A Rapid Synthesis of 4‐Oxazolidinones: Total Synthesis of Synoxazolidinones A and B

Abstract

A five-step total synthesis of the marine natural product synoxazolidinone A was achieved through a diastereoselective imine acylation/cyclization cascade. Synoxazolidinone B and a series of analogues were also prepared to explore the potential of these 4-oxazolidinone natural products as antimicrobial agents. These studies confirmed the importance of the chlorine substituent for antimicrobial activity and revealed simplified dichloro derivatives that are equally potent against several bacterial strains.

Stereoselective Synthesis of Quaternary Pyrrolidine-2,3-diones and β-Amino Acids

“…13 In this method, acylation of N -dimethoxybenzylimines derived from aliphatic aldehydes with arylpyruvic acid chlorides provided 4-oxazolidinone products exclusively, albeit in moderate yields (Table 1, entries 1 and 2). In attempts to improve the efficiency of the cyclization to obtain 4-oxazolidinones, we explored various activated derivatives of phenylpyruvic acid and identified regioisomeric 1,5-dihydropyrrol-2-one products under these alternate conditions (Table 1, entries 3–5).…”

5-Benzylidene-4-oxazolidinones potently inhibit biofilm formation in Methicillin-resistant Staphylococcus aureus

“…Recent efforts in our lab to develop new synthetic methods for the synthesis of these unusual heterocycles culminated in the first total synthesis of (±)-synoxazolidinone A ( ±-1 ) 26 . Enabled by these efforts, initial investigation into structure-activity-relationship (SAR) generated interest in synoxazolidinone analogues with a 2-dichloroalkyl sidechain.…”

“…To enable an expanded exploration into 2-dichloroalkyl-5-benzylidene-4-oxazolidinones, we prepared a panel of analogues using a modification of the method previously described in the total synthesis of (±)-1 (Figure 2. a, b) 26 . Initial challenges accessing the necessary α,α-dichloroimine starting materials were overcome by employing tert -butyl imines for the chlorination in carbon tetrachloride, according to an established literature procedure (Figure S2.)…”

“…C; synthesis of 10 and (±)-1 was previously reported 26 , see SI for synthesis and characterization of compounds 9 30 and 11 ). Table 1 provides minimum inhibitory concentrations (MICs) for these compounds against MRSA (ATCC BAA-44).…”

Direct Access to Highly Functionalized Heterocycles through the Condensation of Cyclic Imines and α-Oxoesters

“…5 These reactions are carried out at room temperature in aprotic solvents (Figure 1b). Building upon this work, and expanding our program directed toward the synthesis of nitrogen heterocycles, 5 we envisioned a concise and general approach to the 2-hydroxy-5,6,7,7a-tetrahydro-3 H -pyrrolizin-3-one and 2-hydroxy-6,7,8,8a-tetrahydroindolizin-3(5 H )-one scaffolds from the condensation-cyclization of 1-pyrroline and 2,3,4,5-tetrahydropyridine, respectively, with α -oxoesters (Figure 1c). …”