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. 2025 Jan 17;90(2):1036-1043.
doi: 10.1021/acs.joc.4c02228. Epub 2025 Jan 8.

Combining Photochemical Oxyfunctionalization and Enzymatic Catalysis for the Synthesis of Chiral Pyrrolidines and Azepanes

Maria Logotheti  1 , Susanne Gehres  1 , Alexandre S França  2 , Uwe T Bornscheuer  1 , Rodrigo O M A de Souza  2 , Matthias Höhne  3
Affiliations

Combining Photochemical Oxyfunctionalization and Enzymatic Catalysis for the Synthesis of Chiral Pyrrolidines and Azepanes

Maria Logotheti et al. J Org Chem. .

Abstract

Chiral heterocyclic alcohols and amines are frequently used building blocks in the synthesis of fine chemicals and pharmaceuticals. Herein, we report a one-pot photoenzymatic synthesis route for N-Boc-3-amino/hydroxy-pyrrolidine and N-Boc-4-amino/hydroxy-azepane with up to 90% conversions and >99% enantiomeric excess. The transformation combines a photochemical oxyfunctionalization favored for distal C-H positions with a stereoselective enzymatic transamination or carbonyl reduction step. Our study demonstrates a mild and operationally simple asymmetric synthesis workflow from easily available starting materials.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Examples of bioactive compounds containing a 3-amino/hydroxy-pyrrolidine or 4-amino/hydroxy-azepane moiety (highlighted in blue).
Figure 2
Figure 2
A. Examples of literature-reported biocatalytic syntheses of enantioenriched 3-aminopyrrolidines and 3-hydroxypyrrolidines. (i). Amine-transaminase (ATA)-catalyzed transamination or keto reductase (KRED)-catalyzed carbonyl reduction of N-protected-3-pyrrolidinone, (ii). ATA-mediated kinetic resolution of racemic N-Boc-3-aminopyrrolidine, (iii). Chemoenzymatic multipot preparation of chiral N-benzyl-3-aminopyrrolidine, with racemic resolution of N-protected-d,l-asparagine esters with proteases as the key step. B. Summarized reaction scheme of the one-pot photoenzymatic conversion of pyrrolidine or azepane into chiral N-Boc-protected 3-amino/hydroxypyrrolidines and 4-amino/hydroxyazepanes.
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References

    1. Vitaku E.; Smith D. T.; Njardarson J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals: Miniperspective. J. Med. Chem. 2014, 57 (24), 10257–10274. 10.1021/jm501100b. - DOI - PubMed
    2. Kittakoop P.; Mahidol C.; Ruchirawat S. Alkaloids as Important Scaffolds in Therapeutic Drugs for the Treatments of Cancer, Tuberculosis, and Smoking Cessation. Curr. Top. Med. Chem. 2013, 14 (2), 239–252. 10.2174/1568026613666131216105049. - DOI - PubMed
    3. Roughley S. D.; Jordan A. M. The Medicinal Chemist’s Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates. J. Med. Chem. 2011, 54 (10), 3451–3479. 10.1021/jm200187y. - DOI - PubMed
    1. Wang S.; Zhang J.-X.; Zhang T.-Y.; Meng H.; Chen B.-H.; Shu W. Enantioselective Access to Chiral Aliphatic Amines and Alcohols via Ni-Catalyzed Hydroalkylations. Nat. Commun. 2021, 12 (1), 277110.1038/s41467-021-22983-7. - DOI - PMC - PubMed
    1. Zhang J.; Wei Y.; Zhou X.; Yang K.; Sun Y.. PARP1 inhibitor and application thereof. CN 117447449A, 2022.
    2. Freeman D. B.; Hopkins T. D.; Mikochik P. J.; Vacca J. P.; Gao H.; Naylor-Olsen A.; Rudra S.; Li H.; Pop M. S.; Villagomez R. A.; Lee C.; Li H.; Zhou M.; Saffran D. C.; Rioux N.; Hood T. R.; Day M. A. L.; McKeown M. R.; Lin C. Y.; Bischofberger N.; Trotter B. W. Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent Cancers. J. Med. Chem. 2023, 66 (23), 15629–15647. 10.1021/acs.jmedchem.3c01233. - DOI - PMC - PubMed
    3. Petri G. L.; Raimondi M. V.; Spanò V.; Holl R.; Barraja P.; Montalbano A. Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds. Top. Curr. Chem. 2021, 379 (5), 3410.1007/s41061-021-00347-5. - DOI - PMC - PubMed
    4. Mikochik P.; Vacca J.; Freeman D.; Tasker A.. Compounds, Compositions, and Methods for Modulating Cdk9 Activity. CA 3118472 A1, 2020.
    5. McGrath N. A.; Brichacek M.; Njardarson J. T. A Graphical Journey of Innovative Organic Architectures That Have Improved Our Lives. J. Chem. Educ. 2010, 87 (12), 1348–1349. 10.1021/ed1003806. - DOI
    1. Hughes D. L. Patent Review of Manufacturing Routes to Fifth-Generation Cephalosporin Drugs. Part 2, Ceftaroline Fosamil and Ceftobiprole Medocaril. Org. Process Res. Dev. 2017, 21 (6), 800–815. 10.1021/acs.oprd.7b00143. - DOI
    1. Hoegenauer K.; Soldermann N.; Zécri F.; Strang R. S.; Graveleau N.; Wolf R. M.; Cooke N. G.; Smith A. B.; Hollingworth G. J.; Blanz J.; Gutmann S.; Rummel G.; Littlewood-Evans A.; Burkhart C. Discovery of CDZ173 (Leniolisib), Representing a Structurally Novel Class of PI3K Delta-Selective Inhibitors. ACS Med. Chem. Lett. 2017, 8 (9), 975–980. 10.1021/acsmedchemlett.7b00293. - DOI - PMC - PubMed

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