Marine microorganisms are widely viewed as an emerging source of novel natural products. A variety of butenolides [or furan-2(5H)-ones], featured with an α,β-unsaturated lactone core, are isolated from different marine fungi, bacteria, and gorgonians, to name a few. Those marine-derived butenolides possess a variety of bioactivities including antifouling by disrupting quorum sensing systems. Butenolides with a long side chain, as the important members of butenolide family, are suffered from the problem in determination of their absolute configuration, especially the remote stereogenic center(s) on the side chain. This thesis presents the efforts and results for the synthesis of four butenolides with remote chirality on the side chain, and for the determination of their absolute...[ Read more ]

Marine microorganisms are widely viewed as an emerging source of novel natural products. A variety of butenolides [or furan-2(5H)-ones], featured with an α,β-unsaturated lactone core, are isolated from different marine fungi, bacteria, and gorgonians, to name a few. Those marine-derived butenolides possess a variety of bioactivities including antifouling by disrupting quorum sensing systems. Butenolides with a long side chain, as the important members of butenolide family, are suffered from the problem in determination of their absolute configuration, especially the remote stereogenic center(s) on the side chain. This thesis presents the efforts and results for the synthesis of four butenolides with remote chirality on the side chain, and for the determination of their absolute configurations. It also includes the attempted study on the total synthesis of cladospolide B via a ring-closing metathesis (RCM) strategy and the preliminary results on the unexpected [1,2]-Wittig rearrangement of chiral boron enolates observed in the syn-selective glycolate aldol reaction.

An introduction to the general background, including isolation, structures, and bioactivity of butenolide natural products is given in chapter 1. It is followed by an illustration of the selected methods for construction of the butenolide core. Also discussed are the typical methods for and problems in stereochemistry determination of some selected natural products which possess remote pair(s) of stereogenic centers.

The results on the total synthesis of 5-(6-hydroxy-6-methyloctyl)-furan-2(5H)-one are compiled in chapter 2. A double Wittig olefination–hydrogenation strategy was used to construct the side chains possessing the stereochemically defined tertiary alcohol at C10. A RCM reaction was used to assemble the butenolide core. Two diastereomeric butenolides, with opposite configuration at C10, have been synthesized in this work and the absolution configuration of the naturally occurring compound produced by Streptomycete strain B 5632 has been determined to be (4S,10S) by comparison of the optical rotation data.

Cladospolides are the 12-membered ring macrolides possessing a conjugate enoate moiety and two free hydroxy groups. Among them, cladospolide B likely shares the same biosynthesis precursor with iso-cladospolide B, which has a butenolide core with the (11R) stereogenic center on the side chain. The corresponding (11S)-epimer, i.e. 11-epi-iso-cladospolide B, has also been isolated from a marine fungal species. As summarized in chapters 3 and 4, a diverted total synthesis strategy based on use of an advanced common intermediate has been investigated in the current work. The synthesis started from a chiral aldehyde followed by a syn-selective glycolate aldol reaction to secure the (4S,5S)-configuration. The butenolide core was assembled by the RCM protocol to afford iso-cladospolide B. On the other hand, 11-epi-iso-cladospolide B was synthesized by inversion of the (11R)-intermediate through the Mitsunobu reaction. Attempted efforts on total synthesis of cladospolide B via a RCM strategy are discussed.

As described in chapter 5, an unexpected [1,2]-Wittig rearrangement of chiral boron enolates, derived from the p-methoxybenzyl glycolate of the norephedrine derivative, was observed in the syn-selective glycolate aldol reaction when excess amounts of Hex₂BOTf were used. The reaction temperatures were optimized and the absolute configuration of the rearranged product was determined by chemical transformation into the known 2-hydroxy-3-(4-methoxyphenyl)propanoic acid. Chiral boron enolates of other electron-rich arylmethyl glycolates were found to undergo the same [1,2]-Wittig rearrangement. These findings may provide further mechanistic insights on this [1,2]-Wittig rearrangement.

The main experimental procedures, the characterization data for the key intermediates and the cited references are found at the end of the thesis. Copies of the original ¹H and ¹³C NMR spectra of some key intermediates are given in the Appendix.