Synthetic approaches towards an indole alkaloid isolated from the marine sponge Halichondria melanodocia

Article abstract of DOI:10.1016/j.tet.2006.09.003

The exocyclic analogue of the indole alkaloid isolated from the marine sponge Halichondria melanodocia has been prepared via olefination of a phosphonoester derived from 3-(2-bromoacyl)indole. The formation of an unexpected indolylazepine is also discusse

Full text of DOI:10.1016/j.tet.2006.09.003

Tetrahedron 62 (2006) 10815–10820
Synthetic approaches towards an indole alkaloid isolated
from the marine sponge Halichondria melanodocia
Ann-Louise Johnsona and Jan Bergmana,b,
*
aUnit for Organic Chemistry, Department of Biosciences and Nutrition, Karolinska Institute, Novum Research Park,
SE-141 57 Huddinge, Sweden
bSo€derto€rn University College, SE-141 04 Huddinge, Sweden
Received 13 June 2006; revised 14 August 2006; accepted 1 September 2006
Available online 2 October 2006
Abstract—The exocyclic analogue of the indole alkaloid isolated from the marine sponge Halichondria melanodocia has been prepared via
olefination of a phosphonoester derived from 3-(2-bromoacyl)indole. The formation of an unexpected indolylazepine is also discussed.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
evaluated, neither have their structures been confirmed via
synthesis. It also seems to be uncertain whether the alkaloids
are produced by the sponge itself or by the associated algae
and bacteria.
Marine organisms, such as sponges and tunicates, constitute
a unique and vast resource for the discovery of bioactive
molecules with novel structures. Many marine alkaloids
have generated interest not only due to their various and
often striking pharmacological activities but also as chal-
lenging problems for structure elucidation and synthesis.1
2. Results and discussion
Our continuous interest in marine indole alkaloids3 attracted
our attention towards compound 2. Since chloroacetylaza-
homoadamantane (4) (Fig. 2) has been reported to react with
triethyl phosphonoacetate at the a-position,4 we believed
that 2-chloro-1-(1H-indol-3-yl)-ethanone (5)5 could simi-
larly afford the appropriate building block in our attempts
to synthesise 2. It was conceived that such a phosphonoester
building block should provide a possibility to introduce the
double bond in the correct position of the lactam.
As far back as in 1979 two lactams were isolated from the
isopropanol extracts of an algae-infested Caribbean sponge,
Halichondria melanodocia.2 The structures of the lactams
were assigned as the related phenol and indole derivatives
1 and 2, respectively (Fig. 1). Although structure 3 was
discussed as an alternative for 2, it was disregarded since
it was incompatible with the chemical shift data.
To the best of our knowledge, the biological activity of the
lactams isolated from H. melanodocia has not yet been
Hence, triethyl phosphonoacetate was treated with a base
(NaH) followed by the Boc-protected chloroacyl indole
6a. The yields of 7a were quite modest, under the conditions
initially evaluated (NaH, THF), seldom over 30%, largely
depending on the co-formation of product 84 together with
unreacted starting material (Scheme 1). Other bases were
O
O
O
O
O
H
N
NH
O
NH
N
N
HO
H
H
O
O
1
2
3
N
Cl
Cl
Figure 1.
N
H
Keywords: Halichondria melanodocia; Indole alkaloids; Exocyclic; Lac-
tams.
4
5
* Corresponding author. Tel.: +46 8 608 92 04; fax: +46 8 608 15 01; e-mail:
jan.bergman@biosci.ki.se
Figure 2.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.003

10816
A.-L. Johnson, J. Bergman / Tetrahedron 62 (2006) 10815–10820
tried as well (BuLi, t-BuOK, LDA, DBU) with the result of
either inferior yields or more by-product formation. Solvent
and temperature changes did not improve the yield but, since
we noticed that in the presence of a catalyst (NaI or Bu4NI)
the yields improved (less than 10% product without cata-
lyst), we suspected that other 3-(2-haloacyl)indoles could
give superior results. As expected, changing the chlorine
atom to bromine or iodine (compounds 6b–d) improved
the yields significantly. As a consequence, the formation
of 8 was minimised. Changing to a polar aprotic solvent
improved the yields even further.
proceed in a very modest yield. Using BuLi as the base
afforded compound 11a and 11b in low yields, around
20%. Other bases tried (DBU, LDA, t-BuOK,
[(CH3)3Si]2NK, NaH) failed to give the desired product
(Scheme 3).
The plan was to remove the Boc-protecting groups and
cyclise the amine to the desired lactam. However, treatment
of 11a with 20 equiv TFA and subsequent treatment with
NaHCO3 gave the seven-membered heterocycle 12 instead
of the expected free amine or the six-membered heterocycle
2. Also, quite surprisingly, the indole nitrogen remained
Boc-protected despite the acid treatment. Due to the rather
unstable enamine character of compound 12, optimal condi-
tions for preparation and isolation are still an issue, as is the
deprotection of this compound.
