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. 2025 Sep 8;64(37):e202513532.
doi: 10.1002/anie.202513532. Epub 2025 Jul 22.

Ligand Type Guided Keto-Arylation Enables Modular Total Synthesis of Polycyclic CBS Xanthones

Jonas W Meringdal  1 , Vivienne Prangenberg  1 , Tim Treiber  1 , Andreas J Schneider  1 , Leon Honsdorf  1 , Dirk Menche  1
Affiliations

Ligand Type Guided Keto-Arylation Enables Modular Total Synthesis of Polycyclic CBS Xanthones

Jonas W Meringdal et al. Angew Chem Int Ed Engl. .

Abstract

The first total synthesis of the potent polycyclic xanthone antibiotics CBS72, CBS87 and CBS100 was accomplished by a modular strategy featuring a very demanding intermolecular aromatic keto-arylation. Central to the solution was a recently-developed ligand type approach, rather than brute force screening, demonstrating the usefulness of this novel concept in complex target synthesis. Additional key features include an asymmetric Davis hydroxylation proceeding with only catalytic amounts of base, thus enabling the conversion of a highly sensitive, elaborate substrate. Furthermore, a late-stage aminolysis completed the polycyclic framework, circumventing laborious protective group chemistry. Together, this strategy provides a concise, high-yielding access, confirming the full architecture of this most potent class of polyaromatic xanthones, and establishes ligand types as a powerful design tool for sophisticated cross-couplings.

Keywords: Davis oxidation; Keto‐arylation; Ligand types; Polycyclic xanthones; Total synthesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Antimicrobial polycyclic xanthone natural products. Minimal inhibitory concentrations in grey. Glc, glucoside, see ref. [2].
Figure 2
Figure 2
Fragment coupling and oxygenation strategies.
Figure 3
Figure 3
Unified retrosynthetic analysis.
Figure 4
Figure 4
Isocoumarin fragment preparation. dba, dibenzylideneacetone; DIPEA, diisopropylethylamin; HMDS, hexamethyldisilazide; PhDavePhos, 2‐diphenylphosphino‐2′‐(N,N‐dimethylamino)‐biphenyl; SEM, 2‐(trimethylsilyl)ethoxymethyl; TMS, trimethylsilyl.
Figure 5
Figure 5
Xanthone fragment preparation. DMS, dimethyl sulfate; MOM, methoxymethyl.
Figure 6
Figure 6
Ligand type dependent aromatic keto‐arylation. Ad, adamantyl; cy, cyclohexyl; dbpf, 1,1′‐bis(di‐tert‐butylphosphino)ferrocene. dppf, 1,1′‐bis(diphenylphosphino)ferrocene; tol, tolyl; XPhos, 2‐dicyclohexylphosphino‐2′,4′,6′‐triisopropylbiphenyl.
Figure 7
Figure 7
Total synthesis of CBS100. Si = SEM. NMI, N‐methylimidazole; TBS, tert‐butyldimethylsilyl.
Figure 8
Figure 8
Total synthesis of CBS87.
Figure 9
Figure 9
Total synthesis of CBS72. py, pyridine.
See this image and copyright information in PMC

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