Synthetic Studies Towards the Core Structure of Nakadomarin A by a Thioamide‐Based Strategy

Abstract

The tricyclic BCD substructure of the marine natural product nakadomarin A has been synthesised. The strategy utilised a key carbon–carbon bond-forming reaction between a furan and an N-acyliminium ion derived from a secondary thiolactam. In addition, a novel three-component coupling reaction between a thioamide, an allylic bromide and an isocyanate, leading to the establishment of two new stereogenic centres, is reported.Two key steps in a projected total synthesis of nakadomarin A have been realised by using the unique chemistry of thioamides. Formation of the carbocyclic B ring can be effected by nucleophilic attack of a furan on a thiolactam-derived iminium ion, and the key quaternary centre can be established by a novel three-component coupling reaction.

Recent developments in the total synthesis of natural products using the Ugi multicomponent reactions as the key strategy

“…23 In addition to the total synthesis of natural products by themselves, several formal total syntheses of natural products employing the Ugi reactions (Fig. 1) have been reported, such as those of massadine ( 6) 24 and nakadomarin A (7), 25 as well as the preparation of the core structures of various natural products including halichonadins K (8), L (9), and others, 26 14 Nlabelled-desacetoxytubulysin H (10a) a labelled synthetic analog of the natural tubulysin H (10b), 27 (±)-plicamine (11), 28 lapidilectine B (12) grandolodine C (13), 29 and (−)-chimonanthine (14). 30 Critical portions or precursors of natural products, like the tripeptide part of the jaspamide and chondramide alkaloids, 31 and analogs of natural products, such as 3′-hydroxy pacidamycin D, 32 11-methoxy mitragynine pseudoindoxyl, 33 15-deoxyspergualin, 34 and pretubulysin 35 have also been prepared by the use of this reaction.…”

Functionalised Nitrogen Heterocycles and the Search for New Antibacterials and Bioactives

“…62 Similar lactam homologation 65 has been applied for the formation of (-)-lepadiformine 66 and epibatidine 67 and bicyclic thiolactam homologation has been applied to the synthesis of nakadomarin A. 68…”

Natural Product Repertoire of the Genus Amphimedon

“…Several Amphimedon metabolites were targets for chemical synthesis such as nakadomarin A, owing to its interesting biological applications including antibacterial, cytotoxic and antimicrobial properties [72]. Synthesis was carried out by using a thioamide based strategy [73]. Marine diterpenoid diisocyanoadociane is another example that was synthesized by using intramolecular Michael reaction due to its potent antimalarial activity [74].…”