t-Butyl 2-t-Butyl-3-methyl-4-oxo-1-imidazolidinecarboxylate


[119838-44-7]  · C13H24N2O3  · t-Butyl 2-t-Butyl-3-methyl-4-oxo-1-imidazolidinecarboxylate  · (MW 256.34) (S)-(-)-(1)


(chiral glycine derivatives1 for the synthesis of amino acids)

Alternate Names: N-t-butoxycarbonyl-2-t-butyl-3-methylimidazolidin-4-one; Boc-BMI.

Physical Data: mp 68-70 °C; [a]rtD = 14.6° (c = 1.18, CHCl3).

Solubility: sol all common organic solvents.

Form Supplied in: colorless crystalline solid.

Preparative Method: the commercial glycine N-methylamide hydrochloride is converted to the racemic imidazolidinone (2) by imine formation with Pivalaldehyde and cyclization under acidic conditions (eq 1).1,2 The mandelate salt of like configuration is less soluble and is used for highly efficient resolution; subsequent treatment with Boc anhydride (Di-t-butyl Dicarbonate) gives the enantiomeric Boc-BMI (1) (eq 2).

Handling, Storage, and Precautions: stable in a bottle at rt for years.

Reactions of Boc-BMI with Electrophiles.

The enolate of Boc-BMI is generated with Lithium Diisopropylamide in THF at -75 °C; the resulting solutions of this highly nucleophilic reagent are stable up to 0 °C. All reactions occur from the face of the enolate trans to the t-Bu group at C(2). Alkylations1,3-6 even with secondary alkyl halides are so efficient, to give (3), that one-pot double alkylations, which yield (4), are possible; the sequence in which two different alkyl halides are employed determines the absolute configuration of the a-branched a-amino acids eventually obtained.

The method has been used to prepare isotopically labelled amino acids.3,7 While Boc-BMI enolate adds to aldehydes with only moderate diastereoselectivity, reduction of the acylation products (5) gives allothreonine derivatives (6).8 Michael additions to a,b-unsaturated esters,9 ketones,10 and nitro compounds1 lead to products of type (7) and (8) (for a general discussion see Suzuki and Seebach9).

Preparation of and Michael Addition to 5-Alkylidene Boc-BMI.

Radical bromination to give (9) (eq 3),11 Arbuzov reaction, and alkenation lead to (E)-5-alkylidene-Boc-BMI, to which cuprates add highly diastereoselectively with formation of the imidazolidinones (10) containing two new stereogenic centers (eq 4).12

Hydrolysis to Nonproteinogenic Amino Acids.

Numerous amino acids, including a-branched ones, have been prepared from Boc-BMI. Only a few examples can be alluded to here: (11) from (S)-(1), EtI, and Br(CH2)4Cl;3 (12) from (S)-(1), 3-methylbutanoyl chloride, and Lithium Triethylborohydride;8 (13) from (R)-(1), butanal, and dibutylcuprate;12 (14) from (S)-(1) and 4-phenylbut-2-enoate.9

The method is applicable to the synthesis of amino acids with extremely bulky substituents in the a-position.4b

Chiral Imidazolidinones with Other Substitution Patterns.

The intermediate imidazolidinone (2) can also be N-acylated by Benzoyl Chloride or Benzyl Chloroformate, and other substituents on the acetal center and/or on the N(3) nitrogen can be present, depending upon the aldehyde used for the imine formation and upon the glycine amide employed at the beginning of the synthesis. Chiral substituents, such as the 1-phenylethyl group may be placed on N(3), and the imidazolidinone may be derived from a dipeptide. Some examples are collected for (15), with references, in Table 1.1,5,13-17 These different derivatives have advantages of their own, depending on the particular synthetic application. An access to Boc-BMI by kinetic resolution has recently been described.18

Other Synthetic Building Blocks from Boc-BMI.

Deoxygenation of Boc-BMI leads to the imidazolidine (16) which can be lithiated on the methylene group next to N(1), and thus converted to compounds (17); from the corresponding ester (RE = CO2Me), 2,3-diaminopropionic acid derivatives (18) and (19) are available.19

Related Reagents.

1-Benzoyl-2-t-butyl-3,5-dimethyl-4-imidazolidinone; (2S,4S)-3-Benzoyl-2-t-butyl-4-methyl-1,3-oxazolidin-5-one; N-Benzyloxycarbonyl-L-serine b-Lactone; N-t-Butoxycarbonyl-N-methylaminomethyllithium; (R)-2-t-Butyl-6-methyl-4H-1,3-dioxin-4-one; N,N-Diethylaminoacetonitrile; Ethyl N-(Diphenylmethylene)glycinate; Ethyl Isocyanoacetate; Methyl a-Phenylglycinate.

1. Fitzi, R.; Seebach, D. T 1988, 5277.
2. Seebach, D.; Fitzi, R. Ger. Patent 3 604 591, 1986 (CA 1988, 108, 94 944j).
3. Seebach, D.; Dziadulewicz, E.; Behrendt, L.; Cantoreggi, S.; Fitzi, R. LA 1989, 1215.
4. (a) Seebach, D.; Gees, T.; Schuler, F. LA 1993, 785. (b) Studer, A.; Seebach, D. LA 1995, 217.
5. Müller, W.; Lowe, D. A.; Neijt, H.; Urwyler, S.; Herrling, P. L.; Blaser, D.; Seebach, D. HCA 1992, 75, 855.
6. Morton, M. E.; Leanna, M. R. TL 1993, 34, 4481; Hawthorne, M. F. AG 1993, 105, 997.
7. Lemaire, C.; Plenevaux, A.; Cantineau, R.; Christiaens, L.; Guillaume, M.; Comar, D. Appl. Radiat. Isot. 1993, 44, 737.
8. Blank, S.; Seebach, D. LA 1993, 889.
9. Suzuki, K.; Seebach, D. LA 1992, 51.
10. Seebach, D.; Pfammatter, E.; Gramlich, V.; Bremi, T.; Kühnle, F.; Portmann, S.; Tironi, I. LA 1992, 1145.
11. Zimmermann, J.; Seebach, D. HCA 1987, 70, 1104.
12. Schickli, C. P.; Seebach, D. LA 1991, 655 (CA 1991, 115, 72 163w). Seebach, D.; Bürger, H. M.; Schickli, C. P. LA 1991, 669 (CA 1991, 115, 72 164x).
13. Polt, R.; Seebach, D. JACS 1989, 111, 2622.
14. Amoroso, R.; Cardillo, G.; Tomasini, C. TL 1990, 31, 6413.
15. Seebach, D.; Miller, D. D.; Müller, S.; Weber, T. HCA 1985, 68, 949. Seebach, D.; Juaristi, E.; Miller, D. D.; Schickli, C. P.; Weber, T. HCA 1987, 70, 237.
16. Lowe, C.; Pu, Y.; Vederas, J. C. JOC 1992, 57, 10.
17. Juaristi, E.; Rizo, B.; Natal, V.; Escalante, J.; Regla, I. TA 1991, 2, 821.
18. Coggins, P.; Simpkins, N. S. SL 1991, 515.
19. Pfammatter, E.; Seebach, D. LA 1991, 1323.

Armido Studer & Dieter Seebach

Eidgenössische Technische Hochschule Zürich, Switzerland

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