Novel synthesis of bromoindolenine with spiro-β-lactam in chartelline

Article abstract of DOI:10.1055/s-2004-830885

Model compounds containing an indolenine β-lactam moiety in chartelline were synthesized by nucleophilic substitution at the nitrogen atom of O-sulfonylated hydroxamic acid prepared from 2-methylindole-3-acetic acid.

Full text of DOI:10.1055/s-2004-830885

LETTER
2025
Novel Synthesis of Bromoindolenine with Spiro-b-lactam in Chartelline
N
ovel Synthesis
o
of Bromoin
s
dolenine hio Nishikawa,*a,b Shigeo Kajii,a Minoru Isobe*a
a
Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan
Fax +81(52)7894111; E-mail: nisikawa@agr.nagoya-u.ac.jp
b
PRESTO, Japan Science and Technology Agency (JST), Kawaguchi, 332-0012, Japan
Received 14 May 2004
In the course of our synthetic studies, we have reported
the synthesis of a model compound 4 (R = Me) containing
oxindole-b-lactam and its enamide 5 (R = Me) for char-
telline (Figure 2).3 However, further elaboration of the ox-
indole 4 (R = Bn or MOM)4 to the indolenine structure
with a substituent at the 2-position proved to be difficult,
because of instability of the b-lactam under deprotection
conditions of the Bn or MOM group.
Abstract: Model compounds containing an indolenine b-lactam
moiety in chartelline were synthesized by nucleophilic substitution
at the nitrogen atom of O-sulfonylated hydroxamic acid prepared
from 2-methylindole-3-acetic acid.
Key words: chartelline, indole, b-lactam, cyclization, marine natu-
ral product
Chartelline A (1) and its analogs were isolated by Chris-
tophersen and co-workers from marine bryozoan Chartel-
la papyracea collected in the North Sea. X-Ray and
spectroscopic analyses determined them to be unprece-
dented unique structures comprising a highly unsaturated
10-membered ring fused with polybrominated indolenine
spiro-b-lactam and bromoimidazole (Figure 1).1 The ex-
traordinary novel structure prompted us to initiate syn-
thetic studies directed towards the total synthesis of
chartellines.2
O
O
Cl
NH
N
Ph
N
R
4
N
R
5
O
O
Figure 2
To overcome this problem, we considered alternative
routes for the indolenine spiro-b-lactam moiety for char-
telline. Retrosynthetic disconnection between C-3 and the
lactam nitrogen of indolenine-b-lactam 6 led us to find
two modes of cyclization as shown in Scheme 1: (a) nu-
cleophilic substitution at the amide nitrogen with the C-3
position of indole 7, (b) nucleophilic addition of an amide
anion to the C-3 position of indole 8 bearing a leaving
group at N-1 (e.g. 1-hydroxyindole derivative).5 These
routes were particularly attractive because two important
functional groups such as indolenine and b-lactam would
arise from the simple indole derivative at the same time.
The type (b) of b-lactam formation has been employed in
the synthesis of the b-lactam antibiotics such as penicillin
and cephalosporin,6 while few examples for the type (a)
reaction have been reported to date. To our knowledge,
only one example of the type (a) b-lactam formation was
reported by Scott.7 From these two possibilities, we now
describe the successful realization of the type (a) reaction
for the synthesis of indolenine spiro-b-lactam for char-
tellines.
A precursor such as 7 for the type (a) b-lactam formation
was synthesized from a commercially available 2-meth-
ylindole-3-acetic acid (9a) as shown in Scheme 2.
Methylation of the carboxylic acid, protection of the in-
dole nitrogen with a Boc group and alkaline hydrolysis of
the ester8 gave N-Boc-2-methylindole-3-acetic acid (10a)
in 81% overall yield. Transformation of carboxylic acid
10a to N-methylhydroxamic acid 13a was carried out
through the corresponding succinimide ester;9 DCC
Figure 1 Structure and conformation of chartelline.
SYNLETT 2004, No. 11, pp 2025–2027
0
6
.0
9
.2
0
0
4
Advanced online publication: 05.08.2004
DOI: 10.1055/s-2004-830885; Art ID: U13804ST
© Georg Thieme Verlag Stuttgart · New York

