The iejimalide natural products--each composed of a 24-membered ring bearing a peptide tail--pose a considerable synthetic challenge, because the seven C=C double bonds throughout the cycle labilize adjacent chiral centers. Moreover, as Fürstner et al. discovered in preliminary explorations, the most apparently selective site for closing the ring--an ester linkage--proves uncooperatively prone to side reactions. The authors instead relied on olefin metathesis for the cyclization, demonstrating remarkable selectivity for the desired reaction site in the presence of so many alternative double bonds. A further advantage of the metathesis protocol was the efficiency of the catalyst at ambient temperature, which protected the precarious molecular framework from thermal rearrangement or decomposition. Having prepared iejimalide B, the authors adapted their synthetic strategy to diversify the structure of the peptide tail. The key was the use of a trimethylsilylethylcarbonate protecting group on nitrogen, which could be easily removed after the cyclization step and replaced by a range of acyl or sulfonyl substituents. Like the natural product itself, these analogs proved surprisingly adept at actin depolymerization in cells, raising the prospect of multiple biochemical investigations with this compound class. -- JSY
J. Am. Chem. Soc. 129, 10.1021/ja072334v (2007).
