Studies on the Second-Generation Approach to Loline Alkaloids: Synthesis of N-Bus-norloline through N-tert-Butanesulfinyl Imine Based Asymmetric Vinylogous Mannich Reaction

Abstract

A strategy is outlined for the synthesis of loline alkaloids. This second-generation approach features direct access to the requisite vicinal diamino motif by a Cu(OTf)₂-mediated highly trans-diastereoselective vinylogous Mannich reaction (VMR) of Ellman N-tert-butanesulfinyl imine derived from isopropylidene-protected (S)-glyceraldehyde, with N-Boc-2-tert-(butyldimethylsilyloxy)pyrrole (TBSOP). Fleming’s method was employed for the introduction of a hydroxyl group at C4 of the adduct, which gave the undesired diastereomer in 40% yield. The intramolecular S_N reaction of the pyrrolizidine derivative to build the etheral bridge proved to be difficult, and produced N-Bus-norloline in only 20% yield. In light of the valuable information gained during this investigation, an improved version of the second-generation approach is being investigated, which is expected to provide a concise and efficient access to the challenging loline alkaloids.

Key words

loline alkaloids - vinylogous Mannich reaction - vicinal diamine - asymmetric synthesis

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