Bioinspired Network Analysis Enabled Divergent Syntheses and Structure Revision of Pentacyclic Cytochalasans

Abstract

We accomplished the divergent total syntheses of ten pentacyclic cytochalasans (aspergillin PZ, trichodermone, trichoderones, flavipesines, and flavichalasines) from a common precursor aspochalasin D and revised the structures of trichoderone B, spicochalasin A, flavichalasine C, aspergilluchalasin based on structure network analysis of the cytochalasans biosynthetic pathways and DFT calculations. The key steps of the syntheses include transannular alkene/epoxyalkene and carbonyl‐ene cyclizations to establish the C/D ring of pentacyclic aspochalasans. Our bioinspired approach to these pentacyclic cytochalasans validate the proposed biosynthetic speculation from a chemical view and provide a platform for the synthesis of more than 400 valuable cytochalasans bearing different macrocycles and amino‐acid residues.

Recent advances in the total synthesis of cytochalasan natural products using bioinspired strategies

“…4d Based on bioinspired structure network analysis, Deng and colleagues completed the synthesis of flavichalasines A, C and D from their common biogenetic precursor, aspochalasin D (8) (Scheme 5). 18 Their synthesis started with selective epoxidation of aspochalasin D (8) at the C19-C20 double bond to give aspochalasin H (80) in the presence of DBU and TBHP. Then the key Prins cyclization was initiated by SnCl 4 and yielded flavichalasine C (81) in 75% yield, whose structure was confirmed by X-ray crystallographic analysis.…”

“…Inspired by this hypothesis, Deng and colleagues reported the divergent synthesis of flavipesines in 2021. 18 Their synthesis commenced with aspochalasin B (78) via a selective reduction of the C19-C20 double bond with Zn/ NH 4 OAc to afford the desired precursor aspochalasin P (6) in 16 and Trauner (2018). 17 aspochalasin Q (84) in 64% yield.…”

“…In 2021, Deng and coworkers achieved the synthesis and structural reversion of trichoderone B under the guidance of the postulated biogenetic pathway of trichoderone B and DFT calculations. 18 Their synthesis started from the conversion of aspochalasin D (8) to aspergillin PZ (9), which was realized through a p-TsOH•H 2 O (PTSA) promoted Prins-type cyclization, in 95% yield. Further stereoselective epoxidation of the C6-C7 double bond by the treatment of m-CPBA released β-epoxide 87 in 77% yield, and the structure was confirmed by X-ray crystallographic analysis.…”

Collective total syntheses of cytochalasans and merocytochalasans

“…Of note, Deng and co-workers also completed the total syntheses of asperchalasines A (9), D (7), E (8), and H (18) independently at the same time [21]. More recently, a number of other merocytochalasans and polycyclic cytochalasans have also been accomplished by the Deng and Trauner groups consecutively [22][23][24]. Promoted by these seminal works, herein we provide a comprehensive summary of our own progress on this long-term project, which has culminated in the collective syntheses of an array of tricyclic, polycyclic, hetero-dimeric and -trimeric cytochalasans and merocytochalasans.…”

Reprogramming of the biosynthetic network of Daphniphyllum alkaloids into a chemically synthetic network through generalized biomimetic strategies

“…The common pattern of natural product biomimetic synthesis is that a substrate identical (or highly similar) to its counterpart in the biosynthesis undergoes chemical reactions mechanistically similar to the corresponding enzymatic (or sometimes non-enzymatic) reactions in the biosynthesis, in the order defined by the biosynthetic pathway, to give the target molecule. Some advanced patterns have also emerged in the evolution, for instance, a) biomimetic assembly of a complex natural product with multiple natural products as building blocks (A + B + … → Z) [5][6][7] and b) biomimetic construction of a natural product network (B ← A → C → … → Z) [8][9][10] , which significantly enhance the structural complexity and diversity generated by biomimetic synthesis.…”