O
OEt
O
O
O
X
X
OEt
(a)
+
P(OEt)2
O
N
N
R
It seems likely that the azepine formation could be induced
by the electron withdrawing Boc-protecting group on the
indole nitrogen, which would render the carbonyl at the 3-
position of the indole more susceptible for attack than the
ester functionality. Consequently, removal of the benzene-
sulfonyl group of 11b under standard conditions afforded
13, which was further reacted with N-hydroxysuccinimide
(HOSu). Surprisingly, during hydrolysis of the ester of
11a the acidic workup also removed the indole Boc-protect-
ing group, affording compound 13. This situation is in
contrast with the treatment of 11a with trifluoroacetic
acid or formic acid where the amine group is more easily
deprotected.
N
R
R
8 X = Cl, R = Boc
6a X = Cl, R = Boc
6b X = Br, R = Boc
6c X = I, R = Boc
7a R = Boc
7b R = SO2Ph
6d X = Br, R = SO2Ph
Scheme 1. (a) NaH; other reagents and conditions see Table 1.
Table 1
Indole derivative
Solvent Other conditions
Yield Yield
7a/7b 8 (%)
(%)
6a X¼Cl, R¼Boc
6a X¼Cl, R¼Boc
6a X¼Cl, R¼Boc
THF
THF
THF
Bu4NI, rt, 18 h 27
Bu4NI, reflux, 4 h 42
14
n.i
n.i
Attempts to accomplish the cyclisation to the lactam
under basic conditions, prior to removal of the amine-
protecting group were unsuccessful and did not afford
the six-membered ring. Instead, treatment of 14 with
DBU at ꢀ78 ꢁC actually demonstrated the nucleophilic
behaviour of DBU, resulting in an N-3-caprolactam
derivative.10
Bu4NI, 0 ꢁC to
rt, 18 h
24
6a X¼Cl, R¼Boc
6a X¼Cl, R¼Boc
6a X¼Cl, R¼Boc
Toluene Bu4NI, reflux, 3 h 22
DMF
THF
n.i
—
26
—
n.i
n.i
n.i
—
—
—
—
NaI, 60 ꢁC, 36 h
NaI, rt, 18 h
NaI, rt, 1.5 h
rt, 18 h
—
26
72
8
6d X¼Br, R¼SO2Ph THF
6a X¼Cl, R¼Boc
6c X¼I, R¼Boc
6b X¼Br, R¼Boc
6c X¼I, R¼Boc
THF
THF
THF
DMF
rt, 18 h
rt, 18 h
rt, 18 h
NaI, rt, 18 h
rt, 18 h
rt, 18 h
56
49
70
56
71
64
The N-succinimide ester 14 was treated with TFA, and
thereafter with a biphasic mixture of aqueous NaHCO3
solution and CH2Cl2. A six-membered lactam could thereaf-
ter be isolated from the mixture (Scheme 4). However, when
comparing the data for this particular lactam with the data
reported for the natural compound, it was realised that
the exocyclic compound 15 was the product, rather than
6d X¼Br, R¼SO2Ph DMF
6b X¼Br, R¼Boc
DMF
6d X¼Br, R¼SO2Ph DMF
rt¼Room temperature, n.i.¼not isolated.
Compound 6d6 was synthesised via bromination of 3-
(1-benzenesulfonyl-1H-indolyl)-ethanone (9)7 using pyridi-
nium hydrobromide perbromide.8 The minor co-product, the
dibromo derivative 10, could easily be separated from the
main product by column chromatography (Scheme 2).
1
the endocyclic natural alkaloid. In the H NMR spectrum
of compound 15, it was quite evident that the double bond
had migrated, since all three methylenic groups are coupled
and one proton singlet appears at d 6.40. For the natural
product, a one proton triplet appears at d 6.64, which is
coupled with one methylene group, also the methylene
bridge appears as a broad singlet. Whether the exocyclic
lactam 15 is the kinetic product in this reaction is uncertain,
but there are indications from similar examples in the
literature.11
Br
O
O
O
Br
Br
(a)
+
N
N
N
SO2Ph
SO2Ph
SO2Ph
The exocyclic analogue of the indole alkaloid isolated
from the marine sponge H. melanodocia has thus been
prepared in our laboratory. All attempts to produce the
endocyclic lactam and thus to be able to confirm the
structure assigned for the natural product to date have been
unsuccessful.
9
6d (55%)
10 (10%)
Scheme 2. (a) Py$HBr3, CHCl3, reflux 30 min.
