Total synthesis of marine sponge bis(indole) alkaloids of the topsentin class

Article abstract of DOI:10.1021/jo070286r

(Chemical Equation Presented) The synthesis of four natural bis(indole) alkaloids of topsentin class 1 and 2 is described. Their bis(indole) α-carbonylimidazoline and subsequently bis(indole) α- carbonylimidazole moieties have been built via the condensation between indolic α-ketothioimidate salts 4 and l-(indol-3′-y1)-1,2-diaminoethane 3. This compound results from the β-amino indolic hydroxylamine 5 by a two-step sequence. This is the first total synthesis of compounds 1d, 2a, and 2b.

Full text of DOI:10.1021/jo070286r

Total Synthesis of Marine Sponge Bis(indole)
Alkaloids of the Topsentin Class
Xavier Guinchard, Yannick Valle´e, and Jean-Noe¨l Denis*
De´partement de Chimie Mole´culaire (SERCO), UMR-5250,
ICMG FR-2607, CNRS, UniVersite´ Joseph Fourier, BP-53,
38041 Grenoble Cedex 9, France
Jean-Noel.Denis@ujf-grenoble.fr
ReceiVed February 12, 2007
FIGURE 1. Structures of several topsentins 1 and 4,5-dihydro-
topsentins 2.
and their novel structural features have made them attractive
targets for both biomedical and synthetic purposes.
The synthesis of a few of them has been described, mainly
natural topsentins 1a,b,7a-e and synthetic O-methyltopsentin 1e,7f
containing the R-carbonylimidazole moiety. Surprisingly, the
synthesis of natural 4,5-dihydrotopsentins 2, containing the
R-carbonylimidazoline unit, is not described. In this paper, we
report a common convergent approach to these moieties through
the synthesis of natural topsentin D 2a, spongotine B 2b,
topsentin A 1a, isobromodeoxytopsentin 1d, and synthetic
O-methyltopsentin 1e from the same starting building block,
â-amino indolic N-hydroxylamine 5.8,9 Indeed, this precursor
contains the 1-(indol-3′-yl)-1,2-diaminoethane unit 3, the key
The synthesis of four natural bis(indole) alkaloids of topsen-
tin class 1 and 2 is described. Their bis(indole) R-carbon-
ylimidazoline and subsequently bis(indole) R-carbonylimi-
dazole moieties have been built Via the condensation between
indolic R-ketothioimidate salts 4 and 1-(indol-3′-yl)-1,2-
diaminoethane 3. This compound results from the â-amino
indolic hydroxylamine 5 by a two-step sequence. This is the
first total synthesis of compounds 1d, 2a, and 2b.
In the search of novel bioactive natural substances, biologists
turned their attention to the studies of marine organisms.1
Among them, sponges appear to be one of the richest phyla in
toxicogenic species because of their ability to produce a wide
variety of metabolites2 that, in several cases, are responsible of
the observed toxicity. To this aim, bioactive crude extracts of
sponges were selected, and bioassay-guided fractionation led
to the isolation of bis(indole) alkaloids such as nortopsentins,
topsentins, dragmacidins, and hamacanthins.3
Topsentins 1 and 4,5-dihydrotopsentins 2 were found in
several marine sponges, including Mediterranean Topsentia
genitrix and Carribbean or Korean Spongosorites sp. (Figure
1).3,4 These metabolites have received considerable attention
because of their potent properties such as antitumor, antiviral,
and antiinflammatory activities.5 This wide range of bioactivity6
(4) (a) For the first isolation of topsentins 1a-c, see: Bartik, K.;
Braekman, J.-C.; Daloze, D.; Stoller, C.; Huysecom, J.; Vandevyver, G.;
Ottinger, R. Can. J. Chem. 1987, 65, 2118. See also ref 6b therein for the
isolation of topsentins 1a and 1c. (b) For isolation of isobromodeoxy-
topsentin 1d, see: Shin, J.; Seo, Y.; Cho, K. W.; Rho, J.-R.; Sim, C. J. J.
Nat. Prod. 1999, 62, 647. (c) For isolation of topsentin D 2a, see: Braekman,
J. C.; Daloze, D.; Moussiaux, B.; Stoller, C.; Deneubourg, F. Pure Appl.
Chem. 1989, 61, 509. (d) For isolation of (+)-spongotine B 2b, see: Bao,
B.; Sun, Q.; Yao, X.; Hong, J.; Lee, C.-O.; Cho, H. Y.; Jung, J. H. J. Nat.
