(2S,4S)-3-Benzoyl-2-t-butyl-4-methyl-1,3-oxazolidin-5-one1

[104057-64-9]  · C15H19NO3  · (2S,4S)-3-Benzoyl-2-t-butyl-4-methyl-1,3-oxazolidin-5-one  · (MW 261.32)

(cyclic acetal of N-benzoylalanine; reagent for the preparation of enantiopure a-methyl-a-aminocarboxylic acids;2 precursor to the 4-methylidene derivative;3a a radicalophile;3b a Michael acceptor;4 and an ene component for Diels-Alder additions,5 with formation of more complex a-amino acids)

Physical Data: mp 94.2-94.5 °C; [a]rtD = -29.3° (c = 1.0, CHCl3).

Solubility: sol THF, poorly sol hexane.

Preparative Methods: the sodium salt of the pivalaldehyde imine of (S)-alanine is cyclized to the oxazolidinone by reaction with PhCOCl in CH2Cl2 at low temperature; the cis/trans ratio in the crude product depends upon the exact reaction conditions, it is usually 4:1; purification by a combination of crystallization and chromatography gives the pure cis derivative in 60-70% yield.2

Handling, Storage, and Precautions: the solid material is stable for years when stored in a bottle.

Generation of the Enolate and Reactions with Electrophiles.

The enolate of the title reagent (1) is generated with lithium amide bases and reacts with electrophiles such as benzylic bromides or tricarbonyl(fluorobenzene)chromium to give the corresponding 4,4-disubstituted derivatives of type (2), which are hydrolyzed under acidic conditions2,6-8 to, for instance, the amino acids2,7 (3) and (4).

In the overall process the a-hydrogen of the alanine has been replaced by benzyl or phenyl stereoselectively (an application of the principle of self-regeneration of the stereogenic center). The analogous 2-t-butyl-3-benzoyloxazolidinones of valine,2 phenylalanine,2 methionine,2,9 and lysine6 have also been prepared and alkylated to give a-branched amino acids.

Other Oxazolidine as well as Thiazolidine Derivatives for Branching Amino Acids.

The cyclic derivative of alanine and other amino acids employed most frequently for a-alkylation is not (1) but rather the benzaldehyde acetal (5), either with a benzoyl5,10 or with a Cbz11 group on nitrogen. These compounds were used for the preparation of 2-methyl-2-aminobutanoic acid, a-methylphenylalanine, a-methyllysine, 2-methylaspartic acid, and 2-methylglutamic acid. Bicyclic compounds containing oxazolidinone rings such as (6) (from alanine, leucine, and phenylalanine)12 and (7) (from azetidinecarboxylic acid,13 proline,14 hydroxyproline,15 and cysteine16) have also been applied to the synthesis of branched amino acids.

Finally, the enolates (8), (9), and (10) of oxazolidine and thiazolidine carboxylates have been used for the synthesis of enantiopure a-substituted serine,17 cysteine,18 threonine,17 allo-threonine,17 and b-hydroxyleucine.19

a-Bromination-dehydrobromination of oxazolidinone (1) (NBS, then DBU) or an alternative preparation starting from cysteine gives the methylene derivative (11) which combines with cyclopentadiene and cyclohexadiene in [4 + 2] cycloadditions; these reactions were used for the synthesis of (R) and (S)-2-aminobicyclo[2.2.1]heptane-2-carboxylic acids as shown in eq (1).3-5

(R)- and (S)-2-t-Butyl-1,3-oxazolidin-5-ones: Chiral Glycine Derivatives.

Since the oxazolidinone enolates are good diastereoselective nucleophiles, and since the products are much more readily hydrolyzed to the free amino acids than those derived from imidazolidinones, it was also desirable to make available the corresponding glycine derivative (12). This was achieved by preparative HPLC resolution on Chiraspher, Chiracel OD, or Pirkle columns (up to 10 g per injection, separation factors a up to 2.35).8,20 The enolate of the 2-t-butyl-substituted N-Cbz oxazolidinone was especially useful for the synthesis of a large variety of (R)- and (S)-threonines; see, for instance, the cyclosporin component MeBmt (13)21 and the p-nitrophenylserine (14)22 in eq (2).

Related Reagents.

