(S)-(+)-5,5-Dimethyl-4-phenyl-2-oxazolidinone

[168297-84-5]  · C11H13NO2  · (MW 191.23)

(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 a-acetoxy carboxylic acids14)

Alternate Name: (4S)-Phenyl SuperQuat.

Physical Data: mp 151-156 °C; [a]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 a-amino acid via esterification (MeOH/SOCl2) followed by Grignard addition to afford the 1,2-amino alcohol (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.

While this methodology is applicable to a variety of a-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 (2). Initially, an N-Boc-a-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 (2) proceeds in good yield and with little or no racemization.11,15

The N-Boc protecting group is critical in this synthetic strategy. Not only does it prevent racemization by disfavoring deprotonation at the a-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 a-amino acid methyl esters are commercially available, they tend to be significantly more expensive than the corresponding a-amino acids. They can, however, be synthesized easily from the parent a-amino acid, albeit in two steps. It has also been reported16 that 4-substituted-5,5-dimethyloxazolidin-2-ones can be prepared as illustrated in 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 (3).

While this methodology is not intended for the preparation of oxazolidinones that can be generated in a more concise route from their parent a-amino acid (vide supra), it does allow for the preparation of 4-substituted-5,5-dimethyloxazolidin-2-ones in which the parent a-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.

Introduction

The stoichiometric use of a chiral auxiliary has become one of the most prevalent and dependable methods to effect asymmetric transformations.1-8 In this context, the use of homochiral 4-substituted oxazolidin-2-ones2,17 has proven to be extremely effective in controlling facial diastereoselectivity in a wide variety of reactions of attached N-acyl fragments. While these ‘Evans’ auxiliaries’ allow for facile attachment of the N-acyl fragment and impart a high degree of stereocontrol, their major drawback is the difficulty in removing of the chiral auxiliary from some products.18 When the attached acyl fragment is either sterically demanding or branched at the a-position, there is a tendency for the auxiliary to undergo endocyclic hydrolysis. This affords the undesired ring-opened amide rather than the desired carboxylic acid and recovered auxiliary19 resulting from exocyclic cleavage (4).

Although this problem can be overcome by using lithium hydroperoxide,20 the use of this reagent on large scale can be hazardous. In order to completely circumvent this problem, Davies and Sanganee have developed 4-substituted-5,5-dimethyloxazolidin-2-ones, or ‘super Quats’.9 The key feature of this auxiliary is the gem-dimethyl groups at the C-5 position (5). The rationale for the design of this auxiliary is three-fold: (i) the gem-dimethyl groups at C-5 prevent endocyclic ring opening by blocking the required Burgi-Dunitz (109°) approach of the incoming nucleophile to C-2 during hydrolysis; (ii) the presence of the gem-dimethyl groups serve to enhance the diasterofacial selectivity during enolate formation via a secondary interaction with the C-4 substituent; and (iii) the highly crystalline nature of these species makes them amenable to purification by recrystallization.

Diastereoselective Enolate Formation and Alkylation

These ‘super Quat’ auxiliaries are easily N-acylated via deprotonation with butyllithium followed by quenching with the desired acid chloride. Treatment of the N-acylated ‘super Quat’ with LDA followed by the addition of an alkylating agent results in the formation of the functionalized acyl fragment in good to excellent yield with a high de. Presumably, as with the Evans’ auxiliaries, the high degree of asymmetric induction is a result of a carbonyl-metal-carbonyl transition state that results in the formation of a Z-enolate in which the C-4 substituent governs the diastereofacial bias of alkylation.1,7 As illustrated in eqs 6 and 7, reaction of N-propionyl and N-hydrocinnamoyl ‘super Quats’ with LDA, followed by treatment with benzyl bromide or methyl iodide, respectively, affords the corresponding pairs of diastereomers in acceptable yields and % de. In all cases, the de was increased to >99% by a single recrystallization.9

Unlike the Evans’ auxiliaries, however, removal of the ‘super Quat’ auxiliary is easily accomplished upon treatment with either lithium hydroxide or lithium alkoxide. Thus, hydrolysis with LiOH affords the enantionmerically pure a-substituted carboxylic acid and near quantitative recovery of the chiral auxiliary (8).

Diastereoselective Michael Additions

The ‘super Quats’ have also proven to be effective auxiliaries in diastereoselective conjugate additions to a,b-unsaturated carbonyl species.9,13 The use of such auxiliaries for this type of 1,2-addition is best exemplified by the asymmetric synthesis of aplysillamide B, an antifungal, antibacterical alkaloid isolated from the marine sponge Psammaplysilla purea. Thus, (S)-(+)-5,5-dimethyl-4-phenyl-2-oxazolidinone was N-acylated via treatment with butyllithium followed by exposure to trans-crotonyl chloride to afford the desired N-substituted oxazolidinone. To this amide was added an organocuprate prepared from n-heptylmagnesium bromide according to the standard Hruby protocol.21,22 The functionalized acyl fragment was next removed from the chiral auxiliary by treatment with 1,4-diaminobutane to afford the desired amino amide, which was converted to the target in two steps (9).

