Synthesis of the C20−C26 Building Block of Halichondrins via a Regiospecific and Stereoselective S_N2‘ Reaction

Abstract

[reaction: see text] A regiospecific and stereoselective S(N)2' reaction to convert the trisylate into the vinyl iodide is presented. The homoallylic alcohol is used to direct the delivery of LiCu(Me)(2).

Progress in the trans-Reduction and trans-Hydrometalation of Internal Alkynes. Applications to Natural Product Synthesis

“…110 This fragment had formerly been prepared by a trans-hydrostannation under radical conditions, which the authors tried to avoid (Table 5, Entry 3). 113 To this end, a ruthenium catalyzed trans-hydrosilylation of the homopropargylic alcohol 160 was carried out using (Me 2 SiH) 2 NH as the reagent, which gave oxasilacyclohexene 161 after cleavage of the primary TESether. Mesylation of the resulting allylic alcohol 161 followed by stereoselective S N 2¤ substitution with LiCu(Me)(CN) paved the way to the required building block.…”

“…113 Although the desired product was favored, the hydrostannation furnished a mixture (55:6:2:1) of all four possible isomers. As those were separable, this approach opened access to the C20 C26 fragment of halichondrin B, a potently cytotoxic macrolide derived from a marine sponge.…”

Exploring the Boundaries of “Practical”: De Novo Syntheses of Complex Natural Product-Based Drug Candidates

“…The epoxide was opened through nucleophilic addition of the trimethylsilylacetylene anion, followed by mesylation of the resultant secondary alcohol and vinyl iodide formation, generated 64. 39 Asymmetric Nozaki−Hiyama−Kishi coupling between 64 and aldehyde 65, promoted by catalyst 66, preceded the acid-promoted tetrahydrofuran formation and the subsequent removal of the benzoyl group to generate 67 isolated in high yield as a 9:1 diastereomeric mixture. Finally, oxidation of the primary alcohol to aldehyde and coupling with 68 under the conditions depicted in Scheme 11 generated 69 in good yield and 5.3:1 stereoselectivity.…”

“…The route commenced with the epoxidation of protected alcohol 62 followed by Jacobsen’s hydrolytic kinetic resolution of the obtained epoxide to furnish 63 . The epoxide was opened through nucleophilic addition of the trimethylsilylacetylene anion, followed by mesylation of the resultant secondary alcohol and vinyl iodide formation, generated 64 . Asymmetric Nozaki–Hiyama–Kishi coupling between 64 and aldehyde 65 , promoted by catalyst 66 , preceded the acid-promoted tetrahydrofuran formation and the subsequent removal of the benzoyl group to generate 67 isolated in high yield as a 9:1 diastereomeric mixture.…”

“…The union of intermediates 80 and 84 was then achieved by an asymmetric Nozaki–Hiyama–Kishi coupling between the two, adopting the previously developed and highly optimized conditions. ,,, This set of conditions involved the use of the chiral ligand 85 , which was selected to induce stereoselectivity. In addition, it was fortuitously found to increase the reaction rate.…”