1-Benzoyl-2-t-butyl-3,5-dimethyl-4-imidazolidinone; t-Butyl 2-t-Butyl-3-methyl-4-oxo-1-imidazolidinecarboxylate; (R,R)-2-t-Butyl-5-methyl-1,3-dioxolan-4-one; Diethyl Acetamidomalonate; N-(Diphenylmethylene)aminoacetonitrile; Ethyl N-(Diphenylmethylene)glycinate; Methyl N-Benzylidenealaninate.


1. Seebach, D.; Imwinkelried, R.; Weber, T. In Modern Synthetic Methods; Springer: Berlin, 1986; Vol. 4, pp 125-259.
2. Seebach, D.; Fadel, A. HCA 1985, 68, 1243.
3. (a) Zimmermann, J.; Seebach, D. HCA 1987, 70, 1104. (b) Beckwith, A. L. J.; Chai, C. L. L. CC 1990, 1087.
4. Crossley, M. J.; Tansey, C. W. AJC 1992, 45, 479.
5. Pyne, S. G.; Dikic, B.; Gordon, P. A.; Skelton, B. W.; White, A. H. AJC 1993, 46, 73.
6. Gander-Coquoz, M.; Seebach, D. HCA 1988, 71, 224 (CA 1988, 109, 110 880p).
7. Chaari, M.; Jenhi, A.; Lavergne, J.-P.; Viallefont, Ph. JOM 1991, 401, C10 (CA 1991, 114, 164 736t).
8. Seebach, D.; Gees, T.; Schuler, F. LA 1993, 785.
9. Beck, A. K.; Seebach, D. C 1988, 42, 142.
10. Nebel, K.; Mutter, M. T 1988, 44, 4793; Fadel, A.; Salaün, J. TL 1987, 28, 2243.
11. Karady, S.; Amato, J. S.; Weinstock, L. M. TL 1984, 25, 4337; Abell, A. D.; Taylor, J. M. JOC 1993, 58, 14; Altmann, E.; Nebel, K.; Mutter, M. HCA 1991, 74, 800.
12. Zydowsky, T. M.; de Lara, E.; Spanton, S. G. JOC 1990, 55, 5437.
13. Seebach, D.; Vettiger, T.; Müller, H. M.; Plattner, D. A.; Petter, W. LA 1990, 687.
14. Seebach, D.; Naef, R. HCA 1981, 64, 2704; Seebach, D.; Boes, M.; Naef, R.; Schweizer, B. JACS 1983, 105, 5390; Calderari, G.; Seebach, D. HCA 1985, 68, 1592 (CA 1986, 105, 133 326u); Thaisrivongs, S.; Pals, D. P.; Lawson, J. A.; Turner, S. R.; Harris, D. W. JMC 1987, 30, 536; Williams, R. M.; Glinka, T.; Kwast, E. JACS 1988, 110, 5927; Orsini, F.; Pelizzoni, F.; Forte, M.; Sisti, M.; Bombieri, G.; Benetollo, F. JHC 1989, 26, 837; Beck. A. K.; Blank, S.; Job, K.; Seebach, D.; Sommerfeld, Th. OS 1994, 72, in press.
15. Weber, T.; Seebach, D. HCA 1985, 68, 155 (CA 1985, 103, 88 182q).
16. Seebach, D.; Weber, T. TL 1983, 24, 3315; Seebach, D.; Weber, T. HCA 1984, 67, 1650 (CA 1985, 102, 185 449u).
17. Seebach, D.; Aebi, J. D.; Gander-Coquoz, M.; Naef, R. HCA 1987, 70, 1194 (CA 1988, 108 187 232r) and earlier work cited therein.
18. Mulqueen, G. C.; Pattenden, G.; Whiting, D. A. T 1993, 49, 5359.
19. Sunazuka, T.; Nagamitsu, T.; Matsuzaki, K.; Tanaka, H.; &OOmacr;mura, S. JACS 1993, 115, 5302.
20. Seebach, D.; Müller, S. G.; Gysel, U.; Zimmermann, J. HCA 1988, 71, 1303 (CA 1989, 110, 114 764x); Kinkel, J. N.; Gysel, U.; Blaser, D.; Seebach, D. HCA 1991, 74, 1622.
21. Blaser, D.; Ko, S. Y.; Seebach, D. JOC 1991, 56, 6230.
22. Blaser, D.; Seebach, D. LA 1991, 1067.

Andrea Rolf Sting & Dieter Seebach

Eidgenössische Technische Hochschule Zürich, Switzerland



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