DP4+-Based Stereochemical Reassignment and Total Synthesis of Polyenic Macrolactam Muanlactam.

Abstract

The total synthesis of the stereoisomer of muanlactam predicted by DP4+ calculations, which differed from that reported for the natural product on the relative configuration at C19, was completed, and the structure of the polyenic macrolactam was fully confirmed. Construction of the stereocenters involved the iterative enantio- and diastereoselective Krische's allylation reaction for the formal syn-1,3-diol and the addition of a propargylic Grignard reagent to Ellman's chiral nonracemic tert-butylsulfinamide for the enantiopure amine fragment. The conjugated triene and diene units were constructed by Suzuki-Miyaura cross-coupling reactions of the corresponding alkenylboronates and alkenyl iodides. Formation of the conjugated tetraene by Horner-Wadsworth-Emmons condensation of the functionalized partners was followed by challenging macrolactamization using hexafluorophosphate azabenzotriazole tetramethyluronium and N,N-diisopropylethylamine. The NMR data of the synthetic polyenic macrolactam matched those of the natural product, thus correcting the relative configuration of muanlactam at C19, which had previously been assigned by DP4.