The Horner–Wadsworth–Emmons olefination of 7a and 7b
with N-Boc-3-aminopropionaldehyde9 did however only

A.-L. Johnson, J. Bergman / Tetrahedron 62 (2006) 10815–10820
10817
O
O
O
HN
O
O
OEt
(b)
OEt
P(OEt)2
(a)
OEt
NHBoc
O
N
N
N
R
R
R
7a R = Boc
7b R = SO2Ph
11a R = Boc (27%)
11b R = SO2Ph (20%)
12 R = Boc (50%)
Scheme 3. (a) BuLi, N-Boc-3-aminopropionaldehyde, THF, ꢀ78 ꢁC to rt, 18 h; (b) (i) TFA, CH2Cl2, rt, 4 h, (ii) aq satd NaHCO3; (c) TFA.
O
O
O
O
O
O
O
N
OH
NHBoc
OEt
NHBoc
(a)
(b)
O
O
N
N
N
NHBoc
H
R
H
11a R = Boc
11b R = SO2Ph
13 (95%)
14 (59%)
(c)
O
O
NH
N
H
15 (27%)
Scheme 4. (a) (i) 1 M KOH, EtOH, reflux, 1 h, (ii) 1 M HCl; (b) HOSu, EDCI, DMF, rt, 18 h; (c) (i) TFA, CH2Cl2, rt, 4 h, (ii) aq NaHCO3, CH2Cl2.
3. Experimental
(DMSO-d6): d 8.73 (s, 1H), 8.23–8.20 (m, 1H), 8.12–8.10
(m, 1H), 7.47–7.36 (m, 2H), 5.10 (s, 2H), 1.67 (s, 9H); 13C
NMR (DMSO-d6): d 187.6 (s), 148.4 (s), 134.8 (s), 134.0
(d), 126.8 (s), 125.7 (d), 124.5 (d), 121.7 (d), 116.6 (s),
115.0 (d), 85.7 (s), 47.1 (t), 27.6 (q); MS (ESI) m/z 294
(M+H)+. Anal. Calcd for C15H16ClNO3: C, 61.33; H, 5.49;
N, 4.77. Found: C, 61.31; H, 5.55; N, 4.65.
3.1. General
NMR spectra were recorded on a Bruker Avance 300 DPX at
300 MHz for 1H and 75 MHz for 13C. NMR spectra were re-
corded in DMSO-d6 or CDCl3, using the solvent signal as
reference. d Values are given in parts per million, coupling
constants are given in hertz. The IR spectra were acquired
using a ThermoNicolet Avatar 330 FT-IR instrument. Ele-
mental analyses were performed by H. Kolbe Mikroanaly-
3.1.2. 3-(2-Bromo-acetyl)-indole-1-carboxylic acid tert-
butyl ester (6b). 3-(2-Bromo-acetyl)-indole-1-carboxylic
acid tert-butyl ester (6b) was prepared from 2-bromo-1-
(1H-indol-3-yl)-ethanone12 as described above. Crystallisa-
tion from 2-propanol gave the title compound as a white
amorphous solid. Yield: 76%.
€
tisches Laboratorium, Mulheim an der Ruhr, Germany.
High-resolution mass spectroscopic (HRMS) analyses
were performed by E. Nilsson, University of Lund, Sweden.
€
Melting points were determined on a Buchi B-545, using the
capillary method and are uncorrected. All reagents used
were purchased from Aldrich, Lancaster, Merck or Biosynth
and were used as received. All solvents were purified by dis-
tillation or were of analytical grade. THF was distilled from
sodium/benzophenone. Chromatographic separations were
performed on silica gel 60 (230–400 mesh).
Mp 149.0–150.5 ꢁC; IR (neat): 2980, 1730, 1658, 1550,
1448, 1364, 1146, 1093, 837, 750 cmꢀ1
;
1H NMR
(DMSO-d6): d 8.77 (s, 1H), 8.23–8.20 (m, 1H), 8.12–8.09
(m, 1H), 7.46–7.36 (m, 2H), 4.88 (s, 2H), 1.68 (s, 9H); 13C
NMR (DMSO-d6): d 187.7 (s), 148.4 (s), 134.9 (s), 134.5
(d), 126.9 (s), 125.7 (d), 124.5 (d), 121.7 (d), 116.5 (d),
114.9 (s), 85.7 (s), 34.1 (t), 27.6 (q). Anal. Calcd for
C15H16BrNO3: C, 53.27; H, 4.77; N, 4.14. Found: C,
53.31; H, 4.68; N, 4.05.
3.1.1. 3-(2-Chloro-acetyl)-indole-1-carboxylic acid tert-
butyl ester (6a). To a stirred suspension of 2-chloro-1-
(1H-indol-3-yl)-ethanone5 (9.65 g, 50 mmol) in CH3CN
(120 mL) was added Boc2O (12.0 g, 55 mmol), followed
by DMAP (37 mg, 0.3 mmol) in small portions. The reaction
mixture was stirred for 12 h and the solvent was thereafter
evaporated under reduced pressure. The residue was crystal-
lised from EtOH to give 3-(2-chloro-acetyl)-indole-1-car-
boxylic acid tert-butyl ester (6a) as a cream coloured
amorphous solid (13.1 g, 89%).
