[139119-52-1]  · C16H22N2O2  · (274.36)

(reagent used for the enantioselective synthesis of b-amino acids; in particular, a- and a,a-substituted b-amino acids.)

Physical Data: mp 99-100°C; [a]D29 +51.2 (c 1, CHCl3).

Solubility: soluble in THF and most organic solvents.

Preparative Methods: 1,2,3 Step 1:

According to the procedure described by Lakner et al.,1 with benzoyl chloride instead of methyl chloroformate, 13.2 g (0.2 mol) of KOH and 300 mL of water are placed in a 1 L round-bottomed flask before the addition of 30.0 g (0.2 mol) of L-(S)-asparagine with vigorous stirring. The resulting mixture is cooled to 0°C and treated with 25.0 mL (19.8 g, 0.23 mol) of pivalaldehyde. Stirring is continued for 1 h at 0°C and for 5 h at ambient temperature. The reaction mixture is cooled to 0°C before the addition of 16.8 g (0.2 mol) of NaHCO3 and 23.2 mL (28.1 g, 0.2 mol) of benzoyl chloride, and stirring is continued for 2 h at ambient temperature prior to quenching with 73 mL of 10% aqueous HCl. The desired product, which precipitates from solution, is filtered, washed with cold water, and dried under vacuum to afford 54.0 g (88%) of 1-benzoyl-2(S)-tert-butyl-6(S)-carboxy-perhydropyrimidin-4-one [(2S,6S)-1], mp 202-203°C; [a]D29 -107.0 (c 1, EtOH). Step 2:

In a 3 L round-bottomed flask provided with a magnetic stirrer, 28.0 g (92 mmol) of (2S,6S)-1 is dissolved in 900 mL of dry THF, 700 mL of toluene, and 11.2 mL (11.0 g, 138.4 mmol) of pyridine. The resulting solution is treated with 3.7 g (18.4 mmol) of copper diacetate monohydrate, and the resulting suspension is stirred at ambient temperature for 2 h. The reaction flask is then submerged in an ice-water bath before the addition of 61.6 g (138.8 mmol) of lead tetraacetate. The cooling bath is removed and the reaction mixture is heated to 80-90°C for 12 h. The precipitate is removed by filtration and washed several times with EtOAc until the extracts come out free of product (TLC). The organic extracts are combined with the original filtrate, dried over anhydrous Na2SO4, and concentrated. The crude product is purified by flash chromatography (eluent hexane-EtOAc, 80:20 r 50:50) to give 16.0 g (73%) of 1-benzoyl-2(S)-tert-butyl-2,3-dihydro-4(H)-pyrimidin-4-one [(S(-2], mp 209-210°C; [a]D29 +556.4 (c 1, CHCl3). Step 3:

N-Methylation of (S)-2 is best accomplished following the procedure of Juaristi et al.3 In a 50 mL round-bottomed flask provided with magnetic stirrer is placed 3.0 g (11.6 mmol) of (S)-2 and 15 mL of acetonitrile. The resulting solution is treated with 1.1 mL (11.6 mmol) of dimethyl sulfate (slow addition) and 0.5 g (11.6 mmol) of NaOH (slow addition). The reaction mixture is stirred for 3 h at 45-50°C (mineral oil bath) and the acetonitrile is removed at reduced pressure. The residue is suspended in 50 mL of water and extracted with three 50 mL portions of EtOAc. The combined organic extracts are dried over anhydrous Na2SO4 and concentrated to give the crude product that is purified by flash chromatography (hexane-EtOAc, 80:20 r 50:50) to afford 2.7 g (84%) of 1-benzoyl-2(S)-tert-butyl-3-methyl-2,3-dihydro-4(H)-pyrimidin-4-one, mp 141-142°C; [a]D29 +560.2 (c 1, CHCl3). Step 4:

According to the procedure of Juaristi et al.,2 heterocycle (S)-3 (5.0 g, 18.4 mmol), 40 mL of EtOAc, 0.5 g of 10% Pd(C), and 0.4 mL of acetic acid is placed in a hydrogenation flask. The reaction mixture is pressurized to 75 atm of hydrogen, heated to 45°C, and stirred for 24 h. The catalyst is removed by filtration over Celite, the filtrate is washed with aqueous 10% NaHCO3, dried over anhydrous Na2SO4, filtered, and evaporated at reduced pressure to give 4.5 g (90%) of 1-benzoyl-2(S)-tert-butyl-3-methylperhydropyrimidin-4-one [(S(-4], mp 99-100°C; [a]D29 +51.2 (c 1, CHCl3). The overall yield in the preparation of (S)-4 from (S)-asparagine (four steps) is 49%.