Prod. 2007, 70, 2.
(5) For patent literature, see: (a) Gunasekera, S. P.; Cross, S. S.; Kashman
Y.; Lui M. S. Eur. Patent 272 810, 1988; Chem. Abstr. 1988, 109, 129417q.
(b) Gunasekera, S. P.; Cross, S. S. Eur. Patent 304 157, 1989; Chem. Abstr.
1989, 111, 160196g. (c) Gunasekera, S. P.; Cross, S. S.; Kashman, Y.; Lui,
M. S.; Rinehart, K. L.; Tsujii, S. U.S. Patent 4 866 084, 1989; Chem. Abstr.
1990, 112, 185775d. (d) Sun, H. H.; Sakemi, S.; Gunasekera, S.; Kashman,
Y.; Lui, M.; Burres, N.; McCarthy, P. U.S. Patent 4 970 226, 1990; Chem.
Abstr. 1991, 115, 35701z. (e) McConnell, O. J.; Saucy, G.; Jacobs, R. U.S.
Patent 5 290 777, 1994; Chem. Abstr. 1994, 120, 236178m. (f) Wright, A.
E.; Mattern, R.; Jacobs, R. S. Patent WO 2000002857, 2000.
(6) Oh, K.-B.; Mar, W.; Kim, S.; Kim, J.-Y.; Lee, T.-H.; Kim, J.-G.;
Shin, D.; Sim, C. J.; Shin, J. Biol. Pharm. Bull. 2006, 29, 570.
(7) (a) Braekman, J. C.; Daloze, D.; Stoller, C. Bull. Soc. Chim. Belg.
1987, 96, 809. (b) Tsujii, S.; Rinehart, K. L.; Gunasekera, S. P.; Kashman,
Y.; Cross, S. S.; Lui, M. S.; Pomponi, S. A.; Diaz, M. C. J. Org. Chem.
1988, 53, 5446. (c) Achab, S. Tetrahedron Lett. 1996, 37, 5503. (d)
Kawasaki, I.; Katsuma, H.; Nakayama, Y.; Yamashita, M.; Ohta, S.
Heterocycles 1998, 48, 1887. (e) Miyake, F. Y.; Yakushijin, K.; Horne, D.
A. Org. Lett. 2000, 2, 2121. (f) Kawasaki, I.; Katsuma, H.; Nakayama, Y.;
Yamashita, M.; Ohta, S. Heterocycl. Commun. 1996, 2, 189.
* Author to whom correspondence should be addressed. Phone: 33-476-51-
44-26. Fax: 33-476-63-59-83.
(1) (a) Gul, W.; Hamann, M. T. Life Sci. 2005, 75, 442. (b) Li, H.-y.;
Matsunaga, S.; Fusetani, N. Curr. Org. Chem. 1998, 2, 649. (c) Alvarez,
M.; Salas, M. Heterocycles 1991, 32, 1391. (d) Kobayashi, J.; Ishibashi,
M. Chem. ReV. 1993, 93, 1753.
(2) (a) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
Prinsep, M. R. Nat. Prod. Rep. 2005, 22, 15 and earlier reports in this series.
(b) Walker, R. P.; Thompson, J. E.; Faulkner, D. J. Mar. Biol. 1985, 88,
27. (c) Braekman, J. C.; Daloze, D. Pure Appl. Chem. 1986, 58, 357.
(3) For a review on marine bis(indole) alkaloids, see: Yang, C.-G.;
Huang, H.; Jiang, B. Curr. Org. Chem. 2004, 8, 1691 and references cited
therein.
(8) (a) Chalaye-Mauger, H.; Denis, J.-N.; Averbuch-Pouchot, M.-T.;
Valle´e, Y. Tetrahedron 2000, 56, 791. (b) Denis, J.-N.; Mauger, H.; Valle´e,
Y. Tetrahedron Lett. 1997, 38, 8515.
10.1021/jo070286r CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/20/2007
3972
J. Org. Chem. 2007, 72, 3972-3975

SCHEME 1. Synthesis of Diamine 3
FIGURE 2. Retrosynthetic analysis of topsentins 1 and 4,5-dihydro-
topsentins 2.
substructure of the indolic alkaloid targets. Our strategy is based
on (i) the easy and efficient transformation of this precursor 5
into the key intermediate indolic 1,2-diamine 3, (ii) its conden-
sation with 3-indolyl R-ketothioimidate salts 4 to give the 4,5-
dihydrotopsentin family compounds 2, including 2a and 2b, and
(iii) the oxidation of the obtained imidazoline spacer into the
corresponding imidazole core providing topsentins 1a, 1d, and
1e (Figure 2). To the best of our knowledge, this is the first
total synthesis of natural topsentin 1d and 4,5-dihydrotopsentins
2a and 2b.
