Enantioselective synthesis of the aminoimidazole segment of dragmacidin D

Article abstract of DOI:10.1016/S0040-4039(01)02331-0

A facile enantioselective synthesis of the 2-aminoimidazole side-chain of dragmacidin D has been developed, which involved the regio- and stereoselective opening of the chiral epoxide 9 by a diindolylcuprate reagent, followed by further steps to give 5-substituted N-(1H-imidazol-2-yl)acetamide 2.

Full text of DOI:10.1016/S0040-4039(01)02331-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1063–1066
Enantioselective synthesis of the aminoimidazole segment of
dragmacidin D
Cai-Guang Yang, Jun Wang and Biao Jiang*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, PR China
Received 18 September 2001; revised 27 November 2001; accepted 6 December 2001
Abstract—A facile enantioselective synthesis of the 2-aminoimidazole side-chain of dragmacidin D has been developed, which
involved the regio- and stereoselective opening of the chiral epoxide 9 by a diindolylcuprate reagent, followed by further steps to
give 5-substituted N-(1H-imidazol-2-yl)acetamide 2. © 2002 Elsevier Science Ltd. All rights reserved.
Dragmacidin D (1, Fig. 1), a novel secondary metabo-
lite, was first isolated from a deep-water marine sponge
of the genus Spongosorites by Wright and co-workers in
1992.1 In 1995, Capon and co-workers also reported the
isolation and structure determination of 1 from a Spon-
gosorites collected during a trawling operation off the
southern coast of Australia.2 It inhibited the growth of
the feline leukemia virus, the opportunistic fungal
pathogens Cryptococcus neoformans and Candida albi-
cans, and the P388 and A549 tumor cell lines. Further
biological studies indicated that dragmacidin D, and its
co-metabolite dragmacidin E, have been identified as
potent inhibitors of serine–threonine protein phos-
phatases, and dragmacidin D was a selective inhibitor
of PP1.3 The structure of 1 was exclusively determined
by NMR methods, including one- and two-dimensional
NMR spectroscopy. Structurally, it varied from the
previously reported dragmacidins4 in the further oxida-
tion of the piperazine ring to a 1(2H)-pyrazinone and
the addition of a 2-aminoimidazole-containing side-
chain on one of the indole rings. However, the absolute
configuration remains unknown at the present time. Its
unique structure and wide range of biological and
pharmacological activities attracted our attention and
prompted us to undertake the total synthetic study. We
previously reported the synthesis of the bis(indol-3-yl)-
N
O
AcHN
OH
N
H
Br
OTr
N
Ts
N
Ts
N
TBS
OMe
OMe
OMe
11
2
19
O
OH
H
N
OTr
H
N
9
Br
O
OH
H
N
N
NH2
N
TBS
N
Br
N
H
OMe
3
8
1 Dragmacidin D
Figure 1.
Keywords: enantioselective; 2-aminoimidazole; dragmacidin D.
* Corresponding author. E-mail: jiangb@pub.sioc.ac.cn
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02331-0

1064
C.-G. Yang et al. / Tetrahedron Letters 43 (2002) 1063–1066
arise from a regio- and stereoselective opening of epox-
Br
1. 98% H2SO4
rt, 26 h
Br2, HOAc,
6 h, 98%
ide 9 using the higher order cuprate reagent prepared
from the 4,7-disubstituted indole 8, which in turn could
be obtained using Leimgruber–Batcho indole synthetic
methodology.10
3
NO2
2. HNO3 + H2SO4
0 oC, 2 h, 59%
NO2
OH
OH
5
4
1. DMFDA,
pyrrolidine
DMF, 110 oC,
14 h
MeI, K2CO3
reflux, 100%
On the basis of the synthetic plan, we initially prepared
disubstituted indole 8 as follows (Scheme 1). The start-
ing material 3 was converted to the known nitro com-
Br
Br
BuLi, TBSCl
82%
pound
4 by selective sulfonation, nitration and
8
acid-induced desulfonation in 59% yield.11 Treatment of
4 with bromine in the presence of acetic acid gave
p-bromophenol 5 in high yield, which in turn could be
protected by methylation to give intermediate 6 quanti-
tatively.12 The 4,7-disubstituted indole 7 was prepared
in 75% yield via Batcho–Leimgruber indole synthesis
from nitrotoluene 6 by reaction with dimethylfor-
mamide dimethyl acetal, followed by reduction of the
intermediate enamine with hydrazine hydrate in the
presence of Raney-Ni as the catalyst.13 The indole 7
was protected with tert-butyldimethylsilyl chloride
(TBSCl) using n-butyllithium as the base in THF to
provide compound 814 in 82% yield along with the
unconverted starting material.15
2. Raney-Ni
NH2NH2H2O
THF/MeOH
75%
N
H
NO2
OMe
7
OMe
6
Scheme 1.
