Total Synthesis of Cavicularin and Riccardin C: Addressing the Synthesis of an Arene That Adopts a Boat Configuration

Abstract

A transannular ring contraction induced by the addition of an aryl radical intermediate to a proximal arene facilitated the construction of the highly strained macrocyclic core of cavicularin (1). The precursor, an iodinated derivative of another natural product, riccardin C, was prepared from four commercially available arenes in a highly convergent sequence.

Syntheses of Macrocyclic Bis(bibenzyl) Compounds Derived from Perrottetin E

“…Isolation from liverworts [4] Biological activities [17,18] Total synthesis 6 riccardin C Reboulia hemisphaerica (1982) [9] et al [4] COX inhibition [4] 1990 [27] Ptagiochasm intermedlum (2010) [19] cytotoxic [20,21] 1998 [5] inhibitory activities against HIV-1 RT [21] 2005 [28] inhibition of NOS [22,23] 2009 [25] LXRα agonist but LXRβ antagonist [24,25] antifungal [19] apoptosis of human prostate cancer [26] 8 plagiochin H ---9 isoriccardin C Marchantia polymorpha, M. palmata (1987) [10] COX inhibition [4] Plagiochasma rupestre (1999) [29] Ptagiochasm intermedlum (2010) [19] …”

“…For riccardin C (6) several synthetic routes have been published. [5,25,27,28] We now present a new approach through our improved strategy based on coupling of 20 and the aldehyde 67 as the b-d unit (obtained from the THPprotected iodorarene 66 [38] and the boronic acid 45) and subsequent Wittig macrocyclization (Scheme 13).…”

“…It is noteworthy that the syntheses of the highly ortho-substituted biaryls b-d as well the macrocyclization step are crucial in some cases due to steric hindrance as well as ring strain ( Figure 1). The common "southern" diaryl ether fragment was provided as the phosphonium salt 20 by an approach similar to that published for the synthesis of cavicularin [28] (Scheme 3).…”

(Me3Si)3SiH: Twenty Years After Its Discovery as a Radical‐Based Reducing Agent

“…[40] Radical initiator is not necessary for the good performance of the reaction since oxygen plays this role and simultaneously facilitates the oxidative rearomatization. Harrowven et al completed the first total synthesis of cavicularin, [45] in which an analogous reaction was used with an aryl iodide for a radical-induced transannular ring contraction. For this key step, (Me 3 Si) 3 SiH was used together with AIBN in toluene at 90 8C.…”

Functionalisation of Macroheterocycles with Preserving and Changing Their Sizes

“…The resulting target cavicularin (247) and riccardin C (251) that is present in Chinese liverwort Plagiochasma intermedium are readily separated using column chromatography (Scheme 55). [124] The formation of the dihydropyran fragment occurs in the intramolecular interaction of the triple bond with the hydroxyl group, which is applicable to synthesis of bryastatines of sea mats Bigula neritina [125] and polycavernoside (252) that is glycosylated macrolide of poisonous red algae Gracilaria edulis (Polycavernosa tsudai). [126] Thus, metathesis cyclization of diyne (253) over a molybdenum catalyst (254) forms the required macrocycle (255), and transannular reaction therein over alkynophile gold catalyst (256) -an additional six-membered cycle.…”