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. 2024 Mar 6;26(8):4593-4599.
doi: 10.1039/d4gc00019f. eCollection 2024 Apr 22.

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

Aitor Maestro  1   2 , Bhanwar K Malviya  2   3 , Gerald Auer  4 , Sándor B Ötvös  2   3 , C Oliver Kappe  2   3
Affiliations

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

Aitor Maestro et al. Green Chem. .

Abstract

Asymmetric organocatalysis has been recognized as one of the "top 10 emerging technologies" in chemistry by IUPAC in 2019. Its potential to make chemical processes more sustainable is promising, but there are still challenges that need to be addressed. Developing new and reliable enantioselective processes for reproducing batch reactions on a large scale requires a combination of chemical and technical solutions. In this manuscript, we combine a robust immobilized chiral phosphoric acid with a new packed-bed reactor design. This combination allows scaling up of the enantioselective addition of thiols to imines from a few milligrams to a multi-decagram scale in a continuous flow process without physical or chemical degradation of the catalyst.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Scheme 1
Scheme 1. A) Pericàs's PS-TRIP catalyst. (B) Enantioselective synthesis of N,S-ketals. (C) Selected examples of pharmaceuticaly active N,S-ketals.
Fig. 1
Fig. 1. Catalyst bed design. (A) Initial set up. Imine and thiol are premixed before entering the catalyst bed. (B) Second design, no pre-mixing before the packed bed reactor. (C) Final setup with spiral mixing element installed inside the packed-bed reactor.
Scheme 2
Scheme 2. A) Optimized set-up and long run. (B) Conversion and ee of 3a over the time (HPLC area %). (C) Evolution of the product precipitation in the quench flask over 2 h. (D) Isolated product after 6 h run.
Scheme 3
Scheme 3. Scope of thiols explored in the flow reaction. a 4.0 mL min−1, collected for 5 min. b 2.0 mL min−1, collected for 10.0 min. c 1.0 mL min−1, collected for 20.0 min.
Fig. 2
Fig. 2. Catalyst characterization: (A) FTIR, as-prepared PS-TRIP. (B) Optical microscopy, as prepared PS-TRIP. (C) SEM, as prepared PS-TRIP. (D) FTIR, used PS-TRIP. (E) Optical microscopy, used PS-TRIP. (F) SEM, used PS-TRIP.
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