Highly diastereoselective synthesis of 3-indolyl-N-substituted glycine derivatives via TFA-promoted Friedel-crafts type reaction of indoles with chiral cyclic glyoxylate imine

Article abstract of DOI:10.1055/s-2003-39905

A method based on the highly diastereoselective Friedel-Crafts type reaction of indoles with chiral cyclic glyoxylate imines in the presence of TFA toward the stereoselective synthesis of 3-indolyl-N-substituted glycine derivatives is presented. The absolute configuration of the newly formed chiral center was determined by a single-crystal X-ray analysis.

Full text of DOI:10.1055/s-2003-39905

1160
LETTER
Highly Diastereoselective Synthesis of 3-Indolyl-N-Substituted Glycine
Derivatives via TFA-Promoted Friedel–Crafts Type Reaction of Indoles with
Chiral Cyclic Glyoxylate Imine
Synthesisof
3
e
-Indoly-
N
-S
i
ubstituted G
l
L
ycine
D
erivativ
e
es i, Yong-Jun Chen,* Yong Sui, Li Liu, Dong Wang*
Laboratory of Chemical Biology, Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100080,
China
E-mail: dwang210@iccas.ac.cn
Received 24 March 2003
this increasingly important functional array, the subject
Abstract: A method based on the highly diastereoselective
still constitutes an active area of research, especially giv-
Friedel–Crafts type reaction of indoles with chiral cyclic glyoxylate
ing the number of unsolved aspects related to either the
functional diversity and the availability of the starting ma-
imines in the presence of TFA toward the stereoselective synthesis
of 3-indolyl-N-substituted glycine derivatives is presented. The ab-
solute configuration of the newly formed chiral center was deter- terials or the generality of the reaction.
mined by a single-crystal X-ray analysis.
The Friedel–Crafts (F–C) reaction promoted by Lewis
Key words: Friedel–Crafts reaction, Brönsted acid, chiral cyclic
acid or Brönsted acid is one of the most efficient methods
for the construction of carbon-carbon bonds to aromatics
and hetroaromatics.10 However, the F–C type reaction of
imines with indole, which would afford the interesting in-
dolyglycine derivatives, has received limited attention.5c,7
On the other hand, the chiral cyclic glyoxylate imines,
avoiding E/Z isomer equilibrium that existed in acyclic
alkyl glyoxylate imines, have been shown to be a type of
good chiral template in some asymmetric synthesis.11 Re-
cently, Fukuyama12 has reported that the chiral cyclic gly-
oxylate imine (Figure 1) could serve as an excellent chiral
template for the synthesis of optically pure phenylgly-
cines in the Brönsted acid (TFA)-promoted F–C type re-
action. Although it has been reported that imines can be
employed for the synthesis of aminoalkylindoles under
acidic conditions,13 the asymmetric version of this type is
lacking. The tendency of electron-rich indole to poly-
merize under acidic conditions still makes this approach
challenging.14 Accordingly, our own interest in the devel-
opment of new protocols for the synthesis of optically
pure arylglycine derivatives15 promoted us to investigate
the feasibility of Brönsted acid-mediated F–C type reac-
tion of indoles with readily available chiral cyclic glyox-
ylate imines.