SCHEME 2. Synthesis of r-Ketothioimidate Salts 4a-c
The â-amino indolic N-hydroxylamine 58,9 was transformed
by a three-step sequence into 1-(indol-3′-yl)-1,2-diaminoethane
3. The first step consists of the reduction of the N-hydroxylamine
into the corresponding amine by cleavage of the N-O bond.
One of the known methods uses TiCl3 in acidic medium.10 This
procedure is highly efficient and the reaction is fast (0.25-0.5
h). Treatment of â-amino N-hydroxylamine 5 by TiCl3 (2 equiv)
in a methanol-aqueous HCl mixture led to indolic diprotected
diamine 6 in a nearly quantitative yield. In the next step,
hydrogenation of the benzyl group with Pearlman’s catalyst (Pd-
(OH)2) afforded the corresponding indolic monoprotected di-
amine 7 in 93% yield. During this work, we found that this
compound could be obtained in one step directly from indolic
N-hydroxylamine 5, by catalytic hydrogenation with Pd(OH)2
in a MeOH-AcOH mixture (96/4) at room temperature for 50
h (Scheme 1).
Removal of the Boc group with 8% solution of HCl in
methanol11 or in pure formic acid afforded quantitatively the
expected indolic 1,2-diamine salts 8a and 8b, respectively. These
compounds are easily isolated by evaporation of excess reactants
and solvent (HCl/MeOH or HCO2H) under vacuum and purified
by a simple wash with CH2Cl2. These compounds are stable
and could be stored at 0 °C over long periods without any
degradation. Basic treatment of these salts 8a or 8b with an
aqueous 20% NaOH solution led to the expected free indolic
1,2-diamine 3 with 81% and 78% yields, respectively. However,
this compound is unstable and should be immediately engaged
in the subsequent reaction. We therefore decided to use the salt
8a as starting material in the following work.
With salt 8a in hands, we found that 3-indolyl R-ketothio-
imidate salts 4a-c would be the appropriate partners. Indeed,
aliphatic thioimidate salts are known for their great ability to
react with aliphatic 1,2-diamines in order to incorporate an
imidazoline moiety as an amide bond replacement in peptides.12
The salts 4a-c have been synthesized from the commercially
available indoles 9a-c in four steps as depicted in Scheme 2.
The known 3-indolyl-R-oxoacetyl chloride derivatives 10a-c
were prepared by reaction of the corresponding indoles 9a-c
with oxalyl chloride in ether.13 Treatment with Bu3SnH in ethyl
acetate14 gave the intermediate aldehydes which were im-
(9) The â-amino indolic N-hydroxylamine 5 has been prepared in a two-
step sequence from N-(tert-butoxycarbonyl)-aminoacetaldehyde in 84%
overall yield. This aldehyde is commercially available. However, for a recent
and efficient synthesis of this compound, see: Myers, M. C.; Pokorski, J.
K.; Apella, D. H. Org. Lett. 2004, 6, 4699.
(12) Gilbert, I. H.; Rees, D. C.; Crockett, A. K.; Jones, R. C. F.
Tetrahedron 1995, 51, 6315.
(10) (a) Murahashi, S.-I.; Kodera, Y. Tetrahedron Lett. 1985, 26, 4633.
(b) Kodera, Y.; Watanabe, S.; Imada, Y.; Murahashi S.-I. Bull. Chem. Soc.
Jpn. 1994, 67, 2542.
(11) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T. Tetrahedron
Asymmetry 1997, 8, 2381.
(13) (a) Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002,
124, 13179. (b) Shaw, K. N. F.; McMillan, A.; Gudmundson, A. G.;
Armstrong, M. D. J. Org. Chem. 1958, 23, 1171. (c) Hashem, M. A.;
Sultana, I.; Hai, M. A. Indian J. Chem. Sect. B 1999, 38, 789.
