Elaboration of Sterically Hindered δ-Lactones through Ring-Closing Metathesis: Application to the Synthesis of the C1–C27 Fragment of Hemicalide

Abstract

The synthesis of the C1-C27 fragment of hemicalide, a marine metabolite displaying a unique potent antiproliferative activity, has been accomplished. The synthetic approach highlights a remarkably efficient ring-closing metathesis reaction catalyzed by Nolan ruthenium indenylidene complexes to elaborate the highly substituted δ-lactone framework.

Assembly of the Entire Carbon Backbone of a Stereoisomer of the Antitumor Marine Natural Product Hemicalide

“…Comparison of the NMR spectra of structurally related model compounds with those of hemicalide allowed for the relative stereochemical assignment of the C8–C13 hexad and the C36–C42 subunit, which was confirmed by gauge‐invariant atomic orbital (GIAO) NMR chemical shifts calculations coupled with a probability program (DP4) . The relative configuration of C24 and C18 was first tentatively attributed by analysis of the NMR spectra of some simplified model compounds possessing a silyloxy substituent at C17; the assignment of C18 was subsequently revised by the GIAO–DP4 method and through the synthesis of more realistic model compounds possessing a trisubstituted alkene at C16‐C17 (Figure ) …”

“…The low yield (13 %, two steps from 15 ) was attributable to the poor efficiency of the borylation reaction which could not be optimized at this stage. Cleavage of the protecting groups from compound 18 was attempted as reported with truncated model compounds, first by treatment with tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF; DMF, RT) which resulted in the cleavage of the trimethylsilylethyl ester, one TBS and the three TES ethers. Exposure of the crude resulting product to buffered HF⋅Py complex [HF (70 %)⋅Py/Py (1:2), THF, 10–15 °C] effectively cleaved the silylene ketal but a remaining TBS group on the alcohol at C40 or C45 did not fall off under these conditions and compound 19 (91 %) was isolated (Scheme ) .…”

“…[9,10] The relative configurationo fC 24 and C18w as first tentatively attributed by analysiso ft he NMR spectra of some simplified model compounds possessing as ilyloxy substituent at C17; [11] the assignment of C18 was subsequently revised by the GIAO-DP4 method [10] and throught he synthesis of more realistic modelc ompounds possessing at risubstituted alkene at C16-C17 ( Figure 1). [10,12] Here, we report our synthetic efforts towards the assembly of the entire carbon backboneofas tereoisomero fh emicalide, with the priority goal of validating af irst-generation convergent strategyt owards this challenging natural product. The aim was also to evaluate the impacto fa rbitrarily selected (yet unassigned) configurations on the NMR data and to get insight into the final deprotection steps.…”

“…The synthesis of subunits A, [7] B, [19] C [12] and E [8] has been achievedp reviously during the course of our studies on the stereochemical assignment of hemicalide, but the critical issue was to determine whether these compounds could withstand the coupling reactionse nvisioned for the assembly of the entire carbon framework. Our efforts therefore focusedo ns ubunit D,a nd the Julia-Kocienski olefination of aldehyde E was planned as the first coupling event.T his strategy entails metalation of sulfone D at C34 and as econdary alcohol at C29 was considered as as uitable precursor for the methyl ketone in the actual C28-C34 subunit, the synthesis of which was carriedo ut from aldehyde 2 (available in two steps from ethyl 3-hydroxybutyrate, 70 %y ield).…”

“…The boron enolate generated from ketone 11 (Cy 2 BCl, Et 3 N, Et 2 O, À78 to 0 8C) (2 equiv) was added to aldehyde 12 at À78 8C, prepared from (S)-citronellol according to our recently reported route. [12] After separation (and quantitativer ecovery) of excessm ethyl ketone Scheme1.Retrosynthesis of hemicalide stereoisomer 1.P= unspecified protecting group.…”