeric units, 5‐epi‐korupensamine E and 8‐O‐methylkorupensamine A. These two naphthylisoquinolines were synthesized atroposelectively by applying the ′lactone method′. As an alternative to the largely separate synthesis of the two monomers, both of them were provided simultaneously, by the – intentionally non‐selective – O‐demethylation of a late joint precursor, thus shortening the synthesis substantially. Oxidative coupling of a 1:1 mixture of the two monomers provided mbandakamine A as a single atropisomer, along with four further naphthylisoquinoline dimers, nearly all of them based on new coupling types. Some of these new quateraryls showed excellent antiplasmodial activities, in particular the 6’‐6’’‐coupled main product.

The Stereoselective Total Synthesis of Axially Chiral Naphthylisoquinoline Alkaloids

“…5,15,17,51 Following the same strategy, two closely related NIQs, 8-Omethylkorupensamine A (43a) and its regioisomer 42a (Scheme 11), have more recently been synthesized, permitting their biomimetic oxidative cross-coupling to achieve the first total synthesis of the highly unsymmetric dimer mbandakamine A (44). 2 The lactone method, originally developed for the very first synthetic access to naphthylisoquinoline alkaloids, 15,17,28,29 has meanwhile been applied to the total synthesis of a broad series of NIQs with no less than five out of seven coupling sites (Scheme 2), 1,2,5,17,28−31 has also been used for the synthesis of various other axially chiral natural products. 5,50,52…”

“…J.20162297929796 SchiesC.SeupelR.FeineisD.GehroldA.SchrautM.KaiserM.BrunR.BringmannG. Schies, C. Seupel, R. Feineis, D. Gehrold, A. Schraut, M. Kaiser, M. Brun, R. Bringmann, G. 20183940945 …”

“…Significantly more challenging is the construction of NIQs with three ortho -substituents next to the axis, such as korupensamine A ( 3a ), in a regio- and stereoselective manner. Such alkaloids display enhanced steric hindrance that is not abundantly high, yet high enough to effect stable axial chirality. , Therefore, and because of their promising bioactivities, ,,, this is a major subgroup of NIQs that have been addressed by several synthetic chemists ,,− by profiting from internal asymmetric induction through chiral groups present ,,,,− or introduced or from external asymmetric induction using chiral coupling catalysts. − Some of these syntheses involve the direct, convergent coupling of the entire bicyclic moieties, ,,,,,, whereas others, mostly to avoid the high steric load, are based on the coupling of a bicyclic entity to a monocyclic precursor of the other moiety, with completion of the second half after the coupling step. ,,,,, …”

“…Chemis-trySelect 2018, 3, 940−945. 2 This article presents the atropo-selective preparation of two regioisomeric natural 8-O-methylkorupensamines as a reliable basis for their oxidative cross-coupling, permitting the first total synthesis of the highly unsymmetric NIQ dimer mbandakamine A.…”

Interplay between σ Holes, Anion···H–C, and Cation−π Interactions in Dibromo[2,2]paracyclophane Complexes

“…It is a good example of a molecule with a forced “face to face” arrangement of aromatic rings. The Mbandakamine molecule, − from a newly isolated compound from a plant in Congo, is another example of natural molecule with forced face to face arrangement of aromatic rings. Based on the geometric criteria only, one can expect π–π stacking interactions in 1 and its derivatives.…”