A highly stereoselective synthesis of indolyl N-substituted glycines

Article abstract of DOI:10.1016/S0040-4039(01)00229-5

Optically active α-indolyl N-substituted glycines were synthesized by reaction of an indolyl boronic acid with glyoxylic acid using chiral methylbenzylamine as the chiral auxiliary with high diastereoselectivity. The absolute configuration of the product was determined by a single-crystal X-ray analysis.

Full text of DOI:10.1016/S0040-4039(01)00229-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2545–2547
A highly stereoselective synthesis of indolyl N-substituted
glycines
Biao Jiang,a,* Cai-Guang Yanga and Xiao-Hui Gub
aShanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, PR China
bAlcohol and Drug Abuse Research Center, McLean Hospital-Harvard Medical School, 115 Mill Street, Belmont,
MA 02478-9106, USA
Received 25 October 2000; revised 29 January 2001; accepted 7 February 2001
Abstract—Optically active a-indolyl N-substituted glycines were synthesized by reaction of an indolyl boronic acid with glyoxylic
acid using chiral methylbenzylamine as the chiral auxiliary with high diastereoselectivity. The absolute configuration of the
product was determined by a single-crystal X-ray analysis. © 2001 Elsevier Science Ltd. All rights reserved.
Much attention has been paid to the search for concise
and flexible methods leading to the formation of opti-
cally active amino acids due to their significant biologi-
cal activities.1 Indolylglycine derivatives are one of the
non-proteinogenic amino acids important in new drug
discovery.2 Optically pure indolylglycines have been
used in the synthesis of potent antibiotics of the
cephalosporin type,3 however, there are few reports on
the asymmetric synthesis of indolylglycines. A major
challenge in the synthesis of indolylglycines is the facile
base-catalyzed epimerization which makes it difficult to
prepare optically pure indolylglycines.4 The presently
known methods, such as the asymmetric Strecker syn-
thesis,5 cannot be employed to prepare these molecules
due to the products being very unstable, easily reverting
to the starting materials.6 Johannsen reported the syn-
thesis of optically active ethyl 3-indolyl-N-tosyl glyci-
nate using a complex of copper(I) salts and Tol-BINAP
to catalyze the enantioselective addition of N-
tosylimino esters of ethyl glyoxylate to indole. This
Lectka system7 required low temperature and critical
oxygen and moisture free conditions.8 In this communi-
cation, we wish to describe a concise, and highly
diastereoselective synthesis of optically active 3-indolyl-
N-substituted glycines via a chiral amine-mediated 3-
indolylboronic acid Mannich reaction.
Recently a new practical approach to unsaturated
amino acids, by reaction of alkenyl boronic acids with
glyoxylic acids and amines, was reported by Petasis.9
This prompted us to investigate the stereocontrolled
synthesis of indolyl glycines by the reaction of indolyl-
3-boronic acids. To test the reactivity of indolyl boronic
acids with an amine and glyoxylic acid, the synthesis of
racemic indolyl glycines was first studied. After mixing
the three components, N-tosyl-3-indolylboronic acid 1,
Scheme 1.
Keywords: indolyl boronic acid; indolylglycine; stereoselectivity.
* Corresponding author. Tel.: +86-21-64163300; fax: +86-21-64166128; e-mail: jiangb@pub.sioc.ac.cn
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00229-5

2546
B. Jiang et al. / Tetrahedron Letters 42 (2001) 2545–2547
Scheme 2.
aminodiphenylmethane and glyoxylic acid monohy-
drate in dichloromethane and stirring the mixture at
ambient temperature for 12 h, we were able to isolate
indolyl glycine 5, in 94% yield, simply by filtering the
insoluble product from the reaction mixture. Further
examination of the reaction of indolylboronic acids
bearing indole ring substrates 2–4, demonstrated that
all of the reactions gave the desired products 6–8 in
excellent yields (Scheme 1). It was noteworthy that this
process does not require anhydrous or oxygen-free con-
ditions. The insolubility of the products in the reaction
solvent makes for a very simple isolation procedure.
screened. As shown in Scheme 2, all the reactions gave
the (S)-indolyl-N-substituted glycines, stereoselectively
with 99% de11,12 in good yields.
In conclusion, the reaction of indolyl boronic acids,
chiral amines, and glyoxylic acid monohydrate provides
a highly efficient stereoselective synthesis of indolyl
N-substituted glycines in optically pure form. The
present one-pot synthesis of indolyl N-substituted
glycines has the advantage of mild reaction conditions,
readily available reagents and simple product isolation.
With the above results in mind, our attention turned to
the asymmetric synthesis of indolylglycines using a
chiral amine as substrate. The reaction of N-tosyl-3-
indolylboronic acid 1, glyoxylic acid and (R)-a-methyl-
Acknowledgements
We are grateful to the Shanghai Municipal Committee
of Science and Technology for financial support of this
research.
benzylamine at room temperature for 24
h in
dichloromethane gave the crude product 9 which could
be crystallized from methanol to afford a single
diastereoisomer in 99% de and 77% chemical yield. To
determine the stereochemistry at the a-carbon of com-
pound 9, the indolyl glycine 9 was converted into its
methyl ester with diazomethane and the amino group in
the glycine moiety masked with an acetyl group to
afford 13 in 72% yield. The X-ray structure analysis of
a single crystal of 13 revealed that the absolute configu-
ration at the a-carbon of 13 was S.10 Thus, use of
(R)-a-methylbenzylamine as the chiral auxiliary created
the S configuration of the indolyl glycine 11 with a
specific rotation of +68, while (S)-a-methylbenzylamine
gave the R enantiomer with a specific rotation of −68 in
99% de and 64% yield. To test the scope of the reaction,
a variety of substituted indolyl boronic acids 2–4 were
References
1. (a) Williams, R. M. Synthesis of Optically Active h-Amino
Acids; Pergamon Press: Oxford, 1989; (b) Duthaler, R. O.
Tetrahedron 1994, 50, 1539.
2. (a) Shen, T.-Y. US Patent, 3316260, 1968; (b) Blaszczak,
L. C.; Turner, J. R. EP 122157, 1984; (c) Clark, B. P.;
Harris, J. R. Synth. Commun. 1997, 27, 4223.
3. Blaszczak, L. C.; Turner, J. R. US Patent, 4492694, 1985.
4. (a) Davis, F. A.; Portonovo, P. S.; Reddy, R. E.; Chiu,
Y. H. J. Org. Chem. 1996, 61, 440; (b) Iyer, M. S.;
Gigstad, K. M.; Namdev, N. D.; Lipton, M. J. Am.
Chem. Soc. 1996, 118, 4910; (c) Ishitani, H.; Komiyama,

