Second-generation, biomimetic total synthesis of chaetominine

Article abstract of DOI:10.1055/s-0029-1216923

A straightforward total synthesis of the potent anticancer agent (-)-chaetominine is reported. Central to this synthesis was a biomimetic oxidative cyclization of a tryptophanyl-alanine dipeptide, which provided a fully elaborated 1,2,3,4-tetrahydropyrido[ 2,3-b]indole. Reduction of this intermediate followed by spontaneous cyclization and installation of the side chain provided synthetic chaetominine in a nine-step sequence in 14% overall yield starting from commercially available, inexpensive starting materials. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216923

PAPER
2927
Second-Generation, Biomimetic Total Synthesis of Chaetominine
Total
S
ynthesis of
l
Chaeto
e
minine xis Coste, Ganesan Karthikeyan, François Couty, Gwilherm Evano*
Institut Lavoisier de Versailles, UMR CNRS 8180, Université de Versailles Saint Quentin en Yvelines, 45 Avenue des Etats-Unis,
78035 Versailles Cedex, France
Fax +33(1)39254452; E-mail: evano@chimie.uvsq.fr
Received 1 July 2009
Abstract: A straightforward total synthesis of the potent anticancer
agent (–)-chaetominine is reported. Central to this synthesis was a
O
biomimetic oxidative cyclization of a tryptophanyl-alanine dipep-
tide, which provided a fully elaborated 1,2,3,4-tetrahydropyri-
do[2,3-b]indole. Reduction of this intermediate followed by
spontaneous cyclization and installation of the side chain provided
synthetic chaetominine in a nine-step sequence in 14% overall yield
starting from commercially available, inexpensive starting materi-
als.
OH
H
N
O
N
N
N
O
(–)-chaetominine (1)
Key words: alkaloids, total synthesis, oxidative cyclization, anti-
cancer agents, peptides
Figure 1 Chaetominine (1)
mentation batches), and this has prevented a complete
understanding of its bioactivity and mode of action.
Cancer is a leading cause of death worldwide. According
to recent studies from the World Health Organization, it
accounted for 7.9 million deaths (13% of all deaths) in
2007 and its incidence continues to rise.1 Although new
anticancer agents are emerging, there is still a strong need
for more potent and selective drugs with fewer side ef-
fects. Natural products and natural-product-like mole-
cules will undoubtedly play a crucial role in this area.
They have been a rich source of agents of value in medi-
cine and their role in the drug discovery and development
process is undeniable. They have inspired, at various lev-
els, the fashioning of nonnatural agents of pharmaceutical
import.2
Structurally, chaetominine (1) possesses a unique com-
pact tetracyclic framework built upon D-tryptophan, L-
alanine, and anthranilic acid. Due to its intriguing molec-
ular architecture and its potential as lead compound for
anticancer drugs, chaetominine has attracted immediate
interest from the synthetic community, and this culminat-
ed in a total synthesis by the Snider group.5,6
In continuation of our studies on the use of copper-cata-
lyzed cyclization reactions for the synthesis of alkaloids,7
we reported in 2008 the second synthesis of this natural
product, based on the strategy outlined in Scheme 1.8 Key
steps include a copper-catalyzed cyclization reaction from
iodinated dipeptide 3, which allowed for the formation of
the tricyclic scaffold 4. Introduction of the two adjacent
stereocenters at the ring junction was effected by consec-
utive diastereoselective oxidation and reduction after
deprotection of the indole.
In the area of cancer, over the time frame from around the
1940s to 2006, of the 155 anticancer agents released, 73%
were other than purely synthetic, with 47% actually being
either natural products or directly derived therefrom.3
Clearly, by building libraries around natural products,
chances of finding an active compound are increased.
They serve as lead agents, providing the chemist with a
structural platform that can be elaborated upon or simpli-
fied to yield therapeutically valuable molecules.
While the key cyclization proved to be efficient to con-
struct the tricyclic core of chaetominine and the oxida-
tion–reduction
reaction
sequence
was
highly
diastereoselective, it did require protection–deprotection
of the indole, as well as its iodination with mercury salts,
which somehow reduced the overall efficiency of the syn-
thesis and limited its scale-up. We report in this article a
second-generation synthesis, which addresses these limi-
tations and provides a more efficient access to synthetic
chaetominine (1). This scalable synthetic route allowed us
to access this natural product in a nine-step sequence in
14% overall yield from D-tryptophan.
With IC50 values of 21.0 and 28.0 nM against human leu-
kemia K562 and colon cancer SW1116 cell lines, respec-
tively, chaetominine (1) (Figure 1) most certainly falls
into this category and could serve as a lead structure for
the development of new anticancer agents.4 However, the
isolation of this natural product from Chaetomium sp.
IFBE015, an endophytic fungus found on apparently
healthy Adenophora axilliflora leaves, is extremely labo-
rious (18 mg of 1 isolated from 3 kg of dehydrated fer-
The strategy of our second-generation synthesis is depict-
ed in Scheme 2. We felt that we could considerably short-
en the synthesis by constructing the pyridoindole
framework of chaetominine by oxidative cyclization from
dipeptide 7 in a biomimetic way. We postulated that expo-
SYNTHESIS 2009, No. 17, pp 2927–2934
Advanced online publication: 30.07.2009
x
x.
x
x
.
2
0
0
9
DOI: 10.1055/s-0029-1216923; Art ID: C02909SS
© Georg Thieme Verlag Stuttgart · New York

2928
A. Coste et al.
PAPER
NPhth
NPhth
O
NPhth
O
NPhth
O
E
1. CbzCl, NaOH
n-Bu4NHSO4
E+
O
HN
HN
I
HN
HN
N
H
N
N
R
N
R
2. Hg(O2CCF3)2
then I2
Cbz
MeO
2
MeO
3
MeO
7
MeO
8
78%
O
O
O
O
CuI
NHMe
NHMe
64%
E
NPhth
NPhth
K3PO4, toluene
110 °C
– HE
N
R
N
O
N
R
N
O
OH
H
NPhth
NPhth
OMe
OMe
1. H2, Pd/C
2. DMDO, –85 °C
95%, de >95%
10
O
9
O
N
N
O
N
N
O
E+
E+
OMe
Cbz
OMe
R = H
R = H
O
O
5
4
E
E
NPhth
1. NaBH3CN
AcOH
2. silica gel
NPhth
– HX
N
N
O
N
E
N
O
90%
de >95%
H
OMe
OMe
O
OH
OH
12
O
11
O
NPhth
N
N
5 steps
Scheme 2 Proposed oxidative cyclization process
N
N
O
N
N
O
H
H
coupled with L-alanine methyl ester under standard condi-
tions, and the indole of the resulting dipeptide was next
protected with either a tosyl group or a carbamate under
phase-transfer conditions (Scheme 3).
O
O
6
(–)-chaetominine (1)
Scheme 1 First-generation synthesis of chaetominine (1)
The reactivity of these substrates with oxidants was first
examined. The results of these investigations of the oxida-
tive cyclization process are collected in Table 1.
sure of tryptophanyl-alanine 7 to an electrophile would re-
sult in the formation of a transient iminium ion, which
would be trapped by the amide to give 9. Subsequent
elimination could then generate the aromatized tricyclic
compound 10. Alternatively, the absence of a protecting
group on the aromatic amine would allow for a second re-
action with the electrophile. Elimination from 11 would in
this case give the functionalized imine 12, which could
also be directly formed from 10. While similar strategies
have proven to be quite successful for the preparation of
pyrroloindoles9 and for the formation of tryptophan-
aniline10 and tryptophan–imidazole linkages,11 its use in
the construction of tricyclic pyridoindoles has not been
documented to date.
