Total Synthesis and Structural Reassignment of Laingolide A

Abstract

The asymmetric total synthesis of four diastereomers of laingolide A was achieved, which led to the unambiguous assignment of the stereochemistry of the natural product. The salient features of the convergent, fully stereocontrolled approach were a copper-catalysed stereospecific Kumada-type coupling, a Julia-Kocienski olefination and an RCM/alkene migration sequence to access the desired macrocyclic enamide.

Total Synthesis of Sanctolide A and Formal Synthesis of (2S)-Sanctolide A

“…Subsequent RCM with the Grubbs G-II catalyst in refluxing CHCl 3 delivered a complex mixture of 2 R ,2 S and E , Z diastereomers (2 R , E , Z )-, (2 S , E , Z )- 19 that were fully characterized. Subsequent olefin isomerization of the α,β-unsaturated lactone amide, using (PPh 3 ) 3 RuH­(CO)­Cl ,, in refluxing toluene, generated the final mixture of inseparable enamide diastereomer products, (2 S )- 1 and (2 R )- 1 , in 51% yield in a diastereomeric ratio of dr = 1:3, C2- R :C2- S , as evident by the signature doublets in the respective 1 H NMR spectra occurring at 7.17 ppm for the C2- S epimer as noted by Brimble and at 6.73 ppm for the C2- R epimer as noted by Yadav …”

“…Subsequent RCM macrocyclization of the diene (2 R )- 2 furnished the macrolide core (2 R )- 19 as a 1:1 inseparable mixture of E and Z diastereomers. Ensuing olefin isomerization of the N -allylamide moiety into the corresponding enamide using (PPh 3 ) 3 RuH­(CO)­Cl ,, afforded the natural product sanctolide A (2 R )- 1 in 51% yield. The spectral data for the synthesized macrolide were in a good agreement with the spectral data of the reported natural product and the macrolide synthesized by Yadav and co-workers (Supporting Information, Tables S6 and S7). , Interestingly, a similar decomposition of the final enamide macrolide upon standing conditions over several days was observed, as reported by Yadav and co-workers …”

“…Brimble lactone (2 S )- 5 was derived from 1-heptene via epoxide 6 in 10 steps using an iterative sequence of epoxidation, hydrolytic kinetic resolution with the Jacobsen ( S , S )-salenCo III -OAc catalyst, and vinyl-Grignard addition, followed by acryloylation and RCM with the second-generation Grubbs catalyst G-II . In 2018 and 2021, Dai and Ye reported a similar RCM macrocyclization/olefin isomerization sequence developed by Brimble to generate the N -methylenamide moiety in the syntheses of related natural productsnamely, the laingolides A/B, and (−)-palmyrolide A. , …”

“…The PKS and NRPS modules work together to generate PK–NRP hybrids . The PK–NRP hybrid family of cyclic enamide-/amide-containing natural products is relatively small, comprising the 14-membered cyclic enamide sanctolide A ( 1 ), (+)- ent -palmyrolide A, madangolide, , laingolides, , tricholides, unnarmicin D, and nemamides (Figure ). …”

Marine natural products

“…The bromoiesol structure class was shown to selectively inhibit the growth of T. brucei rhodesiense. 117 The rst total syntheses of 14 cyanobacterial metabolites were accomplished in 2021, laingolide A 240, 118 112 27-deoxylyngbyabellin A, 120 laucysteinamide A, 121 oscillatoxins E and F, 122 and (−)-majusculoic acid. 123 The asymmetric synthesis of four diastereomers of laingolide A 240 led to the unambiguous assignment of the stereochemistry for this MNP.…”