Methyl 2-Bromo-N-(t-butoxycarbonyl)glycinate

[135924-45-7]  · C8H14BrNO4  · Methyl 2-Bromo-N-(t-butoxycarbonyl)glycinate  · (MW 268.13)

(reagent for amino acid synthesis)

Solubility: sol THF, CH2Cl2.

Form Supplied in: oil.1

Preparative Method: N-Bromosuccinimide bromination of methyl N-Boc-glycinate.2

Handling, Storage, and Precautions: can be stored at -20 °C for several months. It has to be protected from moisture to avoid hydrolysis. Use in a fume hood.

Reactions under Basic and Neutral Conditions.

Methyl 2-bromo-N-(t-butoxycarbonyl)glycinate (1), is a building block for a-amino acid synthesis.3 A variety of analogs with different N-acyl and ester groups have been obtained in the same manner. The replacement of the bromine with nucleophiles allows the incorporation of side chains at the a-carbon of glycine. Thus with phosphites, a-phosphonyl esters2,4,5 are accessible, which are converted to (Z)-dehydroamino acid derivatives by means of the Horner-Wadsworth-Emmons reaction (eq 1).6

When reagent (1) is treated with tertiary amines an N-acylimino acetate intermediate is formed which smoothly adds organometallic reagents,7,8 b-dicarbonyl compounds,7 silyl enol ethers,7 and other C-nucleophiles9 to the C=N group. In the case of cyclic enamines10 the addition can be achieved with remarkably high stereoselectivity (eq 2).

As illustrated in eq 3, the use of an 8-phenylmenthyl ester enables the diastereoselective addition of Grignard reagents.11 The difficulties in hydrolyzing the sterically hindered ester can be circumvented by the use of Oppolzer's auxiliary (eq 4).12 In this case the free amino acid is easily accessible by treatment of the product with Boron Tribromide.

Alternatively, enantiopure amino acids can be obtained by enzymatic resolution of the racemic products.7,13 Thus treatment of 2-acetylamino-4-oxo-4-phenylbutyric acid with hog renal acylase provides the pure L-amino acid in high overall yield (eq 5).7

Reactions under Acidic Conditions.

2-Methoxy- and 2-haloglycinate esters with acid-stable urethane protecting groups can be used for acid-catalyzed amidoalkylations14 of arenes,15 vinylsilanes,16 allylsilanes,8b,17 and silyl enol ethers.18 The glycine reagents can be obtained from glyoxylic acid hydrate by condensation with an O-alkylcarbamate followed by appropriate transformation of the resulting a-hydroxyglycine derivative. Electrochemical oxidation offers an alternative approach to these compounds.19 Upon treatment of the a-methoxyglycine reagents with Lewis acids, highly electrophilic N-acyliminium intermediates are formed.20 The scope of this method is illustrated by the stereoselective amidoalkylation of anisole (eq 6)21 and the Sakurai-type addition of allylsilanes (eq 7).17

Radical Reactions.

Treatment of the a-bromo compounds with stannanes in the presence of Azobisisobutyronitrile induces radical reactions which lead to the formation of 2-deuteroglycine,22 2-allylglycine, and 2-propargylglycine derivatives.22b,23 Again the reaction with an 8-phenylmenthyl ester proceeds with excellent diastereoselectivity (eq 8).24

The reactions of 2-bromoglycinates with nucleophiles and radicals have recently been extended to peptide derivatives1,25 and the synthesis of a,a-disubstituted a-amino acids.17b,26

Related Reagents.

10-Dicyclohexylsulfonamidoisoborneol; Ethyl N-Benzylideneglycinate; Ethyl N-(Diphenylmethylene)-2-acetoxyglycinate; Ethyl N-Benzylideneglycinate; Glyoxylic Acid; Methyl Glyoxylate; (-)-8-Phenylmenthol.