3.1.3. 3-(2-Iodo-acetyl)-indole-1-carboxylic acid tert-
butyl ester (6c). 3-(2-Iodo-acetyl)-indole-1-carboxylic
acid tert-butyl ester (6c) was prepared from 2-iodo-1-(1H-
indol-3-yl)-ethanone12 as described above. Crystallisation
from 2-propanol gave the title compound as a cream col-
oured amorphous solid. Yield: 79%.
Mp 142.0–144.0 ꢁC; IR (neat): 2980, 1728, 1651, 1547,
Mp 156.0–157.0 ꢁC; IR (neat): 2979, 1730, 1675, 1542,
1446, 1365, 1145, 1084, 836, 746 cmꢀ1 1H NMR
;
(DMSO-d6): d 8.78 (s, 1H), 8.21–8.18 (m, 1H), 8.11–8.09
1447, 1367, 1139, 1108, 836, 747 cmꢀ1
;
1H NMR

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A.-L. Johnson, J. Bergman / Tetrahedron 62 (2006) 10815–10820
(m, 1H), 7.44–7.37 (m, 1H), 4.63 (s, 2H), 1.68 (s, 9H); 13
C
NMR (DMSO-d6): d 8.67 (s, 1H), 8.20 (d, J¼7.9, 1H),
8.12 (d, J¼7.9, 1H), 7.45–7.33 (m, 2H), 4.16–4.08 (m,
6H), 3.70–3.36 (m, 3H), 1.68 (s, 9H), 1.30–1.17 (m, 9H).
Anal. Calcd for C23H32NO8P: C, 57.37; H, 6.70; N, 2.91.
Found: C, 57.57; H, 6.81; N, 2.84.
NMR (DMSO-d6): d 189.8 (s), 148.5 (s), 135.0 (s), 134.4
(d), 127.0 (s), 125.6 (d), 124.4 (d), 121.9 (d), 116.0 (s),
114.9 (d), 85.7 (s), 27.6 (q), 6.3 (t). Anal. Calcd for
C15H16INO3: C, 46.77; H, 4.19; N, 3.64. Found: C, 46.87;
H, 4.27; N, 3.57.
3.1.6. 4-(1-Benzenesulfonyl-1H-indol-3-yl)-2-(diethoxy-
phosphoryl)-4-oxo-butyric acid ethyl ester (7b). Com-
pound 7b was prepared from 3-(1-benzenesulfonyl-1H-
indol-3-yl)-2-bromo-ethanone (6d) using the procedure
described above. Silica gel column chromatography
using hexane/EtOAc (60:40) with increasing amounts of
EtOAc as eluent afforded compound 7b as pale yellow oil.
Yield: 64%.
3.1.4. 3-(1-Benzenesulfonyl-1H-indol-3-yl)-2-bromo-
ethanone (6d) and 3-(1-benzenesulfonyl-1H-indol-3-yl)-
2,2-dibromo-ethanone (10). 3-(1-Benzenesulfonyl-1H-
indol-3-yl)-ethanone7 (9) (2.99 g, 10.0 mmol) and pyridi-
nium hydrobromide perbromide (3.84 g, 12.0 mmol) were
suspended in chloroform (50 mL) and heated at reflux
for 30 min. The reaction mixture was allowed to cool
and thereafter transferred to a separatory funnel, washed
with H2O (50 mL), dried over Na2SO4 and evaporated
to dryness. The residue was subjected to column chromato-
graphy using CH2Cl2/hexane (80:20) as eluent to give
10 (0.44 g, 10%) followed by 6d (2.07 g, 55%) as white
solids.
IR (neat): 2982, 1731, 1669, 1538, 1446, 1384, 1250, 1164,
1135, 1018, 750, 727 cmꢀ1; 1H NMR (DMSO-d6): d 9.00 (s,
1H), 8.23–8.13 (m, 3H), 7.98 (d, J¼8.2, 1H), 7.76–7.63 (m,
3H), 7.43–7.36 (m, 2H), 4.17–4.07 (m, 6H), 3.75–3.46 (m,
3H), 1.30 (dt, J¼1.9, 7.0, 6H), 1.20 (t, J¼7.1, 3H); HRMS
(FAB+) m/z calcd for C24H29NO8PS (M+H)+ 522.1351,
found 522.1350.
