Ytterbium triflate catalyzed electrophilic substitution of indoles: The synthesis of unnatural tryptophan derivatives

Article abstract of DOI:10.1016/S0040-4039(02)00736-0

Benzylamine was combined with ethyl glyoxylate to form the intermediate imine which in the presence of catalytic amount of Yb(OTf)₃ underwent electrophilic substitution on the 3-position of a variety of indoles to produce unnatural tryptophan d

Full text of DOI:10.1016/S0040-4039(02)00736-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4271–4274
Ytterbium triflate catalyzed electrophilic substitution of indoles:
the synthesis of unnatural tryptophan derivatives
Adam Janczuk,a Wei Zhang,a Wenhua Xie,a Sanzhong Lou,b JinPei Chengb and Peng G. Wang*
aDepartment of Chemistry, Wayne State University, Detroit, MI 48202, USA
bDepartment of Chemistry, Nankai University, Tianjin 300071, PR China
Received 4 March 2002; revised 5 April 2002; accepted 8 April 2002
Abstract—Benzylamine was combined with ethyl glyoxylate to form the intermediate imine which in the presence of catalytic
amount of Yb(OTf)3 underwent electrophilic substitution on the 3-position of a variety of indoles to produce unnatural
tryptophan derivatives. Penicillin-G-acylase mediated N-acylation produced optically active tryptophan derivatives. © 2002
Elsevier Science Ltd. All rights reserved.
Indole and indole derivatives have been a topic of
research interest for over a century.1 This, in part, is
due to the fact that indole derivatives, such as tryp-
tophan, are abundantly found in a variety of naturally
found compounds that exhibit various physiological
properties.2 Tryptamine, serotonin, sumatriptan, and
N,N-dimethylamines are but a few tryptophan deriva-
tives that exhibit neurophysiological effects.3,4 Ondans-
teron,5 another tryptophan derived pharmaceutical, is a
potent 5-HT3 which is used clinically for the treatment
of nausea associated with conventional chemotherapy.
Clearly, facile synthesis into these types of
aminoalkylindole compounds is of great significance.
the utility of this reaction we explored Yb(OTf)3-cata-
lyzed synthesis of amino-indole-3-yl acetic acids.
Herein, we report the successful lanthanide catalyzed
alkylation of a variety of indole derivatives as well as
and enzymatic approach to obtain optically active
products (Scheme 1).
The two-step tryptophan derivative synthesis was car-
ried out in a one-pot procedure. Benzyl amine and ethyl
glyoxylate were dissolved in CH2Cl2. Na2SO4 was uti-
,
lized instead of 4 A molecular sieves to absorb the
evolution of water during the course of the reaction.
Commercially available indole and indole derivatives
were added to the in situ generated imine 1 followed by
the addition of 5 mol% Yb(OTf)3. The corresponding
substituted indoles 2a–e were obtained in yields ranging
from 60 to 85% (Table 1).
While there are many available methods for the synthe-
sis of tryptophan derivatives, one of the most efficient is
the Mannich carbonꢀcarbon bond reaction.6 Other
methods have employed the use of imines, under acidic
conditions, for the synthesis of aminoalkylindoles.7 Pre-
viously, our group demonstrated that lanthanide tri-
flates are effective catalysts in promoting electrophilic
aromatic substitution.8 In order to further investigate
Enzymatic resolution appeared to be a quick and
potentially useful way of obtaining optically active
indole derivatives. Extensive work has been done using
enzymes in catalyzing several asymmetric transforma-
Scheme 1.
* Corresponding author. Fax: (313)-577-2554; e-mail: pwang@chem.wayne.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00736-0

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A. Janczuk et al. / Tetrahedron Letters 43 (2002) 4271–4274
of phenylacetic acid.11 Most examples using PGA
demonstrate the ability of the enzyme to selectively
hydrolyze the phenyl acetyl moiety. However, Zmijew-
ski and co-workers were one of the first to pioneer the
use of PGA in selective acylation.12 Since then there has
been other literature precedence in which, depending on
the conditions, the enzyme can selectively acylate.10a,c,13
Table 1. Yb(OTf)3-catalyzed substitution
Entry
1
Indole derivative
Product
Yield%
82
BnHN
COOEt
N
H
In order to evaluate the possibility of using PGA in
obtaining optically active derivatives a model study was
carried out using product 2a. However, compound 2a
required conversion to the free amine 3a prior to the
enzymatic resolution. This was accomplished by simple
catalytic hydrogenation to remove the benzyl moiety.