(14) Kuivila, H. G. J. Org. Chem. 1960, 25, 284.
J. Org. Chem, Vol. 72, No. 10, 2007 3973

SCHEME 3. Synthesis of Topsentins 1 and 4,5-Dihydrotopsentins 2
mediately reacted with solid sulfur and piperidine in pyridine15
to afford the expected 3-indolyl-R-ketothioamides 11a-c.
Finally, these compounds were converted to the corresponding
S-methylthioimidate salts 4a-c in excellent yields by treatment
with an excess of methyl iodide at reflux. Because of their
relative instability (slow decomposition), these intermediates
were rapidly used.
N-hydroxylamine 5.9 These syntheses involved the construction
of the R-ketoimidazoline and R-ketoimidazole units Via con-
densation of 3-indolyl R-ketothioimidate salts 4a-c with
1-(indol-3′-yl)-1,2-diaminoethane 3. This approach constitutes
the first method for the synthesis of bis(indol-3′-yl)-R-ketoimi-
dazolines 2 and a new way for the preparation of bis(indol-3′-
yl)-R-ketoimidazole derivatives 1.
Salts 4a-c were then condensed with 1-(indol-3′-yl)-1,2-
diaminoethane 3, prepared in situ from 8a by treatment with
Amberlyst A21 in MeOH, to give the racemic bis(indole)
ketoimidazolines 2a-c, including natural topsentin D 2a and
spongotine B 2b. Finally, oxidation of compounds 2a-c with
o-iodoxybenzoic acid (IBX, 1.1 equiv) in dry DMSO16 afforded
the expected topsentin A 1a, isobromodeoxytopsentin 1d (with
a nonoptimized yield), and O-methyltopsentin 1e (Scheme 3).
For these synthetic compounds 1, mixtures of slowly inter-
converting tautomers (ratios: 55/45) were observed by 1H and
13C NMR in neutral solution (CD3COCD3) as previously
Experimental Section
1-[N-(Benzyl)-amino]-2-[N′-(tert-butoxycarbonyl)amino]-1-
(indol-3′-yl)ethane (6). To a stirred solution of 0.42 g (1.10 mmol)
of indolic N-hydroxylamine 5 in 6 mL of methanol was added 2.07
mL (2.50 g, 2.40 mmol) of a 15% aqueous solution of TiCl3. The
resulting mixture was stirred at rt during 2 h. A large excess of an
aqueous solution of 20% NaOH, saturated with NaCl, was added.
Methanol was removed under vacuum, and the crude mixture was
extracted three times by EtOAc. The combined organic layers were
washed with water and brine and dried over anhydrous MgSO4.
After removal of the solvent, the residue was purified by column
chromatography on silica gel (eluent: EtOAc). The protected
diamine 6 was obtained (0.36 g, 0.98 mmol) as a white solid.
Yield: 89%. Mp: 45-48 °C. IR (neat): 3416, 3310, 3059, 2978,
1
described for 1a4a,b and 1e7f (eq 1). H NMR spectra show a
splitting of all signals, which could be suppressed by addition
of 1% of CF3COOD into the deuterated solvent. 1H NMR
chemical shifts and coupling constants of synthetic topsentins
correspond to those previously described in the literature for
topsentins.4a,b,7f
2880, 1696, 1502, 1453, 1393, 1341, 1250, 1104, 1031 cm-1. H
1
NMR (CDCl3, 300 MHz): δ ) 1.42 (s, 9H), 1.81 (bs, 1H), 3.38-
3.60 (m, 2H), 3.72 (AB, JAB ) 13.4 Hz, δA - δB ) 18.0 Hz, 2H),
4.11 (t, J ) 5.8 Hz, 1H), 4.99 (bs, 1H), 6.95-7.40 (m, 9H), 7.66
(d, J ) 7.5 Hz, 1H), 8.76 (s, 1H). 13C NMR (CDCl3, 75.5 MHz):
δ ) 28.3, 45.4, 51.3, 54.6, 79.2, 111.4, 115.6, 119.3, 122.0, 122.3,
126.2, 126.8, 128.1, 128.3, 136.6, 140.4, 156.3. LRMS (DCI, NH3
+ isobutane): m/z ) 366 [(M + H)+], 259, 235, 203, 108. Anal.
calcd for C22H27N3O2: C, 72.33; H, 7.40; N, 11.51. Found: C,
72.71; H, 7.48; N, 11.41.
