Synthesis of ecteinascidin 743 analogues from cyanosafracin B: Isolation of a kinetically stable quinoneimine tautomer of a 5-hydroxyindole

Article abstract of DOI:10.1002/ejoc.200500882

Phthalimido derivatives of cyanosafracin B have been synthesized as analogues of the antitumor agent ecteinascidin 743. As part of this study, a quinoneimine has been prepared, which is a kinetically stable tautomer of a 5-hydroxyindole. This quinoneimine tautomer is stable under acidic and mild basic conditions. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500882

FULL PAPER
DOI: 10.1002/ejoc.200500882
Synthesis of Ecteinascidin 743 Analogues from Cyanosafracin B: Isolation of a
Kinetically Stable Quinoneimine Tautomer of a 5-Hydroxyindole
Plácido A. Ceballos,[a] Marta Pérez,[b] Carmen Cuevas,[b] Andrés Francesch,[b]
Ignacio Manzanares,[c] and Antonio M. Echavarren*[a,c]
Keywords: Quinones / Indoles / Tautomerism / Antitumor agents / Natural products
Phthalimido derivatives of cyanosafracin B have been syn-
thesized as analogues of the antitumor agent ecteinascidin
743. As part of this study, a quinoneimine has been prepared,
which is a kinetically stable tautomer of a 5-hydroxyindole.
This quinoneimine tautomer is stable under acidic and mild
basic conditions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
Yondelis (1) (Ecteinascidin 743, trabectidin) is a tetra-
hydroisoquinoline alkaloid of the ecteinascidin family iso-
lated from Ecteinascidia turbinata[1] that displays highly
cytotoxic activity against a variety of tumor cells (Fig-
ure 1).[2,3] Yondelis is currently in advanced stages of clin-
ical development worldwide.[4] Therefore, the ecteinascidins
have aroused significant synthetic interest. Total syntheses
of 1 have been reported by Corey,[5] Fukuyama,[6] and
Zhu.[7] Other groups have also described synthetic ap-
proaches towards 1 and related tetrahydroisoquinoline al-
kaloids.[8–13]
Corey and Schreiber discovered an analogue of 1, named
phthalascidin (2),[14] which exhibits comparable biological
activity to that of 1. Similarly, Myers developed a synthesis
of bishydroquinone-saframycin analogues, with greater ac-
tivity in antiproliferative assays than the natural product.[15]
These findings have aroused considerable interest and have
led to a search of other simplified tetrahydroisoquinolines
with similar or more potent antitumor efficacies to those
displayed by the parent naturally occurring compound 1.
A practical synthesis of 1 from cyanosafracin B (3) (Fig-
ure 1) has been accomplished by Cuevas, Manzanares and
co-workers.[16] Key for the success of this semisynthetic
method was the ready availability of 3 by a fermentation
process. That approach was also applied for the preparation
of other natural ecteinascidins.[17] Considering the excellent
Figure 1. Ecteinascidin 743 (1), phthalascidin (2), and cyanosafra-
cin B (3).
activity displayed by phthalascidin (2), we embarked on the
synthesis of several analogues such as 4 (Figure 2) that
could be defined as safracin-phthalimide derivatives. These
compounds have the same basic functionalization of 2 but
with a phthalimide as the C-subunit anchored through the
alanine side chain. As part of these studies, we have also
prepared a quinoneimine derivative 5 that is remarkably
stable and does not isomerize to the more stable 5-hy-
droxyindole under acidic or mild basic conditions. Here we
report the synthesis of 4, as well as the preparation and
reactivity of the stable quinoneimine 5.
[a] Departamento de Química Orgánica, Universidad Autónoma
of Madrid,
Cantoblanco, 28049 Madrid, Spain
[b] PharmaMar,
S. A. Avda. de los Reyes 1, P. I. La Mina-Norte, 28770 Col-
menar Viejo, Madrid, Spain
[c] Institute of Chemical Research of Catalonia (ICIQ),
Av. Països Catalans 16, 43007 Tarragona, Spain
Fax: +34-977-920-225
E-mail: aechavarren@iciq.es
1926
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1926–1933

Synthesis of Ecteinascidin 743 Analogues from Cyanosafracin B
FULL PAPER
Et3N (2.1 equiv.) in CH2Cl2, which provided 7 in excellent
yield. Protection of the free phenol of 7 with Boc2O
(1.2 equiv.), pyridine (1.5 equiv.) and DMAP (0.01 equiv.)
in CH2Cl2 gave carbonate 8 in good yield. This two step
sequence could also be carried out in one pot in 88% over-
all yield.
Saponification of the vinilogous ester 8 was performed
with an excess of NaOH under high-dilution conditions to
give hydroxy derivative 9 after acidification of the reaction
mixture to pH5. Immediate catalytic hydrogenation of 9
with Pd/C in DMF, followed by reaction with CH2BrCl and
Cs2CO3 at 100 °C gave rise to methylenedioxy derivative 10
in 18% yield for the three steps (Scheme 2). The low overall
yield reflects the lability of hydroxyquinone derivative 9.
Acetylation of the phenol group of 10 with AcCl
(1.2 equiv.) and pyridine (2 equiv.) in CH2Cl2 gave 11 in
81% yield. Deprotection of the Boc group could not be
effected with TFA, which led only to unchanged starting
material. However, reaction of 11 with HCl in dioxane at
40 °C gave 12 (61%), along with small amounts of diphenol
13. At higher temperatures, diphenol 13 was exclusively ob-
tained. Diphenol 13 was also obtained by cleavage of the
Boc group of 10 under similar acidic conditions. Finally,
substitution of the cyano group by a hydroxy was achieved
with AgNO3 in aqueous MeCN[16] to give 4 in 70% yield.
Thus, 4 was obtained in 8 steps from 3 in 5% overall yield.
Table 1 summarizes the results on in vitro activities of
Figure 2. Phthalimido derivative 4 and quinoneimine 5.
Results and Discussion
Synthesis of Phthalimide Derivative 4: For the synthesis
of target 4 we planned to form first the phthalimide from
the free amino group, followed by subsequent transforma-
tion of the p-benzoquinone into the methylenedioxy aryl
ring by the route developed by Cuevas, Manzanares and co-
workers.[16] However, reaction of 3 with phthalic anhydride
failed to provide the expected phathalimide 7, leading exclu-
sively to the phthalimidic acid 6 under all the conditions
examined. Phthalimidic acid 6 did not react with carbonyl
diimidazole or triphosgene as activating agents. However,
in an attempt at protecting the phenol and carboxylic acid
groups as MOM derivatives, we finally succeeded in prepar- compounds of Scheme 1 and Scheme 2 against three human
ing 7. Thus, reaction of 6 with MOMBr and iPr2NEt in tumor cell lines. Among all the derivatives examined, only
CH2Cl2 gave the 7 in 60–74% yields (Scheme 1). A more 12 and 4, with structures more closely related to that of 2,
direct synthesis of this phthalimide derivative was achieved display significant in vitro antitumor activity in the order
by treatment of 3 with phthaloyl dichloride (1.0 equiv.) and of 10–2 µ concentrations.