2a
2
70
BnHN
MeO
MeO
COOEt
N
H
We proceeded in using immobilized PGA on Eupergit®
C14 in catalyzing the acylation of the free amine
(Scheme 2). Phenyl acetic acid and methylphenyl acet-
ate were chosen as substrates for the N-acylation. Sev-
eral reaction conditions were examined (Table 2) and
we found that the most effective solvent system was
Tol:H2O in a 98:2 ratio. This coincides with pervious
studies in which the rate of saponification of methyl
phenylacetate by PGA, a competing reaction that
reduces the rate of N-acylation, is significantly retarded
when a non-polar solvent such as toluene is used
instead of ethyl acetate. The reaction was monitored
using TLC until approximately 50% conversion was
achieved. In prolonged conditions and higher concen-
trations, the enzyme has been known to eventually
acylate both isomers. Product 5a was isolated and
purified by column chromatography to give a crys-
talline product. Compound 5a was then evaluated for
optical activity using polarimetry. The standard optical
rotation of the compound was found to be [h]2D5=
+92.9°. Substrate 4a was also isolated and evaluated for
optical rotation as well. The standard optical rotation
of compound 4a was observed to be [h]2D5=−88.0°.
Enantiomer excess of both product 5a and substrate 4a
N
H
2b
3
4
5
68
85
58
BnHN
Ph
COOEt
Ph
N
H
N
H
2c
BnHN
Me
COOEt
Me
N
H
N
H
2d
BnHN
COOEt
N
was determined by 1H NMR using (+)-Eu(hfc)3 or
15
Me
synthesizing a Mosher derivative.16 From the initial
results it appears that methyl phenylacetate is the most
suitable substrate for the resolution of the racemate 3a
leading to substrate (−)-4a and product (+)-5a in both
fair yields and high enantiomeric excess (entry 4).
Phenyl acetic acid also demonstrated to be a useful
substrate for the enzyme-catalyzed reaction (entry 1);
however, the yield and enantiopurity was somewhat
diminished for substrate 4a.
N
Me
2e
tions.9 One particular area of research interest has been
the synthesis of b-amino acids. Numerous studies have
been carried out using penicillin G acylase (PGA) (E.C.
3.5.1.11) as a resolving agent.10 It is known that PGA
has a high affinity to phenyl acetic acid derivatives. The
enzyme exhibits moderate to excellent stereochemical
discrimination of a-aminoalkylphosphonic acids, a-, b-,
and g-amino acids, sugars, amines, peptides, and ester
A typical procedure for the electrophilic addition is as
follows: A suspension of 1.0 g of benzyl amine, 1 equiv.
of ethyl glyoxylate (50% in tol) and 5.0 g of anhydrous
Na2SO4 was stirred in 20 mL of CH2Cl2. After approx-
Scheme 2.

A. Janczuk et al. / Tetrahedron Letters 43 (2002) 4271–4274
4273
Table 2. Enzymatic resolution
Entry
R
Conditions
5a
4a
% Yielda
% eeb
% Yield
% eec
1
2
3
4
H
H
H
Me
Tol:H2O (98:2) 12 h, rt
H2O:EtOH (50:50) 72 h, rt
EtOAc:H2O (90:10) 36 h, rt
Tol:H2O (98:2) 36 h, rt
43
0
10
42
98 (+)
–
95 (+)
98 (+)
40
\95
70
69 (−)
–
38 (−)
83 (−)
39
a Isolated product after column chromatography.
b Determined by 1H NMR using (+)-Eu(hfc)3 as a chiral shift reagent.
c Determined by 1H NMR by Mosher techniques.16
Acknowledgements
imately 1 h, or until the disappearance of ethyl glyoxyl-
ate as monitored by TLC (1:1 EtOAc:hex), 1.1 equiv. of
indole was introduced followed by 5 mol% Yb(OTf)3.
