Enantioselective Flow Synthesis of a Tetrahydroquinoline SERM Enabled by Immobilized Chiral Phosphoric Acid Catalysis and Diboronic Acid Mediated Selective Nitro Reduction

Abstract

An asymmetric enantioselective flow process is reported for the formal synthesis of a 1,2,3,4‐tetrahydroquinoline selective estrogen receptor modulator. Starting from an easily available 2‑nitrochalcone, the first part of the process comprised a telescoped nitro reduction/intramolecular cyclocondensation sequence using diboronic acid as a simple reductant. Subsequent enantioselective transfer hydrogenation in the presence of an immobilized phosphoric acid organocatalyst followed by telescoped N‐alkylation furnished the targeted chiral intermediate. The approach ensures flexibility regarding the scale of the synthesis, whilst minimizing the need for intermediate purifications and ensuring environmentally benign metal‐free conditions.

A robust heterogeneous chiral phosphoric acid enables multi decagram scale production of optically active N,S-ketals

“…13 To date, PS-TRIP and closely related catalysts have mostly been used in reactions that require several hours to complete and with no or limited background reaction ensuring high chemical selectivity. 12–14 Analyzing the performance of PS-TRIP towards a reaction with a strong background effect represents a challenge since a minimal decrease in the catalyst activity with respect to the corresponding homogeneous variant would lead to a drastic decrease in enantiocontrol.…”

“…Developing highly recyclable catalysts that can be used in continuous processes with similar performance to the analogous batch reactions would increase the productivity, minimizing the effect of the high environmental factor ( E -factor) known for the preparation of some organocatalysts. 11 Following our previous work on immobilized chiral phosphoric acids, 12 we aimed to evaluate the robustness of the immobilized TRIP (PS-TRIP) catalyst ( Scheme 1A ), developed by Pericàs in 2016. 13 To date, PS-TRIP and closely related catalysts have mostly been used in reactions that require several hours to complete and with no or limited background reaction ensuring high chemical selectivity.…”