2026
T. Nishikawa et al.
LETTER
the desired b-lactam 15a12,13 and an unexpected N-
methylamide 16a14 was obtained in low yield (entry 1).
The reaction with n-butyllithium or potassium t-butoxide
as a base proceeded at the lower temperature, but gave a
mixture of 15a and 16a (entries 2 and 3). We found that
use of LDA improved the preferential formation of 15a
although the yield was poor (entry 4). Further screening of
amide bases revealed that use of lithium hexamethyl-
disilazide (LiHMDS) at –78 °C was the best condition to
give 15a in moderate yield without 16a (entry 7).
O
X
N
R2
R1
(Br)n
O
(a)
N
7
N
R2
R1
3
O
(Br)n
(b)
R2
N
N
6
R1
(Br)n
Table 1 b-Lactam Formation
N
X
8
Me
O
N
H
Scheme
(X = leaving group).
1
Retrosynthetic analysis for indolenine b-lactam
NMe
Me
O
base
THF
+
Me
14a,b
N
N
H
X
X
coupling of 10a with N-hydroxysuccinimide (HOSu)
gave the active ester 11a, which was subjected to reaction
with MeNHOH·HCl neutralized with Et3N. The reaction
was found to proceed via an O-acyl compound 12 as an
initial intermediate to yield N-acyl product 13a in good
overall yield.10 The product 13a was treated with p-ni-
trobenzenesulfonyl chloride (p-NsCl)7 and then deprotec-
tion of the Boc group with TFA provided 14a,11 the
precursor for b-lactam formation.
15a X = H
15b X = Br
16a X = H
16b X = Br
Entry
14
Conditions
Products
Yield (%) Ratio
Base
Temp
(15:16)a
2:1
3:2
3:1
7:1
–
1
2
3
4
5
6
7
8
9
14a
EtMgBr
n-BuLi
t-BuOK
LDA
Reflux
–78 °C
0 °C
31
44
We next examined the cyclization of 14a employing a va-
riety of bases as shown in Table 1. When indolylmagne-
sium bromide prepared from 14a and EtMgBr was
refluxed in THF, an inseparable mixture of about 2:1 of
25
–78 °C
–78 °C
21
KHMDS
Complex
NaHMDS –78 °C
LiHMDS –78 °C
LiHMDS –78 °C
19
50
0
1:0
1:0
–
COOR
Me
COOH
Me
d
14b
N
H
N
X
X
Boc
a, b, c
b, c
LiHMDS –78 °C to 26
40 °C
1:0
(81%)
(85%)
9a X = H, R = H
9b X = Br, R = Et
10a X = H
10b X = Br
10
LiHMDS –78 to r.t. 62
1:0
O
MeHN
a The ratios were determined by integration values of 1H NMR
spectra.
O
O
O
N
O
O
e
Me
Me
With a view to the synthesis of naturally occurring char-
telline, we then examined the effect of a bromo substituent
on the indole ring in the b-lactam formation. Thus, the
brominated substrate 14b was prepared from a known 6-
bromo-2-methylindole-3-acetic acid ethyl ester (9b)15 in
an analogous manner to the synthesis of 14a as shown
in Scheme 2. In contrast to 14a, the brominated precur-
sor 14b was surprisingly inert under the conditions that
we had optimized; no b-lactamization was observed at
–78 °C (entry 8 in Table 1), while the reaction proceeded
slowly at –40 °C (entry 9). We finally found that the reac-
tion conducted at –78 °C and then allowed to warm up to
room temperature furnished 62% of b-lactam 15b (entry
10).16 The difference in reactivity between 14a and 14b
might be due to the inductive effect of the bromo substit-
uent, which decreased nucleophilicity of the anion gener-
N
N
X
X
Boc
Boc
11a X = H
11b X = Br
12
Me
Me
N
OH
N
Op-Ns
O
O
f, g
Me
Me
N
N
H
X
X
Boc
(77%)
(68%)
(69%)
(73%)
13a X = H
13b X = Br
14a X = H
14b X = Br
Scheme 2 Reagents and conditions: (a) HCl aq., MeOH, r.t.; (b)
Boc2O, DMAP, CH2Cl2, r.t.; (c) NaOH aq., MeOH, r.t.; (d) HOSu,
DCC, Et3N, CH2Cl2, 0 °C to r.t.; (e) MeNHOH·HCl, Et3N, CH2Cl2,
r.t.; (f) p-NsCl, Et3N, CH2Cl2, 0 °C; (g) TFA, CH2Cl2, 0 °C.
Synlett 2004, No. 11, 2025–2027 © Thieme Stuttgart · New York

