Fumiko Fujisaki, N. Abe, K. Sumoto
Apr 5, 2005
Citations
0
Influential Citations
0
Citations
Journal
ChemInform
Abstract
much attention for showing an interesting new class of synthetic antibacterial activity. Many of the target compounds for investigations of new drug candidates have two substituents at the N-3 and C-5 positions of the oxazolidin-2-one ring. We have recently developed a new synthetic method for synthesizing the racemic b-aminoalanine derivatives (1). One of the applications of this unique amino acid for the synthesis of N-[2-(1-piperidinyl)ethyl]benzamides (2) has been reported recently. These b-aminoalanine derivatives (1) are also expected to be applicable for the ring formation of novel oxazolidin-2-one derivatives such as (3), which has two substituents on N-3 and C-4 of the oxazolidin-2-one ring and this mimics the fundamental structural framework of Linezolid (4). These derivatives (3) are selected as the target heterocycles for one of the synthetic applications of the above unique amino acid b-aminoalanine derivatives (1) (Fig. 1). The molecular modification (4Æ3) is one of the well-known procedures in the search for biologically active compounds, the so-called disjunctive approach in medicinal chemistry. In this paper, we report a new conventional route to the synthesis of the above novel oxazolidin-2-one derivatives. Results and Discussion The starting compounds (1) and the N-benzoyl derivatives (5a—f) were prepared according to the procedure described previously. Benzoylation of these amino acids (1) with substituted benzoyl chlorides under Schotten–Baumann reaction conditions easily proceeded and gave the desired 5a—f in good to excellent yields. The physical data of the compounds (5a—f) are summarized in Table 1, and spectroscopic data are given in the Experimental section. From these data, the structures of 5a—f were easily elucidated. Thus the introduced substituted benzoyl group and a tert-amino group (–NR2R3) were confirmed in both Hand C-NMR spectra. Full assignments of these data for the structures of 5a—f (represented in Chart 1) are recorded in the Experimental section. These assignments and correlations of Hand CNMR signals were supported by two-dimensional (2D) spectroscopic analysis. Interestingly, IR spectra (KBr) showed two typical strong absorption bands at 1647—1662 and 1570—1584 cm 1 attributable to the amide C O and carboxylate (COO ) groups, respectively. This apparently indicates these compounds require the well-known twitterion structure between the carboxy (COOH) and basic tert-amino groups in the solid state (see Table 1). The reductions of both these two carbonyl groups (N-benzoyl amide and COOH) in the derivatives (5a—f) were successfully achieved by treatment with NaAlH2(OCH2CH2OCH3)2 in anhydrous benzene to afford the corresponding amino alcohols 6a—f. These compounds (6a—f) were relatively sensitive to exposure to air and included trace amounts of unknown contaminants upon TLC analysis. The purification of the products to remove these unknown contaminants resulted in a great loss of the target compounds (6a—f). Therefore we used the above obtained material for the next cyclization process without further purification (see Experimental). The procedure for the cyclization step with the treatment of 6a—f with diethyl carbonate in the presence of sodium methoxide in anhydrous benzene was effective, and resulted in the formation of 3a—f in good yields (58—81%) (Chart 1), which were comparable with the results reported by Homeyer. The physical data on the compounds (3a—f) are summarized in Table 2, and Hand C-NMR spectroscopic data are reported in the Experimental section. The structures of the target oxazolidin-2-ones (3a—f) were easily confirmed from the above elemental and spectroscopic analysis. Thus IR spectra of 3a—f showed a typical