The use of dimethyldioxirane (DMDO), which proved to
be the most efficient reagent in a number of related cy-
clization reactions,9a–d was rather disappointing in our
case. While it failed to promote the cyclization of any sub-
strates (Table 1, entry 1) at low temperature, extensive
degradation was observed when the reaction mixtures
were warmed to room temperature (Table 1, entry 2). Sac-
NPhth
NH
2 1. phthalic anhydride
py, reflux
O
O
HO
2. L-Ala-OMe, EDC
HOBt, NMM, DMF
0 °C to r.t.
HN
N
H
N
H
Provided that the reaction pathway could be controlled
and that suitable levels of diastereoselectivity could be ob-
tained, this would save us between three to five steps com-
pared to our first-generation synthesis and would
therefore provide a straightforward access to chaetomi-
nine (1).
MeO
79%
D-tryptophan
2
O
TsCl, NaOH
n-Bu4NHSO4
CH2Cl2, r.t.
CbzCl, NaOH
n-Bu4NHSO4
CH2Cl2, r.t.
95%
72%
With this goal in mind, the effect of various electrophiles
on three different tryptophanyl-alanine derivatives 2, 13,
and 14 was examined. We decided to protect the N-termi-
nus of tryptophan as a phthalimide, due to concerns that
other protecting groups such as carbamates might not pre-
vent the nitrogen atom from interfering in the oxidative
coupling. Accordingly, N-phthaloyl-D-tryptophan was
NPhth
O
NPhth
O
HN
HN
N
N
Ts
Cbz
MeO
MeO
14
13
O
O
Scheme 3 Synthesis of cyclization substrates
Synthesis 2009, No. 17, 2927–2934 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Chaetominine
2929
Table 1 Attempted Cyclization with Oxidants
Entry
Substrate
2, 13, 14
2, 13, 14
Electrophile
DMDO
DMDO
Bu
Conditions
Results
1
2
CH2Cl2, –78 °C
no reaction
CH2Cl2, –78 °C to r.t.
extensive degradation
O
3
4
2, 13, 14
13, 14
MeOH, r.t.
CH2Cl2, r.t.
no reaction
no reaction
N
S
O2
MCPBA
MCPBA
O
NPhth
O
HN
5
2
CH2Cl2,–40 °C to r.t.
NH
O
H
MeO
O
15 85%
charin-derived oxaziridine12 was equally inefficient imine 5 upon purification. Experimental evidence that
(Table 1, entry 3) and protected substrates 13 and 14 were support this scenario are the clean conversion of 17 into an
found to be completely inert towards m-chloroperoxyben- unstable mixture of 20 (characterized by mass spectrome-
zoic acid (Table 1, entry 4). A clean reaction was finally try from the crude reaction mixture) and 5, and the quan-
observed by treating unprotected indole 2 with m-chloro- titative conversion of 20 into 5 upon purification on silica
peroxybenzoic acid but the product of this reaction, 15, gel. In addition, the absence of light considerably slowed
frustratingly turned out to result from cleavage of the in- down the reaction. It is worth noting that this reaction did
dole ring (Table 1, entry 5).13
not require the presence of a photosensitizer, irradiation,
or reductive workup.
Disappointed by these results, we next turned our atten-
tion to the use of N-halosuccinimides as cyclization pro-
moters (Scheme 4). Protected substrates were mostly
unreactive (data not shown), which could be attributed to
the strong deactivation of the indole ring. In contrast, a
dramatic difference of reactivity towards the activating
agents was noted when unprotected indole derivative 2
was used as substrate. Of the halosuccinimides examined,
N-chlorosuccinimide proved the most effective, since the
long-awaited cyclized product 17 was obtained in 82%
yield. We were especially surprised to isolate, in addition
to this cyclized product, minor amounts of hydroxyimine
5 from the crude reaction mixture. Intrigued by this result
and excited by the idea of saving one additional step, we
concentrated our efforts on the optimization of this side
reaction. After considerable experimentation, we eventu-
ally found that this biomimetic reaction could simply be
promoted by reacting dipeptide 2 with N-chlorosuccin-
imide and triethylamine under an atmosphere of oxygen
(Scheme 5). The use of this simple modification allowed
the isolation of hydroxyimine 5 as a single diastereoiso-
mer and in 64% yield.
NIS, Et3N
no reaction
CH2Cl2
0 °C to r.t.
NPhth
O
NPhth
O
NBS, Et3N
HN
HN
Br
N
H
N
H
CH2Cl2
0 °C to r.t.
MeO
MeO
51%
2
16
O
O
NPhth
O
NCS, Et3N
N
H
MeO
N
CH2Cl2
0 °C to r.t.
82%
17
O
Scheme 4 Cyclization promoted by N-halosuccinimides
NPhth
A possible explanation for this unexpected and remark-
able reactivity, which saved us four steps compared to our
previous synthetic route, is shown in Scheme 6. The first
step involves, as mentioned above, activation of the indole
to form the activated iminium ion 18, which, after cycliza-
tion and rearomatization, gives tricyclic compound 17.
Photooxidation with oxygen14 would then give hydroper-
oxide 20, which is spontaneously reduced to hydroxy-
OH
NPhth
O
O
NCS, Et3N, O2
HN
N
H
N
N
CH2Cl2
0 °C to r.t.
MeO
MeO
2
5
O
O
64%
Scheme 5 One-pot cyclization–oxidation procedure with oxygen
Synthesis 2009, No. 17, 2927–2934 © Thieme Stuttgart · New York

2930
A. Coste et al.
PAPER
NPhth
NPhth
O
of the second stereocenter at the ring junction and forma-
tion of the g-lactam ring (Scheme 7). Following our pre-
vious strategy, imine 5 was diastereoselectively reduced
with sodium cyanoborohydride, and the formation of the
last ring of the compact tetracyclic chaetominine skeleton
was induced by simply stirring the crude resulting amino
ester with silica gel in a mixture of dichloromethane, ace-
tone, ethanol, and aqueous ammonia. Protection of the ter-
tiary alcohol in 6 as a triethylsilyl ether, followed by
deprotection of the phthalimide with hydrazine, and fur-
ther reaction with isatoic anhydride then gave amino
amide 21,5 which was finally converted into synthetic
chaetominine (1) by reaction with triethyl orthoformate
and deprotection of the alcohol with hydrofluoric acid.5
Cl
O
NCS
HN
HN
N
H
N
H
MeO
O
MeO
2
18
O
Cl
NPhth
NPhth
O
Et3N
N
H
MeO
N
H
MeO
N
O
N
H
17 O
19 O
1O2, CH2Cl2, r.t.
84%
OH
OH
1O2
NPhth
NaBH3CN, AcOH
NPhth
O
HO
then silica gel
90%, de >95%
O
N
N
O
N
N
OH
NPhth
O
H
NPhth
O
MeO
silica gel
O
6
N
N
O
5
N
N
MeO
MeO
1. TESOTf, 2,6-lutidine
CH2Cl2, 0 °C to r.t.