LETTER
Novel Synthesis of Bromoindolenine
2027
(1 H, td, J = 7.5 Hz, indole), 7.21 (1 H, br d, J = 7.5 Hz,
indole), 7.25 (1 H, br d, J = 7.5 Hz, indole), 7.84 (1 H, br s,
NH of indole), 8.09 (2 H, br d, J = 9.0 Hz, phenyl), 8.21 (2
H, d, J = 9.0 Hz, phenyl). 13C NMR (100 MHz, CDCl3): d =
11.8, 29.5, 39.5, 103.0, 110.4, 117.6, 119.7, 121.6, 124.1,
127.4, 128.1, 129.0, 130.7, 132.9, 135.0, 139.3, 151.2,
174.7. HRMS (FAB): m/z calcd for C18H18N3O6S1 [M + H]:
404.0916. Found: 404.0933.
ated from indole with the base. The structures of the
indolenine-b-lactam 15a and 15b were confirmed by
comparison of the NMR and IR spectra with those of char-
telline and a model compound reported by Weinreb.2a
In summary, we have demonstrated a novel synthesis of
indolenine spiro-b-lactam.17 The realization of this type of
b-lactam formation should open a new way to the synthe-
sis of chartelline-type marine alkaloids. Further synthetic
studies towards chartelline are currently under investiga-
tion.
(12) Data for 15a: IR (KBr): 3423, 2956, 1763, 1589, 1459, 1377
cm–1. 1H NMR (400 MHz, CDCl3): d = 2.35 (3 H, s, -CH3),
2.57 (3 H, s, -N-CH3), 3.26 (1 H, d, J = 15.0 Hz, -CHAHB-),
3.32 (1 H, d, J = 15.0 Hz, -CHAHB-), 7.27 (1 H, br t, J = 7.5
Hz, indole), 7.38 (1 H, d, J = 7.5 Hz, indole), 7.42 (1 H, td,
J = 7.5 Hz, indole), 7.54 (1 H, d, J = 7.5 Hz, indole). 13
C
Acknowledgment
NMR (100 MHz, CDCl3): d = 15.0, 26.7, 46.1, 69.1, 120.9,
122.2, 126.3, 130.4, 133.5, 154.2, 165.8, 180.4. HRMS
(FAB): m/z calcd for C12H13N2O1 [M + H]: 201.1028.
Found: 201.1000.
This work was financially supported by PRESTO, JST and a Grant-
in-Aid for the 21st century COE program from MEXT.
(13) In contrast to the report by Weinreb (2-vinyl substituent
instead of 2-methyl substituent) (ref.2a), products 15a and
15b were stable enough to purify on silica gel
References
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(14) N-Methylamide 16a was separated as its Boc derivative
from the mixture of 15a and 16a with Boc2O and DMAP.
The structure of 16a was determined by the following
spectroscopic data. IR (KBr): 3296, 2976, 2933, 1732, 1653,
1541, 1459, 1358, 1324, 1137 cm–1. 1H NMR (400 MHz,
CDCl3): d = 1.70 (9 H, s, -Boc), 2.55 (3 H, s, -CH3), 2.71 (3
H, d, J = 5.0 Hz, -NH-CH3), 3.65 (2 H, s, -CH2-), 5.50 (1 H,
br s, -NH-Me), 7.22–7.32 (2 H, m, indole), 7.41 (1 H, br d,
J = 7 Hz, indole), 8.12 (1 H, br d, J = 8.0 Hz, indole). 13
C
NMR (100 MHz, CDCl3): d = 14.0, 26.4, 28.3, 32.0, 84.2,
111.6, 115.6, 117.8, 123.0, 124.1, 129.3, 135.7, 135.8,
150.5, 170.9. HRMS (FAB): m/z calcd for C17H23N2O3 [M +
H]: 303.1709. Found: 303.1672.
(4) The oxindole-b-lactam 4 (R = Bn, MOM) was synthesized
in an analogous way to those described in ref.3; however, the
yields were poor.
(5) Somei, M. Heterocycles 1999, 50, 1157.
(15) Piper, J. R.; Stevens, F. J. J. Heterocycl. Chem. 1966, 95.
(16) Data for 15b: IR (KBr): 3312, 2928, 1762, 1586, 1456, 1377
cm–1. 1H NMR (400 MHz, CDCl3): d = 2.34 (3 H, s, -CH3),
2.55 (3 H, s, -N-CH3), 3.23 (1 H, d, J = 15.0 Hz, -CHAHB-),
3.30 (1 H, d, J = 15.0 Hz, -CHAHB-), 7.24 (1 H, d, J = 8.0 Hz,
indole), 7.41 (1 H, dd, J = 8.0, 1.5 Hz, indole), 7.67 (1 H, d,
J = 1.5 Hz, indole). 13C NMR (100 MHz, CDCl3): d = 15.0,
26.8, 46.1, 69.0, 123.2, 124.0, 124.4, 129.1, 132.5, 155.5,
165.3, 182.2. Anal. Calcd for C12H11BrN2O: C, 51.63; H,
3.97; N, 10.04. Found: C, 51.64; H, 4.05; N, 10.01.
(17) Quite recently, a synthesis of indolenine-3 spiro compounds
through intramolecular SN2-type reaction at the oxime
nitrogen was reported, see: Tanaka, K.; Mori, Y.; Narasaka,
K. Chem. Lett. 2004, 33, 26.
(6) For examples, see: (a) Nakatsuka, S.; Tanino, H.; Kishi, Y.
J. Am. Chem. Soc. 1975, 97, 5008. (b) Nakatsuka, S.;
Tanino, H.; Kishi, Y. J. Am. Chem. Soc. 1975, 97, 5010.
(c) Baldwin, J. E.; Au, A.; Christie, M.; Haber, S. B.;
Hesson, D. J. Am. Chem. Soc. 1975, 97, 5957.
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Tetrahedron Lett. 1976, 17, 1137.
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6, 95.
(11) Spectral Data for 14a: Mp 144–148 °C. IR (KBr): 3367,
2914, 1773, 1715, 1534, 1349, 1193 cm–1. 1H NMR (400
MHz, CDCl3): d = 2.29 (3 H, s, -CH3), 3.35 (3 H, s, -N-CH3),
3.64 (2 H, s, -CH2-), 7.03 (1 H, br t, J = 7.5 Hz, indole), 7.11
Synlett 2004, No. 11, 2025–2027 © Thieme Stuttgart · New York