Preparation of the Geranyl-α-pyrone (±)-Aurantiacone via a New Pyrone Synthesis

Abstract

The structure of the leaf resin geranyl-a-pyrone aurantiacone isolated from Mimulus ( = Diplacus) aurantiacus (Curtis) Jeps. (Scrophulariaceae) was confirmed through synthesis. The key step is lactonization of the sensitive 5-hydroxy-3-oxopent-4-enoic acid under mild conditions, which can be released from the corresponding bispotassium salt. The latter is accessible in a few steps from an N-acyl aziridine and an ethyl acetoacetate.Mimulus (= Diplacus) aurantiacus (Curtis) Jeps. (Scrophulariaceae) is a chaparral subshrub that mainly occurs in California. It produces striking amounts of leaf surface resins in excess of 30% of leaf dry weight. 1 This resin is remarkable since it reduces growth and survival of its primary herbivore, the larvae of Euphydryas chalcedona. 2 It consists of at least five geranyl flavonoids of known structure. 1,3 Additional compounds of the leaf surface resins have been isolated, but their structures have not been elucidated yet. 3a Figure 1 The two structural proposals for aurantiacone In 1989, Wollenweber et al. were the first to report on the isolation of a geranyl-a-pyrone from the leaf resin of Diplacus aurantiacus with a molecular weight of 306. 3a Based on the NMR spectroscopic data they proposed structure 1 but at the same time noted that structure 2 was also conceivable (Figure 1). Recently, this compound was again isolated from the leaf resin of Mimulus (= Diplacus) aurantiacus by Hare et al. 1b,c,4 Detailed NMR investigations led them to conclude that the initial structure assignment was incorrect. They suggested 2 as the structure of the natural product which was referred to as aurantiacone.Biogenetic considerations also support structure 2. Given that the biosynthesis of aurantiacone involves a triketo thioester cyclizing to produce an a-pyrone which then reacts with geranyl diphosphate, nothing else but 2 can be the correct structure, as 1 cannot be produced by this pathway. Scheme 1 Reagents and conditions: (a) LDA (2 equiv), THF, -78 °C → 0 °C; NH 4 Cl (aq); (b) KOH, EtOH, r.t.; (c) tartaric acid, 0 °C; (d) Ac 2 O, py, -20 °C → 0 °C; (e) K 2 CO 3 , MeOH, r.t.In order to confirm the structure of aurantiacone we performed a synthesis of this natural product. The procedure we applied relies on a method for the preparation of 4-hydroxy-2H-pyran-2-ones 9 (Scheme 1), which has recently been developed in our laboratory. 5 Our protocol is based on the assembly of 5-hydroxy-3-oxopent-4-enoic acid esters 5 through selective g-acylation of the dianion of ethyl acetoacetates 4 with N-acyl-2-methyl aziridines 3 6 and the transformation of 5 into the corresponding stable bispotassium salts 6. The free 5-hydroxy-3-oxopent-4-enoic acid 7 is released from 6 by treatment with tartaric acid and cyclized under mild conditions with acetic anhydride-pyridine. The primarily formed O-acetyl derivatives 8 are finally hydrolyzed with potassium carbonate to give the 4-hydroxy-2H-pyran-2-ones 9. In most cases 7 can be transformed into 9 in one synthetic step using trifluoroacetic acid-trifluoroacetic...