2. NH2NH2⋅H2O
THF–EtOH, r.t.
3. isatoic anhydride
benzene, reflux
20
O
5
O
Scheme 6 Mechanism of the oxidative cyclization mediated by
N-chlorosuccinimide–oxygen
36%
Attack of oxygen from the less hindered face of 17 prob-
ably accounts for the complete diastereoselectivity of this
photooxidation,15 which is in accordance with the selec-
tivity observed with DMDO on the same substrate during
our first-generation synthesis.8 Basic AM1 geometry
optimization16 of pyridoindole 17 shows that the phthal-
imide protecting group most probably also acts as an effi-
cient directing group (Figure 2).
O
OTES
1. HC(OEt)3, PTSA
benzene, reflux
NH NH2
(–)-chaetominine
2. HF, MeCN, r.t
85%
N
N
O
1
H
O
21
Scheme 7 Completion of the synthesis
In summary, we have developed an efficient biomimetic
synthesis of (–)-chaetominine in nine steps and 14% over-
all yield starting from D-tryptophan and L-alanine as
building blocks. Central to our synthetic approach is an ef-
ficient domino process involving a diastereoselective ox-
idative cyclization followed by photooxidation of a
tryptophanyl-alanine dipeptide, which provides a straight-
forward route to the chaetominine skeleton. The conver-
gent approach reported here should be easy to apply to the
synthesis of analogues for further biological testing,
which will be reported in due course.
All reactions were carried out in an oven or flame-dried glassware
under an argon atmosphere, except for reactions involving molecu-
lar oxygen, and standard techniques in handling air-sensitive mate-
rials were employed. All solvents were reagent grade. Benzene was
freshly distilled from sodium/benzophenone under argon. MeCN,
CH2Cl2, and DMF were freshly distilled from CaH2. MeOH was
distilled from Mg turnings and I2. 2,6-Lutidine, NMM, and Et3N
were distilled over CaH2. All other reagents were used as supplied.
Unless otherwise noted, reactions were magnetically stirred and
Figure 2 Diastereoselectivity of the photooxidation
Having designed a convenient and straightforward route
to advanced tricyclic intermediate 5, which was used for
our first-generation total synthesis of chaetominine (1),
we moved to the next steps of the synthesis:8 installation monitored by TLC using Merck Kieselgel 60F254 plates. Flash chro-
matography was performed on silica gel 60 (particle size 35–70 mm)
Synthesis 2009, No. 17, 2927–2934 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Chaetominine
2931
supplied by SDS. Yields refer to chromatographically and spectro-
scopically pure compounds, unless otherwise noted. 1H NMR spec-
tra were recorded using an internal deuterium lock at ambient
temperature on a Bruker 300 MHz spectrometer. Internal references
of dH = 7.26 and dH = 2.50 were used for CDCl3 and DMSO-d6, re-
spectively. Resonances that are either partially or fully obscured are
denoted by the abbreviation ‘obs’ (obscured); ‘app’ is used for ‘ap-
parent’. 13C NMR spectra were recorded at 75 MHz. Internal refer-
ences of dC = 77.16 and dC = 39.52 were used for CDCl3 and
DMSO-d6, respectively. Optical rotations were recorded on a Per-
kin Elmer 341 polarimeter at 589 nm. Melting points were recorded
on a Buchi B-545. Mass spectra were obtained on an HP MS 5989B
spectrometer. HRMS was carried out on an LCT Micromass-Waters
spectrometer (TOF).
134.2, 131.7, 127.0, 123.6, 123.2, 123.0 (rotamers), 119.8, 118.7,
111.4, 111.0, 110.9 (rotamers), 54.8, 54.7 (rotamers), 52.6, 48.6,
25.7, 25.4 (rotamers), 18.3.
ESI-MS (positive mode): m/z = 474.3, 442.2.
ESI-HRMS: m/z [M + Na]+ calcd for C23H21N3O5Na: 442.1379;
found: 442.1371.
[Phthaloyl-(1-carbobenzyloxy-D-tryptophanyl)]-L-alanine
Methyl Ester 13
n-Bu4NHSO4 (441 mg, 1.3 mmol) and freshly finely powdered
NaOH (2.7 g, 67.5 mmol) were successively added to a soln of 2
(5.6 g, 13.3 mmol) in anhyd CH2Cl2 (170 mL). The resulting pale
yellow soln was stirred for 15 min, and then CbzCl (5.8 mL, 40.6
mmol) was added in three portions over 15 min. The resulting slurry
was vigorously stirred for 90 min and quenched by the addition of
H2O (100 mL). The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (2 × 100 mL). The combined or-
ganic layers were washed with brine (100 mL), dried (MgSO4), fil-
tered, and concentrated. The crude residue was purified by flash
chromatography (silica gel, CH2Cl2, then CH2Cl2–Et2O, 95:5); this
yielded the desired protected dipeptide 13 as a pale yellow solid.
Phthaloyl-D-tryptophan
Phthalic anhydride (6.5 g, 44 mmol) was added to a soln of D-tryp-
tophan (9.0 g, 44 mmol) in py (70 mL). The resulting soln was re-
fluxed overnight and concentrated by distillation. The residue was
cooled to 0 °C, treated with 6 M aq HCl (200 mL) and stirred at 0 °C
for 2 h. The precipitate was filtered, washed with cold H2O, and dis-
solved in EtOAc (200 mL), and the organic soln was washed with a
mixture of brine and 1 M aq HCl (1:1; 200 mL), dried (MgSO4), fil-
tered, and concentrated. This gave the desired protected tryptophan
as a pale brown solid, which was used without further purification
in the next step.
Yield: 7.0 g (95%); mp 82 °C; [a]D20 +52 (c 1.0, CHCl3).
IR (film): 3370, 2950, 1747, 1711, 1532, 1383, 1219, 715 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.24 (br d, J = 6.9 Hz, 1 H), 7.66–
7.70 (m, 2 H), 7.57–7.60 (m, 2 H), 7.50 (app dd, J = 8.3, 1.6 Hz, 1
H), 7.29–7.38 (m, 6 H), 7.21 (app td, J = 6.0, 1.1 Hz, 1 H), 7.14 (app
td, J = 7.5, 1.2 Hz, 1 H), 6.70 (br d, J = 7.1 Hz, 1 H), 5.28 (s, 2 H),
5.16 (dd, J = 9.0, 7.1 Hz, 1 H), 4.57 (app q, J = 7.2 Hz, 1 H), 3.60
(app d, J = 6.9 Hz, 2 H), 3.61 (s, 3 H), 1.30 (d, J = 7.2 Hz, 3 H).
Yield: 15.0 g (quant); mp 97 °C; [a]D20 +187 (c 1.3, EtOH).
IR (film): 3390, 3047, 1778, 1711, 1388, 707 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 13.37 (br s, 1 H), 10.77 (s, 1
H), 7.75–7.83 (m, 4 H), 7.52 (d, J = 7.9 Hz, 1 H), 7.28 (d, J = 7.9
Hz, 1 H), 7.06 (d, J = 1.9 Hz, 1 H), 7.02 (t, J = 7.9 Hz, 1 H), 6.92 (t,
J = 7.9 Hz, 1 H), 5.16 (X of ABX, J = 9.2, 6.6 Hz, 1 H), 3.57–3.58
(m, 2 H).