2(1H) pyrazinone core of 1 through the condensation
of N-Boc-indolyl glycine with indol-3-yl-N-methyl-O-
methoxyglycinamide, followed by selective reduction
and intramolecular cyclization.5 In this letter, we wish
to report the enantioselective synthesis of the 2-
aminoimidazole segment of dragmacidin D.
Several classes of marine natural products possessing
the 2-aminoimidazole structure have been discovered
and identified over recent years.6 However, only a
limited number of the methods described the direct
synthesis of the corresponding 2-aminoimidazole
derivatives.7 As shown in Fig. 1, our strategy for assem-
bling the 2-aminoimidazole system of dragmacidin D
relied on the cyclization reaction of a-bromo ketone 19
and N-acetylguanidine as a guanidine equivalent in
dimethylformamide at room temperature to give 5-sub-
stituted N-(1H-imidazol-2-yl)acetamide 2.8 a-Bromo
ketone 19 would be derived from 11 as a result of
regioselective protection, Swern oxidation,9 and nucleo-
philic substitution. Compound 11 was expected to
The epoxide 9 was prepared according to an established
method as a single enantiomer.16 The initial attempt to
realize the epoxide opening with the indolyllithium
reagent from 8 was unsuccessful. Reaction of com-
pound 9 with TBS-protected indole 8, n-butyllithium
and BF3 etherate produced the tris(indol-4-yl) borane
1014 in 38% yield, but none of the expected epoxide-
opened product.17 However, as shown in Scheme 2,
reaction of bromoindole 8 sequentially with n-butyl-
lithium, copper(I) cyanide, BF3 etherate, and epoxide 9
proceeded regio- and stereoselectively to give 1114 as a
single isomer in 92% yield.18 This procedure establishes
the desired stereochemistry as either the R- or S-
OMe
TBS
BuLi, THF, -78 oC
N
BF3Et2O, 9, 38%
8
B
NTBS
MeO
OMe
TBSN
10
BuLi, THF, -78 oC
OH
O
BF3Et2O, CuCN
1. (COCl)2, DMSO
Et3N, -40 oC,
OTr
X
9, 92%
acetylguanidine
8
2
DMF, rt, 96h
32%
2. Silica
separation
87%
N
R
N
Ts
OMe
OMe
11 R = TBS
12 R = H
13 R = Ts
TBAF, 98%
14 X = OH
18 X = OMs
19 X = Br
MsCl/Et3N, 96%
LiBr, 88%
TsCl, NaH, 89%
Scheme 2.

C.-G. Yang et al. / Tetrahedron Letters 43 (2002) 1063–1066
1065
O
O
OTr
SMe
OTr
Cl
Swern oxidation
11
+
N
H
N
TBS
OMe
OMe
16 10%
15 58%
conc. HCl
89%
O
OH
Cl
N
H
OMe
17
Scheme 3.
configuration at the 3-position of the newly produced
compound 11.
in acetone to give the a-bromo ketone 19 in 88% yield.
