Total Synthesis of Dysoxylactam A

Abstract

The total synthesis of a potent multi-drug-resistant reverser, dysoxylacatam A (1), was achieved in a highly efficient and stereocontrolled fashion. The highlights of the strategy enlisted an iterative combination of lithiation–borylation tactics including Aggarwal homologation and Matteson homologation, Brown crotylation, Krische allylation, and ring-closing metathesis to forge the macrocycle.

Total Synthesis and Structural Reassignment of Laingolide A

“…Under the optimum conditions investigated, each aldehyde ( 12 or 15 ) underwent condensation with 1.2 molar equivalent of sulfone ( 8 or ent - 8 ) treated with 1.2 molar equivalent of NaHMDS in toluene at −78 °C to afford the corresponding alkene as a mixture of geometrical isomers (Z:E ≈ 3–7:1) in high yield. Next, each of the resultant internal alkenes ( 16 , 20 , 24 , 28 ) was separately subjected to palladium-chloride-mediated hydrogenation in ethanol with the concomitant removal of the TBS ethers that furnish the corresponding diol ( 17 , 21 , 25 , 29 ) [ 46 ]. The primary alcohol of the above diol was selectively oxidised with TEMPO in the presence of bis-acetoxyiodobenzene (BAIB) [ 47 ] and the resulting carboxylic acid was then coupled with the N -methylallylamine by utilising EDCI-HOAt and DMAP as a base to provide the corresponding amide ( 18 , 22 , 26 , 30 ).…”

Brown Allylation: Application to the Synthesis of Natural Products

“…The aldehyde precursor reacted with Brown's (Ipc) 2 B-(Z)-crotyl (1), prepared from (+)-(Ipc) 2 B-OMe, and yielded the syn homoallylic alcohol in 87 % yield (Scheme 12). [48] Fungal natural products Penicillinolide A (15) ia a bioactive metabolite of the marine fungus Penicillium sp. SF-5292 with anti-inflammatory activity, isolated in 2013.…”

“…The aldehyde precursor reacted with Brown's (Ipc) 2 B‐(Z)‐crotyl (1), prepared from (+)‐(Ipc) 2 B‐OMe, and yielded the syn homoallylic alcohol in 87 % yield (Scheme 12). [48] …”

Synthesis of Dysoxylactam A Using Iterative Homologation of Boronic Esters

“…The macrocycle was formed via a macrolactamisation. Ye's synthesis [3] comprised 15 steps installing the stereochemistry using an Aggarwal homologation and Brown and Krische allylations, with the macrocycle being constructed using a ring‐closing metathesis. The third synthesis of dysoxylactam A was reported by Yu in 17 steps, [4] using diastereoselective aldol and alkylation chemistry utilising Evans‐type auxiliaries, with the macrocycle being constructed again by ring‐closing metathesis.…”