Unprecedented Stereocontrol in the Synthesis of 1,2,3‐Trisubstituted Tetrahydro‐β‐carbolines through an Asymmetric Pictet–Spengler Reaction towards Sarpagine‐Type Indole Alkaloids

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‐β‐carbolines, TH β Cs) and 1,3‐ trans ‐(1,2,3‐trisubstituted TH β Cs). 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 TH β Cs. 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.