The cyclization reaction of ketone 19 and N-acetyl-
guanidine in dimethylformamide at room temperature
for 4 days gave 5-substituted N-(1H-imidazol-2-yl)-
acetamide 214 in 32% yield as a single enantiomer24
(Scheme 2).
Swern oxidation of the secondary alcohol 11 to the
ketone was carried out by treatment with oxalyl chlo-
ride, dimethyl sulfoxide and triethylamine at −40°C to
room temperature. On the basis of NMR spectroscopy,
the resulting major product was shown to be 3-
chloroindole 15 in 58% yield, while the minor product
was 3-methylthio indole 16 in 10% yield.19 In order to
determine the structure of 15, we deprotected 15 with
conc. HCl in methanol to give 1714 in 89% yield and
99% ee,20 the structure of which was confirmed by
X-ray analysis (Scheme 3). The reason for the chlorina-
tion of the indole at the 3-position is that the electron-
donating property of the TBS-protection makes the
indole ring electron-rich, and electrophilic substitution
occurs more easily. The known facile tetra-
butylammonium fluoride induced cleavage of the TBS
protecting group from 11 gave 12 in 98% yield, which
was regioselectively protected as the tosylamide using
sodium hydride as base to provide 13 in 89% yield.
Oxidation of 13 under Swern conditions directly gave
the desired a-hydroxy ketone 14 in 87% yield (Scheme
2).
Acknowledgements
We are grateful for financial support from the Shanghai
Municipal Committee of Science and Technology.
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1066
C.-G. Yang et al. / Tetrahedron Letters 43 (2002) 1063–1066
NMR (DMSO-d6, 300 MHz) l 11.60 (br s, 1H), 7.41
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(d, J=2.5 Hz, 1H), 6.67 (s, 2H), 4.91 (q, J=7.0 Hz,
1H), 4.14 (d, J=18.3 Hz, 1H), 4.01 (d, J=18.3 Hz,
1H), 3.90 (s, 3H), 1.36 (d, J=7.0 Hz, 3H); 13C NMR
(DMSO-d6, 75 MHz)
l 210.5, 145.3, 125.8, 124.1,
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123.2, 123.0, 122.2, 118.6, 102.6, 66.1, 55.3, 41.6, 17.6;
EIMS m/z: 267; anal. calcd for C13H14ClNO3: C, 58.43;
H, 5.24; N, 5.24. Found: C, 58.25; H, 5.50; N, 4.95.
For compound 2: [h]D20 −18 (c 0.50, CHCl3); IR (KBr)
9. (a) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org.
Chem. 1978, 43, 2480; (b) Mancuso, A. J.; Brownfain,
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11. (a) Gibson, G. B. J. Chem. Soc. 1923, 1269; (b) Ek, A.;
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12. MacKenzie, A. R.; Moody, C. J.; Rees, C. W. Tetra-
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13. Batcho, A. D.; Leimgruber, W. Org. Synth. 1984, 63,
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3374, 1679, 1607, 1172 cm−1 1H NMR (CDCl3, 400
;
MHz) l 7.82 (d, J=4.0 Hz, 1H), 7.73 (d, J=8.4 Hz,
2H), 7.27 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.0 Hz, 1H),
6.63 (d, J=4.0 Hz, 1H), 6.59 (d, J=8.0 Hz, 1H), 6.50
(br s, 1H), 4.33 (q, J=7.2 Hz, 1H), 3.65 (s, 3H), 2.39
(s, 3H), 2.15 (s, 3H), 1.62 (d, J=7.2 Hz, 3H); EIMS
m/z: 452.
15. Amart, M.; Hadida, S.; Sathyanarayana, S.; Bosch, J.
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1988, 53, 4730.
