Abstract:
Mānuka honey, derived form the nectar of Leptospermum scoparium, has stoked scientific interest due to its non-peroxide antibacterial activity. This activity, combined with perceived benefits to human health, has raised the commercial value of this product. Lack of robust regulation regarding honey identification has left the manuka honey industry vulnerable to counterfeit products. This work describes the isolation, structural elucidation and total synthesis of a known compound, 3,6,7-trimethyllumazine (78), a pteridine derivative, from mānuka honey. Isolation by flash and preparative thin layer chromatography gave lumazine 78 in sufficient quantities for structural analysis, which was contingent on a 1H-15N HMBC experiment. The structural assignment was confirmed by total synthesis from commercially available 6-aminouracil (88). Since the natural product was a pteridine derivative isolated from Leptosperumum honey, it was named lepteridine. This compound is potentially a good biomarker for genuine Mānuka honey. The isolation of this lumazine prompted a wider investigation into the occurrence of lumazines in nature. The penilumamide family of lumazine-containing natural products piqued our interest, as did the more structurally complex pseudoanchynazines. A total synthesis of the penilumamides 254 was devised. This synthesis proved more challenging than initially expected, due to the difficulty in generating key lumazine acids 152 and 357 and the reluctance of methyl anthranilate (260) to participate in amide forming reactions. Lumazine acids 152 and 357 were successfully synthesised using an inverse electron demand Diels-Alder reaction between oxadiazinones 316 and 360 and enamine 324. Amides containing methyl anthranilate (260) residues were synthesised via reactions with amino acid fluorides 408. Lumazine alcohol 133, required for the synthesis of pseudoanchynazine B (185), also proved challenging to synthesise. This alcohol was also available via an inverse electron demand Diels-Alder reaction, employing in this case silyl enol ether 472 as a cycloaddition partner for oxadiazinone 316. While the lumazine tryptophan core 413 of pseudoanchynazine B (185) was successfully assembled, this intermediate could not be elaborated into the natural product within the time frame of this project.