(<i>S</i>)-(+)-5,5-Dimethyl-4-phenyl-2-oxazolidinone (2002)

[168297-84-5] C11H13NO2 (MW 191.23) InChI = 1S/C11H13NO2/c1-11(2)9(12-10(13)14-11)8-6-4-3-5-7-8/h3-7,9H,1-2H3,(H,12,13)/t9-/m0/s1 InChIKey = HSQRCAULDOQKPF-VIFPVBQESA-N (versatile chiral auxiliary used for asymmetric synthesis1-8 in diastereoselective enolate formation,9-12 and Michael additions;9, 13 also used in the kinetic resolution of α-acetoxy carboxylic acids14) Alternate Name: (4S)-Phenyl SuperQuat. Physical Data: mp 151–156 °C; [α]D25 +71 (c 2.0, CHCl3). Solubility: THF, EtOAc, dichloromethane. Form Supplied in: white crystalline solid; commercially available. Analysis of Reagent Purity: 1H NMR, 13C NMR, IR, GCMS, chiral HPLC. Preparative Methods: the original literature9 reports that the desired 4-substituted-5,5-dimethyloxazolidin-2-one is readily accessible from the corresponding α-amino acid via esterification (MeOH/SOCl2) followed by Grignard addition to afford the 1,2-amino alcohol (eq 1). The formation of the oxazolidinone is then achieved either indirectly by treatment with tricholoracetyl chloride followed by base-catalyzed cyclization, or directly through reaction with carbonyldiimidazole. (1) While this methodology is applicable to a variety of α-amino acids on a small scale, large-scale syntheses have proven problematic in that they are either low yielding or result in partial racemization of the desired auxiliary. In order to circumvent this difficulty, an alternative preparation has been developed (eq 2). Initially, an N-Boc-α-amino acid methyl ester is reacted with an excess of methylmagnesium iodide to generate the corresponding tertiary alcohol. Subsequent cyclization into the desired 4-substituted-5,5-dimethyloxazolidin-2-one upon treatment with tert-BuOK (eq 2) proceeds in good yield and with little or no racemization.11, 15 (2) The N-Boc protecting group is critical in this synthetic strategy. Not only does it prevent racemization by disfavoring deprotonation at the α-center once the carbamate proton is removed, but it also serves as a carbonyl equivalent in the cyclization process. The major drawback to this methodology is that although many N-Boc protected α-amino acid methyl esters are commercially available, they tend to be significantly more expensive than the corresponding α-amino acids. They can, however, be synthesized easily from the parent α-amino acid, albeit in two steps. Table 1. Formation of 4-substituted-5,5-dimethyloxazolidin-2-ones % Overall yield R % Yield(two steps) Method Aa Method Ba Ph 41 25 34 Me 53 47 48 Bn 41 28 33 a Method A: CCl3COCL, pyridine then K2CO3, EtOH. Method B: CDI, CH2Cl2. It has also been reported16 that 4-substituted-5,5-dimethyloxazolidin-2-ones can be prepared as illustrated in eq 3. Initially, stereoselective condensation of an N-acyloxazolidinone enolate with acetone affords a functionalized acyl fragment, which is then hydrolyzed to the carboxylic acid. Reaction of the hydroxy acid with DPPA at elevated temperatures yields the target via formation of the acyl azide, Curtius rearrangement and trapping of the isocyanate intermediate by the hydroxyl group (eq 3). (3) While this methodology is not intended for the preparation of oxazolidinones that can be generated in a more concise route from their parent α-amino acid (vide supra), it does allow for the preparation of 4-substituted-5,5-dimethyloxazolidin-2-ones in which the parent α-amino acid is either not commercially available or exceedingly expensive. Purification: can be recrystallized from EtOAc with pentane. Handling, Storage, and Precautions: stable for prolonged periods when stored in a cool, dry environment; easy to handle; solid; MSDS codes as irritant.