Insights into the Biosynthesis of Cyclic Guanidine Alkaloids from Crambeidae Marine Sponges

Abstract

Among the outstanding chemical diversity found in marine sponges, cyclic guanidine alkaloids, present in species of the family Crambeidae, are particularly attractive, not only because of their unique chemical features, but also due to a broad range of biological activities. Despite a growing interest in these natural products as therapeutic agents, their metabolic pathway has not been experimentally investigated. Ex situ feeding experiments using radiolabeled precursors performed on the Mediterranean sponge Crambe crambe suggest arginine and fatty acids as precursors in the metabolic pathway of crambescins. A subsequent bio‐inspired approach supported the change of paradigm in the metabolic pathway of cyclic guanidine alkaloids. A large part of the chemical diversity of this family would therefore originate from a tethered Biginelli‐like reaction between C‐2/C‐3 activated fatty acids and a central guanidinylated pyrrolinium.

Eight-step total synthesis of (+)-crambescin A

“…Finally, CF 3 CO 2 H promoted removal of the four Boc groups, furnishing the targeted crambescin A (only 8 steps, 10.7% total yield). All of the analytical data including 1 H, 13 C, 2D NMR, and [a] D value of the synthetic 1 were identical to those of the natural product (Tables S1 and S2 †). 11…”

“…12 More recently, a racemic synthesis of crambescin A was reproted by Thomas and co-workers employing a tethered Biginelli-like reaction between C-2/C-3 activated fatty acids and a central guanidinylated pyrrolinium. 13 However, the asymmetric synthesis of crambescin A-C has not been reported. It was not until 2016 that the rst asymmetric route to crambescin A-C derivatives (crambescin A-C carboxylic acid) was delineated by Nishikawa and co-workers.…”

Synthetic Approaches to a Challenging and Unusual Structure—An Amino-Pyrrolidine Guanine Core

“…Reported efforts on the synthesis of a cyclic-guanidine core. Works from: (a) Ascenzi, P., et al [24], (b) Boto, A., et al [25,27], and (c) Silva et al [29].…”

“…Next, we turned our attention to the oxidative decarboxylation of N α -acyl-l-arginine derivatives (3) (Scheme 2). Based on the literature [29], we propose that the oxidative decarboxylation of 3 will generate an iminium intermediate (5), which goes through an intramolecular cyclization to 4. Depending on the reaction conditions, 5 can be trapped by water to the hemiaminal that is further oxidized to the imide (6) or cleavage to the aldehyde (7) and the corresponding amide.…”

“…They also showed that the reaction with proline is limited to N-protected carbamates ( Figure 2b) [27]. In a very recent work, Silva et al [29] on trying to elucidate the metabolic pathway of crambescins, suggested arginine and fatty acids as precursors for the broad chemical diversity of this family. Their hypothesis was corroborated with a bio-inspired synthesis of crambescin A2-448.…”