Scheme 1.
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A. M. Echavarren et al.
FULL PAPER
Scheme 2.
Table 1. In vitro activities (GI50 = concentration causing 50% 14, prepared by reaction of 3 with phenylisothiocyanate, we
growth inhibition) of compounds 4 and 6–13 (µM concentrations)
compared with those of parent 1.
obtained quinoneimine 5 in excellent yield by an intramo-
lecular condensation of the initially formed primary amine
Compound
Breast
(MB-231)
Lung
(A549)
Colon
(HT29)
with the quinone carbonyl (Scheme 3). Unexpectedly, none
of the 5-hydroxyindole derivative 15 was formed in this re-
action. Quinoneimine 5 was recovered unchanged in the
presence of acids such as HCl or trifluoroacetic acid at
room temperature for long reaction times. Furthermore, 5
does not suffer isomerization after being heated with pyri-
dine in CH2Cl2 under refluxing conditions for 14 h. Qui-
noneimine 5 shows only moderate in vitro antitumor ac-
tivity (IC50 = 2.17 µ; murine P388 and melanoma MEL28)
but displays a new type of structure that could be further
functionalized for the synthesis of analogues of 1.
1
0.003
0.03
0.34
0.097
0.31
3.26
0.94
1.02
0.02
1.37
0.003
0.04
0.80
0.14
0.37
4.83
0.73
0.37
0.02
1.18
0.003
0.05
0.80
0.22
0.69
4.57
0.81
0.65
0.03
1.16
4
6
7
8
9
10
11
12
13
Furthermore, 5 is interesting by itself as it represents the
Synthesis of Stable Quinoneimine 5: In the original ap- first quinoneimine that does not spontaneously isomerize
proach developed by Cuevas, Manzanares and co-workers, to give the corresponding hydroxyindole. Simple quinone-
the alanine residue of 3 was removed by an Edman degra- imines 16a[18] and 16b,[19] which cannot suffer tautomerization
dation on a derivative in which the quinone ring had been because of the presence of a quaternary center at C-2, have
refunctionalized to a methylendioxy arene ring. However, been described (Figure 3).[20] On the other hand, ()-α-do-
when the Edman degradation was carried out on thiourea pachrome (17) and ()-α-methyldopachrome (18) are rela-
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Synthesis of Ecteinascidin 743 Analogues from Cyanosafracin B
FULL PAPER
The quinoneimine structure of 5 is preserved under a
variety of reaction conditions (Scheme 4). Reaction of 5
with 1 equiv. of Ac2O, pyridine and DMAP in CH2Cl2 gives
rise to monoacetate 22 in 77% yield. The quinoneimine nu-
cleus is also stable under oxidizing conditions. Thus, treat-
ment of 5 with PhI(OAc)2 in MeOH leads to o-quinone
dimethyl acetal 23 in 81% yield. On the other hand, treat-
ment of 5 with Na2S2O4 in H2O/CH2Cl2 gave rise to indo-
line 24 in 92% yield. However, reduction of 5 with Zn in
HOAc/H2O gave poor results. Derivative 24 is relatively un-
stable, suffering readily reoxidation to give starting qui-
noneimine 5, although it can be handled in the presence of
air for a few minutes. Stable bispivaloyl derivative 25 was
obtained in 48% yield by reaction of freshly prepared 24
with PivCl and Et3N.
Scheme 3.
tively stable derivatives in dilute solutions,[21] although these
compounds are better represented as the o-quinones 17b
and 18b, respectively. At neutral pH, derivatives 17 and 18
spontaneously rearrange via a quinone-methide to give 5,6-
dihydroxyindole-2-carboxylate derivatives.[22,23] Attempts to
synthesize an unsubstituted analogue of 16a–b by deprotec-
tion of quinones 19 with different protecting groups R
failed and complex reaction mixtures were obtained.
Scheme 4.
In contrast to that found in the presence of pyridine,
amines such as Et3N or iPr2NEt promote the isomerization
of 5 to indole derivatives (Scheme 5). Thus, acetate 26 was
obtained in 73% yield by reaction with 10 equiv. of Ac2O
and Et3N. Methanolysis of 26 (MeOH, K2CO3, room tem-
Figure 3. Stable quinoneimines and model compounds.
Semiempirical calculations (PM3 level) show that hy-
droxyindole 15 (∆H°f = –60.7 kcal mol–1) is considerably
more stable than the quinoneimine tautomer 5 (∆H°f =
–36.7 kcal mol–1). This energy difference (∆∆H°f = 24 kcal
mol–1) is higher than that computed at the same level for
the 2,4-cyclohexadienone/phenol equilibrium (∆∆H°f
=
11.8 kcal mol–1). For this equilibrium, ∆∆H (25 °C) =
17.9 kcal mol–1 has been determined experimentally.[24]
Simplified models 20 and 21 of quinoneimine 5 and hy-
droxyindole 15, respectively, reproduce this pattern (Fig-
ure 3) and indicate that there is not any subtle steric or hy-
drogen bond stabilization in quinoneimine 5.
Scheme 5.
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1929

A. M. Echavarren et al.
FULL PAPER
92). The structure of 6 was confirmed by COSY, HMQC, HMBC,
and NOESY correlations.
perature) cleanly gave hydroxyindole 15 in 87% yield. In-
dole 15 could also be obtained by treatment of 5 with either
Et3N or iPr2NEt (68–88% yield).
Phthalimide 7. Method a: To a solution of 6 (800 mg, 1.12 mmol)
and Et3N (0.17 mL, 0.12 mmol) in CH2Cl2 (15 mL) at 23 °C was
added MOMBr (0.10 mL, 1.23 mmol) and the mixture was stirred
at 23 °C for 16 h. After the usual extractive workup and
chromatography (hexane/EtOAc, 1:1), 7 (572 mg, 74%) was ob-
tained as a pale greenish solid.
Summary
In summary, phthalimide derivatives of cyanosafracin B
(2), with the substitution at the A ring of the ecteinascidins,
have been prepared from 3. These compounds display sig-
nificant antitumor activities in vitro at the µ level, al-
though the most active derivatives 4 and 12 are only an
order of magnitude less potent that parent ecteinascidin 743
(1). We have also isolated the first quinoneimine tautomer
of a 5-hydroxyindole, which is remarkably stable under
acidic and mild basic conditions, despite the large difference
in energy that favors tautomerization to the indole. Qui-
noneimine 5 is prepared in two steps from cyanosafracin B
(2), which is readily available by fermentation in large
amounts. Quinoneimine 5 and derivatives such as 15, and
24, are new types of hexacyclic tetrahydroisoquinoline scaf-
folds that could be useful for the preparation of antitumor
compounds.
