[97443-91-9]  · C16H22N2O2  · 1-Benzoyl-2-t-butyl-3,5-dimethyl-4-imidazolidinone  · (MW 274.36) (2S,5S)


(imidazolidinones for generating the enantiomeric enolates derived from alanine;2,3 reagents for the preparation of a-methylated amino acids through enolate alkylation, benzylation, and nitroalkene addition3-5)

Physical Data: (2R,5S)-(1): mp 125 °C; [a]rtD = -47.7° (c = 1.04, CHCl3); (2S,5S)-(1): mp 175 °C; [a]rtD = +44.5° (c = 1.0, CHCl3).

Solubility: sol THF.

Preparative Method: the imine from (S)-alanine N-methylamide and pivalaldehyde is cyclized by heating with benzoic anhydride to give mainly cis-(1) [(2R,5S)-(1)] in modest yields; alternatively, the imine cyclizes to the trans-substituted heterocycle by treatment with HCl in MeOH, and subsequent benzoylation produces trans-(1) [(2S,5S)-(1)] in high yield (eq 1).2

Handling, Storage, and Precautions: both diastereoisomers are readily crystallizable compounds which are stable at rt for years.

Alkylations of the Lithium Enolates.

Treatment of the reagents with Lithium Diisopropylamide (LDA) generates the enolates (2) or ent-(2) (crystal structure of rac-TBDMS-(2)6) which can be alkylated3,5 to give, for instance, (R)-a-methyl-dopa (3) or triacetyl (S)-a-methyl-dopa.3

Benzoylimidazolidinones of Other Amino Acids.

In a similar way, other proteinogenic and nonproteinogenic amino acids have been converted to imidazolidinones (4) and alkylated through enolates to give derivatives of a-branched a-amino acids. Examples of the R group in (4) are as follows: i-Pr,2-4 Bn,2 (CH2)2SMe,2,7,8 CH=CH2,8 Ph,2 (CH2)3NHCO2Bn,5 (CH2)4NHCO2Bn,5 CH2CO2H,9 (CH2)2CO2H.9 The limitation of the method is given by the fact that certain amino acid N-methylamides, the intermediates on the way from the 3-methylimidazolidinones to free amino acids, are very difficult to hydrolyze.10 Except for the procedure described here and for those methods involving enantioselective catalysis, all other syntheses of amino acids rest upon the use of a covalently attached chiral auxiliary which has to be discarded, recovered, or destroyed after use.1c

The Principle of Self-Regeneration of Stereogenic Centers.1,11,12

In the absence of additional chirality the generation of an enolate from a simple amino acid will lead to racemization.13 There are two ways around this: (i) attachment of a chiral auxiliary, and (ii) diastereoselective generation of an additional stereogenic center which makes sure that the subsequently generated enolate is still chiral. In the case of alanine, described here, the acetal chirality center serves this purpose. The most general case is described in eq 2. Thus an a- or b-amino, -hydroxy-, and -mercaptocarboxylic acid may be converted to one of two diastereoisomeric acetals. The original stereogenic center can now be eliminated without forming an achiral species; subsequent reactions at the newly formed trigonal center should be diastereoselective, so that the product of acetal hydrolysis is nonracemic. The trigonal center at the site of the original stereogenic center may be part of an electrophilic or a nucleophilic double bond system, or may be a radical center. In the overall process, a substituent (mostly a hydrogen) at the one and only chirality center of the starting material is replaced by a new substituent stereoselectively. Since no chiral auxiliary is employed, this has been termed the principle of self-regeneration of the stereogenic center (SRSC). The auxiliary is actually the aldehyde, used for generating the second stereogenic center, and it is removed in the final hydrolysis step.

Oxazoline, oxazolidine, dihydropyrimidine, and 1,3-dioxine derivatives can also be used in this way.

Related Reagents.

(2S,4S)-3-Benzoyl-2-t-butyl-4-methyl-1,3-oxazolidin-5-one; t-Butyl 2-t-Butyl-3-methyl-4-oxo-1-imidazolidinecarboxylate; (R)-2-t-Butyl-6-methyl-4H-1,3-dioxin-4-one; (R,R)-2-t-Butyl-5-methyl-1,3-dioxolan-4-one; Diethyl Acetamidomalonate; N-(Diphenylmethylene)aminoacetonitrile; Ethyl N-(Diphenylmethylene)glycinate; Ethyl Isocyanoacetate; Methyl N-Benzylidenealaninate; (R)-Methyl 2-t-Butyl-3(2H)-oxazolecarboxylate.

1. (a) Seebach, D.; Imwinkelried, R.; Weber, T. In Modern Synthetic Methods; Springer: New York, 1986; Vol. 4, pp 125-259. (b) Seebach, D.; Roggo, S.; Zimmermann, J. In Workshop Conferences Hoechst; Verlag Chemie: Weinheim, 1987; Vol. 17, pp 85-126. (c) Williams, R. M. Synthesis of Optically Active a-Amino Acids; Pergamon: Oxford, 1989. (d) Duthaler, R. O. T 1994, 50, 1539.
2. Naef, R.; Seebach, D. HCA 1985, 68, 135 (CA 1985, 103, 71 633q).
3. Seebach, D.; Aebi, J. D.; Naef, R.; Weber, T. HCA 1985, 68, 144.
4. Calderari, G.; Seebach, D. HCA 1985, 68, 1592 (CA 1986, 105, 133 326u).
5. Gander-Coquoz, M.; Seebach, D. HCA 1988, 71, 224 (CA 1988, 109, 110 880p).
6. Seebach, D.; Maetzke, T.; Petter, W.; Klötzer, B.; Plattner, D. A. JACS 1991, 113, 1781.
7. Weber, T.; Aeschimann, R.; Maetzke, T.; Seebach, D. HCA 1986, 69, 1365 (CA 1987, 107, 97 075s).
8. Seebach, D.; Juaristi, E.; Miller, D. D.; Schickli, C.; Weber, T. HCA 1987, 70, 237.
9. Aebi, J. D.; Seebach, D. HCA 1985, 68, 1507 (CA 1986, 105, 97 883n).
10. Seebach, D.; Gees, T.; Schuler, F. LA 1993, 785.
11. Seebach, D.; Naef, R.; Calderari, G. T 1984, 40, 1313.
12. Strijtveen, B.; Kellogg, R. M. T 1987, 43, 5039.
13. For three exceptions see the alkylations of an aspartic acid,13a of an aziridine carboxylic acid,13b and of a cysteine derivative.13c (a) Seebach, D.; Wasmuth, R. AC(E) 1981, 20, 971. (b) Häner, R.; Olano, B.; Seebach, D. HCA 1987, 70, 1676. (c) Beagley, B.; Betts, M. J.; Pritchard, R. G.; Schofield, A.; Stoodley, R. J.; Vohra, S. CC 1991, 924.

Armido Studer & Dieter Seebach

Eidgenössische Technische Hochschule Zürich, Switzerland

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