Vic-Tricarbonyl Compounds: Synthesis of (±)-9-epi-Wailupemycin A

Abstract

A synthesis of the 9-epimer of the marine natural product wailupemycin A is reported. The key reaction sequence consists of a diastereoselective enamine addition to a tricarbonyl monohydrate, the formation of an enol silyl acetal, and finally the stereocontrolled addition of the α-pyrone substructure.The use of vic-tricarbonyl compounds as polyelectrophiles in organic synthesis is mainly restricted to their reaction with O-and N-nucleophiles. 1,2 The stereocontrolled addition of C-nucleophiles has been studied with diethyl ketomalonate. 3 The crotylboration of vic-diketo amides and vic-diketo esters was possible with high diastereoselectivity and complementary regioselectivity. 4 A diastereoselective intramolecular aldol reaction of a vicdiketo ester has been achieved. 5 The asymmetric crotylboration of a vic-tricarbonyl compound was used as a key step in the total synthesis of awajanomycin. 6 Wailupemycin A (1) and wailupemycin B (2) (Figure 1) are α-pyrone containing metabolites from the marine derived actinomycete BD-26T(20) isolated from sediments, which were collected at Wailupe beach south east of Hawai. 7 The structures of both compounds were determined by combined spectroscopic techniques. The wailupemycins were tested for antimicrobial activity against Bacillus subtilis, Staphylococcus areus, and Escherica coli. While wailupemycin B (2) was inactive, wailupemycin A (1) showed activity against E. coli. 7 The biosynthesis of the wailupemycins has been investigated and analogues have been prepared via mutasynthesis. 8 A total synthesis of enantiomerically pure wailupemycin B (2) has been reported by Bach and Kirsch. 9 Here, we present a synthesis of (±)-9-epi-wailupemycin A that focuses on the use of a vic-tricarbonyl compound as the key intermediate. The retrosynthetic consideration of the wailupemycin A structure 3 leads to the vic-triketone 4, acetophenone 5, and the methyl-α-pyrone 6 (Scheme 1). A successive addition of enolates or enolate equivalents of 5 and 6 to the tricarbonyl substructure 4 could be used to assemble the target structure.For initial studies, cyclohexane-1,2,3-trione (10) was chosen as test substrate for the addition of 5 and 6 (Scheme 2). Figure 1 Structures of wailupemycin A (1) and wailupemycin B (2)