Preparation of enantiopure a-substituted b-amino acids2,4

In preliminary studies, racemic 2-tert-butyl-perhydropyrimidinone, rac-4, was alkylated with high diastereoselectivity via its corresponding enolate (eq 5).5 The high stereoselectivity encountered in the reaction of rac-4-Li with various electrophiles was ascribed to steric hindrance generated by the axial disposition of the tert-butyl group at C(2),5,6 which directs approach to the electrophile from the enolate face opposite to this group.

These observations paved the road for the development of a new method for the asymmetric synthesis of a-substituted b-amino acids. Thus, an efficient protocol for the preparation of enantiopure pyrimidinone (S)-4 was developed (vide supra, eq 1-4).

Enolate (S)-4-Li was generated upon treatment of the heterocycle with lithium diisopropylamide (LDA) in THF solution and under a nitrogen atmosphere. The electrophile was then added at -78°C to afford the trans-alkylated products with high diastereoselectivity and in good yields (eq 6, Table 1).

The final step of the overall conversion of (S)-asparagine to 2-alkyl-3-aminopropanoic acid, the hydrolysis of heterocycles 5-8, was achieved by heating with 6 N HCl in a sealed tube at 90-100°C. The free amino acids 9-12 were purified by chromatography on an ion-exchange column (eq 7, Table 2).

Epimerization of adducts 5-8, and hydrolysis to give the enantiomeric a-alkylated b-aminopropionic acids

In principle, a-substituted b-amino acids of opposite configuration, (S)-9-12, can be obtained when enantiomeric pyrimidinone (R)-4 [from (R)-asparagine] is used as the starting material, following the reaction sequence described above. Nevertheless, a practical alternative consisted in the epimerization of trans-adducts 5-8 to afford the cis-diastereoisomers 13-16 (eq 8). Hydrolysis of cis-13-16 provided the desired (S)-a-substituted b-amino acids, (S)-17-20 (eq 9).2

Clearly, protonation (aqueous NH4Cl) of the enolates generated from 5-8 takes place on the face opposite to the tert-butyl group, and this reaction is also highly stereoselective.

Preparation of enantiopure a,a-disubstituted b-amino acids7,8

(2S,5R)-5-8 were alkylated via their corresponding enolates to provide suitable precursors of enantiopure a,a-dialkylated b-amino acids. Thus, enolates (2S)-5-8-Li were generated upon treatment of the appropriate heterocycle with LDA in THF solution and under nitrogen atmosphere. The electrophile (methyl iodide, ethyl iodide, n-butyl bromide, n-hexyl iodide, or benzyl bromide) in solvent N,N-dimethylpropyleneurea (DMPU) was then added at -78°C to afford the dialkylated products with high diastereoselectivity and in excellent yields (Table 3). The use of DMPU as cosolvent was necessary to effect the dialkylation in high yield (eq 10).9

Hydrolysis of geminal disubstituted perhydropyrimidinones 21-26 necessitated drastic conditions: 8 N HCl at 100-140°C in a sealed tube. While these harsh conditions may not be tolerated by sensitive amino acids,10 they proved harmless to the a,a-disubstituted b-amino acids 27-32. Nevertheless, milder conditions could be employed when p-dioxane was used as cosolvent, since improved solubility of the substrate in the aqueous medium resulted in much faster hydrolysis (eq 11).

Related Reagents.

Owing to the high price of pivalaldehyde, we have substituted this aldehyde with isobutyraldehyde in the synthesis of imino ester (2S,6S)-33, which proved to be a convenient substrate for the enantioselective synthesis of a-substituted aspartic acids (eq 12).11,12

Hydrolysis of the alkylated products (2S,6S)-34-37 and isolation of the desired amino acids was facilitated by the presence of the labile imino group.13 Indeed, hydrolysis was achieved by heating with 17% HCl in a sealed tube at 95°C. The free amino acids 38-41 were purified by chromatography on an ion-exchange column (eq 13).8,11

On the other hand, Beaulieu et al.14 have reported the synthesis of unusually functionalized optically active b-substituted b-amino acids via the highly diastereoselective ((95:5) transformation of enantiopure N-(o-iodobenzoyl)-2-tert-butylperhydropyrimidinone [(S)-42] (eq 14).

In this context, dihydropyrimidinone (R)-44 has been exploited by Chu et al.15 and Konopelski et al.16 in the enantioselective synthesis of b-alkyl b-amino acids. Furthermore, N-phenethylperhydropyrimidinone (S)-45,17,18 as well as the 6-substituted analogs 46-48 (configuration not indicated)19-22 are useful substrates for the asymmetric synthesis of a,b-disubstituted b-amino acids.

