Total Syntheses of Crinipellins Enabled by Cobalt‐Mediated and Palladium‐Catalyzed Intramolecular Pauson–Khand Reactions

Abstract

Efficient total syntheses of the naturally occurring, potent antibiotic compounds (−)‐crinipellin A and (−)‐crinipellin B are described. The key advanced intermediate, a fully functionalized tetraquinane core, was constructed by a novel thiourea/palladium‐catalyzed Pauson–Khand reaction. This intermediate can serve as a common intermediate for the collective total synthesis of other members of the crinipellin family.

Applications of Cobalt‐Catalyzed Reactions in the Total Synthesis of Natural Products

“…The amethylene ketone scaffold in crinipellins A and B signifies them a possible permanent probes [141] in the chemical biology and also drug discovery. Efficient total syntheses of (−)‐crinipellin A 140 and (−)‐crinipellin B 141 were accomplished in 2018 by Yang et al [142] . The asymmetric syntheses of (−)‐natural products crinipellin A [(−)‐ 140 ] and (−)‐crinipellin B [(−)‐ 141 ] were accomplished in 17 and 18 steps, respectively.…”

“…The amethylene ketone scaffold in crinipellins A and B signifies them a possible permanent probes [141] in the chemical biology and also drug discovery. Efficient total syntheses of (À )-crinipellin A 140 and (À )-crinipellin B 141 were accomplished in 2018 by Yang et al [142] The asymmetric syntheses of (À )-natural products crinipellin A [(À )-140] and (À )-crinipellin B [(À )-141] were accomplished in 17 and 18 steps, respectively. Total syntheses of (À )-crinipellin A [(À )-140] and (À )-crinipellin B [(À )-141] were started from 4isopropyl-3-methylphenol 137 that after four steps gave precomplexation of enyne ester 138.…”

Application of Pauson–Khand reaction in the total synthesis of terpenes

“…210 In 2014, Lee and co-workers achieved and reported the rst asymmetric total synthesis of 331 through a tandem [3 + 2] cycloaddition reaction for the construction of its tetraquinane scaffold containing three successive quaternary chiral centers. 136,211,212 In 2018, Yang and co-workers 213 accomplished and reported the asymmetric total syntheses of (À)-crinipellin A 331 and (À)-crinipellin B 332 in eighteen steps from the commercialized phenol 316, respectively. These total syntheses featured a developed thiourea/Pd-catalyzed intramolecular Pauson-Khand reaction for the asymmetric construction of the tetraquinane scaffold present in crinipellins.…”

“…Compound 330 was then treated with N -methylanilinium trifluoroacetic acid (TFA) and paraformaldehyde in THF at 70 °C to afford the other natural product, crinipellin B 332 in 74% yield ( Scheme 25 ). 213 …”