Light-induced rearrangement from macrocyclic to bicyclic lactam: A case study of N-chlorinated laurolactam

Zubčić, Gabrijel; Pavić, Kristina; You, Jiangyang; Vrček, Valerije; Portada, Tomislav; Bešić, Erim; Šakić, Davor (2025) Light-induced rearrangement from macrocyclic to bicyclic lactam: A case study of N-chlorinated laurolactam. Acta Pharmaceutica, 74 (4). pp. 725-737. ISSN 1846-9558

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Abstract

Converting macrocycle lactams into bicyclic lactams is proposed as an additional way to further increase the metabolic stability of peptide-based drugs. Unfortunately, the synthesis of bicyclic lactams has to start almost from scratch. This study explores the Hofmann-Löffler-Freytag (HLF) reaction mechanism and products as a potential late-stage functionalisation strategy for facile conversion of macrocyclic to bicyclic ring. Laurolactam, a macrocyclic amide, exhibits significant potential for transformation into bioactive bicyclic structures with smaller, β-, γ-, δ-, and ε-lactam rings, further increasing rigidity and hydrolytic stability. With irradiation provided by a 370 nm lamp, light-induced rearrangement reaction was monitored using nuclear magnetic resonance (NMR), while involved radical intermediates were trapped using N-tert-butyl-α-phenylnitrone (PBN) spin-trap and characterised via EPR. While only two radical adduct types were identified in the electron para magnetic resonance (EPR) (C-centered radical and chlorine radical), all eight possible products are observed in the NMR. Quantum chemical calculations provide deeper insights into reaction thermodynamics and kinetics, explaining why the N-centered radical was not observed. This research highlights the feasibility of using the HLF reaction to transform macrocyclic lactams into stable bicyclic drug candidates, paving the way for new therapeutic developments.

Item Type:	Article
Uncontrolled Keywords:	radical rearrangement ; radical thermodynamics ; ring- contraction ; late-stage functionalisation ; synthetic strategy
Subjects:	NATURAL SCIENCES > Chemistry > Theoretical Chemistry NATURAL SCIENCES > Chemistry > Analytic Chemistry NATURAL SCIENCES > Chemistry > Organic Chemistry BIOMEDICINE AND HEALTHCARE > Pharmacy
Divisions:	Division of Organic Chemistry and Biochemistry Division of Physical Chemistry
Projects:	Project title Project leader Project code Project type Svjetlošću pogonjena funkcionalizacija nereaktivnih pozicija korištenjem oksidacijske aminacije-LIGHT-N-RING Davor Šakić; Mirsada Ćehić UIP-2020-02-4857 HRZZ Jačanje znanstveno-istraživačkih i inovacijskih kapaciteta Farmaceutsko-biokemijskog fakulteta Sveučilišta u Zagrebu-FarmInova Jasmina Lovrić KK.01.1.1.02.0021 EK Kriogeni centar Instituta za fiziku-KaCIF Nikolina Novosel; Josip Buhin KK.01.1.1.02.0012 EK Hrvatski znanstveni i obrazovni oblak Ivan Marić KK.01.1.1.08.0001 UNSPECIFIED Kemijska sudbina zabrinjavajućih farmaceutika u okolišu: eksperimentalno i računalno istraživanje produkata razgradnje i njihovih ekotoksikoloških svojstava Valerije Vrček IP-2022-10-2634 HRZZ
Depositing User:	Lorena Palameta
Date Deposited:	24 Apr 2025 11:03
URI:	http://fulir.irb.hr/id/eprint/9733
DOI:	10.2478/acph-2024-0035

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