Synthesis of model compound containing an indole spiro-β-lactam moiety with vinylchloride in chartellines

Article abstract of DOI:10.1246/cl.2004.440

A model compound containing an indole β-lactam moiety bearing vinylchloride in chartellines was synthesized from the Mannich reaction of isatin imine with ketene silyl acetal, β-lactam formation of the resulting β-amino ester, and copper(I)-mediated coupl

Full text of DOI:10.1246/cl.2004.440

440
Chemistry Letters Vol.33, No.4 (2004)
Synthesis of Model Compound Containing an Indole Spiro-ꢀ-lactam Moiety
with Vinylchloride in Chartellines
Toshio Nishikawa,ꢀy;yy Shigeo Kajii,y and Minoru Isobeꢀy
yLaboratory of Organic Chemistry, Graduate School of Bioagricultural Science,
Nagoya University, Chikusa, Nagoya 464-8601
yyPRESTO, Japan Science and Technology Agency
(Received January 13, 2004; CL-040049)
A model compound containing an indole ꢀ-lactam moiety
4b. Deprotection of the PMP (p-methoxyphenyl) and ester of
4a and 4b was carried out under conventional conditions to give
the precursors (5a–5c) for ꢀ-lactam formation.
bearing vinylchloride in chartellines was synthesized from the
Mannich reaction of isatin imine with ketene silyl acetal, ꢀ-lac-
tam formation of the resulting ꢀ-amino ester, and copper(I)-
mediated coupling with (E)-ꢁ-chloro-ꢀ-iodostyrene.
O
NPMP
O
b
a
O
(62%)
N
N
H
(97%)
Chartelline A (1) and its analogs were isolated from the ma-
rine bryozoan, Chratella papyracea. The structure studies by X-
ray crystallographic analysis and spectroscopic methods re-
vealed an unusual structure including a 10-membered ring con-
densed with ꢀ-lactam, indoline and imidazole rings (Figure 1).1
Despite the unique chemical architecture, few synthetic studies
have been reported. Recently, Weinreb, and co-workers reported
the synthesis of a model compound containing a spiro ꢀ-lactam
and an unsaturated imine moiety,2 which prompted us to disclose
our preliminary result on model experiments of chartelline syn-
thesis, focusing on the synthesis of the spiro ꢀ-lactam and its en-
amide moiety.
H
3
2
COOEt
COOH
NHPMP
O
NHR2
O
N
N
R1
R
d (92%)
e, d (85%)
e, d (64%)
R2 = PMP
R2 = H
5a R1 = H
5b R1 = H
4a R = H
4b R = Me
c (93%)
R2 = H
1
5c R = Me
Scheme 1. Reagents and Conditions, (a) p-anisidine, EtOH, re-
flux; (b) CH2=COEt(OTMS), BF3ꢁOEt2, CH2Cl2, ꢂ20 ꢃC; (c)
NaH, MeI, DMF, rt; (d) aq 1 N NaOH, 2-PrOH, rt; (e) CAN,
aq CH3CN, 0 ꢃC.
O
Cl
R1
R2
Br
N
N
Br
We next examined ꢀ-lactam formation of the ꢀ-amino acids
(5a–5c) (Table 1). Under the conventional conditions employing
(PyS)2/Ph3P or 2-chloro-1-methylpyridinium iodide (7),5 the
substrates 5a and 5b gave the corresponding ꢀ-lactams 6a and
6b in low yields,6 respectively (Entries 1, 2, 4, and 5). N-Methyl
derivative 5c also gave disappointing results under the same con-
ditions (Entries 3 and 6). In this specific case, however, we found
that ꢀ-lactam 6c7 was obtained in good yield when 5c was treat-
ed with tris(2-oxo-3-benzoxazolinyl) phosphine oxide (8)8 and
Et3N (Entry 9). These results indicate the importance of the sub-
stitution of the oxindole NH group as well as the reagent for this
ꢀ-lactam formation.
With the desired ꢀ-lactam 6c in hand, we then attempted di-
rect coupling with vinyliodide for the enamide moiety of chartel-
lines. Palladium- or copper-catalyzed enamide formations
between amide and vinyl halides have been extensively devel-
oped by several groups.9 Among them, we found the conditions
recently reported by Buchwald10 were fruitful. Thus, the ꢀ-lac-
tam 6c and (E)-ꢁ-chloro-ꢀ-iodostyrene (9)11 as a model vinyl
halide were heated with K2CO3, N,N0-dimethylethylenediamine
and copper(I) iodide to give a 5:1 mixture of 10a and 10b in high
yield (Scheme 2).12
N
H
N
chartelline A (1) R1 = Br R2 = Br
chartelline B
chartelline C
R1 = Br R2 = H
R1 = H R2 = H
Figure 1. Structures of chartelline A–C.
With a view to the asymmetric synthesis of chartellines in
the future, we planned to synthesize the spiro ꢀ-lactam from
the corresponding ꢀ-amino acid, which would be prepared by
the Mannich-type reaction of isatin imine with ketene silyl ace-
tal. Generally, imine prepared from ketone is not suited as the
substrate for the Mannich reaction owing to its low reactivity.