3.1.4.1. 3-(1-Benzenesulfonyl-1H-indol-3-yl)-2-bromo-
ethanone (6d). Mp 119.5–121.5 ꢁC (lit.6 130.5–131.0 ꢁC);
IR (neat): 3137, 1669, 1536, 1373, 1176, 1134, 989, 749,
3.1.7. 3-(1-Chloromethyl-2-ethoxycarbonyl-vinyl)-in-
dole-1-carboxylic acid tert-butyl ester (8). To a suspension
of NaH (220 mg, 5.5 mmol) in THF (15 mL) at room tem-
perature was added triethyl phosphonoacetate (0.4 mL,
5.0 mmol) in small portions. After 40 min at room tempera-
ture compound 6a (1.47 g, 5.0 mmol) was added as a solid in
small portions together with NaI (75 mg, 0.5 mmol). After
18 h, H2O (5 mL) was added to the reaction mixture and
THF was evaporated. The residue was redissolved in EtOAc
(20 mL) and washed with H2O (2ꢂ10 mL), brine (15 mL),
dried over Na2SO4 and evaporated. The residue was sub-
jected to column chromatography using hexane/EtOAc
(90:10) with increasing amounts of EtOAc as eluent to
give compound 8 (472 mg, 26%) followed by compound
7a (637 mg, 26%) as pale yellow solids.
1
726, 589 cmꢀ1; H NMR (CDCl3): d 8.36 (s, 1H), 8.31 (d,
J¼8.2, 1H), 7.98–7.93 (m, 3H), 7.63–7.58 (m, 1H), 7.52–
7.47 (m, 2H), 7.42–7.33 (m, 2H), 4.37 (s, 2H); 13C NMR
(CDCl3): d 187.1 (s), 137.4 (s), 135.0 (s), 134.9 (d), 133.0
(d), 129.9 (d), 127.7 (s), 127.3 (d), 126.3 (d), 125.4 (d),
123.2 (d), 118.4 (s), 113.3 (d), 31.6 (t). Anal. Calcd for
C16H12BrNO3S: C, 50.81; H, 3.20; N, 3.70. Found: C,
50.79; H, 3.30; N, 3.65.
3.1.4.2. 3-(1-Benzenesulfonyl-1H-indol-3-yl)-2,2-di-
bromo-ethanone (10). Mp 144.0–145.0 ꢁC; IR (neat):
3123, 1682, 1529, 1371, 1176, 1133, 985, 746, 725,
1
592 cmꢀ1; H NMR (CDCl3): d 8.61 (s, 1H), 8.32–8.29
(m, 1H), 7.99–7.95 (m, 3H), 7.61–7.58 (m, 1H), 7.53–7.48
(m, 2H), 7.42–7.37 (m, 2H), 6.51 (s, 1H); 13C NMR
(CDCl3): d 182.4 (s), 137.2 (s), 135.0 (d), 134.8 (s), 133.4
(d), 129.9 (d), 128.0 (s), 127.4 (d), 126.5 (d), 125.5 (d),
123.3 (d), 114.0 (s), 113.3 (d), 40.3 (d). Anal. Calcd for
C16H11Br2NO3S: C, 42.04; H, 2.43; N, 3.06. Found: C,
41.95; H, 2.44; N, 2.89.
Mp 114–116 ꢁC; IR (neat): 2978, 1735, 1709, 1621, 1450,
1
1367, 1240, 1146, 1106, 1052, 1035, 742 cmꢀ1; H NMR
(CDCl3): d 8.23 (d, J¼7.9, 1H), 7.96 (s, 1H), 7.84–7.81
(m, 1H), 7.40–7.32 (m, 2H), 6.48 (s, 1H), 5.10 (s, 2H),
4.33 (q, J¼7.1, 14.3, 2H), 1.70 (s, 9H), 1.39 (t, J¼7.1,
3H); 13C NMR (CDCl3): d 165.9 (s), 149.4 (s), 146.9 (s),
136.2 (s), 127.8 (s), 126.7 (d), 125.3 (d), 123.7 (d), 120.5
(d), 119.4 (d), 119.3 (s), 115.8 (d), 84.9 (s), 60.7 (t), 40.0
(t), 28.3 (q), 14.5 (q); HRMS (FAB+) m/z calcd for
C19H22ClNO4 (M)+ 363.1237, found 363.1253.
3.1.5. 3-[3-(Diethoxy-phosphoryl)-3-ethoxycarbonyl-
propionyl]-indole-1-carboxylic acid tert-butyl ester (7a).
3.1.5.1. Representative procedure. To a suspension of
NaH (88 mg, 2.2 mmol) in DMF (7 mL) at room tempera-
ture was added triethyl phosphonoacetate (0.4 mL,
2.0 mmol) in small portions. After 40 min at room tempera-
ture compound 6c (770 mg, 2.0 mmol) dissolved in DMF
(5 mL) was added in small portions. After 18 h the reaction
mixture was poured into H2O (15 mL) and extracted with
EtOAc (3ꢂ10 mL). The combined organic phases were
washed with H2O (25 mL), brine (25 mL), dried over
Na2SO4 and the solvents were evaporated. The residue was
subjected to column chromatography using EtOAc/hexane
(70:30) as eluent to give compound 7a as pale yellow solid
(674 mg, 70%).
