Synthesis of chiral α-amino acids

Article abstract of DOI:10.1016/S0040-4039(02)02433-4

A novel method for the synthesis of chiral α-amino acids has been developed where the acid functionality was constructed by oxidizing a hydroxymethyl group introduced by Evans' method in the α-position of an appropriate acid substrate and the amino part came from the amide of the original carboxyl group following a modified Hofmann rearrangement reaction.

Full text of DOI:10.1016/S0040-4039(02)02433-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9691–9693
Synthesis of chiral a-amino acids
Tushar K. Chakraborty* and Animesh Ghosh
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 15 July 2002; revised 17 October 2002; accepted 18 October 2002
Abstract—A novel method for the synthesis of chiral a-amino acids has been developed where the acid functionality was
constructed by oxidizing a hydroxymethyl group introduced by Evans’ method in the a-position of an appropriate acid substrate
and the amino part came from the amide of the original carboxyl group following a modified Hofmann rearrangement reaction.
© 2002 Published by Elsevier Science Ltd.
While there are many forms of amino acids, all of the
important amino acids found in living organisms are
a-amino acids. In addition to the 20 natural ones, there
are many other a-amino acids found in various natural
products.1 Total syntheses of these natural products
depend largely on the efficient construction of these
unusual a-amino acids. Although a large number of
methods are available for the synthesis of a-amino
acids,2 there is always scope for the development of new
and more efficient methods that could be useful for the
synthesis of many of these unusual a-amino acids, en
route to the total synthesis of their parent natural
products. While our earlier method for the diastereose-
lective Strecker synthesis of a-amino acids using a-
phenylglycinol as chiral auxiliary worked well for a-aryl
substrates, the selectivities were not good with a-alkyl-
substituted compounds.3 In this paper, we describe a
new method for the stereoselective synthesis of a-amino
acids that works equally well with both alkyl and
aryl-substituted compounds and can be applied to pre-
The synthesis started with the chiral oxazolidinone 1.
Treatment of 1 with TiCl4 in the presence of diiso-
propylethylamine (DIPEA) in CH2Cl2 provided the Ti-
enolate that was reacted with benzyloxymethyl chloride
following Evans’ method4 to furnish the Bn-protected
a-hydroxymethyl-substituted intermediate 26 with excel-
lent diastereoselectivity (>98%).7 Removal of the chiral
auxiliary8 using LiOH–H2O2 led to the formation of an
acid 36 that was transformed into its amide 4 in the
next step by the mixed anhydride method.9 Treatment
of 3 with ethyl chloroformate in the presence of Et3N
gave an intermediate mixed anhydride which was
reacted in situ with NH4OH to provide the amide 4.
With the amide in hand, the stage was now set to carry
out the crucial Hofmann rearrangement reaction.5
Accordingly, the amide 4 was treated with [bis(tri-
fluoroacetoxy)iodo]benzene[PhI(CF3COO)2]inCH3CN–
H2O (1:1) to provide the corresponding amine that was
treated in situ with Boc2O and Et3N to furnish the
Boc-protected intermediate 5. The Bn-protection was
removed by hydrogenation over Pd(OH)2–C and the
resulting primary hydroxyl of 6 was oxidized to the acid
using RuCl3–NaIO4 furnishing the N-Boc protected
a-amino acids 7 in excellent overall yields. Finally,
treatment with dilute HCl removed the Boc-protection
to give, after evaporation to dryness under reduced
pare both
D- and L-isomers.
Scheme 1 outlines the steps involved in this novel
method of synthesizing a-amino acids. The salient fea-
tures of this route are: (a) the carboxyl group of the
final amino acids was obtained by oxidation of an
a-hydroxymethyl group that was introduced in the
a-position of the corresponding carboxylic substrate by
Evans’ method;4 (b) the original carboxyl group was
converted to an amide that was transformed into the
amino group by a modified Hofmann rearrangement
reaction.5
pressure, the desired
D
-amino acid 8 as its HCl salt.6
Compound 7a on treatment with CH2N2 in ether gave
Boc-
-Ala-OMe that showed rotation, [h]2D2=+45.2 (c
1.75, MeOH), matching with that of commercially
available Boc-
-Ala-OMe.10
D
D
Keywords: a-amino acids; Hofmann rearrangement; oxazolidinone;
Evans’ reaction.