1-Amino-2-[N′-(tert-butoxycarbonyl)amino]-1-(indol-3′-yl)e-
thane (7). Route A: From Indolic N-Hydroxylamine (5). To a
stirred solution of 2.0 g (5.25 mmol) of indolic N-hydroxylamine
5 in 93 mL of methanol and 3.5 mL of acetic acid was added 0.8
g of Pearlman’s catalyst (Pd(OH)2). Argon was replaced by
hydrogen. The resulting mixture was then stirred at rt for 40 h. It
was then filtered through celite. The resulting filtrate was treated
by an aqueous 6 N solution of NaOH. Methanol was evaporated
under vacuum. The resulting aqueous mixture was extracted three
times with EtOAc. Combined organics layers were washed with
brine and dried over anhydrous MgSO4. After removal of the
solvent, the residue was purified by column chromatography on
silica gel (eluent: EtOAc). Product 7 was obtained as a white solid
(1.31 g, 4.75 mmol, 90%). Route B: From Indolic Diamine (6).
To a stirred solution of 0.43 g (1.20 mmol) of indolic diamine 6 in
24 mL of methanol and 1 mL of acetic acid was added 0.17 g of
Pearlman’s catalyst (Pd(OH)2). Argon was replaced by hydrogen.
The resulting mixture was then stirred at rt during 40 h. It was
then filtered through celite. The resulting filtrate was treated by an
aqueous 6 N solution of NaOH. Methanol was evaporated under
vacuum. The resulting aqueous mixture was extracted five times
In summary, we have accomplished the total syntheses of
topsentin D 2a and spongotine B 2b in 65% and 41% overall
yield in three steps, respectively, and of isobromodeoxytopsentin
1d, topsentin A 1a, and O-methyltopsentin 1e, respectively, with
14%, 59%, and 57% overall yields in four steps from indolic
(15) Andrieu, L.; Bitoun, J.; Fatome, M.; Granger, R.; Robbe, Y.; Terol,
A. Eur. J. Med. Chem. Chim. Ther. 1974, 9, 449.
(16) (a) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. Angew.
Chem., Int. Ed. 2003, 42, 4077. (b) Nicolaou, K. C.; Mathison, C. J. N.;
Montagnon, T. J. Am. Chem. Soc. 2004, 126, 5192.
3974 J. Org. Chem., Vol. 72, No. 10, 2007

with EtOAc. Combined organics layers were washed with brine
and dried over anhydrous MgSO4. After removal of the solvent,
the residue was purified by column chromatography (eluant:
EtOAc). Product 7 was obtained as a white solid (0.30 g, 1.1 mmol,
92%). Mp: 145-146 °C. IR (neat): 3404, 3339, 3308, 3053, 2977,
2930, 1703, 1693, 1682, 1537, 1531, 1519, 1514, 1504, 1455, 1393,
1367, 1337, 1251, 1170 cm-1. 1H NMR (CDCl3, 300 MHz): δ )
1.44 (s, 9H), 1.76 (br s, 2H), 3.39 (ddd, J ) 6.5, 7.0 and 13.0 Hz,
1H), 3.57 (ddd, J ) 5.5, 6.5 and 13.0 Hz, 1H), 4.41 (dd, J ) 5.5
and 7.0 Hz, 1H), 4.90 (br s, 1H), 7.12 (ddd, J ) 1.0, 7.5 and 7.5
Hz, 1H), 7.13 (s, 1H), 7.20 (ddd, J ) 1.0, 7.5 and 7.5 Hz, 1H),
7.37 (d, J ) 8.0 Hz, 1H), 7.71 (d, J ) 8.0 Hz, 1H), 8.30 (bs, 1H).
13C NMR (CDCl3, 75.5 MHz): δ ) 28.4, 47.5, 48.7, 79.3, 111.3,
118.6, 119.3, 119.6, 121.0, 122.3, 125.9, 136.6, 156.2. LRMS (DCI,
NH3 + isobutane): m/z ) 276 [(M + H)+]. Anal. calcd for
C15H21N3O2: C, 65.43; H, 7.69; N, 15.26. Found: C, 65.22; H,
7.69; N, 15.19.
