Regioselective acylation at the 5- or 6-position of L-tryptophan derivatives

Article abstract of DOI:10.1016/S0040-4039(02)01580-0

The reaction of 1-acyl tryptophan derivatives with chloroacetyl chloride or the reaction of 1-tosyl tryptophan derivatives with acetyl chloride provides the corresponding 6-acylation products, while acylation of the 3-oxo tryptophan derivative gives a 5-substituted product.

Full text of DOI:10.1016/S0040-4039(02)01580-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7013–7015
Regioselective acylation at the 5- or 6-position of
derivatives
L-tryptophan
Yongwen Jianga and Dawei Mab,*
aDepartment of Chemistry, Fudan University, Shanghai 200433, China
bState Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 5 February 2002; revised 18 July 2002; accepted 29 July 2002
Abstract—The reaction of 1-acyl tryptophan derivatives with chloroacetyl chloride or the reaction of 1-tosyl tryptophan
derivatives with acetyl chloride provides the corresponding 6-acylation products, while acylation of the 3-oxo tryptophan
derivative gives a 5-substituted product. © 2002 Elsevier Science Ltd. All rights reserved.
6-Substituted
logically important molecules such as the cell cycle
modulator, trypostatin A1 and fumitremorgin C,2
reversal agent for multi-drug resistance (MDR). In
addition, 6-substituted tryptophan derivatives have
served as a starting material for synthesizing spiro-
tryprostatin A,3 and are obviously useful intermediates
for synthesizing the teleocidin family of compounds4
which show potent protein kinase C (PKC) activation
activity (Scheme 1).
L
-tryptophan moieties exist in many bio-
In connection with our research on the design and
synthesis of novel and isoform-selective PKC modula-
tors,5 we needed a powerful method to synthesize 6-
a
substituted
L
-tryptophan derivatives of type 2. A
literature survey for the preparation of these com-
pounds indicated that few methods were suitable. Con-
sidering that Friedel–Crafts acylation was a useful
approach to introduce substituents into the aromatic
ring, and that there was not a report concerning this
reaction with
L
-tryptophan derivatives as substrates, we
H
O
H
O
H
14
11
Me
N
9
OH
N13
N
N
O
HN
N
5
4
3
2
MeO
N
H
MeO
N
H
H
H
O
1
N
O
R
6
7
R'
H
fumitremorgin C
trypostatin A
teleocidin family
H
O
N
O
H
H
H
R'
R'
acylation ?
MeO
N
N
O
NHCO2Me
NHCO2Me
R
N
X
N
X
H
2
1
spirotryprostatin A
Scheme 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01580-0