* Corresponding author. Fax: +91-40-7160387, 7160757; e-mail:
chakraborty@iict.ap.nic.in
In conclusion, an excellent method for the synthesis of
a-amino acids has been developed that will find useful
applications in preparing many unusual a-amino acids
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)02433-4

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T. K. Chakraborty, A. Ghosh / Tetrahedron Letters 43 (2002) 9691–9693
Scheme 1. Synthesis of a-amino acids. Reagents and conditions: (i) TiCl4 (1.05 equiv.), DIPEA (1.1 equiv.), CH2Cl2, 0°C, 1 h,
followed by BnOCH2Cl (2.0 equiv.), 0°C, 6 h (92% for 1a, 87% for 1b, 89% for 1c, 80% for 1d and 85% for 1e). (ii) LiOH (2.0
equiv.), aq. H2O2 (30%, 6.0 equiv.), THF–H2O (3:1, 0.05 M conc.), 0°C to rt, 5 h (87% for 2a, 90% for 2b, 91% for 2c, 88% for
2d and 86% for 2e). (iii) Et3N (1.1 equiv.), ClCO2Et (1.0 equiv.), THF, −20°C, 0.5 h, then NH4OH (5.0 equiv.), 0°C, 1.5 h (90%
for 3a, 95% for 3b, 92% for 3c, 90% for 3d and 93% for 3e). (iv) PhI(CF3CO2)2 (1.5 equiv.), CH3CN–H2O (1:1), rt, 2.5 h, then
Boc2O (2.0 equiv.), Et3N (4.0 equiv.), 0°C, 1 h (72% for 4a, 68% for 4b, 73% for 4c, 70% for 4d and 66% for 4e). (v) Pd(OH)2–C
(cat.), H2, MeOH, rt, 1 h (95% for 5a, 96% for 5b, 93% for 5c, 97% for 5d and 90% for 5e). (vi) RuCl3·3H2O (0.01 equiv.), NaIO4
(3.0 equiv.), CCl4–CH3CN–H2O (1:1:1.5), 0°C to rt, 1 h (75% for 6a, 77% for 6b, 68% for 6c, 67% for 6d and 62% for 6e). (vii)
dil. HCl, 0°C to rt, 1 h (95% for 7a).
in either enantiomeric form starting from an appropri-
ate chiral oxazolidinone. While -phenylalanine-based
oxazolidone 1 gives -amino acids, as shown in this
paper, its -isomer could be similarly used to prepare
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L
D
D
the corresponding
progress.
L-amino acids. Further work is in
Acknowledgements
The authors wish to thank CSIR, New Delhi for
research fellowship (A.G.).
References
1. (a) Burja, A. M.; Banaigs, B.; Abou-Mansour, E.;
Burgess, J. G.; Wright, P. C. Tetrahedron 2001, 57,
9347–9377. It is not possible to list here all the references
on the natural products containing unusual amino acids.
However, a search in http://www.heterocycles.jp/hetero/
3. (a) Chakraborty, T. K.; Hussain, K. A.; Reddy, G. V.
Tetrahedron 1995, 51, 9179–9190; (b) Chakraborty, T. K.;
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62, 6918–6920; (d) Waki, M.; Kitajima, Y.; Izumiya, N.
Synthesis 1981, 266–268.
frame db.html will provide a quick access to many of
–
these molecules, their structures and references.
2. For some recent works on the synthesis of a-amino acids,
see: (a) Xiong, C.; Wang, W.; Hruby, V. J. J. Org. Chem.