Method b: A solution of 2 (2.50 g, 4.45 mmol), phthaloyl dichloride
(899 mg, 4.45 mmol), and Et3N (1.3 mL, 9.35 mmol) in CH2Cl2
(30 mL) was stirred at 23 °C for 8 h. After the usual extractive
workup and chromatography (hexane/EtOAc, 1:1), 7 (2.80 g, 91%)
was obtained. Rf = 0.34 (hexane/EtOAc, 1:3). 1H NMR (CDCl3,
300 MHz): δ = 1.19 (d, J = 7.7 Hz, 3 H), 1.62–1.73 (ddd, J = 18.2,
8.5, 1.4 Hz, 1 H), 1.74 (s, 3 H), 2.21 (s, 3 H), 2.33 (s, 3 H), 2.49 (d,
J = 18.2 Hz, 1 H), 3.01–3.21 (m, 5 H), 3.40 (br. d, J = 8.5 Hz, 1
H), 3.72 (s, 3 H), 3.82 (s, 3 H), 3.87 (m, 1 H), 4.06 (m, 1 H), 4.18
(d, J = 2.4 Hz, 1 H), 5.46 (d, J = 6.1 Hz, 1 H), 6.52 (s, 1 H), 7.65–
7.73 (m, 4 H). 13C NMR (CDCl3, 75 MHz, DEPT): δ = 8.42 (CH3),
14.72 (CH3), 15.73 (CH3), 24.26 (CH2), 25.49 (CH2), 41.22 (CH2),
41.73 (CH3), 49.28 (C), 54.65 (C), 54.96 (C), 55.92 (C), 56.24 (C),
58.91 (C), 60.15 (C), 60.32 (C), 116.57 (C), 117.34 (C), 120.61 (CH),
123.32 (CH), 123.39 (CH), 127.68 (C), 129.34 (C), 130.52 (C),
131.44 (C), 134.19 (CH), 135.71 (C), 141.04 (C), 143.18 (C),
147.14 (C), 167.53 (C), 169.25 (C), 180.72 (C), 185.61 (C). API-
ES-MS: m/z (%) 680 [M+ + 1, 100]. FAB-HRMS: m/z calcd. for
C37H37N5O8: 679.2642, found 679.2644. C37H37N5O8 (679.71): C
65.38, H 5.49, N 10.30; found C 65.33, H 5.62, N 10.72. The struc-
ture of 7 was confirmed by COSY, and HMQC correlations.
Experimental Section
General Remarks: The NMR spectra were carried out at 23 °C,
unless otherwise stated. Only the most significant MS fragmenta-
tions are given. The FAB-MS spectra were obtained by using m-
nitrobenzyl alcohol as the matrix. Rf were determined on TLC alu-
minum sheets coated with 0.2 mm GF254 silica gel. All reactions
were carried out under an atmosphere of Ar. Solvents were purified
and dried by standard methods. Chromatographic purifications
were carried out with flash-grade silica gel. “Usual extractive
workup” means pouring the crude reaction mixture onto water,
partitioning between CH2Cl2 and water (or 10% aqueous HCl for
reaction involving bases as reagents), followed by extraction, drying
(MgSO4), and evaporation of the solvent.
Boc-Phthalimide Derivative 8. Method a: A solution of 7 (2.71 g,
4.0 mmol), Boc2O (1.67 g, 8 mmol), pyridine (0.65 mL, 8 mmol),
and DMAP (48 mg, 0.4 mmol) in CH2Cl2 (10 mL) was stirred for
12 h at 23 °C. After the usual extractive workup and chromatog-
raphy (hexane/EtOAc, gradient 3:1 to 1:1), 8 (2.68 g, 86%) was
obtained as a pale greenish solid.
Method b (one-pot preparation from 2): A solution of 2 (3.00 g,
5.46 mmol), phthaloyl dichloride (0.780 mL, 5.47 mmol), and Et3N
(1.6 mL, 11.47 mmol) in CH2Cl2 (15 mL) was stirred at 23 °C for
8 h. To the reaction mixture was added a solution of DMAP
Phthalimidic Acid 6: A solution of 2 (1.00 g, 1.78 mmol), phthalic
anhydride (262 mg, 1.78 mmol), pyridine (0.16 mL, 1.95 mmol), (37 mg, 0.056 mmol), pyridine (0.88 mL, 10.92 mmol), and Boc2O
and DMAP (10 mg, 0.08 mmol) in benzene (15 mL) was stirred at (2270 mg, 10.92 mmol) in CH2Cl2 (10 mL). The mixture was stirred
23 °C for 16 h. After the usual extractive workup, 6 (1123 mg, 89%) at 23 °C for 12 h. After the usual extractive workup and
was obtained as a greenish solid, which was used without further
chromatography (hexane/EtOAc, 1:1), 8 (3.74 g, 88%) was ob-
purification. R = 0.06 (hexane/EtOAc, 1:1). IR (cm–1): ν = 3371,
tained. Rf
=
0.41 (hexane/EtOAc, 1:3). 1H NMR (CDCl3,
˜
f
2922, 1649, 1439, 1354, 1282, 1234, 1165. 1H NMR (CDCl3, 300 MHz): δ = 1.13 (d, J = 7.6 Hz, 3 H), 1.58 (s, 9 H), 1.85 (s, 3
300 MHz): δ = 1.09 (d, J = 6.9 Hz, 3 H), 1.69 (s, 3 H), 1.99–1.85
(m, 1 H), 2.13 (s, 3 H), 2.34 (s, 3 H), 2.57 (d, J = 18.6, 1 H), 3.04
(dd, J = 18.6, 3.6 Hz, 2 H), 3.19 (br. d, J = 10.9 Hz, 1 H), 3.31 (dt,
J = 12.2, 4.1 Hz, 1 H), 3.38 (d, J = 6.9 Hz, 1 H), 3.58–3.47 (m, 1
H), 2.21 (s, 3 H), 2.28 (s, 3 H), 2.57 (d, J = 23.1 Hz, 1 H), 3.02 (br.
