[78342-42-4]  · C9H16N2O2  · (2S)-(+)-2,5-Dihydro-2-isopropyl-3,6-dimethoxypyrazine  · (MW 184.24)

(Schöllkopf-Hartwig bislactim ether reagent for asymmetric synthesis of amino acids by reaction of the metalated reagent with alkyl halides,2 aldehydes,3 ketones,4 epoxides,5 and enones,6 and subsequent hydrolysis of the resulting bislactim ether adduct)

Physical Data: bp 103-104 °C/15 mmHg; d 1.03 g cm-3; [a]20D -109 (c = 1, EtOH).

Solubility: sol ether, THF, n-hexane.

Form Supplied in: colorless liquid.

Analysis of Reagent Purity: NMR.2

Purification: distillation.

Handling, Storage, and Precautions: store refrigerated.

Bislactim Ether Method.

The commercially available bislactim ethers of cyclo(L- and D-Val-Gly) and cyclo(L- and D-Val-Ala)7 are very versatile reagents for the preparation of nonproteinogenic amino acids in high yields and with excellent enantioselectivities (typically >95%).1

Reactions of the Lithiated Bislactim Ether.

The procedure involves metalation with n-Butyllithium in THF at -70 °C and reaction of the resulting azaenolate with alkyl halides (eq 1).2 The latter enters with high diasteroselectivity trans to the isopropyl group. The alkylation products are hydrolyzed under mild acidic conditions to give the desired amino acid ester and the chiral auxiliary L-Val-OMe, which can be separated by distillation or chromatography (eq 1). As well as reacting with primary and secondary alkyl halides and sulfonates,8 the lithiated bislactim ether reacts in good yields and with high trans diastereoselectivities (in general >95%) with a variety of other electrophiles such as ketones,9 acyl chlorides,10 thioketones,11 epoxides,5 a,b-unsaturated esters,12 and arene-manganese tricarbonyl complexes.13

Reaction of the Titanated Bislactim Ether.

The titanium derivative of the bislactim ether of cyclo(L-Val-Gly) reacts with alkyl aldehydes,3 aryl aldehydes,14 and a,b-unsaturated aldehydes15 highly diastereoselectively to give almost exclusively the syn addition products (eq 2). Hydrolysis with dilute Trifluoroacetic Acid3c affords (2R, 3S)-b-hydroxy-a-amino acid methyl esters. a-Amino-g-nitro amino acids can be obtained by 1,4-addition of the titanated bislactim ether to nitroalkenes and subsequent hydrolysis of the adduct.16

Reactions of the Bislactim Ether Cuprate.

The lithiated bislactim ether can be converted to an azaenolate cuprate by treatment with CuBr.SMe2 (see Copper(I) Bromide).6 Conjugate addition of the cuprate to enones (eq 3)6 and dienones,17 or alkylation6 with base labile electrophiles like ethyl 3-bromopropionate, proceeds with high trans diastereoselectivity. Hydrolysis of the Michael adducts and subsequent protection afford (2R,3R)-N-Boc-d-oxo-a-amino acid methyl esters (eq 3).

Reactions of the Bislactim Ether Carbene.

Diazotization of the lithiated bislactim ether generates an electrophilic carbene species, which reacts in good yields and with high diastereomeric excess (<95%) with alkenes18 and aryl alkynes19 (eq 4) to give spirocyclopropanes and spirocyclopropenes, respectively. Hydrolysis of the latter affords the novel (R)-1-amino-2-arylcyclopropene-1-carboxylic acids.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.

1. (a) Hartwig, W.; Schöllkopf, U. Ger. Patent 2 934 252, 1981. (b) Schöllkopf, U. In Organic Synthesis: An Interdisciplinary Challenge, Streith, H.; Prinzbach, G.; Schill, G., Eds.; Blackwell: Oxford, 1985; p 101. (c) Schöllkopf, U. PAC 1983, 55, 1799. (d) Schöllkopf, U. CS 1985, 25, 105. (e) Williams, R. M. Synthesis of Optically Active a-Amino Acids, Pergamon: Oxford, 1989, (f) Schöllkopf, U. Top. Curr. Chem. 1983, 109, 65.
2. (a) Schöllkopf, U.; Groth, U.; Deng, C. AG(E) 1981, 20, 798.
3. (a) Schöllkopf, U.; Nozulak, J.; Grauert, M. S 1985, 55. (b) Grauert, M.; Schöllkopf, U. LA 1985, 1817. (c) Beulshausen, T.; Groth, U.; Schöllkopf, U. LA 1991, 1207.
4. (a) Schöllkopf, U.; Groth, U.; Gull, M.-R.; Nozulak, J. LA 1983, 1133. (b) Neubauer, H.-J.; Balza, J.; Freer, J.; Schöllkopf, U. LA 1985, 1508.
5. Gull, R.; Schöllkopf, U. S 1985, 1052.
6. Schöllkopf, U.; Pettig, D.; Schulze, E.; Klinge, M.; Egert, E.; Benecke, B.; Noltemeyer, M. AG(E) 1988, 27, 1194.
7. Merck Suchardt D-6100 Hohenbrunn, Germany.
8. Baldwin, J. E.; Adlington, R. M.; Bebbington, D.; Russel, A. T. CC 1992, 1249.
9. Schöllkopf, U.; Groth, U. AG(E) 1981, 20, 977.
10. Schöllkopf, U.; Westphalen, K.-O.; Schröder, J.; Horn, K. LA 1988, 781.
11. Schöllkopf, U.; Nozulak, J.; Groth, U. T 1984, 40, 1409.
12. (a) Hartwig, W.; Born, L. JOC 1987, 52, 4352. (b) Schöllkopf, U.; Pettig, D.; Busse, U. S 1986, 737.
13. (a) Pearson, A. J.; Bruhn, P. R.; Gouzoules, F.; Lee, S.-K. CC 1989, 10, 659. (b) Pearson, A. J.; Bruhn, P. R. JOC 1991, 56, 7092.
14. Schöllkopf, U.; Beulshausen, T. LA 1989, 223.
15. Schöllkopf, U.; Bendenhaben, J. LA 1987, 393.
16. (a) Schöllkopf, U.; Kühnle, W.; Egert, E.; Dyrbusch, M. AG(E) 1987, 26, 480. (b) Busch, K.; Groth, U.; Kühnle, W.; Schöllkopf, U. T 1992, 27, 5607.
17. Wild, H.; Born, L. AG(E) 1991, 30, 1685.
18. Schöllkopf, U.; Hauptreif, M.; Dippel, J.; Nieger, M.; Egert, E. AG(E) 1986, 25, 192.
19. Schöllkopf, U.; Hupfeld, B.; Küper, S.; Egert, E.; Dyrbusch, M. AG(E) 1988, 27, 433.

W. Hartwig & J. Mittendorf

Bayer, Wuppertal, Germany

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