Unified Syntheses of Cavicularin and Riccardin C: Addressing the Synthesis of an Arene Adopting a Boat Configuration

Abstract

Concise syntheses of the natural products cavicularin (ten steps) and riccardin C (seven steps) are reported. Key features of the new synthetic route are a convergent strategy to assemble acyclic precursors and a sequence of regioselective reduction and halogenation steps to facilitate Wittig macrocyclisation and transannular ring contraction reactions.

A Corey–Seebach Macrocyclisation Strategy for the Synthesis of Riccardin C and an Unnatural Macrocyclic Bis(bibenzyl) Analogue

“…Drawing on previous experience,, we identified arenes 16 – 19 as the key building blocks required for our synthesis, as all but arene 17 were commercially available compounds (Scheme ). Moreover, the synthesis of 17 from catechol 13 was readily achieved by a sequence of benzylation, triflation, and Wittig methylenation using standard protocols.…”

“…The largest familial group is based on macrocyclic core 2 , and has riccardin C ( 10 ) at its helm (Figures and ) , . A popular synthetic target for many years, riccardin C recently gained prominence when a screening seeking new leads against cardiovascular disease revealed that it acted as an agonist for the cholesterol‐regulating liver X receptor LXRα and an antagonist for LXRβ . Indeed, it has been tested in many pharmacological screenings,, and these have revealed antifungal[4b] and antibacterial activities, and cytotoxic activity against various cancer cell lines .…”

“…Mindful of the fact that syntheses of riccardin C ( 10 ) proceeding via macrocycle 12 also constitute formal total syntheses of cavicularin ( 9 ), , , , and asterelin A ( 11 ) (Figure ), we decided to use a protecting‐group strategy such that the phenol in arene D was protected orthogonally to those in arenes B and C. In previous syntheses, several strategies have been developed to tackle the challenge of forming the 18‐membered ring of riccardin C (Figure ) . These include macrocyclisation protocols using Wurtz, Wittig, and McMurry, reactions to effect closure through either of the ethano bridges, Pd 0 cross‐coupling and S N Ar reactions for closure through the biaryl or biaryl ether linkages, and two approaches to cavicularin based on the de novo construction of arene A . In this paper, we report a new strategy in which a Corey–Seebach reaction is used to achieve the critical macrocyclisation step .…”

Selected synthetic strategies to cyclophanes

“…Riccardin C ( 96 ) is a macrocyclic bis-bibenzyl entity with pharmacological properties, including antimycotic and antibacterial effects, and cytotoxicity against P-388 mouse leukaemia and KB cell lines from nasopharyngeal carcinoma . In view of these useful medicinal properties Harrowven and co-workers [ 115 ] have reported the synthesis of this molecule by using the McMurry reaction. Kawase and co-workers [ 116 ] have reported double-helically twisted macrocycles 97 exhibiting chiral sensor properties.…”

Anti-MRSA activity of isoplagiochin-type macrocyclic bis(bibenzyl)s is mediated through cell membrane damage

“…[1][2][3][4] These compounds have characteristic structures, and exhibit diverse biological activities, [5][6][7][8][9][10][11][12] and so there is great interest in the synthesis of these compounds and their analogs. [13][14][15][16][17][18][19][20] We recently reported that riccardin-class macrocyclic bis-(bibenzyl)-type phenolic compounds, such as riccardin C (1), exhibit potent antibacterial activity towards methicillin-resistant Staphylococcus aureus (anti-MRSA activity), comparable to that of clinically used drugs, such as vancomycin and linezolid. 21,22 In order to understand the structure-activity relationship of riccardin-C class bis(bibenzyl)s, we previously prepared several riccardin C derivatives, and found that the number and position of hydroxyl group(s) on the benzene ring are important for anti-MRSA activity.…”