14. For compound 8: IR (KBr) 2956, 2932, 1569, 1483,
1288 cm−1 1H NMR (CDCl3, 300 MHz) l 7.23 (d,
;
J=3.2 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 6.60 (d, J=
3.2 Hz, 1H), 6.47 (d, J=8.3 Hz, 1H), 3.85 (s, 3H), 0.85
(s, 9H), 0.53 (s, 6H); 13C NMR (CDCl3, 100 MHz) l
146.8, 133.5, 132.5, 131.0, 122.9, 105.4, 105.1, 102.9,
54.2, 26.7, 19.5, −1.8; EIMS m/z: 339/341; anal. calcd
for C15H22BrNOSi: C, 52.94; H, 6.47; N, 4.12. Found:
C, 53.15; H, 6.51; N, 3.94.
17. Itoh, T.; Matsuda, K.; Iwamura, H.; Hori, K. J. Am.
Chem. Soc. 2000, 122, 2567.
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19. Tomita, K.; Terada, A.; Tachikawa, R. Heterocycles
1976, 4, 729.
20. Enantiomeric excess was determined by the 1H and 19F
NMR analysis of the Mosher’s ester of compound 17.
21. Classon, B.; Liu, Z. J. Org. Chem. 1988, 53, 6126.
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24. The enantiomeric excess of compound 2 was deter-
mined by converting 2 into the (S)-MTPA derivative 20
and (R)-MTPA derivative 21, respectively. In the 19F
NMR (CDCl3, 282 MHz) spectra of compounds 20 and
21 only one peak was observed at 1318.52 and 1338.10
Hz, respectively. It was thus revealed that compound 2
was obtained as a single enantiomer.
For compound 10: Mp 158–159°C; IR (KBr) 2932,
1590, 1561, 1280 cm−1 1H NMR (CDCl3, 400 MHz) l
;
7.52 (d, J=7.8 Hz, 3H), 7.30 (d, J=3.1 Hz, 3H), 7.00
(d, J=3.1 Hz, 3H), 6.67 (d, J=7.8 Hz, 3H), 3.94 (s,
9H), 0.91 (s, 27H), 0.56 (s, 18H); EIMS m/z: 792.
HREIMS calcd for C45H66BN3O3Si3: 791.4533, found:
791.4519.
For compound 11: Mp 59–61°C; [h]2D0 −3 (c 1.22,
CHCl3); IR (KBr) 2931, 1583, 1493, 1287 cm−1 1H
;
NMR (CDCl3, 300 MHz) l 7.36 (dd, J=8.3 and 1.3
Hz, 6H), 7.20 (m, 10H), 6.79 (d, J=8.0 Hz, 1H), 6.58
(d, J=3.3 Hz, 1H), 6.50 (d, J=8.0 Hz, 1H), 4.07 (m,
1H), 3.86 (s, 3H), 3.31 (m, 1H), 3.13 (dd, J=9.4 and
6.6 Hz, 1H), 3.05 (dd, J=9.4 and 4.5 Hz, 1H), 1.33 (d,
J=7.0 Hz, 3H), 0.88 (s, 9H), 0.54 (s, 6H); 13C NMR
(CDCl3, 100 MHz) l 145.8, 144.0, 132.3, 131.6, 130.7,
128.7, 128.3, 127.7, 126.9, 118.0, 103.2, 101.7, 86.7,
74.5, 66.0, 53.9, 39.1, 26.9, 19.6, 15.6, -3.2; EIMS m/z:
591; anal. calcd for C38H45NO3Si: C, 77.16; H, 7.61; N,
2.37. Found: C, 77.08; H, 7.82; N, 2.55.
N
N
AcHN
O
AcHN
O
N
N
Ph
OMe
F3C
F3C
Ph
OMe
N
Ts
N
Ts
OMe
OMe
For compound 17: Mp 120°C (dec.); [h]2D0 +270 (c 0.44,
21 (R)-MTPA derivative
20 (S)-MTPA derivative
CHCl3); IR (KBr) 3461, 3216, 2944, 1679 cm−1 1H
;
single peak at 1338.10 Hz
single peak at 1318.52 Hz