13C NMR (75 MHz, CDCl3): d = 173.2, 173.1 (rotamers), 168.0,
167.9 (rotamers), 167.8, 167.7 (rotamers), 135.2, 134.4, 131.6,
130.0, 128.8, 128.7, 128.4, 125.1, 123.7, 123.2, 119.0, 117.1, 116.9
(rotamers), 115.4, 115.1 (rotamers), 68.7, 54.0, 53.9 (rotamers),
52.6, 52.5 (rotamers), 48.6, 25.0, 24.8 (rotamers), 18.5, 18.4 (rota-
mers).
13C NMR (75 MHz, DMSO-d6): d = 170.5, 167.3, 136.1, 134.8,
131.0, 127.0, 123.5, 123.4, 121.1, 118.5, 118.0, 111.5, 109.8, 52.7,
24.2.
ESI-MS (positive mode): m/z = 608.4, 576.3.
ESI-HRMS: m/z [M + Na]+ calcd for C31H27N3O7Na: 576.1747;
found: 576.1750.
MS (CI, NH3 gas): m/z = 352, 335.
ESI-HRMS: m/z [M + Na]+ calcd for C19H14N2O4Na: 357.0851;
found: 357.0845.
[Phthaloyl-(1-p-toluenesulfonyl-D-tryptophanyl)]-L-alanine
Methyl Ester 14
Phthaloyl-D-tryptophanyl-L-alanine Methyl Ester 2
1-Hydroxybenzotriazole (HOBt; 3.0 g, 22.2 mmol) was added to a
soln of phthaloyl-D-tryptophan (6.7 g, 19.7 mmol) and L-alanine
methyl ester hydrochloride (2.8 g, 20.0 mmol) in DMF (70 mL).
EDC·HCl (3.8 g, 19.8 mmol) and NMM (2.8 mL, 25.5 mmol) were
next added at 0 °C and the soln was stirred for 16 h while progres-
sively warmed to r.t. The brown reaction mixture was quenched by
the addition of a sat. aq soln of NaHCO3 (70 mL) and diluted with
EtOAc (70 mL). The aqueous layer was extracted with EtOAc (3 ×
70 mL) and the combined organic layers were washed with brine
(70 mL), dried (MgSO4), filtered, and concentrated. The crude res-
idue was purified by flash chromatography (silica gel, EtOAc–PE,
7:3); this yielded the desired dipeptide 2 as a pale yellow solid.
n-Bu4NHSO4 (42 mg, 0.12 mmol) and freshly finely powdered
NaOH (300 g, 7.5 mmol) were successively added to a soln of 2 (1.0
g, 2.5 mmol) in anhyd CH2Cl2 (25 mL). The resulting pale yellow
soln was stirred for 15 min and TsCl (560 mg, 3.0 mmol) was added
in three portions over 5 min. The resulting slurry was vigorously
stirred for 90 min and quenched by the addition of H2O (25 mL).
The organic layer was separated and the aqueous layer was extract-
ed with CH2Cl2 (2 × 50 mL). The combined organic layers were
washed with brine (50 mL), dried (MgSO4), filtered, and concen-
trated. The crude residue was purified by flash chromatography (sil-
ica gel, CH2Cl2); this yielded the desired protected dipeptide 14 as
a white solid.
Yield: 6.5 g (79%); mp 99 °C; [a]D20 +63 (c 0.7, CHCl3).
Yield: 1.0 g (72%); mp 84 °C; [a]D20 +67 (c 0.8, CHCl3).
IR (KBr): 3355, 3052, 2945, 1777, 1690, 1537, 1199 cm–1.
ESI-MS (positive mode): m/z = 596.6.
IR (film): 3375, 2950, 1711, 1532, 1383, 1209, 717 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.24 (br s, 1 H), 7.72–7.77 (m, 2
H), 7.61–7.67 (m, 3 H), 7.26 (d, J = 7.9 Hz, 1 H), 7.13 (app td,
J = 7.1, 1.2 Hz, 1 H), 7.06 (app td, J = 8.0, 1.2 Hz, 2 H), 6.81 (d,
J = 6.9 Hz, 1 H), 5.27 (dd, J = 9.0, 7.1 Hz, 1 H), 4.57 (app quint,
J = 7.2 Hz, 1 H), 3.61–3.82 (m, 2 H), 3.67 (s, 3 H), 1.35 (d, J = 7.2
Hz, 3 H).
1H NMR (300 MHz, CDCl3): d = 7.77 (d, J = 8.2 Hz, 1 H), 7.65–
7.71 (m, 2 H), 7.58–7.63 (m, 2 H), 7.47 (d, J = 8.4 Hz, 2 H), 7.44
(d, J = 7.2 Hz, 1 H), 7.16 (s, 1 H), 7.16 (td, J = 7.7, 1.3 Hz, 1 H),
7.10 (td, J = 7.3, 1.1 Hz, 1 H), 6.94 (d, J = 8.1 Hz, 2 H), 6.64 (d,
J = 7.1 Hz, 1 H), 5.10 (X of ABX, J = 10.0, 6.3 Hz, 1 H), 4.48 (app
quint, J = 7.2 Hz, 1 H), 3.60 (s, 3 H), 3.57–3.65 (obs m, 2 H), 2.17
(s, 3 H), 1.28 (d, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 173.3, 173.2 (rotamers), 168.5,
168.4 (rotamers), 168.2, 168.1 (rotamers), 136.4, 136.3 (rotamers),
Synthesis 2009, No. 17, 2927–2934 © Thieme Stuttgart · New York

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A. Coste et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 173.1, 167.9, 167.8, 144.8, 135.2,
134.5, 131.5, 130.2, 129.8, 126.8, 125.1, 124.5, 123.8, 123.4, 119.4,
117.7, 113.8, 53.9, 52.7, 48.6, 24.7, 21.6, 18.3.
added, the flask was cooled to 0 °C, and NCS (637 mg, 4.77 mmol)
was added. The resulting mixture was stirred for 5 min and Et3N
(1.0 mL, 7.17 mmol) was added dropwise. The resulting mixture
was allowed to warm to r.t., stirred overnight under argon, and con-
centrated. The crude residue was purified by flash chromatography
(silica gel, EtOAc–PE, 40:60); this yielded the cyclized product 17
as a white solid.
ESI-HRMS: m/z [M + Na]+ calcd for C30H27N3O7SNa: 596.1467;
found: 596.1472.
Methyl [2(2R),2S]-2-({4-[2-(Formylamino)phenyl]-4-oxo-2-
phthalimidobutyryl}amino)propionate (15)
Yield: 815 mg (82%); mp 191 °C; [a]D20 +61 (c 1.5, CHCl3).
A soln of 2 (500 mg, 1.2 mmol) in anhyd CH2Cl2 (25 mL) was treat-
ed with MCPBA (70%, 1.2 g, 4.8 mmol) at –50 °C. The resulting
mixture was warmed to r.t. over 2 h and quenched by the addition
of a 10 wt% aq soln of Na2S2O3 (20 mL) and sat. aq NaHCO3 (20
mL). The organic layer was separated and the aqueous layer was ex-
tracted with CH2Cl2 (2 × 25 mL). The combined organic layers were
washed with brine (25 mL), dried (MgSO4), filtered, and concen-
trated. The crude residue was purified by flash chromatography (sil-
ica gel, EtOAc–PE, 50:50); this yielded the oxidized product 15 as
a white solid.
