Anodic Cyclization Reactions and an Approach to the Chrysosporazine Family of Natural Products

Abstract

Electrochemistry has long offered new opportunities for the construction of biologically relevant molecules. Many of these opportunities are based on the ability that electrochemistry provides for reversing the polarity of known functional groups. For example, consider the brief retrosynthetic analysis shown in the Scheme below. The analysis proposes a route to the Chrysosporazine family of natural products (specifically Chrysosporazine D in this case) from readily available amino acid and lignin derived starting materials. The Chrysosporazines are efflux inhibitors that improve the effectiveness of chemotherapy agents.1 The plan calls for a coupling of the two starting materials to afford a cyclization substrate. However, the proposed cyclization reaction would combine a nucleophilic amide nitrogen with a nucleophile electron rich styrene derivative. In principle, an anodic oxidation reaction can solve this issue by either converting the amide nitrogen into a radical or oxidizing the styrene derivative to form a radical cation. Either mode would effectively reverse the polarity of one of the nucleophilic groups and allow for the cyclization. Previous efforts examining these cyclizations have focused on the generation of a N-radical intermediate.2 Yet while these efforts have been very successful, they require the presence of a phenyl ring on the amide nitrogen in order to lower its pKa. This is essential for the formation of an amide anion that is in turn oxidized to the desired N-radical. Such a plan is not compatible with the synthesis of the Chrysosporazines that simply do not have a phenyl ring on the nitrogen of the amide. Placing one there would prevent the intramolecular cyclization. So, how can this problem be resolved? There are two possible answers to this question. One involves a change in the overall strategy that converts the amide into an electron-rich olefin equivalent that can be oxidized to from a radical cation. The second involves finding an alternative method for dropping the pKa of the amide so that the anion and subsequent N-radical can still be made. In the chemistry to be discussed, both strategies will be examined and the propensity for the cyclic product to undergo over-oxidation shown to be the determining factor for which pathway is preferred; a preference that has led to a new approach to N-based radical cyclizations. 1. Elbanna, A. H., Khalil, Z. G., Bernhardt, P., V., Capon, R. J. Org. Lett. 2019, 21, 8097–8100. 2. Xiong, P.; Xu, H-C. Acc. Chem. Res. 2019, 52, 3339-3350. Figure 1