Synthesis of a Leiodermatolide Analogue with a Dienyl Side Chain

Abstract

We explored the possibility of attaching a side chain to a leiodermatolide fragment by forming the C18/C19 double bond via Julia/Kocienski olefination. This worked with a δ‐lactone surrogate, the meta‐anisole derivative 17 in reasonable yield to give the acyclic pentaene 32. However, due to problems during cleavage of the silyl ether at the 15‐OH, the corresponding macrolactone could not be obtained. Instead, it was possible to convert enal 31 by Tebbe olefination to pentaene 37. This compound could be converted to macrolactone 41 from where the side chain truncated leiodermatolide analogues 42 (9‐O‐carbamoyl) and 43 (7‐O‐carbamoyl) were obtained. Both isomers were moderately cytotoxic highlighting the importance of the side chain with the δ‐lactone.

Recent Applications and Trends in the Julia‐Kocienski Olefination

“…Maier et al . tried the formation of C18−C19 double bond in the fragment synthesis of Leiodermatolide analogues, using Julia‐Kocienski approach [26] . In this synthetic route, aldehyde 54 was reacted with functionalized sulfone 55 , using KN(SiMe 3 ) 2 in DME as solvent, resulting the formation of E ‐olefin 56 with 60% yield (Scheme 9).…”

“…[25] Maier et al tried the formation of C18À C19 double bond in the fragment synthesis of Leiodermatolide analogues, using Julia-Kocienski approach. [26] In this synthetic route, aldehyde 54 was reacted with functionalized sulfone 55, using KN(SiMe 3 ) 2 in DME as solvent, resulting the formation of E-olefin 56 with 60% yield (Scheme 9). But, the resultant product 56 could not give the desired natural product (Leiodermatolide analogues) due to the failure of further steps in the synthetic scheme.…”

Synthesis of Macrocyclic Musk‐Like Compounds through Ring‐Expansion Metathesis and Tebbe Olefination as Key Steps

“…[33] Since then, there have been an increasing number of articles regarding RCM applications, as indicated by different reviews. [34][35][36][37] Given the significance of macrocyclic ketones [38] and our ongoing fascination to prepare polycycles [39][40][41][42] and macrocycles involving CÀ C bond formation [43][44][45][46][47] sequence, we have developed a new strategy to synthesize the 16-and 19-membered macrocycles by utilizing the RCM and Tebbe olefination [48][49][50][51][52][53][54][55][56][57][58][59] sequence.…”

Total Synthesis of Leiodermatolide A via Transfer Hydrogenative Allylation, Crotylation, and Propargylation: Polyketide Construction beyond Discrete Allyl- or Allenylmetal Reagents

“…Leiodermatolide A is an antimitotic marine macrolide that was isolated in 2008 from crude extracts of a deep sea lithistid sponge of the genus Leiodermatium found off the Florida coast (Figure ). In a panel of human cancer cell lines, leiodermatolide A exhibited potent antiproliferative effects, selectively perturbing tubulin dynamics at nM concentrations through a novel mechanism: while incurring abnormal spindle formation at nM concentrations in two different cancer cell lines, purified tubulin remained undisturbed in vitro even at much higher concentrations. , The scarce supply and compelling biology of leiodermatolide A has driven efforts toward its de novo chemical synthesis, resulting in truly impressive total syntheses by Paterson and Fürstner and substructure syntheses by Maier . The synthesis of leiodermatolide analogues ,, have led to additional biological data that reveal mitotic arrest, micronucleus induction, centrosome amplification, and tubulin disruption in human U2OS cells without evidence for direct binding of tubulin in cell-free analyses .…”