IR (film): 3370, 2930, 1716, 1588, 1383 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.15 (s, 1 H), 7.77 (dd, J = 5.3, 3.1
Hz, 2 H), 7.63 (dd, J = 5.5, 3.1 Hz, 2 H), 7.22–7.28 (m, 2 H), 7.02–
7.04 (m, 2 H), 5.62 (q, J = 7.3 Hz, 1 H), 5.18 (X of ABX, J = 13.9,
7.5 Hz, 1 H), 3.68–3.80 (obs m, 1 H), 3.72 (s, 3 H), 3.00 (B of ABX,
J = 14.5, 7.5 Hz, 1 H), 1.53 (d, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 173.5, 167.9, 166.4, 134.3, 133.7,
133.4, 132.0, 126.0, 123.6, 121.1, 120.7, 117.4, 111.5, 94.3, 53.2,
51.4, 50.9, 21.6, 15.8.
Yield: 460 mg (85%); mp 85 °C; [a]D20 +92 (c 0.5, CHCl3).
MS (CI, NH3 gas): m/z = 418.
IR (KBr): 3319, 2950, 1777, 1701, 1527, 1383, 989 cm–1.
ESI-HRMS: m/z [M + Na]+ calcd for C23H19N3O5Na: 440.1222;
found: 440.1227.
1H NMR (300 MHz, CDCl3): d = 11.31 (br s, 1 H), 8.70 (d, J = 8.5
Hz, 1 H), 8.42 (s, 1 H), 8.01 (dd, J = 8.1, 1.3 Hz, 1 H), 7.88 (dd,
J = 5.6, 2.9 Hz, 2 H), 7.75 (dd, J = 5.5, 2.9 Hz, 2 H), 7.55 (t, J = 8.2
Hz, 1 H), 7.18 (t, J = 7.4 Hz, 1 H), 6.66 (d, J = 7.1 Hz, 1 H), 5.54 (X
of ABX, J = 6.8, 6.8 Hz, 1 H), 4.57 (app quint, J = 7.2 Hz, 1 H),
4.27 (A of ABX, J = 18.3, 6.2 Hz, 1 H), 3.93 (B of ABX, J = 18.3,
7.4 Hz, 1 H), 3.67 (s, 3 H), 1.40 (d, J = 7.3 Hz, 3 H).
(1S,3R,4aS)-4a-Hydroxy-1-[1-(methoxycarbonyl)ethyl]-2-oxo-
3-phthalimido-2,3,4,4a-tetrahydropyrido[2,3-b]indole (5)
A 250-mL flask was charged with 2 (630 mg, 1.5 mmol), evacuated
under high vacuum and backfilled with O2. CH2Cl2 (30 mL) was
added, the flask was cooled to 0 °C, and NCS (400 mg, 3.0 mmol)
was added. The resulting mixture was stirred for 5 min and Et3N
(630 mL, 4.5 mmol) was added dropwise. The resulting mixture was
allowed to warm to r.t., vigorously stirred overnight under O2 (bal-
loon), and concentrated. The crude residue was purified by flash
chromatography (silica gel, CH2Cl2–Et2O, 92:8); this yielded 5 as a
white solid.
13C NMR (75 MHz, CDCl3): d = 200.9, 173.0, 167.8, 167.6, 139.8,
135.5, 134.5, 131.5, 130.9, 123.8, 123.3, 121.6, 121.3, 52.5, 49.3,
48.5, 38.7, 18.1.
ESI-MS (positive mode): m/z = 474.1.
ESI-HRMS: m/z [M + Na]+ calcd for C23H21N3O7Na: 474.1277;
found: 474.1274.
Yield: 435 mg (64%); mp 156 °C; [a]D20 +92 (c 0.6, CHCl3).
IR (film): 3411, 2929, 1721, 1578, 1388 cm–1.
[Phthaloyl-(2-bromo-D-tryptophanyl)]-L-alanine Methyl Ester
(16)
1H NMR (300 MHz, CDCl3): d = 7.76–7.93 (br m, 4 H), 7.25–7.43
(m, 3 H), 7.18 (td, J = 5.3, 1.0 Hz, 1 H), 5.66 (X of ABX, J = 11.8,
6.0 Hz, 1 H), 5.52 (q, J = 7.1 Hz, 1 H), 3.73 (s, 3 H), 3.06 (br s, 1
H), 2.82 (A of ABX, J = 12.9, 6.0 Hz, 1 H), 2.62 (B of ABX,
J = 12.9, 11.9 Hz, 1 H), 1.75 (d, J = 7.1 Hz, 3 H).
NBS (42 mg, 0.24 mmol) and Et3N (100 mL, 0.72 mmol) were add-
ed to a soln of 2 (100 mg, 0.24 mmol) in anhyd CH2Cl2 (5 mL) at
0 °C. The resulting mixture was allowed to warm to r.t. and stirred
overnight. The crude reaction mixture was concentrated and puri-
fied by flash chromatography (silica gel, CH2Cl2–Et2O, 95:5); this
yielded the brominated dipeptide 16 as a pale yellow solid.
13C NMR (75 MHz, CDCl3): d = 170.6, 170.5, 167.2, 153.4, 136.1,
134.5, 131.1, 125.4, 123.9, 122.5, 120.4, 77.4, 52.7, 52.5, 46.7,
32.3, 14.9.
Yield: 59 mg (51%); mp 80 °C; [a]D20 +57 (c 0.6, CHCl3).
IR (KBr): 3324, 2925, 1716, 1511, 1383 cm–1.
MS (CI, NH3 gas): m/z = 434.
ESI-HRMS: m/z [M + Na]+ calcd for C23H19N3NaO6: 456.1172;
found: 456.1171.
1H NMR (300 MHz, CDCl3): d = 8.54 (s, 1 H), 7.68–7.75 (m, 2 H),
7.58–7.66 (m, 2 H), 7.48 (d, J = 7.8 Hz, 1 H), 7.16 (d, J = 7.7 Hz, 1
H), 7.04 (td, J = 7.1, 1.2 Hz, 1 H), 6.97 (td, J = 7.1, 1.2 Hz, 1 H),
6.74 (d, J = 7.0 Hz, 1 H), 5.24 (X of ABX, J = 9.1, 7.1 Hz, 1 H),
4.59 (app quint, J = 7.1 Hz, 1 H), 3.67 (s, 3 H), 3.69 (A of ABX,
J = 18.0, 7.1 Hz, 1 H), 3.54 (B of ABX, J = 14.7, 9.4 Hz, 1 H), 1.35
(d, J = 7.1 Hz, 3 H).
Photooxidation of 17 to 5
A 50-mL flask was charged with 17 (80 mg, 0.19 mmol) and
CH2Cl2 (5 mL). The soln was purged with O2, vigorously stirred un-
der an atmosphere of O2 (balloon) for 24 h and concentrated (MS
analysis of the crude reaction mixture showed the presence of hy-
droperoxide 20 and hydroxy imine 5). The crude mixture was puri-
fied by flash chromatography (silica gel, EtOAc–PE, 40:60); this
yielded the photooxidized product 5.
13C NMR (75 MHz, CDCl3): d = 173.2, 168.1, 167.9, 136.1, 134.2,
131.7, 127.3, 123.5, 122.5, 120.3, 117.9, 110.7, 110.3, 109.4, 53.7,
52.6, 48.6, 25.1, 18.3.
