Reaction Blueprints and Logical Control Flow for Parallelized Chiral Synthesis in the Chemputer

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Nov 26

PMID 39592595

Authors

Mindaugas Siauciulis

Christian Knittl-Frank

S Hessam M Mehr

Emma Clarke

Leroy Cronin

Affiliations

Soon will be listed here.

Abstract

Despite recent proliferation of programmable robotic chemistry hardware, current chemical programming ontologies lack essential structured programming constructs like variables, functions, and loops. Herein we present an integration of these concepts into χDL, a universal high-level chemical programming language executable in the Chemputer. To achieve this, we introduce reaction blueprints as a chemical analog to functions in computer science, allowing to apply sets of synthesis operations to different reagents and conditions. We further expand χDL with logical operation queues and iteration via pattern matching. The combination of these new features allows encoding of chemical syntheses in generalized, reproducible, and parallelized digital workflows rather than opaque and entangled single-step operations. This is showcased by synthesizing chiral diarylprolinol catalysts and subsequently utilizing them in various synthetic transformations (13 separate automated runs affording 3 organocatalysts and 12 distinct enantioenriched products in 42-97% yield, up to > 99:1 er), including automated catalyst recycling and reuse.

References

Franzen J, Marigo M, Fielenbach D, Wabnitz T, Kjaersgaard A, Anker Jorgensen K . A general organocatalyst for direct alpha-functionalization of aldehydes: stereoselective C-C, C-N, C-F, C-Br, and C-S bond-forming reactions. Scope and mechanistic insights. J Am Chem Soc. 2005; 127(51):18296-304. DOI: 10.1021/ja056120u. View

Hase F, Roch L, Aspuru-Guzik A . Chimera: enabling hierarchy based multi-objective optimization for self-driving laboratories. Chem Sci. 2018; 9(39):7642-7655. PMC: 6182568. DOI: 10.1039/c8sc02239a. View

Marigo M, Franzen J, Poulsen T, Zhuang W, Anker Jorgensen K . Asymmetric organocatalytic epoxidation of alpha,beta-unsaturated aldehydes with hydrogen peroxide. J Am Chem Soc. 2005; 127(19):6964-5. DOI: 10.1021/ja051808s. View

Albrecht L, Ransborg L, Lauridsen V, Overgaard M, Zweifel T, Anker Jorgensen K . Taming the Friedel-Crafts reaction: organocatalytic approach to optically active 2,3-dihydrobenzofurans. Angew Chem Int Ed Engl. 2011; 50(52):12496-500. DOI: 10.1002/anie.201105819. View

MERRIFIELD R . Automated synthesis of peptides. Science. 1965; 150(3693):178-85. DOI: 10.1126/science.150.3693.178. View

Rohrbach S, Siauciulis M, Chisholm G, Pirvan P, Saleeb M, M Mehr S . Digitization and validation of a chemical synthesis literature database in the ChemPU. Science. 2022; 377(6602):172-180. DOI: 10.1126/science.abo0058. View

M Mehr S, Craven M, Leonov A, Keenan G, Cronin L . A universal system for digitization and automatic execution of the chemical synthesis literature. Science. 2020; 370(6512):101-108. DOI: 10.1126/science.abc2986. View

Frankowski S, Kowalska J, Albrecht A . Pyridylacetic acids and related systems as alkylheteroarene surrogates in asymmetric decarboxylative Michael addition. Chem Commun (Camb). 2021; 57(27):3387-3390. DOI: 10.1039/d0cc08182e. View

Li J, Ballmer S, Gillis E, Fujii S, Schmidt M, Palazzolo A . Synthesis of many different types of organic small molecules using one automated process. Science. 2015; 347(6227):1221-6. PMC: 4687482. DOI: 10.1126/science.aaa5414. View

10.

Bai J, Mosbach S, Taylor C, Karan D, Lee K, Rihm S . A dynamic knowledge graph approach to distributed self-driving laboratories. Nat Commun. 2024; 15(1):462. PMC: 10805810. DOI: 10.1038/s41467-023-44599-9. View

11.

Zheng Z, Perkins B, Ni B . Diarylprolinol silyl ether salts as new, efficient, water-soluble, and recyclable organocatalysts for the asymmetric Michael addition on water. J Am Chem Soc. 2009; 132(1):50-1. DOI: 10.1021/ja9093583. View

12.

Hutchinson G, Alamillo-Ferrer C, Bures J . Mechanistically Guided Design of an Efficient and Enantioselective Aminocatalytic α-Chlorination of Aldehydes. J Am Chem Soc. 2021; 143(18):6805-6809. PMC: 8297727. DOI: 10.1021/jacs.1c02997. View

13.

Burger B, Maffettone P, Gusev V, Aitchison C, Bai Y, Wang X . A mobile robotic chemist. Nature. 2020; 583(7815):237-241. DOI: 10.1038/s41586-020-2442-2. View

14.

Wang Y, Li P, Liang X, Zhang T, Ye J . An efficient enantioselective method for asymmetric Michael addition of nitroalkanes to alpha,beta-unsaturated aldehydes. Chem Commun (Camb). 2008; (10):1232-4. DOI: 10.1039/b717000a. View

15.

Carpintero M, Cifuentes M, Ferritto R, Haro R, Toledo M . Automated liquid-liquid extraction workstation for library synthesis and its use in the parallel and chromatography-free synthesis of 2-alkyl-3-alkyl-4-(3H)-quinazolinones. J Comb Chem. 2007; 9(5):818-22. DOI: 10.1021/cc070051t. View

16.

Reyes-Rodriguez G, Rezayee N, Vidal-Albalat A, Anker Jorgensen K . Prevalence of Diarylprolinol Silyl Ethers as Catalysts in Total Synthesis and Patents. Chem Rev. 2019; 119(6):4221-4260. DOI: 10.1021/acs.chemrev.8b00583. View

17.

Chatterjee S, Guidi M, Seeberger P, Gilmore K . Automated radial synthesis of organic molecules. Nature. 2020; 579(7799):379-384. DOI: 10.1038/s41586-020-2083-5. View

18.

Steiner S, Wolf J, Glatzel S, Andreou A, Granda J, Keenan G . Organic synthesis in a modular robotic system driven by a chemical programming language. Science. 2018; 363(6423). DOI: 10.1126/science.aav2211. View

19.

Plante O, Palmacci E, Seeberger P . Automated solid-phase synthesis of oligosaccharides. Science. 2001; 291(5508):1523-7. DOI: 10.1126/science.1057324. View

20.

Bedard A, Adamo A, Aroh K, Russell M, Bedermann A, Torosian J . Reconfigurable system for automated optimization of diverse chemical reactions. Science. 2018; 361(6408):1220-1225. DOI: 10.1126/science.aat0650. View