156
Letters in Organic Chemistry, 2009, 6, 156-158
A Practical Procedure for Efficient Synthesis of -Amino Acids Shouxin Liu*, Debin Ji, Yihua Yang, Xiaoli Zhen, Xia Tian and Jianrong Han College of Chemical & Pharmaceutical Engineering, Hebei University of Science & Technology, Shijiazhuang 050018, China Received June 01, 2008: Revised December 02, 2008: Accepted December 12, 2008
Abstract: An effective method to prepare racemic -amino acids was developed. The key reactions involve nitrosation of malonate under basic conditions and reduction of -hydroxyimino ester derivatives with zinc powder in the presence of acetic anhydride.
Keywords: -Amino acid, malonate, -hydroxyimino ester. Many methods are known for the synthesis of -amino acids in either racemic or partially resolved form [1]. Developed in 1930’s, the Strecker’s method [2] is a classical route for synthesis of -amino acids. Its major limitation is the harsh conditions for hydrolysis. The Gabriel’s method [3], which is another representative strategy, falls short in the low efficiency of the nucleophilic attack of the C-Br bond by an ammonia equivalent. The aminomalonate route [4] was frequently used for the preparation of -amino acids. Advantages of this method are the easy purification of the substituted acylamino dialkyl malonate intermediates and its generally moderate yield. However, hydrolysis and decarboxylation of the intermediates by heating in a strong acid are
involved in this method. Although many other methods are available for -amino acids synthesis, they are often limited to certain substitution patterns, require multistep synthesis, involve strong Lewis acids or other highly reactive reagents, or utilize very toxic cyanides followed by harsh hydrolysis. We recently reported N-methylsansalvamide A peptide analogues as a new class of potent antitumor agents [5]. As a continuation of our work, we investigated synthetic routes of the -amino acids. Herein, we wish to report a convenient process for synthesis of -amino acids, in which the -arylmethylenemalonic ester derivatives are converted into oximes and then reduced to racemic -acetylamino acid ester derivatives. By utilizing cheap and readily available starting COOMe
CH2(COOMe)2, MeONa ArCH2Br
ArH2C
MeOH
COOMe
2
1
MeONO, MeONa MeOH NHCOCH3 ArH2C
4
NOH Zn/AcOH, (CH3CO)2O
ArH2C
COOMe
COOMe
3
Ar = X
N O
S N
X= H, F, Cl, Br
Scheme 1.
*Address correspondence to this author at the College of Chemical & Pharmaceutical Engineering, Hebei University of Science & Technology, Shijiazhuang 050018, China; Tel: +86-311-88632254; Fax: +86-311-88632254; E-mail:
[email protected]
1570-1786/09 $55.00+.00
materials, nonribosomal amino acids, such as 3-arylalanines and 3-heteroaryl alanines, were prepared under very mild conditions in Scheme 1.
© 2009 Bentham Science Publishers Ltd.
A Practical Procedure for Efficient Synthesis of -Amino Acids
Letters in Organic Chemistry, 2009, Vol. 6, No. 2 COOMe
CH2(COOMe)2, MeONa N
CH2Br
157
0 ~ 50 oC, 2h, 73%
N
COOMe 2a
1a
MeONO, MeONa -20 ~ 0 oC, 12h, 90%
NHCOCH3 N
COOMe
NOH
Zn/AcOH, (CH3CO)2O 50
oC,
3h, 78%.
N
4a
COOMe 3a
Scheme 2.