ESI-MS (positive mode): m/z = 522.1, 520.1.
Yield: 71 mg (84%).
ESI-HRMS: m/z [M + Na]+ calcd for C23H20BrN3O5Na: 520.0484;
found: 520.0472.
(2S,4R,5aS,9cS)-5a-Hydroxy-2-methyl-4-phthalimido-
4,5,5a,9c-tetrahydro-2a,9b-diazacyclopenta[jk]fluorene-1,3-di-
one (6)
Glacial AcOH (385 mL, 6.7 mmol) was added dropwise to a soln of
5 (290 mg, 0.67 mmol) in MeOH (8 mL) at 0 °C. The resulting mix-
ture was stirred for 30 min, treated with NaBH3CN (665 mg, 8.0
(1S,3R)-1-[1-(Methoxycarbonyl)ethyl]-2-oxo-3-phthalimido-
1,2,3,4-tetrahydropyrido[2,3-b]indole (17)
A 100-mL flask was charged with 2 (1.0 g, 2.38 mmol), evacuated
under high vacuum and backfilled with argon. CH2Cl2 (50 mL) was
Synthesis 2009, No. 17, 2927–2934 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Chaetominine
2933
mmol) and slowly warmed to r.t. over 3 h. The resulting mixture
was carefully quenched at 0 °C by the addition of a sat. aq soln of
NaHCO3 (100 mL) and extracted with EtOAc (3 × 50 mL). The
combined organic layers were washed with brine (100 mL), dried
(MgSO4), filtered, and concentrated. The crude residue was dis-
solved in a mixture of CH2Cl2 (22.5 mL), acetone (2 mL), EtOH
(0.5 mL), and 30 wt% aq NH3 soln (0.25 mL), and treated with silica
gel (3 g) for 105 min. The resulting slurry was concentrated and pu-
rified by flash chromatography (silica gel, CH2Cl2–acetone–EtOH–
30 wt% aq NH3, 93:5:1.9:0.1); this yielded the desired tetracyclic
compound 6 as a white solid.
drazine hydrate (3.0 mL, 0.06 mmol) was added. The white soln was
stirred for 8 h at r.t. and the solvents were removed under reduced
pressure. The crude residue was purified by flash chromatography
(silica gel, CH2Cl2–MeOH–30 wt% aq NH3, 96:3.5:0.5); this yield-
ed the free amine as a white solid.
Yield: 25 mg (66%); mp 79 °C; [a]D20 +31 (c 0.5, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.60 (d, J = 7.9 Hz, 1 H), 7.39 (td,
J = 7.5, 1.3 Hz, 1 H), 7.34 (d, J = 7.6 Hz, 1 H), 7.19 (td, J = 7.6, 1.0
Hz, 1 H), 5.30 (s, 1 H), 4.38 (q, J = 6.9 Hz, 1 H), 3.73 (X of ABX,
J = 12.2, 3.2 Hz, 1 H), 2.64 (A of ABX, J = 13.0, 3.4 Hz, 1 H), 2.12
(br s, 2 H), 1.81 (B of ABX, J = 12.6, 12.6 Hz, 1 H), 1.71 (d, J = 6.9
Hz, 3 H), 0.83 (t, J = 8.0 Hz, 9 H), 0.35–0.44 (m, 6 H).
Yield: 243 mg (90%); mp 285 °C; [a]D20 –21 (c 0.6, CHCl3).
IR (film): 3411, 2919, 1711, 1388 cm–1.
13C NMR (75 MHz, CDCl3): d = 173.3, 172.0, 140.3, 134.6, 130.9,
125.7, 125.0, 115.6, 84.1, 79.9, 59.5, 50.0, 43.9, 15.0, 7.0, 6.1.
1H NMR (300 MHz, CDCl3): d = 7.69–7.75 (m, 2 H), 7.60–7.66 (m,
2 H), 7.45 (d, J = 7.9 Hz, 1 H), 7.27 (td, J = 7.7, 1.1 Hz, 1 H), 7.22
(d, J = 7.4 Hz, 1 H), 7.06 (td, J = 7.5, 0.7 Hz, 1 H), 5.30 (s, 1 H),
5.03 (X of ABX, J = 12.9, 3.2 Hz, 1 H), 4.33 (s, 1 H), 4.23 (q,
J = 7.0 Hz, 1 H), 2.81 (A of ABX, J = 12.9, 12.9 Hz, 1 H), 2.34 (B
of ABX, J = 12.9, 3.3 Hz, 1 H), 1.56 (d, J = 7.0 Hz, 3 H).
ESI-HRMS: m/z [M + Na]+ calcd for C20H29N3O3SiNa: 410.1876;
found: 410.1873.
(2S,4R,5aS,9cS)-4-(2-Aminobenzamido)-2-methyl-5a-(triethyl-
siloxy)-4,5,5a,9c-tetrahydro-2a,9b-diazacyclopenta[jk]fluo-
rene-1,3-dione (21)5
13C NMR (75 MHz, CDCl3): d = 171.6, 168.1, 167.8, 165.6, 138.9,
135.3, 134.4, 134.3, 132.0, 131.8, 130.8, 126.1, 124.4, 123.8, 123.7,
115.5, 83.2, 77.4, 60.4, 48.2, 37.4, 29.8, 14.4.
Isatoic anhydride (12.5 mg, 0.074 mmol) was added in one portion
to a soln of (2S,4R,5aS,9cS)-4-amino-2-methyl-5a-(triethylsiloxy)-
4,5,5a,9c-tetrahydro-2a,9b-diazacyclopenta[jk]fluorene-1,3-dione
(19 mg, 0.049 mmol) in anhyd benzene (6.0 mL). The resulting sus-
pension was refluxed for 16 h and the benzene was removed under
reduced pressure. The crude residue was purified by flash chroma-
tography (silica gel, CH2Cl2–Et2O, 91:9); this yielded amino amide
21 as a sticky white solid.
MS (CI, NH3 gas): m/z = 404.
ESI-HRMS: m/z [M + Na]+ calcd for C22H17N3O5Na: 426.1066;
found: 426.1073.
(2S,4R,5aS,9cS)-2-Methyl-4-phthalimido-5a-(triethylsiloxy)-
4,5,5a,9c-tetrahydro-2a,9b-diazacyclopenta[jk]fluorene-1,3-di-
one
Yield: 15.5 mg (63%); [a]D20 –97 (c 0.66, CHCl3).
2,6-Lutidine (1.5 mL, 12.9 mmol) and TESOTf (2.1 mL, 9.3 mmol)
were added dropwise to a soln of 6 (750 mg, 1.86 mmol) in CH2Cl2
(15 mL) at –20 °C. The resulting mixture was slowly warmed to r.t.
over 1 h, stirred for 15 min, and quenched by the addition of a sat.
aq soln of NaHCO3 (15 mL). The organic layer was separated and
the aqueous layer was extracted with CH2Cl2 (3 × 25 mL). The com-
bined organic layers were washed with brine (50 mL), dried
(MgSO4), filtered, and concentrated. The crude residue was purified
by flash chromatography (silica gel, CH2Cl2–Et2O, 95:5); this yield-
ed the desired TES ether as a pale yellow solid.
