Chapter 4: A New Synthetic Approach Towards Analogues of the Natural Product (61) D-(+)-Showdomycin Introduction Background The maleimide ring features prominently in a number of naturally occurring compounds, including farinomalein (35),72 pencolide (60),75 and (61) (Figure D-(+)-showdomycin 13).130 These molecules have shown promising antibiotic behaviour and commonly feature a maleimide that is at the 3-position. Both pencolide (60) and farinomalein (35) have been prepared in the laboratory, with the maleimide 3-substituent being installed through a maleic anhydride precursor; the synthesis of these molecules is discussed in Chapter 1. Figure 13: The structures of three maleimide-containing natural products; farinomalein pencolide and (35), (60) (61). D-(+)-showdomycin The most widely studied maleimide-containing natural product is the C-nucleoside antibiotic (61), which was first isolated from Streptomyces D-(+)-showdomycin by Nishimura and co-workers in 1964.71 contains (61) showdoensis D-(+)-Showdomycin a substituted furanose ring, with the primary alcohol and the maleimide group arranged in a configuration; the structure of 61, drawn as a Haworth projection, is shown in Figure cis 14. The biological activity of (61) is believed to arise from the D-(+)-showdomycin electron-deficient maleimide alkene, which can undergo conjugate addition reactions with nucleophiles, such as the thiol-containing cysteine residues that are found in proteins.131 Figure 14: The structure of (61), drawn as a Haworth projection to D-(+)-showdomycin emphasise the relationship between the 1° alcohol and the maleimide. cis Previous Syntheses of Showdomycin
Chapter 4: A New Synthetic Approach Towards Analogues of the Natural Product D-(+)-Showdomycin (61) Introduction Background The maleimide ring features prominently in a number of naturally occurring compounds, including farinomalein (35),72 pencolide (60),75 and D-(+)-showdomycin (61) (Figure 13).130 These molecules have shown promising antibiotic behaviour and commonly feature a maleimide that is at the 3-position. Both pencolide (60) and farinomalein (35) have been prepared in the laboratory, with the maleimide 3-substituent being installed through a maleic anhydride precursor; the synthesis of these molecules is discussed in Chapter 1. Figure 13: The structures of three maleimide-containing natural products; farinomalein (35), pencolide (60) and D-(+)-showdomycin (61). The most widely studied maleimide-containing natural product is the C-nucleoside antibiotic D-(+)-showdomycin (61), which was first isolated from Streptomyces showdoensis by Nishimura and co-workers in 1964.71 D-(+)-Showdomycin (61) contains a substituted furanose ring, with the primary alcohol and the maleimide group arranged in a cis configuration; the structure of 61, drawn as a Haworth projection, is shown in Figure 14. The biological activity of D-(+)-showdomycin (61) is believed to arise from the electron-deficient maleimide alkene, which can undergo conjugate addition reactions with nucleophiles, such as the thiol-containing cysteine residues that are found in proteins.131 Figure 14: The structure of D-(+)-showdomycin (61), drawn as a Haworth projection to emphasise the cis relationship between the 1° alcohol and the maleimide. Previous Syntheses of Showdomycin
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