-Oximino acids are particularly useful precursors for the synthesis of -amino acids. And -oximino esters are readily available. The esters can be prepared from the reaction of active methylene compounds with alkyl nitrite under basic conditions. As illustrated in Scheme 1, reaction of the dialkly -arylmethylene malonate derivatives with alkyl nitrite in the present of sodium ethoxide leads to the formation of alkyl hydroxyiminoarylpropionate after decarboxylation and tautomerization [6]. However, this procedure is not always effective. Among nitrite esters, methyl and ethyl nitrites are more active, and they are both gases under the reaction conditions, and only are collected at low temperature [7]. So it is not convenient that the esters are used as oximination reagents. A practical approach is directly utilizing the nitrite ester gas to realize the oximination reaction of dialkly substituted malonate. While methyl or ethyl nitrite was generated in one flask, which contains sodium nitrite, methanol, and sulfuric acid [8], the emitted gaseous methyl nitrite was directly introduced into another flask to carry out the oximination; two flasks were jointed together with a tube. The collective procedure of nitrite ester gases was omitted. In most cases, the yields of this reaction are higher than that of literatures [9], above 89%. Ketone oximo can be reduced to N-hydroxyamino by using NaBH3 CN or LiBH3CN [10a], and also be transformed into amino using NaBH4 [10b], Zn/NH4OAc [10c], Zn/AcOH [10d] and Zn/HCOOH [10e]. However, the possibility of producing amino or imino compounds depends on the reduction conditions. It was also reported that -oximino esters can be reduced to corresponding amino acid esters using H2/Ir [10f] and NaBH4/TiCl3 [10g]. Here is a new process of reducing -oximino esters to -acetylamino esters by using zinc powder in the presence of acetic acid and acetic anhydride. Generally, the yields of the reduction were of 75 ~ 92%, and the obtained products were N-acetylamino esters, which can be used directly as starting materials to enzymatically hydrolyze into (L)- or (D)--amino acids. Consequently, the availability of a wide variety of -keto esters, and of the corresponding -oximino esters should make this a useful route for the preparation of a number of unnatural -amino acids. The representative procedure is illustrated by preparation of methyl -acetyl-amino-3-(2-quinoline)-alanine) as shown in Scheme 2: The 2-(bromomethyl)-quinoline was prepared according to the literature [11]. Bromination of 2methylquinoline was carried out in CCl4 by refluxing for 3h
in the presence of NBS and dibenzoyl peroxide. The resulting 2-(bromo-methyl)-quinoline 1a was converted to dimethyl 2-(2-quinolinyl)methyl malonate 2a by alkylation with dimethyl malonate at 50oC for 2h under basic conditions [12]. Following, the freshly produced gasous methyl nitrite was introduced with vigorous stirring into the methanol solution of 2a in the presence of sodium methoxide at the rate of 3 ~ 5 bubbles a second at -20oC for 12h. The nitrosation reaction proceeded smoothly and delivered -hydroxyimino ester derivative 3a in 90% yield. Subsequently, reduction of the oximino ester compound 3a with zinc powder and a catalytic amount of iron dust gave the racemic -acetylamino acid ester derivative 4a in glacial acetic acid and acetic anhydride at 50oC for 3h in 78% yields. The spectral data of synthetic compounds [13] were identical to those reported. These racemic -acetylamino acid esters can be enzymatically hydrolyzed to produce chiral -amino acids by Aspergillus oryzae [14], especially for preparing (L)- or (D)- aromatic and heterocyclic -amino acids. In summary, the nitrosation of malonate derivatives with freshly prepared methyl nitrite in the presence of sodium methoxide provided -hydroxyimino esters in moderate yields. The improved reduction of oxime to organic amine appears to have synthetic value, particularly for 3arylalanine, aromatic and heterocyclic amino acids. ACKNOWLEDGEMENTS We are grateful for the financial supports from the National Natural Science Foundation of China (Grant No. 30472074, 30873139) and the Hebei Natural Science Fundation (No. B2006000302). REFERENCES [1] [2] [3] [4] [5]
Mann, J.; Davidson, R.S.; Hobbs, J.B.; Banthorpe, D.V.; Harborne, J. B. Natural Products: Their Chemistry and Biological Significance, 1st ed., Addison-Wesley Longman: 1994; pp. 131-144. Chakraborty, T.K.; Hussain, K.A.; Reddy, G.V Tetrahedron, 1995, 51(33), 9179-9190. Kubo, A.; Kubota, H.; Takahashi, M.; Nunami, K. Tetrahedron Lett., 1996, 37(28), 4957-4960. Berger, A.; Smolarsky, M.; Kurn, N.; Bosshard, H.R. J. Org. Chem., 1973, 38(3), 457-460. Liu, S.; Gu, W.; Lo, D.; Ding, X.; Ujiki, M.; Adrian, T.E.; Soff, G. A.; Silverman R. B. J. Med. Chem., 2005, 48, 3630-3638.