7014
Y. Jiang, D. Ma / Tetrahedron Letters 43 (2002) 7013–7015
decided to explore the Friedel–Crafts acylation of sev-
eral -tryptophan derivatives.
The initial results outlined in Scheme 2 implied that the
1- and 2-positions of -tryptophan were also active sites
L
L
for acylation. In order to avoid acylation at these two
positions, we decided to protect the 1-position as an
amide or sulfonamide. This protection would not only
block acylation at the 1-position, but would also deacti-
vate the 2-position via both electronic7 and steric
effects. Accordingly, the compounds 1c–1f were pre-
pared by treatment of 1a or 1b with AcCl/TEA/DMAP
or TsCl/NaH in methylene chloride. The yields for
these conversions were 90ꢀ100%. As summarized in
Table 1, in the case of 1c as a substrate, acylation using
acetyl chloride did not occur at room temperature, or
even at higher temperature. However, when the more
active chloroacetyl chloride was employed, the reaction
occurred at room temperature to afford the 6-acylation
Initially, we tested the direct acylation of compounds
1a and 1b derived from -tryptophan through simple
L
operations. When acetyl chloride was used as an
acylation reagent, both 1a and 1b gave 1,6- and 1,5-
diacylation products in the ratio of about 1:1. However,
under the same conditions, only a 2,5-diacylation
product was isolated when chloroacetyl chloride was
reacted with either 1a or 1b (Scheme 2). These observa-
tions indicated that the regioselectivity of the acylation
was highly dependent on the nature of the acylat-
ing agent. A similar phenomenon was noticed when
Nakatsuka and co-workers investigated the acylation
reaction of 1-substituted indoles.6
H
H
H
Ac
R'
R'
R'
AcCl/AlCl3
+
NHCO2Me
NHCO2Me
NHCO2Me
ClCH2CH2Cl
r.t. 70 ~ 80%
N
Ac
N
H
Ac
N
Ac
1a: R' = CO2Me
2a: R' = CO2Me
3a: R' = CO2Me
1b: R' = CH2OAc
2b: R' = CH2OAc
3b: R' = CH2OAc
H
H
R'
ClH2COC
R'
ClCH2COCl/AlCl3
NHCO2Me
NHCO2Me
COCH2Cl
ClCH2CH2Cl
r.t. 76 ~ 80%
N
H
N
H
1a: R' = CO2Me
4a: R' = CO2Me
1b: R' = CH2OAc
4b: R' = CH2OAc
Scheme 2.
Table 1. Acylation of 1-substituted
L
-tryptophan derivativesa
H
H
H
ROC
+
R'
R'
R'
RCOCl/AlCl3
NHCO2Me
NHCO2Me
NHCO2Me
ClCH2CH2Cl
ROC
N
Y
N
X
N
Y
1c: X = Ac, R' = CO2Me
1d: X = Ac, R' = CH2OAc
1e: X = Ts, R' = CO2Me
1f: X = Ts, R' = CH2OAc
2c: Y = Ac, R' = CO2Me, R = CH2Cl
2d: Y = Ac, R' = CH2OAc, R = CH2Cl
2e: Y = Ts, R' = CO2Me, R = Me
2f: Y = Ts, R' = CH2OAc, R = Me
2g: Y = Ts, R' = CH2OAc, R = CH2Cl
2h: Y = Ts, R' = CO2Me, R = CH2Cl
3c: Y = Ts, R' = CO2Me,
R = Me
3d: Y = Ts, R' = CO2Me,
R = CH2Cl
3e: Y = Ts, R' = CH2OAc,
R = CH2Cl
Entry
Substrate
R
Temp. (°C)
Time (h)
Products (yield (%))b
1
2
3
4
5
6
7
8
9
1c
1c
1d
1d
1e
1e
1f
1f
1e
1f
Me
ClCH2
Me
ClCH2
Me
Me
Me
Me
ClCH2
ClCH2
25
25
25
25
0
25
0
25
15
0
48
36
18
24
2
12
1
12
5
–
2c (80)
2b (10)c
2e (64)c
3b (20)c
3c (21)c
2d (31)
2a (80)
2f (91)
2b (90)
2h (45)
2g (42)
3d (45)
3e (43)
10
4
a Reaction conditions: 1 (1 mmol), RCOCl (4.7 mmol), AlCl3 (4.5 mmol) in 10 mL of ClCH2CH2Cl.
b Isolated yield.
c The ratio for 2 and 3 was determined by 1H NMR.

Y. Jiang, D. Ma / Tetrahedron Letters 43 (2002) 7013–7015
7015
MeO2C
NH
H
H
ClH2COC
CO2Me
ClH2COC
1. aq NaOH, MeOH, 0 oC
O
NHCO2Me
NHCO2Me
2. DCC/(S)-alanine methyl
ester
N
N
Ts
Ts
3d
5
Scheme 3.
O
O
H
H
ClH2COC
ClCH2COCl/AlCl3
OAc
OAc
NHCO2Me
ClCH2CH2Cl
r.t. 90%
NHCO2Me
N
H
N
H
7
6
Scheme 4.
Acknowledgements
product, 2c, exclusively. Surprisingly, reaction of
another 1-acyl substrate 1d with acetyl chloride worked
but provided both 6- and 5-acylation products (entry
3), while a lower yield was observed in the case of
chloroacetyl chloride as acylation agent (entry 4). The
two substrates bearing a 1-tosyl group gave more dra-
matic results. Reaction of 1e with acetyl chloride pro-
vided 6- and 5-substituted products 2e and 3c in a ratio
of 3:1 at 0°C (entry 5). Increasing the reaction tempera-
ture afforded 2a (entry 6), where the tosyl group was
cleaved. A similar result was observed in the reaction of
1f with acetyl chloride (entry 8), although it gave a
single 6-acylation product at 0°C (entry 7). Further-
more, either 1e or 1f produced a mixture of 6- and
5-substituted products when chloroacetyl chloride was
used as the acylation agent (entries 9 and 10). Taking
these results together, we concluded that 6-acylation
products could be regioselectively obtained via either
reaction of 1-acyl tryptophan derivatives with
chloroacetyl chloride or reaction of 1-tosyl tryptophan
derivatives with acetyl chloride.
The authors are grateful to the Chinese Academy of
Sciences, National Natural Science Foundation of
China (grant 20132030), Bayer AG, and Qiu Shi Sci-
ence & Technologies Foundation for their financial
support. We thank Dr. J. Scherkenbeck for helpful
discussions.
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acylation reaction (Scheme 3).
Although it was reported that nitration of 3-oxoindoles
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single product (Scheme 4).
In conclusion, we have studied the acylation of several
L
-tryptophan derivatives and found suitable conditions
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