d, J = 23.1 Hz, 1 H), 3.21–3.08 (m, 3 H), 3.41 (t, J = 8.1 Hz, 1 H),
3.73 (s, 3 H), 3.83 (s, 3 H), 3.91–3.82 (m, 2 H), 4.07 (br. d, J =
2.0 Hz, 1 H), 4.31 (q, J = 7.7 Hz, 1 H), 5.66 (m, 1 H), 6.88 (s, 1
H), 3.74–3.65 (m, 1 H), 3.76 (s, 3 H), 3.87 (br. s, 1 H), 3.97 (s, 3 H), 7.75–7.66 (m, 4 H) (two H signals were not observed). 13C
H), 4.14 (d, J = 2.8 Hz, 1 H), 4.18 (s, 1 H), 6.04 (br. s, 1 H), 6.15
(d, J = 6.1 Hz, 1 H), 6.32 (s, 1 H), 7.32 (d, J = 7.7 Hz, 1 H), 7.52
NMR (CDCl3, 75 MHz, DEPT): δ = 8.81 (CH3), 14.84 (CH3),
16.03 (CH3), 24.74 (CH2), 25.15 (CH2), 27.60 (3 CH3), 41.84 (CH2),
(m, 2 H), 7.95 (d, J = 7.7 Hz, 1 H). 13C NMR (CDCl3, 75 MHz, 41.87 (CH3), 49.27 (CH), 54.81 (CH), 54.93 (CH2), 57.41 (CH),
DEPT): δ = 8.21 (CH3), 15.19 (CH3), 17.64 (CH3), 24.49 (CH2), 57.44 (CH), 59.72 (CH3), 61.03 (CH3), 61.12 (CH), 84.41 (C),
24.78 (CH2), 40.05 (CH2), 41.65 (CH3), 49.61 (CH), 54.12 (CH), 110.23 (C), 117.56 (C), 123.11 (C), 123.62 (2 CH), 127.79 (CH),
55.08 (CH), 55.61 (CH), 55.74 (CH), 58.81 (CH), 60.79 (CH3), 128.02 (C), 130.54 (C), 132.08 (C), 132.41 (C), 134.37 (2 CH),
60.91 (CH3), 117.21 (C), 117.73 (C), 120.02 (CH), 128.54 (CH),
135.87 (C), 140.92 (C), 143.17 (C), 148.52 (C), 151.30 (C), 156.46
129.09 (C), 129.84 (CH), 131.04 (CH), 131.78 (C), 132.47 (CH), (C), 167.98 (C), 169.09 (C), 181.22 (C), 185.12 (C). ES-MS: m/z (%)
132.92 (C), 135.92 (C), 137.69 (C), 141.52 (C), 143.08 (C), 147.38 780 [M+ + 1, 100], 753 (M+ – 26, 31). C42H45N5O10 (779.83): C
(C), 156.15 (C), 163.68 (C), 169.44 (C), 173.45 (C), 181.22 (C), 64.69, H 5.82, N 8.98; found C 64.61, H 5.94, N 8.93. The structure
186.11 (C). APCI-MS: m/z (%) 698 [M+ + 1, 100], 550 (M+ – 148,
of 8 was supported by a COSY correlation.
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Synthesis of Ecteinascidin 743 Analogues from Cyanosafracin B
FULL PAPER
Phenol Derivative 10: To a solution of 8 (2000 mg, 2.56 mmol) in
MeOH (300 mL) at 0 °C, was added portionwise a solution of
3.27 (dt, J = 11.7, 3.2 Hz, 1 H), 3.37–3.42 (m, 2 H), 3.44–3.48 (m,
1 H), 3.79 (s, 3 H), 3.95 (q, J = 7.7 Hz, 1 H), 4.04 (m, 2 H), 4.17
NaOH (25 g, 625 mmol) in H2O (400 mL). The purple solution was (d, J = 3.2 Hz, 1 H), 4.73 (s, 1 H), 5.19 (br. t, J = 5.3 Hz, 1 H),
stirred for 1 h at ca. 0 °C. The solution was acidified to pH 5 with
4  HCl and extracted with EtOAc. The organic layer was dried
(MgSO4), filtered and evaporated, affording the vinylogous acid 9
that was used in the next step without further purification. 1H
NMR showed the disappearance of the methoxy group. A solution
5.72 (d, J = 1.6 Hz, 1 H), 5.82 (d, J = 1.6 Hz, 1 H), 6.00 (s, 1 H),
6.53 (s, 1 H), 7.65–7.78 (m, 4 H). 13C NMR (CDCl3, 100 MHz,
DEPT): δ = 8.68 (CH3), 14.52 (CH3), 15.80 (CH3), 25.30 (CH2),
28.71 (CH2), 41.34 (CH2), 41.77 (CH3), 48.84 (CH), 55.26 (CH),
56.33 (CH), 56.51 (CH), 59.63 (CH), 60.69 (CH3), 100.74 (C),
107.71 (C), 117.08 (C), 117.85 (C), 121.21 (CH), 123.46 (CH),
128.79 (C), 130.95 (C), 131.54 (C), 134.14 (CH), 146.97 (C), 167.59
of crude
9 (448 mg, 0.58 mmol) and Pd/C (40 mg, 10%,
0.058 mmol) in DMF (6 mL) was stirred under H2 (1 atm) at 23 °C
for 30 min. Then, the mixture was filtered under Ar and transferred
to a sealed tube containing Cs2CO3 (570 mg, 1.75 mmol). CH2BrCl
(C), 168.55 (C). FAB-MS: m/z (%) 680 [M+ + 1, 25], 653 (M+
27, 38). FAB-HRMS: m/z for C37H38N5O8: calcd. 680.2720, found
–
was added (0.75 mL, 11.6 mmol) and the mixture was heated at 680.2718. The structure of 13 was confirmed by COSY, HMQC,
100 °C for 2 h. The reaction was cooled, filtered through celite, and
after the usual extractive workup and chromatography (hexane/
EtOAc, 1:1), 10 (89 mg, 18%, three steps) was obtained as a pale
yellow solid. Rf = 0.24 (hexane/EtOAc, 2:3). 1H NMR (CDCl3,
300 MHz): δ = 1.25 (d, J = 7.2 Hz, 3 H), 1.52–1.58 (m, 1 H), 1.59
(s, 9 H), 1.97 (s, 3 H), 2.23 (s, 3 H), 2.25 (s, 3 H), 2.65 (dd, J =
15.3, 2.8 Hz, 1 H), 2.68 (d, J = 18.6 Hz, 1 H), 33.03 (dd, J = 17.8,
8.1 Hz, 1 H), 3.24 (dt, J = 11.7, 3.2 Hz, 1 H), 3.42–3.51 (m, 2 H),
3.65 (dd, J = 14.1, 8.0 Hz, 1 H), 3.79 (s, 3 H), 3.92 (d, J = 2.4 Hz,
1 H), 4.03 (br. s, 1 H), 4.13 (d, J = 2.4 Hz, 1 H), 4.19 (q, J = 7.2 Hz,
1 H), 4.77 (s, 1 H), 5.40 (br. t, J = 5.6 Hz, 1 H), 5.77 (d, J = 1.6 Hz,
1 H), 5.85 (d, J = 1.6 Hz, 1 H), 6.93 (s, 1 H), 7.81 (m, 4 H). 13C
NMR (CDCl3, 75 MHz, DEPT): δ = 8.77 (CH3), 14.53 (CH3),
15.93 (CH3), 26.43 (CH2), 27.79 (CH2), 40.45 (CH2), 41.75 (CH3),
49.51 (CH), 54.99 (CH), 55.41 (CH), 56.82 (CH), 57.09 (CH), 59.03
(CH), 60.58 (CH3), 100.92 (CH2), 117.45 (C), 123.13 (C), 125.58 (2
CH2), 127.75 (CH), 130.07 (C), 130.35 (C), 130.49 (C), 130.79 (C),
131.72 (C), 139.17 (C), 143.25 (C), 146.71 (C), 151.78 (C), 164.63
(C), 169.51 (C). FAB-MS: m/z (%) 780 [M+ + 1, 4], 753 (M+ – CN,
4). FAB-HRMS: calcd. for C42H45N5O10: 780.3245, found
780.3257.
and HMBC correlations.