1H NMR (300 MHz, CDCl3): d = 7.62 (d, J = 7.8 Hz, 1 H), 7.46 (dd,
J = 8.0, 1.4 Hz, 1 H), 7.40 (td, J = 7.5, 1.3 Hz, 1 H), 7.38 (d, J = 7.4
Hz, 1 H), 7.23 (t, J = 7.8 Hz, 1 H), 7.21 (t, J = 7.8 Hz, 1 H), 7.12 (d,
J = 5.2 Hz, 1 H), 6.76 (dd, J = 8.2, 0.9 Hz, 1 H), 6.70 (app td,
J = 8.0, 1.1 Hz, 1 H), 5.41 (s, 1 H), 4.85–4.91 (m, 1 H), 4.44 (q,
J = 6.9 Hz, 1 H), 3.12 (A of ABX, J = 12.7, 3.5 Hz, 1 H), 1.76 (B of
ABX, J = 12.4, 12.4 Hz, 1 H), 1.75 (d, J = 7.0 Hz, 3 H), 0.90 (t,
J = 8.1 Hz, 9 H), 0.49 (q, J = 7.7 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 173.0, 169.0, 168.9, 147.8, 140.2,
134.4, 132.7, 130.9, 127.9, 125.8, 125.2, 118.0, 117.6, 116.3,
115.7, 83.9, 80.0, 59.7, 49.1, 41.5, 15.0, 6.2, 5.9.
Yield: 847 mg (88%); mp 93 °C; [a]D20 –22 (c 0.6, CHCl3).
IR (film): 2955, 2873, 1726, 1378, 1332, 748 cm–1.
ESI-MS (positive mode): m/z = 1035.8, 529.3, 507.3, 375.3, 120.0.
ESI-HRMS: m/z [M + Na]+ calcd for C27H34N4O4SiNa: 529.2247;
found: 529.2241.
1H NMR (300 MHz, CDCl3): d = 7.80–7.83 (m, 1 H), 7.73–7.76 (m,
1 H), 7.64–7.67 (m, 2 H), 7.57 (d, J = 7.9 Hz, 1 H), 7.35 (td, J = 7.7,
1.3 Hz, 1 H), 7.22 (d, J = 7.7 Hz, 1 H), 7.14 (td, J = 7.7, 1.0 Hz, 1
H), 5.38 (s, 1 H), 5.14 (X of ABX, J = 12.9, 3.3 Hz, 1 H), 4.35 (q,
J = 6.9 Hz, 1 H), 2.88 (A of ABX, J = 12.9, 12.9 Hz, 1 H), 2.44 (B
of ABX, J = 12.9, 3.3 Hz, 1 H), 1.66 (d, J = 6.9 Hz, 3 H), 0.82 (t,
J = 7.8 Hz, 9 H), 0.36–0.47 (m, 6 H).
(2S,4R,5aS,9cS)-2-Methyl-4-(4-oxo-4H-quinazolin-3-yl)-5a-
(triethylsiloxy)-4,5,5a,9c-tetrahydro-2a,9b-diazacyclopen-
ta[jk]fluorene-1,3-dione (TES-Protected Chaetominine)5
Triethyl orthoformate (225 mL, 1.33 mmol) and PTSA·H2O (5 mg,
0.025 mmol) were added to a soln of 21 (42 mg, 0.083 mmol) in an-
hyd benzene (11.5 mL). The resulting mixture was refluxed for 90
min and the solvent was removed under reduced pressure. The
crude residue was purified by flash chromatography (silica gel,
CH2Cl2–Et2O–30 wt% aq NH3: 88:11.5:0.5); this yielded TES-pro-
tected-chaetominine as a white solid.
13C NMR (75 MHz, CDCl3): d = 172.6, 168.1, 167.6, 165.6, 140.1,
134.4, 134.3, 134.2, 132.1, 132.0, 131.0, 125.7, 125.0, 115.7, 83.9,
80.1, 59.9, 48.3, 39.8, 14.6, 6.9, 6.2.
MS (CI, NH3 gas): m/z = 518.
ESI-HRMS: m/z [M + Na]+ calcd for C28H31N3O5SiNa: 540.1931;
found: 540.1920.
Yield: 39 mg (90%); mp 269 °C; [a]D20 –23 (c 0.45, CHCl3).
1H NMR (300 MHz, CDCl3): d = 8.29 (d, J = 8.5 Hz, 1 H), 7.90 (s,
1 H), 7.71–7.80 (m, 2 H), 7.65 (d, J = 7.9 Hz, 1 H), 7.51 (td, J = 7.3,
1.7 Hz, 1 H), 7.45 (td, J = 7.7, 1.3 Hz, 1 H), 7.34 (d, J = 7.8 Hz, 1
H), 7.22 (td, J = 7.5, 1.0 Hz, 1 H), 5.48 (s, 1 H), 4.45 (q, J = 6.9 Hz,
1 H), 2.64 (app br d, J = 10.3 Hz, 1 H), 2.31 (br m, 1 H), 1.75 (d,
J = 6.9 Hz, 3 H), 0.89 (t, J = 8.0 Hz, 9 H), 0.43–0.52 (m, 6 H) (H14
was not observed due to slow rotation at the C14–N bond).
(2S,4R,5aS,9cS)-4-Amino-2-methyl-5a-(triethylsiloxy)-
4,5,5a,9c-tetrahydro-2a,9b-diazacyclopenta[jk]fluorene-1,3-di-
one
Hydrazine hydrate (5.5 mL, 0.11 mmol) was added to a soln of
(2S,4R,5aS,9cS)-2-methyl-4-phthalimido-5a-(triethylsiloxy)-4,5,5a,9c-
tetrahydro-2a,9b-diazacyclopenta[jk]fluorene-1,3-dione (51 mg,
0.098 mmol) in anhyd THF (0.5 mL) and absolute EtOH (0.5 mL).
The resulting mixture was stirred at r.t. for 16 h and additional hy-
Synthesis 2009, No. 17, 2927–2934 © Thieme Stuttgart · New York

2934
A. Coste et al.
PAPER
(6) (a) For the total synthesis of related natural products, the
13C NMR (75 MHz, CDCl3): d = 172.5, 160.7, 147.2, 140.2, 134.8,
133.9, 131.3, 127.7, 127.4, 127.3, 125.8, 125.0, 122.0, 115.8, 83.9,
80.0, 60.0, 48.3, 39.8, 14.6, 6.9, 6.2 (one amide carbonyl carbon was
not observed due to slow rotation at the C14–N bond).
kapakahines, see: Newhouse, T.; Lewis, C. A.; Baran, P. S.
J. Am. Chem. Soc. 2009, 131, 6360. (b) During the
preparation of this manuscript, a third total synthesis of
chaetominine was reported. See: Malgesini, B.; Forte, B.;
Borghi, D.; Quartieri, F.; Gennari, C.; Papeo, G. Chem. Eur.
J. 2009, 15, DOI: 10.1002/chem.200900793.
ESI-MS (positive mode): m/z = 555.0, 538.9, 517.0.
ESI-HRMS: m/z [M + Na]+ calcd for C28H32N4NaO4Si: 539.2091;
found: 539.2086.
(7) (a) Toumi, M.; Couty, F.; Evano, G. Angew. Chem. Int. Ed.
2007, 46, 572. (b) Toumi, M.; Couty, F.; Evano, G. J. Org.
Chem. 2007, 72, 9003. (c) Toumi, M.; Couty, F.; Evano, G.