2002, 67, 3514–3517; (b) Bøgevig, A.; Juhl, K.;
Kumaragurubaran, N.; Zhuang, W.; Karl Anker
Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790–
1793; (c) Cordova, A.; Notz, W.; Zhong, G.; Betancort,
J. M.; Barbas, C. F., III J. Am. Chem. Soc. 2002, 124,
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T. K. Chakraborty, A. Ghosh / Tetrahedron Letters 43 (2002) 9691–9693
9693
6. All new compounds were characterized by IR, NMR and
mass spectroscopic studies.
3H, CO2Me), 1.20–1.80 (m, 14H, CH2), 1.40 (s, 9H, Boc),
0.90 (t, J=5.6 Hz, 3H, Me). 13C NMR (CDCl3, 50
MHz): l 173.50, 155.50, 79.50, 53.41, 52.09, 32.70, 31.76,
29.28, 29.11, 28.26, 25.21, 22.58, 14.02. [h]2D2=−13.8 (c
1.85, CHCl3). MS (LSIMS): m/z 302 (M++H), 202 (M++
H−C5H8O2). Selected physical data for 7d methyl ester:
1H NMR (CDCl3, 200 MHz): l 4.95 (d, J=7.90 Hz, 1H,
BocNH), 4.25 (m, 1H, ChH), 3.75 (s, 3H, CO2Me),
1.20–1.85 (m, 39H, CH2 and Boc), 0.95 (t, J=5.58 Hz,
3H, Me). 13C NMR (CDCl3, 50 MHz): l 173.50, 155.33,
79.73, 53.41, 52.10, 32.71, 31.86, 29.51, 29.45, 29.33,
29.26, 29.14, 28.27, 27.96, 25.23, 22.63, 14.06. [h]2D2=
−11.51 (c 2.5, CHCl3). MS (LSIMS): m/z 355 (M++H−
7. The other isomer could not be detected by 1H NMR
analysis of the product.
8. Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron
Lett. 1987, 28, 6141–6144.
9. Kawamoto, I.; Endo, R.; Ishikawa, K.; Kojima, K.;
Miyauchi, M.; Nakayama, E. Synlett 1995, 575–577.
10. Selected physical data for 7a methyl ester: 1H NMR
(CDCl3, 200 MHz): l 4.95 (s, 1H, BocNH), 4.28 (m, 1H,
ChH), 3.75 (s, 3H, CO2Me), 1.40 (s, 9H, Boc), 1.36 (d,
J=6.9 Hz, 3H, Me). [h]2D2=+45.2 (c 1.75, MeOH),
matching with that of an authentic sample prepared from
D
-Ala. Selected physical data for 7b methyl ester: 1H
1
CO2CH3). Selected physical data for 7e methyl ester: H
NMR (CDCl3, 300 MHz): l 7.30 (m, 5H, Ph), 5.50 (d,
J=6.6 Hz, 1H, BocNH), 5.25 (d, J=6.6 Hz, 1H, ChH),
3.70 (s, 3H, CO2Me), 1.35 (s, 9H, Boc). [h]2D2=−138.6 (c
1.6, CHCl3), matching with that of an authentic sample
NMR (CDCl3, 200 MHz): l 4.95 (d, J=6.54 Hz, 1H,
BocNH), 4.21 (m, 1H, ChH), 3.70 (s, 3H, CO2Me), 3.32
(t, J=7.27 Hz, 2H, CH2Br), 1.10–1.90 (m, 14H, CH2),
1.40 (s, 9H, Boc). 13C NMR (CDCl3, 50 MHz): l 173.44,
155.30, 79.74, 53.35, 52.12, 33.93, 32.72, 32.67, 29.19,
29.04, 28.62, 28.25, 28.05, 25.17. [h]2D2=−10.42 (c 2.0,
CHCl3). MS (LSIMS): m/z 279, 281 (M+−C5H8O2).
prepared from
D
-Phg. MS (LSIMS): m/z 210 (M++Na−
PhH), 166 (M++H−C5H8O2). Selected physical data for
1
7c methyl ester: H NMR (CDCl3, 200 MHz): l 4.90 (d,
J=6.97 Hz, 1H, BocNH), 4.25 (m, 1H, ChH), 3.70 (s,