Cyano-safracin-phthalimide 12:
A
solution of 11 (27 mg,
0.033 mmol) in dioxane (4 mL) and 4  HCl (3 mL) was heated at
40 °C for 2 h. After the usual extractive workup and chromatog-
raphy (hexane/EtOAc, gradient 2:1 to 1:3), 12 (16 mg, 61%) was
1
obtained. H NMR (CDCl3, 300 MHz): δ = 1.09 (d, J = 7.2 Hz, 3
H), 1.97 (s, 3 H), 2.18 (s, 3 H), 2.30 (s, 3 H), 2.33 (s, 3 H), 2.64 (d,
J = 18.3 Hz, 1 H), 3.12–2.97 (m, 2 H), 3.42–3.32 (m, 3 H), 3.77 (s,
3 H), 4.04 (m, 1 H), 4.10 (m, 2 H), 4.36 (q, J = 7.2 Hz, 1 H), 5.64
(m, 1 H), 5.84 (d, J = 1.6 Hz, 1 H), 5.93 (d, J = 1.6 Hz, 1 H), 6.51
(s, 1 H), 7.64–7.79 (m, 4 H). FAB-MS: m/z (%) 722 [M+ + 1, 29],
695 (M+ – 26, 44). HR-FAB-MS: m/z found for C39H40N5O9: calcd.
722.2826, found 722.2831.
Hydroxy-safracin-phthalimide 4:
A
solution of 12 (8 mg,
0.021 mmol) and AgNO3 (70 mg, 0.41 mmol) in CH3CN (1 mL)
and H2O (1 mL) was stirred at 23 °C for 12 h. After the usual ex-
tractive workup and chromatography (gradient 100:0 to 100:2
CH2Cl2/MeOH), 4 (6 mg, 70%) was obtained as a white solid. Rf
= 0.23 (CH2Cl2/MeOH, 40:1). 1H NMR (CDCl3, 500 MHz): δ =
1.04 (d, J = 7.1 Hz, 3 H), 2.02 (s, 3 H), 2.22 (s, 3 H), 2.34 (s, 3 H),
2.37 (s, 3 H), 2.60 (d, J = 18.1 Hz, 1 H), 2.81 (m, 1 H), 3.04 (dd,
J = 18.4, 8.3 Hz, 1 H), 3.25–3.30 (m, 1 H), 3.31–3.35 (m, 1 H), 3.44
(br. d, J = 11.7 Hz, 1 H), 3.81 (s, 3 H), 4.08–4.21 (m, 2 H), 4.42
(q, J = 7.2 Hz, 1 H), 4.49 (s, 1 H), 4.59 (s, 1 H), 5.78 (d, J = 4.3 Hz,
1 H), 5.89 (d, J = 1.3 Hz, 1 H), 5.96 (d, J = 1.3 Hz, 1 H), 6.57 (s,
1 H), 7.70–7.73 (m, 2 H), 7.78–7.83 (m, 2 H). 13C NMR (CDCl3,
125 MHz, DEPT): δ = 14.14 (CH3), 15.62 (CH3), 22.70 (CH2),
29.72 (CH2), 30.94 (CH), 35.80 (CH), 41.54 (CH2), 101.49 (C),
106.84 (C), 123.29 (C), 133.85 (C), 141.10 (C), 145.85 (CH), 194.10
(C) (signals assigned on the basis of HMQC and HMBC experi-
ments). MALDI-TOF-MS: m/z 713 [M+ + 1], 695 (M+ – 17). FAB-
HRMS: calcd. for C38H38N4O3: 694.2658, found 694.2626. The
structure of 4 was confirmed by COSY, HMQC, and HMBC corre-
lations.
Acetyl Derivative 11: To
a solution of phenol 10 (13 mg,
0.017 mmol), pyridine (1.5 µL, 18.35 µmol), and DMAP (ca. 2 mg)
in CH2Cl2 (0.5 mL) was added acetyl chloride (1.3 µL,
0.018 mmol). The mixture was stirred at 23 °C for 2 h. After the
usual extractive workup and chromatography (hexane/EtOAc, 1:2),
1
11 (10 mg, 81%) was obtained. H NMR (CDCl3, 500 MHz): δ =
1.11 (d, J = 4.3 Hz, 3 H), 1.59 (s, 9 H), 1.86 (dd, J = 16.4, 7.1 Hz,
1 H), 2.21 (s, 3 H), 2.23 (s, 3 H), 2.34 (s, 3 H), 2.45 (s, 3 H), 2.73
(d, J = 10.9 Hz, 1 H), 2.74–2.81 (m, 1 H), 3.15 (dd, J = 10.8,
4.9 Hz, 1 H), 3.31–3.35 (m, 2 H), 3.49 (d, J = 4.6 Hz, 1 H), 3.82
(s, 3 H), 3.81–3.89 (m, 2 H), 4.13 (s, 1 H), 4.17 (d, J = 1.5 Hz, 1
H), 4.48 (q, J = 4.3 Hz, 1 H), 5.65 (m, 1 H), 5.89 (d, J = 0.8 Hz, 1
H), 5.98 (d, J = 0.8 Hz, 1 H), 6.93 (s, 1 H), 7.72–7.75 (m, 2 H),
7.82–7.85 (m, 2 H). 13C NMR (CDCl3, 125 MHz, DEPT): δ = 9.32
(CH3), 15.62 (CH3), 26.87 (CH2), 27.67 (CH2), 41.14 (CH2), 41.29
(CH2), 41.65 (C), 48.49 (C), 51.32 (CH2), 53.64 (C), 55.12 (C),
55.44 (C), 56.65 (C), 57.32 (C), 59.20 (C), 60.51 (C), 61.85 (C),
83.57 (C), 101.61 (C), 119.49 (C), 123.39 (CH), 127.77 (CH), 131.26
(C), 131.93 (C), 133.74 (C), 134.02 (CH), 140.59 (C), 142.90 (C),
167.46 (C). FAB-MS: m/z (%) 822 [M+ + 1, 12], 795 (M+ – 26,
18), 695 (M+ – 126, 24). FAB-HRMS: m/z for C44H48N5O11: calcd.
822.3350, found 822.3336. The structure of 11 was confirmed by
COSY, HMQC, and HMBC correlations.
