Synthesis of 3-Amino-4-(Hydroxymethyl)-β-Lactam Branch Point and Its Late-Stage C4 Functionalization with Ceftaroline-Sidechain Monobactams and Their Biological Evaluation
- 1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia
- 2Institute of Microbiology and Parasitology, Veterinary Faculty, University of Ljubljana, Gerbičeva 60, 1000 Ljubljana, Slovenia
Abstract
Monocyclic β-lactams are an underexplored subclass of β-lactam antibiotics active against Gram-negative pathogens, but access to them requires long sequences reported across the patent and primary literature. We compare two alternative routes to 3-amino-4-(hydroxymethyl)-2-azetidinone, a synthon carrying handles at N1, C3 and C4, starting from ethyl glyoxylate and from (R)-glyceraldehyde acetonide. Both are assembled from published transformations; reported here are isolated yields for every step, including the conditions that failed, and execution of the β-lactam-forming sequence on a 50 g scale. Removal of the 2,4-dimethoxybenzyl group was strongly concentration-dependent, giving 94% on the glyoxylate-derived ester against 70% on the acetonide-derived alcohol, whereas the acetonide route replaces a low-yielding NaBH4 ester reduction (43 to 57%) with a near-quantitative oxidative cleavage/reduction sequence. Diverting one late-stage intermediate through copper-catalyzed azide–alkyne cycloaddition or direct thioether alkylation gave three sulfonated monobactams bearing a ceftaroline-derived C4 sidechain, in 0.10 to 0.29% overall yield over 15 steps. None reduced S. pneumoniae PBP1b activity below 50% at 100 μM, against an IC50 of 4.93 μM for aztreonam, and none inhibited wild-type E. coli or S. aureus at 128 μg/mL; weak inhibition was seen only in efflux-deficient and outer-membrane-permeabilized E. coli. C4 substitution through either linkage supports activity when the appended group also provides an uptake vector, which the ceftaroline-derived side chain does not, and it conferred no measurable target affinity either.
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BibTeX
@article{kavas2026synthesis,
title = {{Synthesis of 3-Amino-4-(Hydroxymethyl)-β-Lactam Branch Point and Its Late-Stage C4 Functionalization with Ceftaroline-Sidechain Monobactams and Their Biological Evaluation}},
author = {Vid Kavaš and Majda Golob and Anže Meden and Martina Hrast Rambaher and Stanislav Gobec},
journal = {Molecules},
year = {2026},
month = oct,
doi = {10.3390/molecules31203637},
url = {https://www.mdpi.com/1420-3049/31/20/3637},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Synthesis of 3-Amino-4-(Hydroxymethyl)-β-Lactam Branch Point and Its Late-Stage C4 Functionalization with Ceftaroline-Sidechain Monobactams and Their Biological Evaluation
AU - Vid Kavaš
AU - Majda Golob
AU - Anže Meden
AU - Martina Hrast Rambaher
AU - Stanislav Gobec
PY - 2026
DA - 2026/10/01
JO - Molecules
DO - 10.3390/molecules31203637
UR - https://www.mdpi.com/1420-3049/31/20/3637
AB - Monocyclic β-lactams are an underexplored subclass of β-lactam antibiotics active against Gram-negative pathogens, but access to them requires long sequences reported across the patent and primary literature. We compare two alternative routes to 3-amino-4-(hydroxymethyl)-2-azetidinone, a synthon carrying handles at N1, C3 and C4, starting from ethyl glyoxylate and from (R)-glyceraldehyde acetonide. Both are assembled from published transformations; reported here are isolated yields for every step, including the conditions that failed, and execution of the β-lactam-forming sequence on a 50 g scale. Removal of the 2,4-dimethoxybenzyl group was strongly concentration-dependent, giving 94% on the glyoxylate-derived ester against 70% on the acetonide-derived alcohol, whereas the acetonide route replaces a low-yielding NaBH4 ester reduction (43 to 57%) with a near-quantitative oxidative cleavage/reduction sequence. Diverting one late-stage intermediate through copper-catalyzed azide–alkyne cycloaddition or direct thioether alkylation gave three sulfonated monobactams bearing a ceftaroline-derived C4 sidechain, in 0.10 to 0.29% overall yield over 15 steps. None reduced S. pneumoniae PBP1b activity below 50% at 100 μM, against an IC50 of 4.93 μM for aztreonam, and none inhibited wild-type E. coli or S. aureus at 128 μg/mL; weak inhibition was seen only in efflux-deficient and outer-membrane-permeabilized E. coli. C4 substitution through either linkage supports activity when the appended group also provides an uptake vector, which the ceftaroline-derived side chain does not, and it conferred no measurable target affinity either.
SN - 1420-3049
ER -