Approaches to Polycyclic 1,4-Dioxygenated Xanthones. Application to Total Synthesis of the Aglycone of IB-00208

Abstract

Hexacyclic xanthone natural products such as IB-00208 present a formidable challenge in organic synthesis. A new approach to polycyclic 1,4-dioxygenated xanthones from benzocyclobutenones has been developed and applied to the first total synthesis of the aglycone of IB-00208. The 22-step synthesis features an acetylide stitching process that joins an aryl aldehyde with an angularly fused benzocyclobutenone, which was prepared by a ring-closing metathesis reaction. The resulting acetylenic benzocyclobutenone diol underwent a Moore rearrangement to give an intermediate that was further elaborated to the aglycone of IB-00208 as a mixture of hydroquinone–quinone tautomers.

A Multifunctional Monooxygenase XanO4 Catalyzes Xanthone Formation in Xantholipin Biosynthesis via a Cryptic Demethoxylation

“…), including xantholipin (1), lysolipin, FD-594, and arixanthomycin, are a subgroup of natural polyketide products, characterized by a highly oxygenated, angular, fused hexacyclic skeleton with a unique xanthone ring nucleus (marked in red in Figure 1) (Winter et al, 2013;Kang and Brady, 2014). Since the isolation of the first member albofungin over 40 years ago, this novel class of molecules has attracted noticeable attention from both the synthetic and biological communities due to their attractive chemical structures and diverse biological activities, such as antibacterial activities (mainly Gram-positive bacteria), antifungal activities, antitumor activities, and anticoccidial activities (Winter et al, 2013;Sloman et al, 2011;Masuo et al, 2009;Butler et al, 2011;Yang et al, 2015). Xantholipin, isolated from the culture broth of Streptomyces flavogriseus in 2003 (Terui et al, 2003), possesses strong antibiotic activity against several Gram-positive bacteria and potent cytotoxicity activity against the leukemia cell line HL60 and the oral squamous carcinoma cell line KB (Zhang et al, 2012).…”

Recent Advances in Total Synthesis via Metathesis Reactions

“…Despite this potential difficulty, the RCM reaction has proven to be highly efficient in many cases. An instructive example of this is demonstrated in the synthesis of the polycyclic xanthone-type antibiotic IB-00208 (84), reported by Martin and co-workers (Scheme 4). 84 Thus, the synthesis of the key cyclobutenone 86 was successfully achieved via a RCM reaction of precursor 85 when subjected to the Grubbs II catalyst (4).…”

“…An instructive example of this is demonstrated in the synthesis of the polycyclic xanthone-type antibiotic IB-00208 (84), reported by Martin and co-workers (Scheme 4). 84 Thus, the synthesis of the key cyclobutenone 86 was successfully achieved via a RCM reaction of precursor 85 when subjected to the Grubbs II catalyst (4). The resulting cyclobutenone was rearranged to the desired xanthone 87 under thermal conditions and represents a general route to construct polycyclic benzoquinones.…”

Calixanthomycin A: Asymmetric Total Synthesis and Structural Determination

“…The challenging structural features and biological potentials of polycyclic xanthones (Figure ), such as FD-594 ( 3 ), kibdelone C ( 4 ), kigamicin A ( 5 ), and arixanthomycins A–C ( 6 – 8 ), have attracted considerable attention from the synthetic community, including the groups of Kelly, Suzuki, Porco, Ready, Martin, and us . We are interested in the biological functions and mechanism studies of this family of natural products, which prompted us to initiate a research program to explore its chemical synthesis .…”