The enantioselective total synthesis of Sealutomicin C Stuart Astle, Sean Guggiari and Jonathan Burton University of Oxford, UK
The sealutomicins are a family of anthraquinone-fused natural products isolated from the actinomycete Nonomuraea sp. MM565M-173N2. 1 Sealutomicins B – D all display in vitro antibacterial activity against a range of gram-positive bacteria; however, due to the scarcity of material isolated, no investigations have yet been made into the mechanism by which this occurs. Furthermore, sealutomicins B – D all bear strong structural similarities to the natural product unciaphenol, which inhibits replication of antiretroviral-resistant HIV strains without concomitant cytotoxicity to host T-cells, raising the possibility of similar antiviral effects being observed for sealutomicins B – D. 2 As such, these natural products are synthetic targets of promising medicinal and therapeutic use.
We have successfully completed the first total synthesis of sealutomicin C in an 18-step route via intermediate A (Figure 2 ). Compound A is prepared in 98% ee from commercially available 2-bromobenzaldehyde and 5-methoxyisatin in a 10-step sequence, which features an enantioselective dihydroquinoline synthesis using a proline-derived catalyst, and an organolithium cyclisation to form a key arene-ketone bond. Subsequent manipulation of the aldehyde handle of A enables installation of the α,β-unsaturated ester side chain, while a Hauser-Kraus annulation is used to access the anthraquinone unit to give the target natural product as a single enantiomer.
Attention has now shifted to the conversion of intermediate A to sealutomicins B and D. We envisage that the aldehyde moiety of A may be used as a handle to access the α-hydroxybutenolide side chain of both natural products, and that the same Hauser-Kraus annulation may be used to install the required anthraquinone units. This presentation will discuss both the synthesis of sealutomicin C and subsequent efforts towards sealutomicins B and D. References 1. J. Antibiot. (Tokyo) , 2021 , 74 , 291 - 299 2. Org. Lett. , 2015 , 17 , 5304 - 5307
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