1. Lakner, F. J.; Ch, K. S.; Negrete, G. R.; Konopelski, J. P., Org. Synth. 1995, 73, 201.
2. Juaristi, E.; Quintana, D.; Balderas, M.; García-Pérez, E., Tetrahedron: Asymmetry 1996, 7, 2233.
3. Juaristi, E.; Rizo, B.; Natal, V.; Escalante, J.; Regla, I., Tetrahedron: Asymmetry 1991, 2, 821.
4. Juaristi, E.; Quintana, D., Tetrahedron: Asymmetry 1992, 3, 723.
5. Juaristi, E.; Quintana, D.; Lamatsch, B.; Seebach, D., J. Org. Chem. 1991, 56, 2553.
6. Seebach, D.; Lamatsch, B.; Amstutz, R.; Beck, A. K.; Dobler, M.; Egli, M.; Fitzi, R.; Gautschi, M.; Herradón, B.; Hidber, P. C.; Irwin, J. J.; Locher, R.; Maestro, M.; Maetzke, T.; Mouriño, A.; Pfammatter, E.; Plattner, D. A.; Schickli, C.; Schweizer, W. B.; Seiler, P.; Stucky, G.; Petter, W.; Escalante, J.; Juaristi, E.; Quintana, D.; Miravitlles, C.; Molins, E., Helv. Chim. Acta 1992, 72, 913.
7. Juaristi, E.; Balderas, M.; Ramírez-Quirós, Y., Tetrahedron: Asymmetry 1998, 9, 3881.
8. Juaristi, E.; Balderas, M.; López-Ruiz, H.; Jímenez-Pérez, V. M.; Kaiser-Carril, M. L.; Ramírez-Quirós, Y., Tetrahedron: Asymmetry 1999, 10, 3493.
9. DMPU has been recommended as solvent in various alkylation reactions: Juaristi, E.; Murer, P.; Seebach, D., Synthesis 1993, 1243, and references cited therein.
10. Seebach, D.; Juaristi, E.; Miller, D. D.; Schickli, C.; Weber, T., Helv. Chim. Acta 1987, 70, 237.
11. Juaristi, E.; López-Ruiz, H.; Madrigal, D.; Ramírez-Quirós, Y.; Escalante, J., J. Org. Chem. 1998, 63, 4706.
12. See also: Seebach, D.; Boog, A.; Schweizer, W. B., Eur. J. Org. Chem. 1999, 335.
13. Compare mild conditions employed to hydrolyze bis-lactimethers: Schöllkopf, U.; Tiller, T.; Bardenhagen, J., Tetrahedron 1998, 44, 5293. Compare mild conditions used to hydrolyze dihydroimidazoles: Blank, S.; Seebach, D., Angew. Chem., Int. Ed. Engl. 1993, 32, 1765.
14. Beaulieu, F.; Arora, J.; Vieth, U.; Taylor, N. J.; Chapell, B. J.; Snieckus, V., J. Am. Chem. Soc. 1996, 118, 8727.
15. (a) Chu, K. S.; Negrete, G. R.; Konopelski, J. P., J. Org. Chem. 1991, 56, 5196. (b) Chu, K. S.; Konopelski, J. P., Tetrahedron 1993, 49, 9183.
16. Konopelski, J. P. In Enantioselective Synthesis of b-Amino Acids, Juaristi, E., Ed. Wiley: New York, 1997, pp 249-259.
17. (a) Amoroso, R.; Cardillo, G.; Tomasini, C.; Tortoreto, P., J. Org. Chem. 1992, 57, 1082. (b) Cardillo, G.; Tolomelli, A.; Tomasini, C., Tetrahedron 1995, 51, 11831.
18. Cardillo, G.; Tomasini, C. In Enantioselective Synthesis of b-Amino Acids, Juaristi, E., Ed. Wiley: New York, 1997, pp 211-248.
19. Juaristi, E.; Escalante, J.; Lamatsch, B.; Seebach, D., J. Org. Chem. 1992, 57, 2396.
20. Juaristi, E.; Escalante, J., J. Org. Chem. 1993, 58, 2282.
21. Escalante, J.; Juaristi, E., Tetrahedron Lett. 1995, 36, 4397.
22. Juaristi, E.; Seebach, D. In Enantioselective Synthesis of b-Amino Acids, Juaristi, E., Ed. Wiley: New York, 1997, pp 261-277.

Eusebio Juaristi

Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México, D.F., México

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