glyoxylate imines, optically active indolyglycines
Non-proteinogenic amino acids, by virtue of their wide-
spread occurrence in biological important natural prod-
ucts and their intrinsic functional array, have found
numerous applications in area such as amino acid mimet-
ics, drug development, and medicinal chemistry.1 As one
of an important class of non-proteinogenic amino acids,
indolylglycines are very useful building blocks for the
synthesis of many biologically important compounds
such as Dragmacidins,2 Etodolac,3a and Pemedolac.3b Op-
tically pure indolylglycines have also been employed in
the synthesis of potent antibiotics of the Cephalosporin
type.4 Although several interesting methods for the syn-
thesis of a range of indolyglycine derivatives have ap-
peared,5 there are few reports on the asymmetric synthesis
of indolylglycines. This is in part due to the pronounced
tendency of a-stereocenter of indolyglycine to undergo
racemization6 that makes it difficult to prepare in optically
pure form. Johannsen7 reported the first catalytic enanti-
oselective addition of N-tosylimino esters of ethyl glyox-
ylate to the electron-rich aromatics such as indole and
pyrrole using Tol-BINAP/Cu(I) complex (the Lectka sys-
tem).8 However, this Lectka catalytic system8 required
low temperature and critical oxygen and moisture free
conditions. Wang5c also presented an enzymatic resolu-
tion method for the synthesis of optically pure indolylgly-
cine derivatives. Recently, Jiang6a reported the
diastereoselective synthesis of optically active 3-indolyl-
N-substituted glycines via reaction of an indolyboronic
acid with glyoxylic acid using (R)-a-methylbenzylamine
as the chiral auxiliary on the basis of Petasis’s pioneering
work.9 Although these methods offer avenues to access
At the outset of our study, we first examined the reaction
of selected indoles with dihydro-1,4-oxazin-2-ones (2a–
d) (Figure 1), the chiral cyclic glyoxylate imines which
were successfully applied as chiral templates in some
radical11b,c and organometallic reagent (Grignard reagent)
additions.11d 2a–d were readily available in two steps to-
tally via oxidative rearrangement of oxazolines,16 which
were readily prepared according to Meyers methodology,
by condensing L-valinol, (R)-(–)-2-phenylglycinol,
(1R,2S)-(–)-2-amino-1,2-diphenylethanol, and (1R,2S)-
(+)-cis-1-amino-2-indanol respectively with ethyl acet-
imidate.17 To the best of our knowledge, these four chiral
Synlett 2003, No. 8, Print: 24 06 2003.
Art Id.1437-2096,E;2003,0,08,1160,1164,ftx,en;U05403ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 3-Indolyl-N-Substituted Glycine Derivatives
1161
cyclic glyoxylate imines have not been used as chiral tem- carboxylate afforded the corresponding addition product
plates on F–C reaction. As such, the potential utility of in 90% yield and 99% de (entry 5). Thus, we chose 2c as
these substrates as electrophiles remains largely unex- a chiral template for further study. The dramatic differ-
plored.
ence on diastereoselectivity between 3-substituted and 3-
unsubstituted indoles in the F–C reaction was not clear
yet.
O
O
N
Table 1 Results of the Indoles with 2a–2d Promoted by TFA
Entry Indole
Imine Product Yield de
(%)
(%)
Fukuyama's imine
1
2
3
2a
2b
2c
3a
3b
3c
83
75
84
39
41
27
O
O
N
O
O
N
O
O
N
O
N
H
O
N
4
5
6
2a
2c
2d
3a*
3c*
3d*
91
90
95
56
99
73
2a
Figure 1
2b
2c
2d
OEt
N
H
O
As illustrated in Scheme 1, the Friedel–Crafts-type reac-
tions were performed according to the Fukuyama’s proce-
dure.18 The procedure is very easy to handle, since inert
or anhydrous conditions are not required. Indoles with
different substituted pattern were employed for screening
reaction. Table 1 shows results. In all cases, both 2- and 3-
substituted indoles reacted with 2a–d smoothly in the
presence of TFA, affording the corresponding addition
product in high yield respectively, regardless of different
substituted pattern of indole. For 3-methylindole in which
3-position was blocked, the addition reaction only oc-
curred at 2-position (entries 1–3). As to 3-unsubstituted-
indole, such as ethyl indolyl-2-carboxylate, the addition
occurred at 3-position exclusively (entries 4–6). As shown
in Table 1, it is evident that chiral cyclic glyoxylate imine
2a, 2b and 2d are not good chiral templates for two types
of indoles in the TFA-promoted F–C reaction. Gratifying-
ly, we were delighted to find that 2c could serve as an ex-
cellent chiral template in the F–C reaction of 3-
unsubstituted indole. It was quite remarkable that the
TFA-promoted F–C reaction of 2c with ethyl indolyl-2-
Figure 2
O
O
R5
R5
O
O
N
TFA
N
H
+
X
R2
CH2Cl2, 0 °C
R2
X
X
O
O
R3
O
O
N
TFA
N
+
H
CH2Cl2, 0 °C
X
R3
1
2c
3
Scheme 1
Synlett 2003, No. 8, 1160–1164 ISSN 1234-567-89 © Thieme Stuttgart · New York