Synlett 2008, 29. (d) Coste, A.; Toumi, M.; Wright, K.;
Razafimahaléo, V.; Couty, F.; Marrot, J.; Evano, G. Org.
Lett. 2008, 10, 3841. (e) Evano, G.; Blanchard, N.; Toumi,
M. Chem. Rev. 2008, 108, 3054. (f) Toumi, M.; Rincheval,
V.; Young, A.; Gergeres, D.; Turos, E.; Couty, F.; Mignotte,
B.; Evano, G. Eur. J. Org. Chem. 2009, 3368. (g) Evano,
G.; Toumi, M.; Coste, A. Chem. Commun. 2009, 4166.
(8) Toumi, M.; Marrot, J.; Couty, F.; Evano, G. Org. Lett. 2008,
10, 5027.
(9) For examples, see: (a) Ohno, M.; Spande, T. F.; Witkop, B.
J. Am. Chem. Soc. 1968, 90, 6521. (b) Savige, W. E. Aust. J.
Chem. 1975, 28, 2275. (c) Kamenecka, T. M.; Danishefsky,
S. J. Chem. Eur. J. 2001, 7, 41. (d) May, J. P.; Fournier, P.;
Pellicelli, J.; Partick, B. O.; Perrin, D. M. J. Org. Chem.
2005, 70, 8424. (e) Depew, K. M.; Marsden, S. P.; Zatorska,
D.; Zatorski, A.; Bornmann, W. G.; Danishefsky, S. J. J. Am.
Chem. Soc. 1999, 121, 11953. (f) Hewitt, P. R.; Cleator, E.;
Ley, S. V. Org. Biomol. Chem. 2004, 2, 2415. (g) Schiavi,
B. M.; Richard, D. J.; Joullié, M. M. J. Org. Chem. 2002, 67,
620. (h) Movassaghi, M.; Schmidt, M. A.; Ashenhurst, J. A.
Angew. Chem. Int. Ed. 2008, 47, 1485.
(–)-Chaetominine (1)4,5
A 49 wt% aq soln of HF (125 mL) was added dropwise to a soln of
TES-protected chaetominine (34 mg, 0.066 mmol) in MeCN (2.3
mL). The resulting mixture was stirred at r.t. overnight, treated with
additional 49 wt% aq HF (35 mL), and stirred at 30 °C for 6 h. The
reaction mixture was next diluted with EtOAc (10 mL), successive-
ly washed with an aq sat. soln of NaHCO3 (10 mL) and brine (10
mL), dried (MgSO4), filtered, and concentrated. The crude residue
was purified by flash chromatography (silica gel, CH2Cl2–Et2O–
MeOH–30 wt% aq NH3, 60:33:6.5:0.5); this yielded synthetic cha-
etominine (1) as a white solid.
Yield: 25 mg (94%); mp 164 °C (Lit.4 161–163 °C, Lit.5 162–
165 °C); [a]D –48 (c 0.45, MeOH) {Lit.4 [a]D –70 (c 0.48,
20
20
MeOH), –49.4 (c 0.26, MeOH)}.
IR (KBr): 3445, 1726, 1670, 1609, 1480, 1383 cm–1.
ESI-MS (positive mode): m/z = 826.8, 441.0, 424.9, 403.0.
1H NMR (300 MHz, DMSO-d6): d = 8.29 (br s, 1 H), 8.18 (br d,
J = 7.7 Hz, 1 H), 7.86 (td, J = 7.6, 1.5 Hz, 1 H), 7.69 (d, J = 7.6 Hz,
1 H), 7.58 (td, J = 7.5, 1.0 Hz, 1 H), 7.51 (d, J = 7.6 Hz, 1 H), 7.49
(d, J = 7.6 Hz, 1 H), 7.43 (td, J = 7.5, 1.0 Hz, 1 H), 7.25 (td, J = 7.5,
1.2 Hz, 1 H), 6.71 (br s, 1 H), 5.90 (br s, 1 H), 5.61 (br s, 1 H), 4.61
(q, J = 6.9 Hz, 1 H), 2.94 (A of ABX, J = 12.8, 12.8 Hz, 1 H), 2.53
(B of ABX, J = 12.8, 3.2 Hz, 1 H), 1.60 (d, J = 6.9 Hz, 3 H).
(10) Bergman, J.; Engqvist, R.; Stålhandske, C.; Wallberg, H.
Tetrahedron 2003, 59, 1033.
(11) He, L.; Yang, L.; Castle, S. L. Org. Lett. 2006, 8, 1165.
(12) Davis, F. A.; Towson, J. C.; Vashi, D. B.; ThimmaReddy,
R.; McCauley, J. P. Jr.; Harakal, M. E.; Gosciniak, D. J.
J. Org. Chem. 1990, 55, 1254.
(13) For related cleavage of double bonds in indoles with
MCPBA, see: (a) Witkop, B.; Fiedler, H. Ann. Chim. 1947,
558, 91. (b) Hino, T.; Yamaguchi, H.; Matsuki, K.; Nakano,
K.; Sodeoka, M.; Nakagawa, M. J. Chem. Soc., Perkin
Trans. 2 1983, 141. (c) Astolfi, P.; Greci, L.; Rizzoli, C.;
Sgarabotto, P.; Marrosu, G. J. Chem. Soc., Perkin Trans. 2
2001, 1634.
(14) For examples of photooxidation of indoles with oxygen,
see: (a) Nakagawa, M.; Watanabe, H.; Kodato, S.; Okajima,
H.; Hino, T.; Flippen, J. L.; Witkop, B. Proc. Natl. Acad. Sci.
U. S. A. 1977, 74, 4730. (b) Kanji, S.; Sainsbury, M.
Phytochemistry 1974, 11, 503. (c) Saito, I.; Matsugo, S.;
Matsuura, T. J. Am. Chem. Soc. 1979, 101, 7332.
(d) Ferroud, C.; Rool, P. Heterocycles 2001, 55, 545.
(e) Baran, P. S.; Guerrero, C. A.; Corey, E. J. J. Am. Chem.
Soc. 2003, 125, 5628. (f) Baran, P. S.; Guerrero, C. A.;
Hafensteiner, B. D.; Ambhaikar, N. B. Angew. Chem. Int.
Ed. 2005, 44, 3892.
13C NMR (75 MHz, DMSO-d6): d = 172.0, 165.5 (br), 160.0, 147.4,
147.0 (br), 138.7, 136.7, 134.7, 129.9, 127.27, 127.23, 126.4, 125.5,
124.9, 121.2 (br), 114.5, 82.5, 76.4, 59.6, 50.0, 38.1 (br), 14.0.
ESI-HRMS: m/z [M + Na]+ calcd for C22H18N4O4Na: 425.1226;
found: 425.1215.
Acknowledgment
The authors thank the CNRS and the ANR (project ProteInh) for fi-
nancial support. A. C. acknowledges the National Cancer Institute
for a graduate fellowship and G. K. acknowledges the University of
Versailles for a postdoctoral fellowship.
References
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(15) Electrostatic repulsion between the phthalimide protecting
group and the incoming electrophile might also account for
the high stereoselectivity observed
(16) ArgusLab 4.0; Mark A. Thompson, Planaria Software LLC:
Seattle; see: http://www.ArgusLab.com.
Synthesis 2009, No. 17, 2927–2934 © Thieme Stuttgart · New York