112.8, 113.3, 115.8, 117.1, 119.7, 120.3, 122.9, 123.0, 123.8, 124.1,
125.2, 126.7, 127.3, 138.6, 138.9, 139.4, 164.4, 180.3. LRMS
(ESI): m/z ) 329 [(M + H)+]. HRMS (ESI) calcd for C20H17N4O:
329.1402. Found: 329.1396 [(M + H)+].
Topsentin A (1a). IBX (0.17 mmol, 47 mg) was added to a
solution of the topsentin D 2a (50 mg, 0.15 mmol) in 0.6 mL of
DMSO. The resulting mixture was stirred at rt during 15 h and
monitored by TLC until completion. It was then quenched by
addition of a saturated aqueous solution of Na2S2O3 (0.38 mL) and
an equal volume of EtOAc. The mixture was treated by a saturated
aqueous solution of NaHCO3. Aqueous layer was then extracted
three times by EtOAc. Combined organic layers were successively
washed with an aqueous saturated solution of NaHCO3 and brine
and then dried over anhydrous MgSO4. After the removal of the
solvent, the residue was purified by column chromatography on
silica gel (eluent: EtOAc/pentane, 1:1). Topsentin A 1a was
obtained as a yellow solid (45 mg, 0.14 mmol). Yield: 91%. Mp:
140 °C (dec). IR (neat): 3392, 2927, 1693, 1589, 1518, 1454, 1428,
1,2-Diamino-1-(indol-3′-yl)ethane Dihydrochloride (8a). A
cold solution of hydrochloric acid was prepared at 0 °C by adding
4.69 mL (5.2 g, 66.5 mmol) of freshly distilled acetyl chloride to
15 mL of dry methanol. The solution was stirred for 15 min at 0
°C. A solution of protected diamine 7 (1.31 g, 4.75 mmol) in 20
mL of methanol was then added into the acidic solution at 0 °C.
The resulting mixture was stirred for an additional 1 h. Methanol
was then slowly evaporated under vacuum, without heating. The
indolic 1,2-diamine salt 8a was obtained as a brown solid (1.28 g,
4.75 mmol). Yield: 100%. Mp: 170 °C (decomposition). IR
(KBr): 3350, 2953, 2672, 1588, 1484, 1459, 1434, 1339, 1099,
1260, 1240, 1111, 852, 749 cm-1 1H NMR (CD3COCD3, 500
.
MHz): Isomer a: δ ) 7.12-7.24 (m, 2H), 7.24-7.29 (m, 2H,),
7.47 (d, J ) 8.0 Hz), 7.54-7.60 (m, 1H), 7.72 (s, 1H), 7.85 (d, J
) 2.0 Hz, 1H), 8.23 (d, J ) 8.0 Hz, 1H), 8.48-8.56 (m, 1H), 9.65
(d, J ) 3.0 Hz, 1H), 10.38 (s, 1H), 11.16 (s, 1H), 12.07 (s, 1H).
Isomer b: δ ) 7.12-7.24 (m, 2H), 7.24-7.29 (m, 2H), 7.52 (d, J
) 8.0 Hz, 1H), 7.54-7.60 (m, 1H), 7.63 (s, 1H), 7.97 (d, J ) 8.0
Hz, 1H), 8.08 (d, J ) 2.5 Hz, 1H), 8.50-8.56 (m, 1H), 9.42 (d, J
1
) 2.5 Hz, 1H), 10.63 (s, 1H), 11.10 (s, 1H), 12.14 (s, 1H). H
NMR (CD3COCD3 + TFA-d + D2O, 500 MHz): δ ) 7.22 (t, J )
7.0 and 8.0 Hz, 1H), 7.25 (t, J ) 7.0 and 8.0 Hz, 1H), 7.28-7.34
(m, 2H), 7.57 (d, J ) 8.0 Hz, 1H), 7.58-7.63 (m, 1H), 7.97 (d, J
) 8.0 Hz, 1H), 8.01 (s, 1H), 8.16 (s, 1H), 8.34-8.38 (m, 1H),
8.90 (s, 1H). DEPT 13C NMR (CD3COCD3, 75.5 MHz): Isomers
a and b: δ ) 106.6, 111.9, 112.3, 112.70, 112.75, 112.78, 115.0,
115.3, 115.4, 120.3, 120.4, 121.0, 121.2, 122.4, 122.7, 122.8, 123.0,
123.0, 123.2, 123.8, 123.9, 124.3, 126.0, 126.4, 127.1, 128.1, 131.0,
137.3, 137.4, 137.6, 137.8, 137.9, 138.1, 140.2, 146.6, 177.1. DEPT
13C NMR (CD3COCD3, TFA-d, D2O, 75.5 MHz): δ ) 103.1,
113.1, 113.5, 114.9, 116.4, 119.7, 121.6, 122.5, 123.6, 123.9, 125.2,
125.4, 126.3, 127.0, 132.3, 137.6, 138.0, 138.3, 141.6, 171.9. LRMS
(ESI): m/z ) 327 [(M + H)+]. HRMS (ESI) calcd for C20H15N4O:
