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Unprecedented stereocontrol in the synthesis of 1,2,3-Trisubstituted Tetrahydro--carbolines through an Asymmetric Pictet-Spengler Reaction towards Sarpagine-Type Indole Alkaloids
Rahman, M. T., & Cook, J. M. (2018). Unprecedented stereocontrol in the synthesis of 1,2,3-Trisubstituted Tetrahydro--carbolines through an Asymmetric Pictet-Spengler Reaction towards Sarpagine-Type Indole Alkaloids. European Journal of Organic Chemistry, 2018(24), 3224-3229. https://doi.org/10.1002/ejoc.201800600
The asymmetric Pictet-Spengler (P-S) reaction of chiral N-b-ethynyl-substituted tryptophan methyl ester derivatives (from both d- and l-tryptophan) with a simple aliphatic aldehyde, exhibited unprecedented selectivity towards either of the diastereomeric products. A simple variation of conditions could alter the outcome of the cyclization from either 100% trans-selective to 100% cis-selective originating entirely from internal asymmetric induction under mild conditions. This resulted in a highly efficient access to both 1,3-cis-(1,2,3-trisubstituted tetrahydro--carbolines, THCs) and 1,3-trans-(1,2,3-trisubstituted THCs). To the best of our knowledge, this type of stereocontrol has never been observed from tryptophan methyl ester derivatives (either D or L) in accessing either 1,3-disubstituted or 1,2,3-trisubstituted THCs. By exploiting this very useful ambidextrous diastereoselectivity, we have set the crucial C-3 and C-5 stereocenters of C-19 methyl-substituted sarpagine/macroline/ajmaline alkaloids beginning with the DNA-encoded and cheaper l-(-)-tryptophan, as well as optionally from commercially available d-(+)-tryptophan.