1162
F. Lei et al.
LETTER
A single crystal X-ray structure of 2c (Figure 2)19 pro- responding addition products in good to high yields. This
vides the basis for understanding stereochemistry of the observation is unsurprising as the tendency for high nu-
reaction discussed above. Since the phenyl group at 6- cleophilic reactivity at 3-position of indole is well docu-
position in dihydro-1,4-oxazin-2-one (2c) takes an equa- mented. It was discovered that the substituent on indole
torial position, phenyl group at 5-position is forced to ring had a profound effect on the diastereoselectivity of
adapt the axial position, shielding re-face of the C=N dou- the reaction. Indeed, the simple indole (1a) without N-pro-
ble bond from addition. Thus, we believed that the indole tecting group offered the product in 83% yield but 64% de
would attack only from si-face of C=N double bond to af- (entry 1). On the contrary, when N-protecting groups of
ford the addition product 3 in S configuration. This as- indole were Tos, Boc, and Cbz, the diastereoselectivity of
sumption was later confirmed by analysis of the single the reaction was improved up to 99% de in each case (en-
crystal X-ray structure of 3hc (Figure 3).20
tries 3–5). Notably, CH3-protected indole also provided
the corresponding addition product in good yield and 99%
de (entry 2). The N-protecting group was not cleaved
under the reaction conditions in each case. It was found
that the presence of electron-donating group (CH3) at 2-
position of indole (1f) was having detrimental effect on
both the reaction yield and diastereselectivity (entry 6).
Conversely, the presence of electron-withdrawing group
(CO2Et) at 2-position of indole (1i) actually improved the
yield and diastereoselectivity of the reaction (entry 9) as
compared to the simple indole (1a). On the other hand,
both 5-hydroxylindole (1g) and 5-bromoindole (1h) also
reacted with 2c smoothly in the presence of TFA, provid-
ing the corresponding F-C product in 99% de and good
yield (entries 7 and 8). The effect of hydroxyl or bromo
group at 5-position of indole on the reaction diastereose-
lectivity is enormous with comparison to the simple in-
dole (1a), although the reason for this phenomena is not
clear yet. The incorporation of functional groups such as
OH, Br in 5-position of indole provides pharmacological-
ly important products and provides an opportunity for fur-
ther structure modification. It is well known that indole 1a
itself is easily polymerized under various acidic condi-
tions to give 3-(indolin-2-yl) indole (the dimer) and/or
3,3¢-(o-aminophenethylidene)di-indole (the trimer).21 In
fact, this was the case when 1a, 1b, 1g or 1h were treated
with TFA alone under the reaction conditions. The corre-
sponding dimer was produced in moderate to good yields.
However, in the case of 1a, we could only isolate 3-(indo-
lin-2-yl) indole in less than 10% yield from the reaction
mixture (entry 1). For other indole substrates tested, no
any corresponding indole dimer was detected from the re-
action mixture. This suggested that the rate of the reaction
of 2c with indole discussed above was much faster than of
the formation of indole dimer in the presence of TFA. Fi-
nally, it was also observed that instead of above indoles,
Figure 3
Next, we investigated the effects of Brönsted acids on the
reaction. As shown in Table 2, a variety of Brönsted acids
except BrCH2COOH (entries 4 and 7) could promote the
F–C reaction of 2c with 3-methylindole or ethyl indole-2-
carboxylate efficiently. The yield of the reaction was not
affected for most of Brönsted acids tested. It appeared that
the pKa value of the Brönsted acid was a crucial factor for
the reaction to complete. A noticeable change was that the
diastereoselectivity of the reaction for 3-methylindole de-
scended as the acidity of Brönsted acid fell (entries 1–3),
while the diastereoselectivity remained unchanged for
ethyl indolyl-2-carboxylate regardless of the Brönsted ac-
ids employed (entries 5 and 6).