327.1246. Found: 327.1243 [(M + H)+].
1
1012 cm-1. H NMR (CD3OD, 300 MHz): δ ) 3.65-3.85 (m,
2H), 5.09 (dd, J ) 6.3 and 8.7 Hz, 1H), 7.18 (dt, J ) 1.3 and 7.0
Hz, 1H), 7.24 (dt, J ) 1.3 and 7.0 Hz, 1H), 7.45-7.51 (m, 1H),
7.69 (s, 1H), 7.77-7.83 (m, 1H). 13C NMR (CD3OD, 75.5 MHz):
δ ) 42.4, 47.1, 107.0, 113.1, 119.0, 121.3, 123.8, 126.7, 126.7,
138.3. LRMS (ESI): m/z ) 176 for C10H14N3 [(M + H)+], 159
for C10H11N2 [(M - NH2)+]. HRMS (ESI): Calcd for C10H14N3:
176.1182. Found: 176.1184 [(M + H)+]. Calcd for C10H11N2:
159.0917. Found: 159.0917 [(M - NH2)+].
Indol-3′-yl-[5′′-(indol-3′’-yl)-4,5-dihydroimidazol-2-yl]ke-
tone (topsentin D) (2a). To a stirred solution of indolic diamine
dihydrochloride 8a (50 mg, 0.20 mmol) and thioimidate iodide 4a
(83 mg, 0.20 mmol) in distilled methanol (1 mL) was added
Amberlyst A21 (200 mg). The resulting mixture was stirred for 60
h at rt. Methanol was then removed under vacuum. To the residue
were added water and ethyl acetate. The aqueous layer was extracted
three times with EtOAc. The combined organic layers were then
washed with brine and dried over anhydrous MgSO4. After removal
of the solvent, the residue was purified by column chromatography
on silica gel (eluent: EtOAc). The R-ketoimidazoline 2a (topsentin
D) was obtained as a white solid (48 mg, 0.15 mmol). Yield: 72%.
IR (KBr): 2919, 2851, 1705, 1617, 1582, 1435, 1421, 1374, 1239,
1128 cm-1. 1H NMR (CD3OD, 300 MHz): δ ) 3.98 (dd, J ) 8.6
and 12 Hz, 1H), 4.31 (t, J ) 12 Hz, 1H), 5.56 (dd, J ) 8.6 and 12
Hz, 1H), 7.04 (dt, J ) 1.0 and 7.9 Hz, 1H), 7.14 (dt, J ) 1 and 7.2
Hz, 1H), 7.25-7.31 (m, 2H), 7.31 (s, 1H), 7.40 (d, J ) 8.2 Hz,
1H), 7.46-7.52 (m, 1H), 7.63 (d, J ) 7.9 Hz, 1H), 8.27-8.33 (m,
1H), 8.47 (s, 1H). 13C NMR (CD3OD, 75.5 MHz): δ ) 56.6, 59.1,
Acknowledgment. We thank the “Association de la Re-
cherche contre le Cancer” (ARC) for financial support. We are
grateful to ACI no. 02L0525: “Nouvelles approches the´rapeu-
tiques du cancer” for financial support. This work was supported
by a grant from the “Ministe`re de la Jeunesse, de l’Education
Nationale et de la Recherche” to X.G.
Supporting Information Available: Experimental procedures
and characterization data for compounds 1d, 1e, 2b, 2c, 4a, 4b,
1
4c, 11a, 11b, 11c, and H and 13C or 13C DEPT NMR spectra for
compounds 1a, 1d, 1e, 2a, 2b, 2c, 4a, 4b, 4c, and 8a This material
is available free of charge via the Internet at http://pubs.acs.org.
JO070286R
J. Org. Chem, Vol. 72, No. 10, 2007 3975