However, we anticipated that an imine derived from isatin could
serve as a good substrate, because the neighboring amide car-
bonyl group would enhance the electrophilicity of the imine.
Thus, we examined the reaction of an imine 3, readily prepared
from isatin (2) and p-anisidine,3 with ketene silyl acetal of ethyl
acetate in the presence of a Lewis acid (Scheme 1). After some
experiments, we found that the reaction proceeded with
BF3ꢁOEt2 in CH2Cl2 at ꢂ20 ꢃC to give ꢀ-amino ester 4a in
62% yield.4 In this case, 2 equivalents of the Lewis acid was nec-
essary to consume the imine 3. Oxindole 4a was treated with
NaH and MeI to afford the corresponding N-methyl derivative
This model study should provide an easy accessible route for
simple analogs of chartellines. Further studies are in progress in
our laboratory.
This work was financially supported by PRESTO, JST,
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.4 (2004)
441
Table 1. ꢀ-Lactam formation
6.82 (1H, d, J ¼ 8 Hz, indole), 7.04 (1H, dt, J ¼ 8, 1 Hz,
indole), 7.24 (1H, dt, J ¼ 8, 1 Hz, indole), 7.34 (2H, d,
J ¼ 8 Hz, indole), 8.15 (1H, br s, NH of indole); 13C NMR
(CDCl3, 75 MHz) ꢃ 13.9, 42.5, 55.3, 61.0, 64.0, 110.5,
114.2, 119.9, 123.0, 124.7, 129.4, 129.5, 138.0, 140.5,
154.3, 169.6, 179.0; Anal. Calcd for C19H20N2O4: C,
67.05; H, 5.92; N, 8.23. Found: C, 67.05; H, 6.00; N, 8.13%.
a) S. Kobayashi, T. Iimori, Y.-F. Wang, T. Izawa, and M.
Ohno, J. Am. Chem. Soc., 103, 2405 (1981). b) H. Huang,
N. Iwasawa, and T. Mukaiyama, Chem. Lett., 1984, 1465.
In the case of Entries 1–3, a small amount of amide derived
from 5a with p-anisidine was obtained, which suggested
elimination of p-anisidine from the activated ester of 5a.
Mp 234–237 ꢃC; IR (KBr) ꢂmax 3279, 1783, 1690, 1618,
O
COOH
NHR2
NR2
O
CH3CN
reflux
O
N
N
R1
R1
R2 = PMP
R2 = PMP
R2 = H
6a R1 = H
5a R1 = H
R2 = H
R11 = H
5
6
7
6b
5b
5c
R11 = H
R2 = H
R2 = H
R = Me
6c
R = Me
a
Entry
Substrate
Reagents
Product
Yield/%
1
2
3
5a
5a
5a
(PyS)2, Ph3P
7, Et3N
6a
6a
6a
15
20
26
1475 cmꢂ1 1H NMR (CDCl3, 400 MHz) ꢃ 3.24 (1H, dd,
;
8, Et3N
J ¼ 14:5, 1 Hz, –CHAHB–), 3.25 (3H, s, NMe), 3.48 (1H,
dd, J ¼ 14:5, 2 Hz, –CHAHB–), 6.30 (1H, brs, –NH), 6.89
(1H, d, J ¼ 8 Hz, indole), 7.15 (1H, dt, J ¼ 8, 1 Hz, indole),
7.39 (1H, dt, J ¼ 8, 1 Hz, indole), 7.46 (2H, d, J ¼ 8 Hz, in-
dole); 13C NMR (CDCl3, 100 MHz) ꢃ 26.6, 51.0, 55.9, 108.8,
123.3, 123.4, 126.6, 130.5, 143.6, 166.6, 175.0. HRMS
(FAB) m=z calcd for C11H11N2O2 203.0821, found
203.0822.
4
5
6
5b
5b
5b
(PyS)2, Ph3P
7, Et3N
6b
6b
6b
13
16
39
8, Et3N
7
8
9
5c
5c
5c
(PyS)2, Ph3P
7, Et3N
6c
6c
6c
13
16
70
8
9
T. Nagamatsu and T. Kunieda, Chem. Pharm. Bull., 36, 1249
(1988).
8, Et3N
a
All reactions were carried out in [0.01 M] as a substrate
concentration.
For examples of Cu-mediated reaction, a) A. Klapars, J. C.
Antilla, X. Huang, and S. L. Buchwald, J. Am. Chem. Soc.,
123, 7727 (2001). b) K. Yamada, T. Kubo, H. Tokuyama,
and T. Fukuyama, Synlett, 2002, 231. c) R. Shen and J. A.
Porco, Jr., Org. Lett., 2, 1333 (2000). For reviews of Pd-
catalyzed reaction, d) B. H. Yang and S. L. Buchwald, J.