Once the reaction was complete, approximately 18 h,
the mixture was filtered and poured over ice cold
saturated NaHCO3 solution. The organic layer was
diluted with methylene chloride and washed (2×10 mL)
with water, then brine (2×10 mL). The organic layer
was then dried over anhydrous Na2SO4, filtered and
concentrated in vacuo. The crude product was purified
by column chromatography using ethyl acetate and
hexane for elution (1:3 EtOAc:hex).17
This work has been generously sponsored by a grant
from the Chinese National Science Foundation (CNSF)
for oversea scholars. We (P.G.W. and C.J.P.) sincerely
acknowledge the support.
References
1. Early examples of indole synthesis: (a) Baeyer, A.; Emmer-
ling, A. Ber. 1869, 2, 679; (b) Fischer, E.; Jourdan, F. Ber.
1883, 16, 2241–2245.
2. Ninomiya; Ichiya J. Nat. Prod. 1992, 55, 541–564.
3. Stolc, S. Life Sci. 1999, 65, 1943–1950.
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5. Du Bois, A. Med. Klin. 1998, 93 (Suppl. 1), 3–17.
6. For recent examples, see: (a) Seela, F.; Chen, Y.; Zulauf,
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H.; Imanishi, T. Chem. Pharm. Bull. 1997, 45, 932–935; (c)
Zhang, H.-C.; Brumfield, K. K.; Jaroskova, L.; Maryanoff,
B. E. Tetrahedron Lett. 1998, 39, 4449–4452; (d) Kim, I.
T.; Elsenbaumer, R. L. Tetrahedron Lett. 1998, 39, 1087–
1090; (e) Jiang, B.; Yang, C.-G.; Gu, X.-H. Tetrahedron
Lett. 2001, 42, 2545–2547.
7. (a) Snyder, H. R.; Matteson, D. S. J. Am. Chem. Soc. 1957,
79, 2217–2221; (b) Van Tamelen, E. E.; Knapp, G. C. J.
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Chen, D.; Yu, L.; Wang, P. G. Tetrahedron Lett. 1996, 37,
4467–4470.
9. For recent reviews in enzyme-catalyzed optical resolution,
see: Wong, C.-H.; Whitesides, G. M. In Enzymes in
Synthetic Chemistry; Baldwin, J. E.; Mangus, P. D., Eds.;
Elsevier Science: New York, 1994; Vol. 12, pp. 41–130.
10. (a) Topgi, R. S.; Ng, J. S.; Landis, B.; Wang, P.; Behling,
J. R. Bioorg. Med. Chem. 1999, 7, 2221–2229; (b) Cardillo,
G.; Tolomelli, A.; Tomasini, C. J. Org. Chem. 1996, 61,
8651–8654; (c) Roche, D.; Prasad, K.; Repic, O. Tetra-
hedron Lett. 1999, 40, 3665–3668.
11. (a) Didziapetris, R.; Drabnig, B.; SehellenBerger, V.;
Jakubke, H.-D.; Svedas, V. FEBS Lett. 1991, 287, 31–33;
(b) Stoineva, I. B.; Galunsky, B. P.; Lazanov, V. S.; Ivanov,
I. P.; Petkov, D. D. Tetrahedron 1992, 48, 1115–1122.
A typical procedure for the use of the enzyme and
isolation of the product is as follows: 50 mg of com-
pound 3a was dissolved in 3 mL of a Tol:H2O (98:2)
solution. Then, 50 mg of immobilized PGA (106 U/g)
was introduced. The suspension was stirred until
approximately 50% conversion was observed, as moni-
tored by TLC (2:1 hex:EtOAc). The solution was then
diluted with toluene (2 mL) and filtered. The filtrate
was then extracted with 1N HCl solutions (3×5 mL).