Cyanosafracin N-Phenylthiourea 14: A solution of cyanosafracin B
(3) (1.50 g, 2.73 mmol) and phenyl isocyanate (650 µL, 738 mg,
5.46 mmol) in CH3CN (15 mL) was stirred at 23 °C for 16 h. The
reaction was evaporated and the residue was purified by flash
chromatography (SiO2, hexane/EtOAc, gradient 10:0 to 1:1) to give
14 as a yellow solid (1.63 g, 87%). m.p. 176–179 °C. Rf = 0.32 (hex-
ane/EtOAc, 2:1). IR (neat film): ν = 3368, 2937, 2854, 1652, 1520,
˜
1501, 1458, 1319, 1236, 1167 cm–1. 1H NMR (CDCl3, 300 MHz):
δ = 0.87 (d, J = 7.3 Hz, 3 H), 1.75 (ddd, J = 12.5, 6.1, 2.2 Hz, 1
H), 1.84 (s, 3 H), 2.14 (s, 3 H), 2.27 (s, 3 H), 2.52 (d, J = 18.2 Hz,
1 H), 3.14–2.92 (m, 4 H), 3.34 (m, 2 H), 3.61 (dd, J = 12.5, 7.3 Hz,
1 H), 3.72 (s, 3 H), 3.84 (br. s, 3 H), 3.87 (s, 3 H), 4.10 (dd, J =
Dihydroxy Derivative 13: A solution of 11 (23 mg, 0.029 mmol) in
dioxane (3 mL) and 4  HCl (2 mL) was heated at 50 °C for 2 h.
After the usual extractive workup and chromatography (hexane/
EtOAc, 1:3), 13 (16 mg, 87%) was obtained. 1H NMR (CDCl3, 9.7, 2.0 Hz, 1 H), 4.19 (t, J = 6.9 Hz, 1 H), 5.69 (t, J = 5.7 Hz, 1
400 MHz): δ = 1.27 (d, J = 7.7 Hz, 1 H), 1.91 (s, 3 H), 2.24 (s, 3 H), 6.03 (s, 1 H), 6.20 (s, 1 H), 6.69 (d, J = 7.6 Hz, 1 H), 7.16 (d,
H), 2.31 (s, 3 H), 2.63 (d, J = 18.2 Hz, 1 H), 3.01–3.09 (m, 2 H),
J = 7.3 Hz, 1 H), 7.24 (t, J = 7.3 Hz, 1 H), 7.38 (t, J = 7.3 Hz, 2
Eur. J. Org. Chem. 2006, 1926–1933
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1931

A. M. Echavarren et al.
FULL PAPER
H), 7.87 (s, 1 H). 13C NMR (CDCl3, 75 MHz, DEPT): δ = 8.74
H), 3.73 (m, 1 H + 1 H), 3.85 (d, J = 2.8 Hz, 1 H), 4.12 (d, J =
(CH3), 15.83 (CH3), 18.52 (CH3), 24.58 (CH2), 25.14 (CH2), 40.23 8.1 Hz, 1 H), 4.14 (s, 3 H), 4.63 (dd, J = 17.8, 7.3 Hz, 1 H), 5.92
(CH2), 41.76 (CH3), 53.51 (CH), 54.74 (CH), 55.03 (CH), 55.82
(CH), 56.34 (CH), 58.60 (CH), 60.81 (CH3), 60.92 (CH3), 116.39
(d, J = 1.6 Hz, 1 H). 13C NMR (CDCl3, 75 MHz, DEPT): δ = 8.97
(CH3), 16.78 (CH3), 24.98 (CH2), 27.91 (CH2), 41.41 (CH3), 49.89
(C), 117.45 (C), 120.24 (CH), 124.42 (CH), 126.84 (CH), 128.69 (CH3), 51.48 (CH3), 52.98 (CH), 54.63 (CH), 59.87 (CH), 60.41
(C), 129.49 (C), 129.91 (CH), 130.56 (C), 135.29 (C), 136.10 (C), (CH3), 66.51 (CH2), 94.09 (C), 115.51 (C), 124.99 (C), 125.47 (CH),
142.45 (C), 185.71 (C), 143.21 (C), 147.01 (C), 155.71 (C), 172.03 125.77 (C), 127.70 (C), 145.21 (C), 147.34 (C), 148.62 (C), 154.86
(C), 178.97 (C), 181.09 (C). C36H40N6O6S (684.80): C 63.14, H
5.89, N 12.27, O 14.02, S 4.68; found C 63.02, H 6.04, N 12.40, O
13.59, S 4.95. The structure of 14 was confirmed by COSY,
HMQC, and HMBC experiments.
(C), 162.14 (C), 188.65 (C), 193.88 (C). EI-MS: m/z (%) 490 (100)
[M+], 464 (M+ – CN, 23). EI-HRMS: calcd. for C27H30N4O5:
490.2216; found 490.2229. The structure of 23 was confirmed by
COSY, NOESY, HMQC, and HMBC experiments.
Quinoneimine 5: To a solution of 14 (800 mg, 1.168 mmol) in
MeOH (30 mL) was added TMSCl (740 µL, 634 mg, 5.84 mmol) at
0 °C. The reaction mixture was stirred at 23 °C during 3 h, and
evaporated under reduced pressure. The resulting residue was di-
luted with CH2Cl2, washed with 5% an aqueous solution of
NaHCO3. After the usual extractive workup and chromatography
(hexane/EtOAc, gradient 4:1 to 1:1), 5 (473 mg, 88%) was obtained
as a pale brown solid. m.p. 188–190 °C; Rf = 0.14 (hexane/EtOAc,
Indoline 24: To a solution of 5 (72 mg, 0.156 mmol) in CH2Cl2
(3 mL) at 23 °C was added a solution of Na2S2O4 (271 mg,
1.56 mmol) in H2O (4 mL) and the mixture was stirred vigorously
for 2 h. After the usual extractive workup, 24 (66 mg, 92%) was
obtained. Indoline 24 is rather unstable and suffers oxidation by air
to give 5. 1H NMR (CDCl3, 500 MHz, COSY, HMQC, HMBC): δ
= 2.06 (s, 3 H), 2.23 (s, 3 H), 2.28 (s, 3 H), 2.45 (dd, J = 10.2, 6.4),
2.53 (d, J = 10.7 Hz, 1 H), 2.88 (dd, J = 10.2, 3.2 Hz, 1 H), 3.02
2:1). IR (neat film): ν = 3428, 2935, 1614, 1442, 1242, 985 cm–1. (dd, J = 10.8, 4.8 Hz, 1 H), 3.06 (dd, J = 6.8, 4.7 Hz, 1 H), 3.42
˜
1H NMR (CDCl3, 500 MHz): δ = 1.90 (s, 3 H), 2.25 (s, 3 H), 2.30
(s, 3 H), 2.55 (d, J = 17.9, 1 H), 2.76 (br. d, J = 19.4, 1 H), 3.07
(dd, J = 18.3, 8.6 Hz, 1 H), 3.42 (m, 1 H), 3.46 (d, J = 10.1 Hz, 1
H), 3.76 (s, 3 H), 3.79 (m, 2 H), 4.16 (s, 3 H), 3.93 (d, J = 2.5 Hz,
1 H), 4.24 (d, J = 3.1 Hz, 1 H), 4.66 (m, 1 H), 5.86 (br. s, 1 H),
(d, J = 5.9 Hz, 1 H), 3.48 (m, 1 H), 3.63 (m, 1 H), 3.73 (s, 3 H),
3.74 (s, 3 H), 3.80 (d, J = 1.6 Hz, 1 H), 4.11 (dd, J = 6.6, 4.3 Hz,
1 H), 4.23 (d, J = 1.9 Hz, 1 H), 4.32 (dd, J = 13.7, 1.3 Hz, 1 H),
5.85 (br. s, 1 H), 6.42 (s, 1 H). 13C NMR (CDCl3, 75 MHz, DEPT):
δ = 9.12 (CH3), 15.73 (CH3), 25.34 (CH2), 25.57 (CH2), 30.99
6.46 (s, 1 H). 13C NMR (CDCl3, 125 MHz, DEPT): δ = 9.44 (CH3), (CH2), 42.13 (CH3), 53.41 (CH), 55.06 (CH), 55.76 (CH), 56.14
16.23 (CH3), 25.27 (CH2), 25.99 (CH2), 42.45 (CH2), 43.44 (CH3), (CH), 59.72 (CH), 60.24 (CH3), 61.47 (CH3), 112.96 (C), 116.44
56.22 (CH), 59.31 (CH), 60.15 (CH), 60.89 (CH), 61.29 (CH), 61.37 (C), 121.42 (CH), 125.85 (C), 126.23 (C), 129.13 (C), 130.50 (C),
(CH3), 67.20 (CH3), 104.34 (C), 116.82 (C), 121.79 (CH), 126.29 133.58 (C), 142.17 (C), 142.83 (C), 146.97 (C), 154.96 (C), 162.23
(C), 128.58 (C), 129.86 (C), 130.61 (C), 143.42 (C), 145.75 (C), (C). The structure of 24 was confirmed by COSY, HMQC, and
147.43 (C), 155.31 (C), 162.65 (C), 186.63 (C). EI-MS: m/z (%) 460
[M+, 21], 434 (M+ – CN, 10). The structure of 5 was confirmed by
COSY, NOESY, HMQC, and HMBC experiments.