Under the preferred reaction conditions, the scope of the
reaction was explored with respect to various 3-unsubsti-
tuted-indoles. Given the results summarized in Table 3,
some comments can be made. In all cases, the F–C reac-
tions occurred at 3-position of indoles, providing the cor-
Table 2 Results of the Indoles with 2c Promoted by Different Brönsted Acids
Entry
Indole
Imine
Acid
pKa
Product
Yield (%)
de (%)
1
2
3
4
2c
2c
2c
2c
CF3COOH
0.25
0.64
1.7
3c
3c
3c
NR
84
84.4
83
27
10
4
CCl3COOH
HN(SO2CF3)2
BrCH2COOH
N
H
2.9
5
6
7
2c
2c
2c
CF3COOH
HN(SO2CF3)2
BrCH2COOH
0.25
1.7
2.9
3c*
3c*
NR
90
85
99
99
OEt
N
H
O
Synlett 2003, No. 8, 1160–1164 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-Indolyl-N-Substituted Glycine Derivatives
1163
(3) (a) Humber, L. G.; Ferdinandi, E.; Demerson, C. A.; Ahmed,
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2,3-benzofuran (1j) and thionaphthene (1k) which were
known to be less reactive than indole toward the aromatic
electrophilic substitution were not suitable substrates for
this F–C reaction (entries 10 and 11).
Table 3 Results of Indole 2c with Various 3-Unsubstituted Indoles
Promoted by TFA
20
En-
try
Indole
R5
Product Yield de
(%) (%)
[a]D
R2
X
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
H
H
H
H
H
H
H
NH
3ac
83
80
82
71
75
43
85
81
64 (S)
(c) Janczuk, A.; Zhang, W.; Xie, W. H.; Lou, S. Z.; Cheng,
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Bloomfield, K. M.; Jin, Y. F.; Dolney, N. Y.; Wang, P. G.
Synlett 1999, 498.
H
NCH3 3bc
N-Tos 3cc
N-Boc 3dc
N-CBz 3ec
99 (S) +114
99 (S) +52
99 (S) +122
99 (S) +136
62 (S)
H
H
H
(6) (a) Jiang, B.; Yang, C. G.; Gu, X. H. Tetrahedron Lett. 2001,
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CH3
NH
3fc
1g
1h
1i
H
OH NH
Br NH
3gc
3hc
99 (S) +68
99 (S) +52
99 (S) +148
H
CO2C2H5
H
H
H
NH
O
3jc (3c*) 90
10 1j
11 1k
H
H
NR
NR
S
In summary, the scope of the TFA-promoted F–C type re-
action of chiral cyclic glyoxylate imine 2c with indoles
has been extended to allow the efficient preparation of
various optically pure 3-indoly-N-substituted glycine de-
rivatives.22 The method is applicable to both electron-rich
and electron-poor indole substrates. Further applications
of the F–C products 3 to synthesize a range of optically
pure a-alkylated indolylglycine derivatives are currently
under investigation in our laboratories.
Acknowledgement
We thank the National Natural Science Foundation of China (No.
20172056, 20232010), Ministry of Science and Technology of Chi-
na (No. 2002CCA03100), and the Chinese Academy of Sciences for
financial supports.
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References
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Synlett 2003, No. 8, 1160–1164 ISSN 1234-567-89 © Thieme Stuttgart · New York

1164
F. Lei et al.
LETTER
(18) Representative experimental procedure: To a solution of
indole (1.2 equiv) and chiral cyclic glyoxylate imine (1.0
equiv) in CH2Cl2 at 0 °C, TFA (5 equiv) was added dropwise
by syringe. After the reaction mixture was stirred for 3 h at
0 °C, usual work-up furnished a residue from which the pure
product was obtained after purification with flash
Å; V = 1291.11 Å3, Z = 4; Dcalcd = 1.293 g/cm3; F0 = 528;
number of reflections measured = 2737, λ = 0.7107 Å.
