Expedient Synthesis of Large‐Ring trans‐Enamide Macrolides by CuI‐Mediated Intramolecular Coupling of Vinyl Iodide with Amide: Total Synthesis of Palmyrolide A

Abstract

An efficient and improved procedure for copper‐catalyzed coupling of vinyl iodide with amide in an intramolecular fashion is described. The protocol utilizes a combination of copper iodide, CsF and (±)‐1,2‐diaminocyclohexane as ligand. The vinyl iodide couples efficiently with the amide to generate an enamide macrolide without any alteration in the double ‐bond geometry. The developed method was applied in the synthesis of several large‐ring enamide macrolides, and for the total synthesis of natural product palmyrolide A and homologated sanctolide A.

Synthesis and biological evaluation of palmyrolide A macrocycles as sodium channel blockers towards neuroprotection

“…s, 1 H), 7.45 (br. s, 1 H), 4.83 (d, J = 10.4 Hz, 1 H), 4.60 (ddd, J = 5.8, 8.9, 12.1 Hz, 1 H), 2.83-2.79 (m, 1 H), 2.52-2.48 (m, 2 H), 2.37-2.32 (m, 1 H), 2.11-1.95 (m, 3 H), 1.86-1.83 (m, 1 H), 1.60-1.56 (m, 2 H), 1.46-1.39 (m, 2 H), 1.23-1.18 (m, 1 H), 1.08-1.04 (m, 2 H), 0.91-0.82 (m, 12 H); 13 (13R,15R,E)-15-(tert-Butyl)-8,13-dimethyl-1-oxa-8azacyclopentadec-6-ene-2,9-dione (14) The trans-enamide 13 (9 mg, 0.03 mmol) was dissolved in dry THF (3 mL), cooled to 0 °C, and treated with sodium hydride (60% dispersion, 5 mg, 0.11 mmol). The cooling bath was removed, the flask was allowed to warm to room temperature and the reaction mixture was stirred for 20 min.…”

“…13 Recently there was another paper reported by the Yadav & Srihari group. 14 Herein, we report the full account of our work on synthesis of palmyrolide A and its analogues followed by their biological evaluation and structure-activity relationship studies.…”

One and Two-Carbon Homologation of Primary and Secondary Alcohols to Corresponding Carboxylic Esters Using β-Carbonyl BT Sulfones as a Common Intermediate

“…However, when it comes to primary and secondary alcohols, in comparison only few options are available when the above-mentioned extensions are attempted. , The standard protocols used to extend an alcohol by one or two carbons requires in principle 3 distinct synthetic operations: (1) activation of the alcohol (transformation to a good-leaving group: GLG); (2) displacement of activated alcohol by C-nucleophile (e.g., cyanide for one carbon extension or carbonyl enolate for two carbon extension); and (3) transformation of the introduced functional group into the desired functionality (e.g., hydrolysis of nitrile to carboxylic acid; hydrolysis and monodecarboxylation of dimethylmalonate, etc. ).…”

Total Synthesis of Laingolide B Stereoisomers and Assignment of Absolute Configuration

“…In addition to the predominant compound types such as modified peptides, depsipeptides, polyketides, and peptide–polyketide hybrids, there is a small group of trans - N -methyl enamide-containing macrolides possessing a tert -butyl carbinol moiety . These unique macrolides include palmyrolide A ( 1 ), − laingolide ( 2 ), laingolide A ( 3 ), , laingolide B ( 4 ), , and madangolide ( 5 ) as depicted in Figure . Palmyrolide A was isolated from a marine cyanobacterial assemblage composed of Leptolyngbya cf.…”