The synthesis of tricholomenyns a and b - novel natural product with potential in cancer chemotherapy

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Project objective

Two novel anti-mitotic natural products, named tricholomenyns A (b and B (@, have recently been . isolated from Tricholoma acerbum, a mushroom collected in Italy. The anti-mitotic activity of . tricholomenyns A (f and B (> was assayed in T Iymphocyte cultures treated as for cytogenic analysis. Anti-mitotic activity was observed at 0.16 pg/ml for the tricholomenyn B (2). The aim of this proposal is to develop synthetic routes to both tricholomenyns A and B which would also be useful for the preparation of simplified analogues for biological screening. The structure of the tricholomenyn A is novel but the nucleus bears a striking resemblance to bromoxone and a simple marine natural product recently prepared by Taylor and al. (L.N.P.S.-U.York). Initial studies will concentrate on the Sonogashira Pd/Cu catalysed coupling of bromoxone with a range of alkynes in order to obtain compounds 7 which should be submitted for biological screening. If problems are encountered with coupling to the highly functionalised nucleus 3, earlier synthetic intermediates, e.g 4 and 5, will be investigated in the process. We will also compare de reactivity of 3, 4 and 5 with the corresponding iodides. With the basic coupling methodology in place, we will proceed to investigate the synthesis of tricholomenyns A (O, starting from the 6-methyl-5-hepten-2-one. The proposed route to tricholomenyn B (2) is very similar. Two different approaches will be 5- investigated so as to prepare the cyclised compound 2: this may be possible via an intramolecular procedure or via a lactonisation. With synthetic routes to racemic material established, we will devise an asymetric sequence.

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Participants

• UNIVERSITY OF YORK · YORKCoordinatorUnited Kingdom

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