HMBC experiments.
Bis(pivaloyl)indoline 25: To a solution of indoline 24 (6 mg,
0.013 mmol) in CH2Cl2 (0.3 mL) at 23 °C was added pyridine
(3.2 µL, 0.04 mmol) and pivaloyl chloride (5 µL, 0.04 mmol). After
the usual extractive workup, 25 (4 mg, 48%) was obtained. 1H
NMR (CDCl3, 300 MHz, COSY, NOE): δ = 1.38 (s, 9 H), 1.41 (s,
9 H), 1.98 (s, 3 H), 2.32 (s, 3 H), 2.36 (s, 3 H), 2.40 (br. dd, J =
17.2, 11.4 Hz, 1 H), 2.54 (d, J = 18.3 Hz, 1 H), 2.78 (dd, J = 18.3,
4.7 Hz, 1 H), 3.08 (dd, J = 18.3, 8.0 Hz, 1 H), 6.43 (s, 1 H), 3.51–
3.44 (m, 3 H), 3.53 (m, 1 H), 3.56 (s, 3 H), 3.79 (s, 3 H), 3.84 (d, J
= 2.3 Hz, 1 H), 5.68 (s, 1 H), 4.49 (d, J = 9.3, 6.7 Hz, 1 H), 4.17
(m, 2 H). 13C NMR (CDCl3, 75 MHz): δ = 9.92 (CH3), 15.56
(CH3), 25.48 (CH2), 25.72 (CH2), 27.46 (CH3), 28.44 (CH3), 38.83
Acetyl Quinoneimine 22: To a solution of quinoneimine 5 (220 mg,
0.48 mmol) and DMAP (3 mg, 0.024 mmol) in CH2Cl2 (15 mL)
was added pyridine (70 µL, 0.50 mmol) and Ac2O (45 µL,
0.48 mmol). The reaction mixture was stirred for 14 h at 23 °C and,
after the usual extractive workup, 22 (185 mg, 77%) was obtained
as a pale yellow solid. Rf = 0.22 (hexane/EtOAc, 2:1). 1H NMR
(CDCl3, 300 MHz): δ = 1.84 (s, 3 H), 2.14 (s, 3 H), 2.25 (s, 3 H),
2.32 (s, 3 H), 2.52 (d, J = 18.5 Hz, 1 H), 2.80 (d, J = 19.4 Hz, 1
H), 3.11 (dd, J = 18.5, 7.9 Hz, 1 H), 3.39 (m, 1 H), 3.46 (d, J =
9.6 Hz, 1 H), 3.78 (s, 3 H), 3.90 (m, 1 H), 3.81 (m, 2 H), 4.18 (s, 3
H), 4.23 (d, J = 3.0 Hz, 1 H), 4.41 (m, 1 H), 6.81 (s, 1 H). 13C (C), 39.32 (C), 42.15 (CH2), 54.94 (CH), 55.89 (CH), 58.07 (CH),
NMR (CDCl3, 75 MHz, DEPT): δ = 8.92 (CH3), 16.14 (CH3), 58.34 (CH), 59.07 (CH), 60.25 (CH3), 60.72 (CH3), 108.03 (C),
21.17 (CH3), 25.60 (CH2), 26.13 (CH2), 41.99 (CH2), 43.12 (CH3), 116.07 (C), 118.86 (C), 121.74 (CH), 124.06 (C), 129.01 (C), 129.22
56.25 (CH), 58.77 (CH), 60.52 (CH), 61.07 (CH), 61.39 (CH), 61.44 (C), 130.49 (C), 143.13 (C), 146.96 (C), 175.72 (C), 177.12 (C).
(CH3), 65.91 (CH3), 105.29 (C), 117.66 (C), 120.88 (C), 127.04 (C),
FAB-MS: m/z 630 (100) [M+], 604 (M+ – CN, 38). The structure of
127.12 (C), 129.84 (C), 131.01 (C), 144.81 (C), 145.53 (C), 146.45 25 was confirmed by COSY and NOESY experiments.
(C), 155.98 (C), 163.11 (C), 182.42 (C), 188.14 (C). EI-MS: m/z (%)
Diacetylindole 26: Ac2O (215 µL, 2.28 mmol) was added to a solu-
502 [M+, 24], 476 (M+ – CN, 17), 434 (12). The structure of 22 was
tion of quinoneimine 5 (105 mg, 0.228 mmol) and Et3N (317 µL,
2.28 mmol) in CH2Cl2 (10 mL), at 23 °C. The reddish solution was
supported by a COSY experiment.
