Asymmetric syntheses of sceptrin and massadine and evidence for biosynthetic enantiodivergence

Abstract

Cycloaddition is an essential tool in chemical synthesis. Instead of using light or heat as a driving force, marine sponges promote cycloaddition with a more versatile but poorly understood mechanism in producing pyrrole–imidazole alkaloids sceptrin, massadine, and ageliferin. Through de novo synthesis of sceptrin and massadine, we show that sponges may use single-electron oxidation as a central mechanism to promote three different types of cycloaddition. Additionally, we provide surprising evidence that, in contrast to previous reports, sceptrin, massadine, and ageliferin have mismatched chirality. Therefore, massadine cannot be an oxidative rearrangement product of sceptrin or ageliferin, as is commonly believed. Taken together, our results demonstrate unconventional chemical approaches to achieving cycloaddition reactions in synthesis and uncover enantiodivergence as a new biosynthetic paradigm for natural products.

Chemo-Enzymatic Synthesis of Chiral Epoxides Ethyl and Methyl (S)-3-(Oxiran-2-yl)propanoates from Renewable Levoglucosenone: An Access to Enantiopure (S)-Dairy Lactone

“…1 H-NMR spectra of samples were recorded in CDCl3 at 300 MHz, chemical shifts were reported in parts per million relative to residual solvent peak (δ = 7.26 ppm). 13 C-NMR spectra of samples were recorded at 75 MHz (CDCl3 residual signal at δ = 77.16 ppm). …”

“…Glutamic acid is first deaminated to give the intermediate (S)-γ-carboxy-γ-butyrolactone, which was first reported by Austin et al using nitrous acid [11]. The protocol then evolved in 1978 with the use of a light excess of sodium nitrite and HCl instead of nitrous acid [12] and, to the best of our knowledge, remains unchanged today [13]. Three different routes have been reported for the reduction of (S)-γ-carboxy-γ-butyrolactone into 2.…”

“…For example, methyl (S)-3-(oxiran-2-yl)propanoate (1a) has been employed for the synthesis of many compounds such as elicitor [1], Streptrubin B [2] or chiral β-3-substituted homopropargyl [3], thiobutyrolactone [4], γ-hydroxyesters [5], diol-γ or δ-lactones [6], keto-esters [7], (+/´)-4-alkanolides [8] (Figure 1). Classically, epoxides such as 1a are obtained from (S)-γ-hydroxymethyl-γ-butyrolactone (2H-HBO, 2), itself derived from glutamic acid (Scheme 1) [9][10][11][12][13][14][15][16][17][18][19], a natural amino acid that is produced by fermentation on a commercial scale [20]. Glutamic acid is first deaminated to give the intermediate (S)-γ-carboxy-γ-butyrolactone, which was first reported by Austin et al using nitrous acid [11].…”

“…Providing 2 in very good yield and high purity through a lipase-based mediated oxidation, this sustainable synthetic pathway has been studied further by our group as an alternative to the one involving L-glutamic acid to achieve the synthesis of epoxides (S)-1a and (S)-1b (Scheme 2). Classically, epoxides such as 1a are obtained from (S)-γ-hydroxymethyl-γ-butyrolactone (2H-HBO, 2), itself derived from glutamic acid (Scheme 1) [9][10][11][12][13][14][15][16][17][18][19], a natural amino acid that is produced by fermentation on a commercial scale [20]. Glutamic acid is first deaminated to give the intermediate (S)-γ-carboxy-γ-butyrolactone, which was first reported by Austin et al using nitrous acid [11].…”

Asymmetric Synthesis of Axinellamines A and B

“…Recently, Romesberg, Baran, and co-workers have found that 1a and 1b display promising activity against both Gram-positive and Gram-negative bacteria and 1a causes membrane destabilization in Escherichia coli. [3] Among several labs that study the synthesis of dimeric pyrroleimidazole alkaloids 1-3, [3][4][5][6][7][8][9][10][11][12][13][14][15][16] Carreira et al reported the first synthetic strategy directed towards 1 [6] using a Diels-Alder reaction to establish its fully functionalized cyclopentyl core. Romo and co-workers subsequently disclosed an oxidative ring-contraction approach that was inspired by Scheuer's biosynthetic hypothesis.…”