3.1.8. 3-(6-tert-Butoxycarbonylamino-3-ethoxycarbonyl-
hex-3-enoyl)-indole-1-carboxylic acid tert-butyl ester
(11a). Compound 7a (2.20 g, 4.57 mmol) was dissolved in
THF (20 mL) and cooled to ꢀ78 ꢁC under a nitrogen atmo-
sphere. To the solution was added n-BuLi (3.14 mL,
5.03 mmol) in a dropwise manner. After the addition the so-
lution was warmed up to 0 ꢁC for 30 min, then again cooled
down to ꢀ78 ꢁC. A solution of N-Boc-3-aminopropionalde-
hyde9 (791 mg, 4.57 mmol) in THF (10 mL) was added in
small portions and the reaction mixture was thereafter
allowed to reach room temperature over night. After 18 h
H2O (2 mL) was added and the solvent was evaporated.
The residue was redissolved in EtOAc (20 mL) and washed
Mp 119.5–121.0 ꢁC; IR (neat): 2980, 1732, 1664, 1447,
1
1365, 1255, 1238, 1146, 1136, 1015, 764, 757 cmꢀ1; H

A.-L. Johnson, J. Bergman / Tetrahedron 62 (2006) 10815–10820
10819
with H2O (20 mL). The aqueous phase was extracted with an
additional portion of EtOAc (20 mL) and the combined
organic phases were washed with brine (20 mL) and dried
over Na2SO4. After evaporation the oily residue was purified
by silica gel column chromatography using hexane/EtOAc
(80:20 to 60:40) to give compound 11a as a yellow oil.
Yield: 610 mg (27%).
3.1.11. 5-tert-Butoxycarbonylamino-2-[2-(1H-indol-3-
yl)-2-oxo-ethyl]-pent-2-enoic acid 2,5-dioxo-pyrrolidin-
1-yl ester (14). Compound 13 (474 mg, 1.27 mmol) was
dissolved in DMF (4 mL). EDCI (269 mg, 1.40 mmol) and
HOSu (161 mg, 1.40 mmol) were added and the resulting re-
action mixture was kept at room temperature for 18 h. The
reaction mixture was poured into H2O (20 mL) and extracted
with EtOAc (3ꢂ10 mL). The combined organic phases were
washed with H2O (20 mL) and brine (20 mL), dried over
Na2SO4 and evaporated. The oily residue was purified on
column chromatography using EtOAc/hexane (50:50 to
70:30) as eluent to give compound 14 as a light brown oil.
Yield: 354 mg (59%).
IR (neat): 3365, 2978, 1742, 1701, 1449, 1364, 1236, 1136,
1100, 749 cmꢀ1; 1H NMR (DMSO-d6): d 8.67 (s, 1H), 8.21
(d, J¼7.7, 1H), 8.12 (d, J¼8.0, 1H), 7.44–7.32 (m, 2H),
6.94–6.89 (m, 2H), 4.11–4.04 (m, 4H), 3.07–3.01 (m, 2H),
2.36–2.29 (m, 2H), 1.67 (s, 9H), 1.35 (s, 9H), 1.14 (t,
J¼7.1, 3H); 13C NMR (DMSO-d6): d 192.7 (s), 166.4 (s),
155.6 (s), 148.5 (s), 142.2 (d), 134.9 (s), 133.3 (d), 127.7
(s), 127.0 (s), 125.4 (d), 124.2 (d), 121.9 (d), 118.9 (s),
114.8 (d), 85.4 (s), 77.5 (s), 60.1 (t), 38.8 (t), 37.6 (t), 29.0
(t), 28.1 (q), 27.5 (q), 14.0 (q); HRMS (FAB+) m/z calcd
for C27H37N2O7 (M+H)+ 501.2601, found 501.2598.
IR (neat): 3230, 2932, 1733, 1700, 1646, 1521, 1204, 1163,
1
1067, 749 cmꢀ1; H NMR (CDCl3): d 9.25 (s, 1H), 8.35–
8.32 (m, 1H), 7.95 (d, J¼3.1, 1H), 7.40–7.37 (m, 1H),
7.30–7.21 (m, 4H), 3.87 (s, 2H), 3.30–3.26 (m, 2H), 2.77
(s, 4H), 2.54–2.47 (m, 2H), 1.41 (s, 9H); 13C NMR (ace-
tone-d6): d 190.8 (s), 170.5 (s), 163.2 (s), 148.6 (d), 137.8
(s), 134.0 (d), 126.9 (s), 125.5 (s), 123.6 (d), 122.9 (d),
122.8 (d), 117.6 (s), 112.7 (d), 78.7 (s), 39.8 (t), 38.0 (t),
30.7 (t), 28.6 (q), 26.3 (t), 26.11 (t); HRMS (FAB+) m/z calcd
for C24H28N3O7 (M+H)+ 470.1927, found 470.1927.