Quinoneimine o-Quinone Dimethyl Acetal 23: To a solution of qui-
noneimine 5 (140 mg, 0.30 mmol) in MeOH (5 mL) was added a
solution of PIDA (193 mg, 0.60 mmol) in MeOH (5 mL). After 2 h
at 23 °C celite was added, the mixture was evaporated under re-
duced pressure and chromatographed (hexane/EtOAc, 1:1) to af-
ford 23 as an orange vitreous solid (119 mg, 81%). Rf = 0.19 (hex-
stirred during 6 h. After the usual extractive workup and
chromatography (hexane/EtOAc, gradient 10:1 to 1:2), 26 (78 mg,
52%) was obtained as a light yellow solid. Rf = 0.78 (hexane/
EtOAc, 2:1). IR (neat film): ν = 3591, 3415, 2138, 1671, 1452, 1248,
˜
1085, 1008 cm–1. 1H NMR (CDCl3, 300 MHz, COSY): δ = 2.15 (s,
3 H), 2.22 (s, 3 H), 2.35 (s, 3 H), 2.36 (s, 3 H), 2.40 (s, 3 H), 2.55
(dd, J = 17.9, 12.3 Hz, 1 H), 2.62 (d, J = 18.2, 1 H), 2.93 (dd, J =
17.9, 7.8 Hz, 1 H), 3.15 (dd, J = 18.2, 9.4 Hz, 1 H), 3.51 (br. d, J
= 9.4 Hz, 1 H), 3.62 (dt, J = 12.3, 7.8 Hz, 1 H), 3.72 (s, 3 H), 3.80
(s, 3 H), 3.82 (m, 1 H), 4.32 (d, J = 2.8 Hz, 1 H), 6.36 (d, J =
1
ane/EtOAc, 1:1). H NMR (CDCl3, 300 MHz): δ = 1.84 (m, 1 H),
1.86 (s, 3 H), 1.90 (d, J = 1.6 Hz, 3 H), 2.10 (d, J = 20.6 Hz, 1 H),
2.25 (s, 3 H), 2.60 (m, 1 H), 2.67 (dd, J = 20.6, 7.6 Hz, 1 H), 3.07
(s, 3 H), 3.26 (m, 1 H), 3.26 (s, 3 H), 3.35 (dt, J = 7.7, 1.6 Hz, 1
1932
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1926–1933

Synthesis of Ecteinascidin 743 Analogues from Cyanosafracin B
FULL PAPER
3.29 Hz, 1 H), 6.78 (s, 1 H), 7.64 (br. s, 1 H). 13C NMR (CDCl3,
75 MHz, DEPT): δ = 9.70 (CH3), 15.64 (CH3), 20.30 (CH3), 20.69
(CH3), 25.35 (CH2), 27.16 (CH2), 41.94 (CH3), 54.68 (CH), 56.97
(CH), 57.36 (CH), 58.28 (CH), 60.37 (CH3), 60.46 (CH3), 104.27
(CH), 113.25 (C), 117.13 (C), 117.63 (C), 119.50 (C), 122.90 (C),
123.99 (C), 127.03 (C), 127.86 (C), 129.90 (C), 131.21 (C), 137.90
(C), 141.67 (C), 147.83 (C), 166.43 (C), 168.30 (C), 168.89 (C).
FAB-MS: m/z (%) 544 (100) [M+], 518 (M+ – CN, 29). The struc-
ture of 26 was supported by a COSY experiment.
[6] A. Endo, A. Yanagisawa, M. Abe, S. Tohma, T. Kan, T. Fukuy-
ama, J. Am. Chem. Soc. 2002, 124, 6552–6554.
[7] J. Chen, X. Chen, M. Bois-Choussy, J. Zhu, J. Am. Chem. Soc.
2006, 128, 87–89.
[8]
a) N. Saito, K. Tashiro, Y. Maru, K. Yamaguchi, A. Kubo,
J. Chem. Soc., Perkin Trans. 1 1997, 53–69; b) N. Saito, H.
Kamayachi, M. Tachi, A. Kubo, Heterocycles 1999, 51, 9–12;
c) N. Saito, M. Tachi, R. Seki, H. Kamayachi, A. Kubo, Chem.
Pharm. Bull. 2000, 48, 1549–1557.
[9]
a) B. Herberich, M. Kinugawa, A. Vazquez, R. M. Williams,
Tetrahedron Lett. 2001, 42, 543–546; b) W. Jin, S. Metobo,
R. M. Williams, Org. Lett. 2003, 5, 2095–2098; c) W. Jin, R. M.
Williams, Tetrahedron Lett. 2003, 44, 4635–4639.
Indole 15. Method a: Formation of the indole 15 by isomerization
of the quinoneimine with base: to a solution of quinoneimine 5
(25 mg, 0.054 µmol) in CH3CN (2 mL) was added iPr2NEt (50 µL,
0.28 mmol) and the mixture was stirred at 23 °C for 24 h. After the
usual extractive workup, 15 (22 mg, 88%) was obtained as a brown-
ish solid.
[10]
a) B. Zhou, S. Edmonson, J. Padron, S. J. Danishefsky, Tetrahe-
dron Lett. 2000, 41, 2039–2042; b) B. Zhou, J. Guo, S. J. Dani-
shefsky, Tetrahedron Lett. 2000, 41, 2043–2046; c) B. Zhou, J.
Guo, S. J. Danishefsky, Org. Lett. 2002, 4, 43–46; d) C. Chan,
R. Heid, S. Zheng, J. Guo, B. Zhou, T. Furuuchi, S. J. Danish-
efsky, J. Am. Chem. Soc. 2005, 127, 4596–4598.
Method b: Formation of 15 by saponification of the diacetylindole
26: To a solution of the 26 (70 mg, 0.128 mmol) in MeOH (1 mL),
at 23 °C, K2CO3 (13 mg, 0.092 mmol) was added in one portion
and the green mixture was stirred for 1.5 h. After the usual extrac-
tive workup, 15 was obtained (51 mg, 87%) as a white solid: Rf
= 0.23 (2:3 hexane/EtOAc). 1H NMR (300 MHz, CDCl3, COSY,
HMQC): δ = 2.21 (s, 3 H), 2.23 (s, 3 H), 2.33 (s, 3 H), 2.52 (dd, J
= 16.6, 11.3 Hz, 1 H), 2.63 (d, J = 18.2 Hz, 1 H), 3.14 (dd, J =
18.2, 8.5 Hz, 1 H), 3.26 (dd, J = 16.6, 3.6 Hz, 1 H), 3.50 (br. d, J
= 8.5 Hz, 1 H), 3.64 (dt, J = 11.3, 2.8 Hz, 1 H), 3.74 (s, 3 H), 3.83
(s, 3 H), 4.29 (d, J = 2.4 Hz, 1 H), 4.34 (d, J = 2.4 Hz, 1 H), 4.51
(br. s, 1 H), 5.92 (br. s, 1 H), 6.41 (d, J = 2.2 Hz, 1 H), 6.44 (s, 1
H), 7.34 (s, 1 H, NH). 13C NMR (75 MHz, CDCl3, DEPT): δ =
9.23 (CH3), 15.67 (CH3), 25.65 (CH2), 25.96 (CH2), 42.08 (CH3),
54.85 (CH), 56.02 (CH), 57.64 (CH), 59.09 (CH), 60.37 (CH3),
60.76 (CH3), 103.91 (CH), 105.89 (C), 113.53 (C), 116.57 (C),
117.38 (C), 119.83 (C), 121.28 (CH), 126.97 (C), 128.92 (C), 130.18
(C), 141.58 (C), 142.87 (C), 146.74 (C). EI-MS: m/z (%) 460 [M+,
9], 434 (M+ – CN, 1).
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Received: November 9, 2005
Published Online: February 9, 2006
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