1. Apitz, G.; Steglich, W. TL 1991, 32, 3163.
2. Kober, R.; Steglich, W. LA 1983, 599.
3. Williams, R. M. Synthesis of Optically Active a-Amino Acids; Pergamon: Oxford, 1989; pp 95.
4. Schmidt, U.; Lieberknecht, A.; Schanbacher, U.; Beuttler, T.; Wild, J. AG(E) 1982, 21, 770.
5. e.g.: (a) Armstrong, R. W.; Tellew, J. E.; Moran, E. J. JOC 1992, 57, 2208. (b) Narukawa, Y.; Juneau, K. N.; Snustad, D.; Miller, D. B.; Hegedus, L. S. JOC 1992, 57, 5453.
6. (a) Schmidt, U.; Lieberknecht, A.; Wild, J. S 1988, 159. (b) Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht, A.; Mangold, R.; Meyer, R.; Riedl, B. S 1992, 487.
7. Bretschneider, T.; Miltz, W.; Münster, P.; Steglich, W. T 1988, 44, 5403.
8. (a) Castelhano, A. L.; Horne, S.; Billedeau, R.; Krantz, A.; TL 1986, 27, 2435. (b) Castelhano, A. L.; Horne, S.; Taylor, G. J.; Billedeau, R.; Krantz, A. T 1988, 44, 5451.
9. Kober, R.; Hammes, W.; Steglich, W. AG(E) 1982, 21, 203.
10. (a) Kober, R.; Papadopoulos, K.; Miltz, W.; Enders, D.; Steglich, W.; Reuter, H.; Puff, H. T 1985, 41, 1693. (b) Münster, P.; Steglich, W. S 1987, 223.
11. (a) Ermert, P.; Meyer, I.; Stucki, C.; Schneebeli, J.; Obrecht, J.-P. TL 1988, 29, 1265. (b) Hamon, D. P. G.; Massy-Westrop, R. A.; Razzino, P. T 1992, 48, 5163.
12. Bretschneider, T.; Steglich, W.; Weckbecker, C. publication in preparation.
13. Roos, E. C.; Mooiweer, H. H.; Hiemstra, H.; Speckamp, W. N. JOC 1992, 57, 6769.
14. Zaugg, H. E. S 1984, 85, 181.
15. (a) Zoller, U.; Ben-Ishai, D. T 1975, 31, 863. (b) Ben-Ishai, D.; Satay, I.; Bernstein, Z. T 1976, 32, 1571. (c) Bernstein, Z.; Ben-Ishai, D. T 1977, 33, 881. (d) Ben-Ishai, D.; Moshenberg, R.; Altman, J. T 1977, 33, 1533. (e) Ben-Ishai, D.; Altman, J.; Bernstein, Z.; Peled, N. T 1978, 34, 467.
16. Angst, C. PAC 1987, 59, 373.
17. (a) Mooiweer, H. H.; Hiemstra, H.; Speckamp, W. N. T 1989, 45, 4627. For the synthesis of 2,2-disubstituted a-amino acids: (b) Roos, E. C.; Hiemstra, H.; Speckamp, W. N.; Kaptein, B.; Kamphuis, J.; Schoemaker, H. E. SL 1992, 451. (c) Roos, E. C.; Lopez, M. C.; Brook, M. A.; Hiemstra, H.; Speckamp, W. N. JOC 1993, 58, 3259.
18. (a) Mooiweer, H. H.; Ettema, K. W. A.; Hiemstra, H.; Speckamp, W. N. T 1990, 46, 2991. (b) Ginzel, K.-D.; Brungs, P.; Steckhan, E. T 1989, 45, 1691.
19. Shono, T.; Matsumara, Y.; Inoue, K. JOC 1983, 48, 1389.
20. Hiemstra, H.; Speckamp, W. N. COS 1991, 2, Chapter 4.5.
21. Harding, K. E.; Davis, C. S. TL 1988, 29, 1891.
22. (a) Baldwin, J. E.; Addlington, R. M.; Lowe, C.; O'Neil, I. A.; Sanders, G. L.; Schofield, C. J.; Sweeney, J. B. CC 1988, 1030. (b) Easton, C. J.; Scharfbillig, I. M.; Tan, E. W. TL 1988, 29, 1565.
23. Easton, C. J.; Peters, S. C. TL 1992, 33, 5581.
24. (a) Hamon, D. P. G.; Razzino, P.; Massy-Westrop, R. A. CC 1991, 332. (b) Hamon, D. P. G.; Massy-Westrop, R. A.; Razzino, P. CC 1991, 722.
25. Apitz, G.; Jäger, M.; Jaroch, S.; Kratzel, M.; Schäffeler, L.; Steglich, W. T 1993, 49, 8223.
26. Ozaki, Y.; Iwasaki, T.; Horikawa, H.; Miyoshi, M.; Matsumoto, K. JOC 1979, 44, 391.

Wolfgang Steglich & Stefan Jaroch

Universität München, Germany

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