3.1.9. 2-[2-(1-Benzenesulfonyl-1H-indol-3-yl)-5-tert-bu-
toxycarbonylamino]-pent-2-enoic acid ethyl ester (11b).
Compound 11b was prepared from 4-(1-benzenesulfonyl-
1H-indol-3-yl)-2-(diethoxy-phosphoryl)-4-oxo-butyric acid
ethyl ester (7b) using the procedure described above. Col-
umn chromatography using hexane/EtOAc (60:40) eluent
afforded compound 11b as pale yellow oil. Yield: 23%.
3.1.12. 3-(4-Ethoxycarbonyl-6,7-dihydro-1H-azepin-2-
yl)-indole-1-carboxylic acid tert-butyl ester (12). Com-
pound 11a (378 mg, 0.76 mmol) dissolved in formic acid
(15 mL) was stirred at room temperature for 4 h. The acid
was evaporated and the residue was dissolved in EtOAc
(20 mL) and washed with satd aq NaHCO3 (3ꢂ15 mL).
The organic phase was washed with H2O (15 mL) and brine
(15 mL), dried over MgSO4 and evaporated. The residue was
purified by column chromatography using hexane/EtOAc
(60:40) with increasing amounts of EtOAc as eluent to afford
the title compound as a yellow oil (144 mg, 50%).
IR (neat): 2978, 1701, 1536, 1376, 1166, 1135, 748, 727,
1
592, 571 cmꢀ1; H NMR (CDCl3): d 8.42 (s, 1H), 8.32–
8.27 (m, 1H), 7.99–7.92 (m, 4H), 7.63–7.58 (m, 1H),
7.53–7.48 (m, 3H), 7.39–7.29 (m, 2H), 7.08 (t, J¼7.8,
1H), 5.11 (br, 1H), 4.20–4.08 (m, 2H), 3.95 (s, 2H), 3.31–
3.29 (m, 2H), 2.50–2.42 (m, 2H), 1.39 (s, 9H), 1.31–1.18
(m, 3H); 13C NMR (CDCl3): d 192.7 (s), 166.9 (s), 156.2
(s), 143.0 (d), 137.8 (s), 135.1 (s), 134.8 (d), 132.6 (d),
129.8 (d), 128.1 (s), 127.9 (s), 127.4 (d), 126.1 (d), 125.1
(d), 123.4 (d), 121.1 (s), 113.2 (d), 77.4 (s), 61.2 (t), 39.6
(t), 38.0 (t), 29.9 (t), 28.5 (q), 14.4 (q); HRMS (FAB+) m/z
calcd for C28H33N2O7S (M+H)+ 541.2008, found 541.2010.
1H NMR (CDCl3): d 8.20 (d, J¼7.9, 1H), 7.91 (d, J¼7.7,
1H), 7.72 (s, 1H), 7.38–7.26 (m, 2H), 6.87 (t, J¼6.15, 1H),
5.80 (s, 1H), 4.36 (br s, 1H), 4.29 (q, J¼7.1, 14.2, 2H),
3.52–3.51 (m, 2H), 2.75–2.70 (m, 2H), 1.69 (s, 9H), 1.34
(t, J¼7.1, 3H); 13C NMR (CDCl3): d 168.4 (s), 149.4 (s),
140.8 (s), 135.6 (s), 133.5 (d), 130.4 (s), 128.5 (s), 124.6
(d), 123.4 (d), 122.9 (d), 121.6 (s), 120.5 (d), 115.2 (d),
94.5 (d), 83.9 (s), 60.7 (t), 45.2 (t), 35.0 (t), 28.1 (q), 14.2
(q); MS (ESI) m/z 383 (M+H)+; HRMS (EI) m/z calcd for
C22H27N2O4 (M+H)+ 383.1971, found 383.1948; HRMS
(EI) m/z calcd for C22H25N2O4 (MꢀH)ꢀ 381.1814, found
381.1841.
3.1.10. 5-tert-Butoxycarbonylamino-2-[2-(1H-indol-3-
yl)-2-oxo-ethyl]-pent-2-enoic acid (13). To compound
11a (429 mg, 0.86 mmol) dissolved in EtOH (10 mL) was
added 1 M KOH (5 mL). The reaction mixture was heated
to reflux for 1 h and was then allowed to cool. EtOH was
evaporated and the residue diluted with H2O (5 mL). The
resulting mixture was cooled on ice and acidified with 1 M
HCl until a precipitate appeared. The solid was collected
by filtration, washed with water and dried to give 13 as a
yellowish solid (302 mg, 95%).
3.1.13. 3-[2-(1H-Indol-3-yl)-2-oxo-ethylidene]-piperidin-
2-one (15). To a solution of compound 14 (500 mg,
1.07 mmol) in CH2Cl2 (20 mL) was added TFA (1.64 mL,
21.3 mmol) and the resulting solution was stirred at room
temperature for 7 h. The solvent was evaporated and the resi-
due was parted between CH2Cl2 (25 mL) and H2O (20 mL),
adding NaHCO3 (540 mg, 6.43 mmol) to reach pH w7–8.