The aqueous layer contained the hydrochloric salt of
substrate 4a. The organic layer was then neutralized
using satd NaHCO3 (2×5 mL). Next, the organic layer
was washed with brine (1×10 mL), dried over anhy-
drous Na2SO4, filtered, and concentrated in vacuo. The
crude residue purified by column (2:1 hex:EtOAc) and
acylated product 5a was isolated. The aqueous layer
containing substrate 4a was made basic (pH 8) using
1N NaOH and extracted with CHCl3 (3×5 mL). The
organic layer was then washed with satd NaHCO3 (2×5
mL), brine (2×5 mL), dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. The compound was
1
then evaluated without further purification. H NMR
results indicated a relatively pure product.18
In conclusion, we have successfully synthesized a series
of indole derivatives using catalytic amounts of
Yb(OTf)3 to promote the electrophilic addition. In
addition, we have demonstrated the use of PGA for
resolving the resulting aminoalkylindole compound into
optically active compounds. This work presents a sim-
ple and efficient means of obtaining a variety of unnat-
ural tryptophan derivatives.

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A. Janczuk et al. / Tetrahedron Letters 43 (2002) 4271–4274
12. Zmijewski, M.; Briggs, B. S.; Thompson, A. R.; Wright,
I. G. Tetrahedron Lett. 1991, 32, 1621–1622.
128.7, 127.3, 121.4, 121.4, 119.9, 119.0, 110.8, 108.0, 61.3,
56.9, 51.3, 14.4, 12.0; MS (M+H)+ m/z 323.08. 2e 1H
NMR (500 MHz, CDCl3) l 7.83 (d, J=7.5 Hz, 1H),
7.46–7.15 (m, 9H), 4.81 (s, 1H), 4.35–4.29 (m, 1H),
4.24–4.18 (m, 1H), 3.94 (q, J=24.0 Hz, 2H), 3.76 (s, 3H),
2.52 (broad s, 1H), 1.31 (t, J=7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3) l 173.9, 140.2, 137.5, 128.7, 128.69,
127.8, 127.4, 126.9, 122.2, 119.9, 119.7, 111.9, 109.7, 61.3,
57.8, 51.9, 33.0, 14.5; MS (M)+ m/z 322.17. 2a was
dissolved in dry methanol followed by the addition of a
catalytic amount of Pd(OH)2–C. The reaction vessel was
then charged with 30 PSI of hydrogen gas and agitated
for 12 h followed by standard work-up procedures to
13. (a) Basso, A.; Braiuca, P.; Martin, L. D.; Ebert, C.;
Gardossi, L.; Linda, P. Tetrahedron: Asymmetry 2000, 11,
1789–1796; (b) Cainelli, G.; Giacomini, D.; Galletti, P.;
DaCol, M. Tedrahedron: Asymmetry 1997, 8, 3231–3235.
14. PGA on Eupergit® C is available from Fluka (106 U/g).
15. Parker, D. Chem. Rev. 1991, 91, 1441–1457.
16. Sullivan, G. R.; Dale, J. A.; Mosher, H. J. Org. Chem.
1973, 38, 2143–2147.
1
17. 2a H NMR (500 MHz, CDCl3) l 8.34 (s, 1H), 7.73 (d,
J=8.5 Hz, 1H), 7.37–7.31 (m, 5H), 7.29–7.25 (m, 1H),
7.21–7.18 (m, 1H), 4.72 (s, 1H), 4.27–4.21 (m, 1H),
4.17–4.10 (m, 1H), 3.84 (q, J=21.5 Hz, 2H), 2.40 (broad
s, 1H), 1.22 (t, J=7.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3) l 173.3, 139.8, 136.6, 128.7, 128.6, 127.3, 126.3,
123.2, 122.5, 120.1, 119.7, 113.3, 111.5, 61.3, 57.7, 51.8,
14.4; MS (M+H)+ m/z 309.12. 2b 1H NMR (400 MHz,
CDCl3) l 8.40 (s, 1H), 7.38–7.25 (m, 5H), 7.19–7.07 (m,
3H), 6.84 (dd, J=8.8, 2.4 Hz, 1H), 4.67 (s, 1H), 4.28–4.21
(m, 1H), 4.18–4.11 (m, 1H), 3.89–3.79 (m, 5H), 2.24
(broad s, 1H), 1.22 (t, J=7.0 Hz, 3H); 13C NMR (100
MHz, CDCl3) l 173.8, 154.3, 139.9, 131.6, 128.7, 128.69,
127.4, 126.7, 123.8, 113.0, 112.9, 112.3, 101.0, 61.3, 57.5,
1
afford compound 3a H NMR (400 MHz, CDCl3) l 8.62
(s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H),
7.25–7.10 (m, 3H), 4.91 (s, 1H), 4.26–4.18 (m, 1H),
4.15–4.07 (m, 1H), 2.12 (broad s, 2H), 1.20 (t, J=7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) l 174.8, 136.7, 125.6,
122.6, 122.5, 120.0, 119.4, 115.3, 111.6, 61.5, 52.1, 14.4;
MS (M)+ m/z 218.10.
