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Macrocidin A (1) and macrocidin B (2) represent a new family of plant pathogens produced by Phoma macrostoma, a microorganism parasitic to Canadian thistle. [1] The intriguing structure of 1, which includes a tetramic acid [2] group installed in a cyclophane skeleton, was determined by extensive 2D NMR studies and single-crystal X-ray analysis, although the absolute configuration remains to be addressed because of a paucity of the natural sample. The macrocidins have significant herbicidal activity on broadleaf weeds but not on grasses, which makes them a potential lead for new herbicide design. Their biological activity and novel chemical structures have made these compounds attractive targets for chemical synthesis. Whilst construction of the macrocyclic skeleton has been addressed, [3] the synthesis of the full structure remains to be achieved. Herein, we describe the first total synthesis of macrocidin A (1) using macrolactam formation followed by cyclization.Scheme 1 outlines our retrosynthetic analysis based upon the construction of the acyltetramic acid moiety using the Lacey-Dieckmann cyclization [4] of macrolactam I, which in turn would be accessible by the intramolecular trapping of an acylketene species (a) that may be thermally generated from dioxinone precursor II. [5] This key intermediate (II) could be assembled from the stereodefined epoxy alcohol III and tyrosine unit IV. One of the challenges in the synthesis of III was the establishment of the C12 stereogenic center, [6] for which we planned to employ either a substrate-or catalystcontrolled diastereoselective hydrogenation of trisubstituted olefin V. Finally, olefin V could be obtained from phosphonate VI and aldehyde VII.Scheme 2 shows the preparation of trisubstituted olefins 10 and 11, which began with the two-step conversion of propargyl alcohol into allyl alcohol 5. [7] Epoxide 6, which was prepared by a Katsuki-Sharpless asymmetric epoxidation reaction (93 % ee), [8] was silylated and subjected to rhodiumcatalyzed hydroboration, [9] followed by oxidation to give alcohol 8. Swern oxidation of 8, followed by a Horner-Emmons reaction with chiral phosphonate 12 [10] afforded olefin 10 (E/Z = 9:1). Recrystallization (n-hexane/ethyl acetate) gave pure (E)-10, which had a stereodefined trisubstituted olefin and a menthone chiral auxiliary [11] ready for diastereoselective hydrogenation. The substrate for the catalyst-controlled diastereoselective hydrogenation, aceto-Scheme 1. Retrosynthetic analysis of macrocidin A.

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