After 12 h at room temperature a beige solid was collected
by filtration from the biphasic mixture, washed with water
and dried to give the title compound. Yield: 72 mg (27%).
Mp 168–170 ꢁC; IR (neat): 3267, 2978, 1693, 1638, 1515,
1
1428, 1244, 1154, 1135, 746 cmꢀ1; H NMR (DMSO-d6):
d 12.18 (s, 1H), 11.94 (s, 1H), 8.40 (d, J¼3.1, 1H), 8.15–
8.12 (m, 1H), 7.49–7.46 (m, 1H), 7.21–7.16 (m, 2H),
6.91–6.84 (m, 2H), 3.91 (s, 2H), 3.07–3.00 (m, 2H), 2.33–
2.26 (m, 2H), 1.36 (s, 9H); 13C NMR (DMSO-d6): d 191.6
(s), 168.3 (s), 155.6 (s), 141.2 (d), 136.5 (s), 133.9 (d),
128.8 (s), 125.4 (s), 122.7 (d), 121.6 (d), 121.3 (d), 115.9
(s), 112.1 (d), 77.5 (s), 39.0 (t), 37.0 (t), 29.0 (t), 28.2 (q).
Anal. Calcd for C20H24N2O5: C, 64.50; H, 6.50; N, 7.52.
Found: C, 64.37; H, 6.70; N, 7.39.
Mp 200.0–201.5 ꢁC; IR (neat): 3232, 2938, 1746, 1683,
1
1642, 1587, 1575, 1523, 1426, 1132, 795, 738 cmꢀ1; H

10820
A.-L. Johnson, J. Bergman / Tetrahedron 62 (2006) 10815–10820
4. Miryan, N. I.; Isaev, S. D.; Kovaleva, S. D.; Petukh, N. V.;
Dvornikova, E. V.; Kardakova, E. V.; Yurchenko, A. G. Russ.
J. Org. Chem. 1999, 35, 857.
NMR (DMSO-d6): d 11.74 (s, 1H), 8.16–8.13 (m, 1H), 7.84
(d, J¼2.7, 1H), 7.56 (br s, 1H), 7.47–7.44 (m, 1H), 7.22–7.14
(m, 2H), 6.40 (s, 1H), 3.24–3.19 (m, 2H), 2.62–2.58 (m, 2H),
1.90–1.84 (m, 2H); 13C NMR (DMSO-d6): d 189.8 (s), 163.1
(s), 136.7 (s), 134.8 (d), 133.8 (d), 133.7 (s), 125.3 (s), 122.5
(d), 121.3 (d), 121.2 (d), 116.5 (s), 112.0 (d), 41.41 (t), 30.0
(t), 22.8 (t). HRMS (FAB+) m/z calcd for C15H15N2O2
(M+H)+ 255.1134, found 255.1141.
€
5. Bergman, J.; Backvall, J.-E.; Lindstrom, J.-O. Tetrahedron
€
1973, 29, 971.
6. Suzuki, H.; Furukawa, T.; Yamada, C.; Shibuya, I.; Kurumi,
M.; Yokoyama, T.; Murakami, Y. Heterocycles 2002, 56, 519.
7. Ketcha, D. M.; Gribble, G. W. J. Org. Chem. 1985, 50, 5451.
8. Ando, R.; Sakaki, T.; Jikihira, T. J. Org. Chem. 2001, 66, 3617.
9. Delfourne, E.; Kiss, R.; Le Corre, L.; Dujols, F.; Bastide, J.;
Collignon, F.; Lesur, B.; Frydman, A.; Darro, F. J. Med.
Chem. 2003, 46, 3536.
References and notes
1. Pindur, U.; Lemster, T. Curr. Med. Chem. 2001, 8, 1681.
2. Gopichand, Y.; Schmitz, F. J. J. Org. Chem. 1979, 44, 4995.
10. Lammers, H.; Cohen-Fernandes, P.; Habraken, C. L. Tetra-
hedron 1994, 50, 865.
€
3. (a) Wahlstrom, N.; Stensland, B.; Bergman, J. Tetrahedron
11. Campi, E. M.; Chong, J. M.; Jackson, W. R.; van der Schoot, M.
Tetrahedron 1994, 50, 2533.
2004, 60, 2147; (b) Janosik, T.; Johnson, A.-L.; Bergman, J.
Tetrahedron 2002, 58, 2813; (c) Johnson, A.-L.; Bergman, J.;
€
12. Bergman, J.; Backvall, J.-E. Tetrahedron 1975, 31, 2063.
€
Sjogren, M.; Bohlin, L. Tetrahedron 2004, 60, 961.