Synthetic Studies towards Leiodermatolide: Rapid Stereoselective Syntheses of Key Fragments

Abstract

The synthesis of three key fragments of the novel 16-membered macrolide leiodermatolide is described. The stereotetrad-containing building block was prepared via a Marshall-Tamaru reaction on an aldehyde obtained by organocatalysis. For a second building block, a Marshall-Tamaru reaction was used as well. The side-chain fragment containing a hydroxy d-lactone could be obtained by intramolecular Reformatsky reaction.Leiodermatolide (1) is a potent antimitotic agent, recently isolated by the group of Amy Wright from the sponge Leiodermatium, which belongs to the order Lithistida (Scheme 1). 1 It displays cytotoxicity at nanomolar level against a variety of human tumor cell lines 2 while showing reduced toxicity to normal cell lines. Leiodermatolide does not show much similarity to other cytotoxic polyketides, however, it shares a carbamate function, for example with palmerolide 3 and discodermolide. 4 This novel polyketides features a 16-membered macrolide, with a six-membered lactone ring on the side chain and has nine stereocenters together with a Z,Z-and E,E-diene system. Although, the initial report of Wright et al. 1 just contained a flat structure of this macrolide, more recently additional data with stereochemical information as shown in Scheme 1 appeared on the web. 5Taking into account the remarkable potent antiproliferative activity and the unique structural features which are calling for proof, leiodermatolide (1) deserves attention for total synthesis. As outlined in the retrosynthetic plan in Scheme 1, we decided to remove part of the side chain by cutting the C18-C19 trans double bond (JuliaKocienski olefination). 6 For macrolactone formation a ring-closing metathesis approach was considered. 7,8 Alternatively, other C-C bond-forming reactions or lactonization reactions (Yamaguchi/Mitsunobu) might be options. The internal Z,Z-diene would come from an enyne precursor. This way, a Sonogashira cross-coupling followed by Z-selective reduction is obvious. This leads to two building blocks 4 and 5, both having roughly equal size. For these, we decided to apply a Marshall-Tamaru reaction 9,10 that would secure the anti stereochemistry at C6/C7 and C14/C15 carbons.The synthesis of alkyne 4 started from known aldehyde (+)-6, which was obtained via L-proline-catalyzed crossaldol reaction of a-silyloxyacetaldehyde using a known literature procedure (Scheme 2). 11,12 With this aldehyde in hand, which was used as a mixture of diastereomers, we tested the Marshall-Tamaru conditions hoping for separable diastereomeric diols. To our surprise, when (R)-mesylate 13 7 (2.0 equiv) was added into the reaction mixture containing Pd(OAc) 2 (0.05 equiv), Ph 3 P (0.05 equiv) and aldehyde 6 followed by slow addition of diethyl zinc (3.0 equiv) and stirred for 48 hours, diol 8 was isolated as a single isomer in 61% yield after chromatographic purification. This reaction outcome can be understood based on Felkin-Anh-like transition state A which is akin to attack of an E-enolate to an a-substituted aldehyde (Scheme 2). Due to an...