B. Jiang et al. / Tetrahedron Letters 42 (2001) 2545–2547
2547
,
measured=2562, u=0.7109 A.
S.; Kobayashi, S. Angew. Chem., Int. Ed. Engl. 1998, 37,
3186; (d) Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1,
157 and references cited therein.
11. All compounds gave satisfactory spectral data. Represen-
tative experimental procedure: To a solution of indolyl
boronic acid 1 (316 mg, 1 mmol) in CH2Cl2 (8 mL), was
added glyoxylic acid monohydrate (92 mg, 1 mmol),
followed by (R)-methylbenzylamine (121 mg, 1 mmol).
The reaction mixture was stirred vigorously at room
temperature for 24 h. Upon evaporation of the solvent,
the resulting crude product was crystallized from
methanol to afford 9 in 77% yield. After product 9 was
methylated with diazomethane, the diastereoselectivity
was determined by HPLC on OD-H column in 99%.
Selected data for compound 9: [h]2D0 +94.5 (c 0.825,
CHCl3); FTIR (KBr) wmax 3340, 2959, 1739, 1598, 1448,
5. (a) Jiang, B.; Gu, X.-H. Heterocycles 2000, 53, 1559; (b)
Katz, A. H.; Demerson, C. A.; Shaw, C.-C.; Asselin, A.
A.; Humber, L. G.; Conway, K. M.; Gavin, G.;
Guinosso, C.; Jensen, N. P.; Mobilio, D.; Noureldin, R.;
Schmid, J.; Shah, U.; Engen, D. V.; Chau, T. T.; Weich-
man, B. M. J. Med. Chem. 1988, 31, 1244.
6. Jiang, B.; Smallheer, J. M.; Amaral-Ly, C.; Wuonola, M.
A. J. Org. Chem. 1994, 59, 6823.
7. Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J. Am.
Chem. Soc. 1998, 120, 4548.
8. Johannsen, M. Chem. Commun. 1999, 2233.
9. (a) Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetra-
hedron 1997, 53, 16463; (b) Petasis, N. A.; Zavialov, I. A.
J. Am. Chem. Soc. 1997, 119, 445.
10. X-Ray analysis of 13: The crystal used for the X-ray
study had the dimensions 0.20×0.20×0.30 mm. Crystal
1373, 1175, 1095 cm−1 1H NMR (CDCl3) l 1.32 (d,
;
J=6.6 Hz, 3H), 2.33 (s, 3H), 3.55 (q, J=6.6 Hz, 1H),
4.44 (s, 1H), 7.16–7.34 (m, 9H), 7.44 (s, 1H), 7.61 (d,
J=7.9 Hz, 1H), 7.77 (d, J=8.3 Hz, 2H), 7.99 (d, J=8.3
Hz, 1H); anal. calcd for C25H24N2O4S: C, 66.96; H, 5.36;
N 6.25. Found: C, 67.14; H, 5.47; N, 6.09.
data: C28H28N2O5S,
M 504.60; orthorhombic; space
group, P21; lattice parameters, a=11.323(3), b=
12. Diastereoselectivity of the methyl esters were determined
by HPLC on Chiralcel OD-H or OJ-H column with
eluted solvent.
3
,
,
27.501(7), c=8.212(4) A; V=2557(1) A , Z=4; Dcalcd
=
1.310 g/cm3; F0=1064.00; number of reflections
.
.