Studies on Enantioselective Total Synthesis of Ascospiroketal B (I)

Abstract

Ascospiroketal B (1) was isolated from the Ascochyta slicorniae, a marine-derived fungus known as rich sources of secondary metabolites, by OSMAC (One Strain-Many Compounds) approach. Although the relative structure of ascospiroketal B (1) was elucidated by G. M. Konig in 2007 by use of H NMR, C NMR, IR, 2D HSQC, 2D NOSEY and so on, the relative configurations at C2’, C3’ and C15 still need to be determined, probably due to the flexibility of the side chain. Key structural features include a tricyclic spiro skeleton and eight stereogenic centers with one quaternary carbon center at C2 position. We report herein the first synthesis of C1-C10 fragment 20 of ascospiroketal B (1). Retrosynthetic strategy is summarized in Figure 1. The C11C12 bond would be introduced by Stille coupling of the vinyl tin 2 and C1-C11 fragmenet 3. Fragment 3 should be derived from the intermediate 4 and the intermediate 4 could be synthesized from NHK reaction between vinyl iodide 5 and aldehyde 6. We envisioned that installation of the quaternary chiral center at C2 of ascospiroketal B (1) would be accomplished by asymmetric alkylation protocol. Key intermediate 10 was prepared from the commercially available 1,4-butanediol (7) (Scheme 1). After mono-protection of the diol 7 using NaH, PMBCl, and TBAI in THF in 64% yield, the primary hydroxyl group was converted quantitatively to the aldehyde by Swern oxidation. Aldehyde was subsequently converted to α,β-unsaturated ester using stabilized Wittig reagent in benzene, and hydrolysis using 2 N NaOH in MeOH provided the carboxylic acid 8 in 81% two-step yield. Pivaloylation of the acid moiety in 8 by pivaloyl chloride afforded the mixed anhydride, which was immediately treated with the lithium salt of (S)-4-isopropyloxazolidin-2-one to give the intermediate 9 in 73% yield. Quaternary center at C2 of the intermediate 9 was constructed with NaHMDS and BOMCl to provide the desired C-alkylation product 10(59%) along with the O-alkylated product 11(11%). Use of HMPA as additive gave the O-alkylation product 11 only. The chiral auxiliary in 10 was removed using LiOH and H2O2 in aqueous THF in 83% yield (Scheme 2). Although Sharpless asymmetric dihydroxylation of carboxylic acid 12 took 2 days using AD-mix-α and methanesulfonamide in tBuOH and H2O at 0 C, the resulting 1,2-diol was cyclized