1 - The stereospecific and enantiospecific synthesis of indole alkaloids which culminated in the ambidextrous Pictet–Spengler reaction for the C-19 methyl–substituted sarpagine family

Abstract

The Pictet-Spengler reaction continues to be widely employed in the synthesis of bioactive natural products, as well as synthetic compounds containing the THβC and THIQ moieties. The asymmetric version of this reaction has been central to the enantiospecific total synthesis of >150 sarpagine/macroline/ajmaline alkaloids. The diastereospecific Pictet-Spengler reaction under thermodynamic control is crucial to the large-scale synthesis of the important tetracyclic bicyclo[3.3.1] core in >98% ee towards many indole alkaloids from this superfamily. Extensive exploration of the Pictet-Spengler reaction for the emerging class of C-19 methyl-substituted sarpagine/macroline/ajmaline alkaloids has resulted in the ambidextrous version, which has enabled access to both the natural and unnatural enantiomers of alkaloids starting with either D- or L-tryptophan, at will. Some noteworthy recent applications of the large scale Pictet-Spengler reaction in the total synthesis of sarpagine-related alkaloids and the development of the ambidextrous Pictet-Spengler reaction are described in this chapter.