18. 4a [h]2D5=−88.0° (c 0.434 g/100 mL, CH2Cl2); 1H NMR
(500 MHz, CDCl3) l 8.36 (s, 1H), 7.74 (d, J=8.0 Hz,
1H), 7.34 (d, J=8.5 Hz, 1H), 7.21 (t, J=8.5 Hz, 1H),
7.16–7.12 (m, 2H), 4.91 (s, 1H), 4.26–4.19 (m, 1H),
4.15–4.09 (m, 1H), 2.03 (broad s, 2H), 1.21 (t, J=7.5 Hz,
3H); 13C NMR (125 MHz, CDCl3) l 174.6, 136.6, 125.6,
122.7, 122.5, 120.1, 119.4, 115.2, 111.7, 61.6, 52.1, 14.3;
MS (M)+ m/z 218.11. 5a [h]2D5=+92.9° (c 0.165 g/100 mL,
CH2Cl2); 1H NMR (500 MHz, CDCl3) l 8.62 (s, 1H),
7.53 (d, J=8.0 Hz, 1H), 7.32–7.24 (m, 6H), 7.21 (t,
J=8.5 Hz, 1H), 7.17–7.04 (m, 2H), 6.46 (d, J=6.5 Hz,
1H), 5.80 (d, J=7.0 Hz, 1H) 4.22–4.16 (m, 1H), 4.12–4.06
(m, 1H), 3.59 (q, J=20.5 Hz, 2H), 1.16 (t, J=7.0 Hz,
3H); 13C NMR (125 MHz, CDCl3) l 171.3, 170.9, 136.5,
134.7, 129.6, 129.1, 127.5, 125.4, 123.9, 122.7, 120.3,
119.1, 111.8, 110.7, 61.9, 50.5, 43.6, 14.2; MS (M)+ m/z
336.14.
1
56.0, 51.8, 14.5; MS (M)+ m/z 338.17. 2c H NMR (500
MHz, CDCl3) l 8.62 (s, 1H), 7.52 (d, J=7.5 Hz, 1H),
7.61–7.59 (m, 2H), 7.42–7.31 (m, 3H), 7.30–7.14 (m, 8H),
4.88 (s, 1H), 4.27–4.21 (m, 1H), 4.18–4.09 (m, 1H), 3.68
(q, J=25.5 Hz, 2H), 2.59 (broad s, 1H), 1.21 (t, J=7.0
Hz, 3H); 13C NMR (125 MHz, CDCl3) l 173.7, 139.9,
137.8, 136.3, 132.6, 129.1, 129.0, 128.7, 128.5, 127.2,
127.1, 122.6, 120.5, 120.4, 11.4, 109.3, 61.4, 57.1, 51.3,
14.4; MS (M)+ m/z 384.18. 2d 1H MNR (400 MHz,
CDCl3) l 8.25 (s, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.34–7.25
(m, 5H), 7.20–7.11 (m, 4H), 4.70 (s, 1H), 4.25–4.17 (m,
1H), 4.13–4.05 (m, 1H), 3.81 (q, J=22.0 Hz, 2H), 2.55
(broad s, 1H), 2.25 (s, 3H), 1.18 (t, J=7.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) l 173.6, 140.0, 135.5, 134.0,