Organomet. Chem., 576, 125 (1999). e) J. F. Hartwig,
Angew. Chem., Int. Ed. Engl., 37, 2046 (1998).
Ph
I
O
O
Cl
Ph
Cl
H
9
H
N
+
N
6c
a
I
O
O
N
H
N
Ph
(91%)
10 L. Jiang, G. E. Job, A. Klapars, and S. L. Buchwald, Org.
Lett., 5, 3667 (2003); The first report of Cu-mediated
emamide formation: T. Ogawa, T. Kiji, K. Hayami, and H.
Suzuki, Chem. Lett., 1991, 1443.
11 S. Uemura, H. Okazaki, A. Onoe, and M. Okano, J. Chem.
Soc., Perkin Trans. 1, 1977, 676.
Me
Me
10a
10b
Scheme 2. Reagents and Conditions, (a) (CH2NHMe)2, CuI,
K2CO3, toluene, reflux.
Grant-in-Aid for the 21st Century COE Program from the
Ministry of Education, Culture, Sports, Science and Technology
of Japan (MEXT).
12 10a: IR (KBr) ꢂmax 1776, 1727, 1617, 1470 cmꢂ1; 1H NMR
(CDCl3, 400 MHz) ꢃ 2.87 (3H, s, NMe), 3.11 (1H, d, J ¼
15 Hz, –CHAHB–), 3.48 (1H, d, J ¼ 15 Hz, –CHAHB–),
6.51 (1H, d, J ¼ 8 Hz, indole), 6.78 (1H, s, vinyl), 6.98
(2H, d, J ¼ 7:5 Hz, phenyl), 7.03–7.10 (3H, m, aromatic),
7.15 (1H, t, J ¼ 7:5 Hz, Ph), 7.20 (1H, d, J ¼ 7 Hz, indole),
7.27 (1H, dt, J ¼ 8, 1.5 Hz, indole); 13C NMR (CDCl3,
100 MHz) ꢃ 26.5, 32.2, 50.8, 61.7, 108.9, 117.8, 121.7,
122.9, 123.1, 124.0, 127.5, 127.7, 128.7, 129.2, 130.3,
134.7, 143.2, 163.4, 172.8; HRMS (FAB) calcd for
C19H16N2O2Cl1 339.0900, Found 339.0901. 10b: IR (KBr)
References and Notes
1
a) L. Chevolot, A.-M. Chevolot, M. Gajhede, C. Lasen, U.
Anthoni, and C. Christophersen, J. Am. Chem. Soc., 107,
4542 (1985). b) U. Anthoni, L. Chevolot, C. Larsen, P. H.
Nielsen, and C. Christophersen, J. Org. Chem., 52, 4709
(1987).
a) X. Lin and S. M. Weinreb, Tetrahedron Lett., 42, 2631
(2001). b) C. Sun, X. Lin, and S. M. Weinreb, 19th Interna-
tional Congress of Heterocyclic Chemistry, Colorado,
August, 2003, Abstr., p 324.
2
ꢂmax 1763, 1725, 1617, 1472 cmꢂ1
;
1H NMR (CDCl3,
400 MHz) ꢃ 2.80 (3H, s, NMe), 3.13 (1H, d, J ¼ 15 Hz,
–CHAHB–), 3.40 (1H, d, J ¼ 15 Hz, –CHAHB–), 6.46 (1H,
d, J ¼ 8 Hz, indole), 6.77 (2H, d, J ¼ 7 Hz, Ph), 6.78 (1H,
s, vinyl), 7.03–7.17 (4H, m, aromatic), 7.25 (1H, dt, J ¼ 8,
1 Hz, indole), 7.35 (1H, d, J ¼ 8 Hz, indole); 13C NMR
(CDCl3, 100 MHz) ꢃ 26.1, 47.8, 50.5, 67.8, 108.4, 116.1,
123.1, 123.4, 125.3, 126.0, 127.5, 128.4, 128.8, 129.8,
130.5, 132.9, 142.4, 164.0, 173.2; HRMS (FAB) m=z calcd
for C19H16N2O2I1 431.0257, found 431.0260.
3
4
M. Rajopadhye and F. D. Popp, J. Heterocycl. Chem., 21,
289 (1984).
Mp 172–175 ꢃC. IR (KBr) ꢂmax 3193, 1735, 1616,
1235 cmꢂ1 1H NMR (CDCl3, 300 MHz) ꢃ 1.16 (3H, t,
;
J ¼ 7 Hz, OCH2CH3), 2.89 (1H, d, J ¼ 15 Hz, –CHAHB–),
2.98 (1H, d, J ¼ 15 Hz, –CHAHB–), 3.62 (3H, s, –OMe),
4.10 (2H, m, OCH2CH3), 4.91 (1H, br s, NH), 6.42 (2H,
dt, J ¼ 9, 3 Hz, PMP), 6.54 (2H, dt, J ¼ 9, 3 Hz, PMP),
Published on the web (Advance View) March 20, 2004; DOI 10.1246/cl.2004.440