Bioinspired chemical synthesis of monomeric and dimeric stephacidin A congeners

Abstract

Stephacidin A and its congeners are a collection of secondary metabolites that possess intriguing structural motifs. They stem from unusual biosynthetic sequences that lead to the incorporation of a prenyl or reverse-prenyl group into a bicyclo[2.2.2]diazaoctane framework, a chromene unit or the vestige thereof. To complement biosynthetic studies, which normally play a significant role in unveiling the biosynthetic pathways of natural products, here we demonstrate that chemical synthesis can provide important insights into biosynthesis. We identify a short total synthesis of congeners in the reverse-prenylated indole alkaloid family related to stephacidin A by taking advantage of a direct indole C6 halogenation of the related ketopremalbrancheamide. This novel strategic approach has now made possible the syntheses of several natural products, including malbrancheamides B and C, notoamides F, I and R, aspergamide B, and waikialoid A, which is a heterodimer of avrainvillamide and aspergamide B. Our approach to the preparation of these prenylated and reverse-prenylated indole alkaloids is bioinspired, and may also inform the as-yet undetermined biosynthesis of several congeners.

Figure 1 ∣. Selected reverse-prenylated indole alkaloid congeners.

Monomeric compounds 1-6 consist of a prenyl or reverse-prenyl group, a bicyclo[2.2.2] diazaoctane framework and a chromene unit. Homo- and heterodimeric compounds 7-9 arise from the non-symmetric association of monomeric units (bonds that give rise to the non-symmetric dimers are highlighted in red).

Figure 2 ∣. Hypotheses for the biosynthesis of stephacidin A congeners.

a, Prevailing biogenetic hypotheses for the biosynthesis of stephacidin A and 6-epi-stephacidin A. b, Proposed biosynthesis of stephacidin B from 2 equiv. avrainvillamide.

Figure 3 ∣. Synthetic strategy for stephacidin A and the application of C6 halogenation.

a, Retrosynthesis of (+)-stephacidin A from ketopremalbrancheamide (11) and the Simpkins route to 11. b, Syntheses of malbrancheamide C (16) and malbrancheamide B (17) from 11. DIBAL-H, diisobutylaluminium hydride.

Figure 4 ∣. Syntheses of stephacidin A and congeners.

a, Synthesis of (+)-stephacidin A from 11. b, Syntheses of stephacidin congeners notoamide I, aspergamide B, notoamide F, notoamide R and sclerotiamide from 1. B₂(pin)₂, bis(pinacolato)diboron; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; MS, molecular sieve; NIS, N-iodosuccinimide; TMEDA, tetramethylethylenediamine; TPAP, tetrapropylammonium perruthenate.

Figure 5 ∣. Conjugation possibilities for aspergamide B and avrainvillamide.

Homocoupling of aspergamide B (4) and avrainvillamide (5) afforded the aspergamide B dimer (24) and stephacidin B (8), respectively, whereas the heterodimerization of aspergamide B (4) and avrainvillamide (5) produced waikialoid A (7). We hypothesize that the newly isolated versicoamide G (25) and versicoamide H (26) would similarly arise from the dimerization of aspergamide B or avrainvillamide with formal kojic acid. The stereochemistry of the aspergamide B dimer (24) is supported by X-ray analysis.