(20) X-Ray analysis of 3hc: The crystal used for the X-ray study
had the dimensions 0.53 × 0.09 × 0.04 mm. Crystal data:
C24H19BrN2O2, M 447.32; Monoclinic; space group, C2;
lattice parameters, a = 26.817 Å, b = 7.9070 Å, c = 9.8754
Å; V = 2083.1 Å3, Z = 4; Dcalcd = 1.426 g/cm3; F0 = 912;
number of reflections measured = 4268, λ = 0.7107 Å.
(21) Ishii, H.; Murakami, K.; Sakurada, E.; Hosoya, K.;
Murakami, Y. J. Chem. Soc., Perkin Trans. 1 1988, 2377.
(22) Several methods have existed for the removal of the chiral
template from the similar compounds without notable
racemization: (a) Aldous, D. J.; Drew, M. G. B.; Hamelin, E.
M.-N.; Harwood, L. M.; Jahana, A. B.; Thurairatnam, S.
Synlett 2001, 1836. (b) Cox, G. G.; Harwood, L. M.
chromatography on silica gel [all new compounds were
subjected to 1H NMR, 13C NMR, IR, MS(FAB) analysis].
The diastereoselectivity was determined by 1H NMR and 13
NMR spectra. All compounds gave satisfactory spectral
data. Selected data for compound 3c*: mp: 234–236 °C,
[a]D20 +148.57 (c 0.7, acetone); FTIR (KBr) 3338, 1734,
1693, 1538, 1454, 1377, 1343, 1319, 1256, 1217, 1190,
C
1086, 1014 cm–1; 1H NMR(300 Hz, CDCl3): d 1.38 (t, J = 7
Hz 3 H), 2.54 (br s, 1 H), 4.43 (m, 2 H), 4.90 (d, J = 4 Hz,
1 H), 5.90 (s, 1 H), 6.14 (d, J = 4 Hz, 1 H), 7.11–7.29 (m, 12
H), 7.39–7.45 (m, 2 H), 7.79 (d, J = 8 Hz, 1 H), 8.96 (br s,
1 H); 13C NMR(75 Hz, CDCl3) d 14.5, 52.8, 58.3, 61.6, 85.4,
113.4, 121.4, 121.8, 125.7, 126.0, 127.6, 128.2, 128.4,
128.6, 128.9, 129.3, 137.2, 138.0, 138.5, 162.3, 169.3;
HRMS (FAB): m/z 441.1811 for [MH+] C27H25N2O4
requires 441.1808.
Tetrahedron: Asymmetry 1994, 5, 1669. (c) Harwood, L.
M.; Macro, J.; Watkin, D.; Williams, E.; Wong, L. F.
Tetrahedron: Asymmetry 1992, 3, 1127; and also refs.11d,e,12
.
(d) Although we did not study this issue systematically, the
preliminary result showed that when 3bc was subjected to
the hydrogenolysis in aqueous methanol using Pearlman’s
catalyst [Pd(OH)2/C] and TFA under 1 atmosphere of
hydrogen gas for 5 h, the corresponding optically active
amino acid was obtained in 82% yield, [a]D20 +57 (c 0.35,
CH3OH).
(19) X-Ray analysis of 2c: The crystal used for the X-ray study
had the dimensions 0.29 × 0.17 × 0.08 mm. Crystal data:
C16H13NO2, M 251.27; orthorhombic; space group, P21;
lattice parameters, a = 5.9439 Å, b = 8.4943 Å, c = 25.5719
Synlett 2003, No. 8, 1160–1164 ISSN 1234-567-89 © Thieme Stuttgart · New York