Kinetic Resolution of a-acetoxy Carboxylic Acids

One of the most recent applications for the ‘super Quat’ family of chiral auxiliaries is the kinetic resolution of a-substituted-a-acetoxy carboxylic acid chlorides.14 Upon reaction of the lithium salt of the ‘super Quat’ auxiliary with 2 equiv of (±)-O-acetylmandelic chloride at -100 °C, the corresponding N-acylated ‘super Quat’ auxiliary was isolated in excellent yield with acceptable de (10). The des that result from this type of resolution appear to be dependent on both solvent polarity and steric interactions at the a-position. The use of a less polar solvent causes a decrease in % de, while an increase in steric bulk tends to increase the % de. In all cases, however, a single recrystallization from hexane provide the N-acylated ‘super Quat’ auxiliary in >95% de.

Related Reagents.

(S)-4-Benzyl-5,5-dimethyl-2-oxazolidinone; (S)-5,5-dimethyl-4-iso-propyl-2-oxazolidinone; (S)-5,5-dimethyl-4-methyl-2-oxazolidinone; (S)-5,5-diphenyl-4-iso-propyl-2-oxazolidinone; (R)-4-benzyl-5,5-dimethyl-2-oxazolidinone.


1. (a) Evans, D. A., In Asymmetric Synthesis, Morrison, J. D., Ed.; Academic Press: New York, 1984; Vol. 3, Part B, pp 2-101. (b) Cowden, C. J., In Organic Reactions, Paquette, L. A., Ed.; John Wiley & Sons: New York, 1997; Vol. 51, pp 1-200.
2. Evans, D. A., Aldrichimica Acta. 1982, 15, 23.
3. Ager, D. J.; Prakash, I.; Schaad, D. R., Chem. Rev. 1996, 96, 835.
4. Ager, D. J.; Prakash, I.; Schaad, D. R., Aldrichimica Acta. 1997, 30, 3.
5. Seebach, D.; Hintermann, T., Helv. Chim. Acta. 1998, 81, 2093.
6. Regan, A. C., J. Chem. Soc., Perkin Trans. 1 1999, 4, 357.
7. Arya, P.; Qin, H., Tetrahedron. 2000, 56, 917.
8. Seebach, D.; Beck, A. K.; Heckel, A., Angew. Chem., Int. Ed. Eng. 2001, 40, 92.
9. Davies, S. G.; Sanganee, H. J., Tetrahedron: Asymm. 1995, 6, 671.
10. Bull, S. D.; Davies, S. G.; Key, M. S.; Nicholson, R. L.; Savory, E. D., Chem. Comm. 2000, 18, 1721.
11. Bull, S. D.; Davies, S. G.; Jones, S.; Sanganee, H. J., J. Chem. Soc., Perkin Trans. 1 1999, 4, 387.
12. Gibson, C. L.; Gillon, K.; Cook, S., Tetrahedron Lett. 1998, 39, 6733.
13. Davies, S. G.; Sanganee, H. J.; Szolcsanyi, P., Tetrahedron. 1999, 55, 3337.
14. Bew, S. P.; Davies, S. P.; Fukuzawa, S. I., Chirality. 2000, 12, 483.
15. Bull, S. D.; Davies, S. G.; Jones, S.; Polywka, M. C.; Prasad, R. S.; Sanganee, H. J., Synlett. 1998, 519.
16. Takacs, J. M.; Jaber, M. R.; Vellekoop, A. S., J. Org. Chem. 1998, 63, 2742.
17. Evans, D. A.; Ennis, M. D.; Mathre, D. J., J. Am. Chem. Soc. 1982, 104, 1737.
18. Evans, D. A.; Britton, T. C.; Ellman, D. J., Tetrahedron Lett. 1987, 28, 6141.
19. Evans, D. A.; Bartroli, J., Tetrahedron Lett. 1982, 23, 807.
20. Evans, D. A.; Chapman, K. T.; Bisaha, J., J. Am. Chem. Soc. 1988, 110, 1238.
21. Hruby, V. J.; Russel, K. C.; Nicolas, E., J. Org. Chem. 1993, 58, 766.
22. Hruby, V. J.; Lou, B.; Lung, F., J. Org. Chem. 1995, 60, 5509.

Doug M. Krein & Todd L. Lowary

The Ohio State University, Columbus, Ohio, USA



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