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Letters in Organic Chemistry, 2009, Vol. 6, No. 2 a) Shivers, J.C.; Hauser, C.R. J. Am. Chem. Soc., 1947, 69, 12641265; b) Hauser, C.R.; Reynolds, G.A. J. Am. Chem. Soc., 1948, 70, 4250. Liu, S.; Liu, H.; Yan, W.; Zhang, L.; Bai, N.; Ho, C. Bioorg. Med. Chem., 2005, 13, 2783-2789. Johnson, J.R.; Carothers, W.H.; Hartman, W.W.; Fieser, L.F.; Noller, C.R.; Fuson, R.C. Organic Syntheses; Johnson, J.R. Ed.; John Wiley & Sons, Inc.: New York, 1936: Vol. 16, pp. 44. Gilchrist, T.L.; Roberts, T.G. J. Chem. Soc. Perkin Trans. I, 1983, 1283-1292. a) Cooper, A.J.L.; Griffith, O.W. J. Biol. Chem. 1979, 254, 27482953; b) Lapis, A.A.M.; Kreutz, O.C.; Pohlmann, A.R.; Costa, V.E.U. Tetrahedron Asymmetry, 2001, 12, 557-561; c) Adamczyk, M.; Mattingly, P.G.; Reddy, R.E. Steroids, 1997, 62, 462-467; d) Wu, Y.; Ahlberg, P. J. Org. Chem., 1992, 57, 6324-6327; e) Kitagawa, T.; Khandmaa, D.; Fukumoto, A.; Asada, M. Chem. Pharm. Bull., 2004, 52, 1137-1139; f) Xie, Y.; Mi, A.; Jiang, Y.; Liu, H. Synth. Commun., 2001, 31, 2767-2771; g) Hoffman, C.; Tanke, R.S.; Miller, M.J. J. Org. Chem., 1989, 54, 3750-3751. Carreno, M.C.; Garcia Ruano, J.L.; Sanz, G.; Toledo, M.A.; Urbano, A. J. Org. Chem., 1995, 60, 5328-5331. Eistetter, K.; Wolf, H.P.O. J. Med. Chem., 1982, 25, 109-113. Spectral data of synthetic compounds: 1a15: 1HNMR (500MHz, CDCl3 , ppm): 8.19 (d, J = 8.5Hz, 1H), 8.08 (d, J = 8.5Hz, 1H), 7.82 (d, J = 8.0Hz, 1H), 7.74 (t, J = 7.5Hz, 1H), 7.58 (d, J = 8.0Hz, 1H), 7.57 (t, J = 7.5Hz, 1H), 4.73 (s, 2H); IR(film): 3019, 1599, 1504, 1425, 1210, 1125, 826, 755 cm-1.
Liu et al.
[14] [15]
2a: 1HNMR (500MHz, CDCl3 , ppm): 8.06 (d, J = 8.5Hz, 1H), 7.97 (d, J = 8.0Hz, 1H), 7.77 (d, J = 8.0Hz, 1H), 7.67 (t, J = 7.5Hz, 1H), 7.49 (t, J = 7.5Hz, 1H), 7.31 (d, J = 8.5Hz, 1H), 4.36 (t, J = 7.5Hz, 1H), 3.76 (s, 6H), 3.61 (d, J = 7.5Hz, 2H); 13CNMR (125MHz, CDCl3, ppm): 169.80(2), 157.88, 147.63, 136.22, 129.35, 128.92, 127.42, 126.85, 125.99, 121.55, 52.60(2), 50.25, 36.77; IR(film): 2983, 2360, 1748, 1731, 1601, 1504, 1337, 1153, 1036, 823, 751 cm-1. 3a: 1HNMR (500MHz, CD3OD, ppm): 8.21 (d, J = 8.5Hz, 1H), 7.97 (d, J = 8.5Hz, 1H), 7.86 (d, J = 8.5Hz, 1H), 7.72 (t, J = 8.0Hz, 1H), 7.54 (t, J = 8.0Hz, 1H), 7.36 (d, J = 8.0Hz, 1H), 4.32 (s, 2H), 3.79 (s, 3H); 13CNMR (125MHz, CD 3OD, ppm): 165.99, 159.0, 150.1, 148.6, 138.5, 130.9, 128.9, 128.8, 128.4, 127.4, 122.2, 52.9, 34.6; IR(film): 2997, 2368, 1708, 1510, 1453, 1280, 1199, 1124, 1029, 966, 819, 782, 754 cm-1. 4a: 1HNMR (500MHz, CDCl3 , ppm): 8.09 (d, J = 8.5Hz, 1H), 7.98 (d, J = 8.0Hz, 1H), 7.80 (d, J = 8.0Hz, 1H), 7.70 (t, J = 7.5Hz, 1H), 7.53 (t, J = 7.0Hz, 1H), 7.26 (d, J = 8.5Hz, 1H), 7.17 (br, s, 1H), 5.11 ~ 5.07 (dd, J = 5.0Hz, J = 8.0Hz, 1H), 3.71 (s, 3H), 3.64 ~ 3.59 (dd, J = 5.0Hz, J = 10.5Hz, 1H), 3.47 ~ 3.43 (dd, J = 4.5Hz, J = 11.0Hz, 1H), 2.01 (s, 3H); 13 CNMR (125MHz, CDCl3, ppm): 172.08, 169.83, 157.66, 147.37, 136.65, 129.58, 128.78, 127.57, 126.83, 126.23, 121.72, 52.33, 51.03, 39.03, 23.19; IR(film): 3274, 3053, 2955, 2846, 1739, 1657, 1601, 1557, 1179, 1018, 958, 833, 758 cm-1. Harada, T. Ind. Eng. Chem., 1931, 23(12), 1424-1427. Rieger, B.; Abu-Surrah, A.S.; Fawzi, R.; Steiman, M. J. Organomet. Chem., 1995, 497, 73-79.
