A straightforward total synthesis of (-)-chaetominine

Article abstract of DOI:10.1002/chem.200900793

A total synthesis of the tripeptide alkaloid (-)-chaetominine (1) was achieved in 9.3% overall yield starting from commercially available Dtryptophan methyl ester, based on a short and straightforward (nine steps) sequence. The early stage introduction (f

Full text of DOI:10.1002/chem.200900793

DOI: 10.1002/chem.200900793
A Straightforward Total Synthesis of (À)-Chaetominine
Beatrice Malgesini,[a] Barbara Forte,[b] Daniela Borghi,[a] Francesca Quartieri,[a]
Cesare Gennari,[c] and Gianluca Papeo*[b]
Dedicated to the Centenary of the Italian Chemical Society
Abstract: A total synthesis of the tri-
peptide alkaloid (À)-chaetominine (1)
was achieved in 9.3% overall yield
starting from commercially available d-
tryptophan methyl ester, based on a
short and straightforward (nine steps)
sequence. The early stage introduction
(first step) of the quinazolinone moiety
and the late stage introduction (penul-
timate step) of the hydroxy group al-
lowed a synthetic strategy devoid of
protective groups. The key step of the
process is the a–c tricyclic ring con-
struction via an unprecedented NCS-
mediated N-acyl cyclization on an
indole ring to give tetrahydro-1H-
16 resulting from the attack of the oxa-
ziridine to the double bond face oppo-
site to the c–d ring substituents. In the
last step, the complete stereocontrol of
the Et3SiH/TFA reduction of com-
pound 16, probably involving a N-acyli-
minium ion, can be attributed to ring
constrain, which forces the b–c ring
junction in the more stable cis-orienta-
tion. (À)-Chaetominine (1) showed a
negligible inhibitory activity on several
cancer cell lines.
pyridoACTHNUGRTNEUNG[2,3-b]indole 11. In the penulti-
mate step, oxidation of the tetracyclic
intermediate 14 with oxaziridine 15
gave only one of the four possible dia-
stereoisomers, the cis-diastereoisomer
Keywords: alkaloids · amino acids ·
lactams
·
natural products
·
total synthesis
Introduction
and chaetoglobosins[7]), terpenes (e.g., heptelidic acid[8] and
FR207944[9]) and phenols (e.g., globosumones[2] and orsel-
lides[10]), that show a broad spectrum of biological activities.
The strain IFB-E015, pertaining to this species and coloniz-
ing the leaves of Adenophora axilliflora (family of Campa-
nulaceae), was reported in 2006 by Tan and co-workers[11] to
produce a novel tripeptide alkaloidal metabolite, (À)-chae-
tominine (1, Figure 1). This secondary metabolite was nicely
demonstrated to possess an unprecedented framework, par-
tially shared by the non-Chaetomium species-derived tetra-
peptide alkaloids tryptoquivalines,[12] [for example, trypto-
quivalin G (2), Figure 1] (rings a–b, d and e–f), the fumiqui-
nazolines[13] [for example, fumiquinazoline A (3), Figure 1]
and the cyclic peptides kapakahines[14] [for example, kapaka-
hine B (4), Figure 1] (rings a–d). The intriguing topology of
1, associated with the reported[11] cytotoxic activity in the
double-digit nanomolar range on a couple of human cancer
cell lines, left (À)-chaetominine (1) undefeated by total syn-
thesis for a very short period of time. By capitalizing on an
advanced intermediate along the preparation of fumiquina-
zolines,[15] the Snider group published in 2007 a synthesis of
1,[16] less than one year after its isolation.
Endophytic fungi[1] represent one of the largest (conserva-
tively 1.5ꢀ106 species) and relatively unexplored resource of
secondary metabolites.[2] As a single strain is supposed to
produce multiple bioactive principles,[3] the overall chemical
diversity is virtually uncountable, thus rendering these mi-
croorganisms an excellent source of new potential drug
leads.[4] Among the endophytic fungi, the Chaetomium spe-
cies produces a vast array of structurally different natural
products, such as alkaloids (e.g., chetomin,[5] chaetocin,[6]
[a] Dr. B. Malgesini, Dr. D. Borghi, Dr. F. Quartieri
Chemical Core Technologies, Nerviano Medical Sciences
Viale Pasteur 10, 20014 Nerviano (MI) (Italy)
[b] Dr. B. Forte, Dr. G. Papeo
Medicinal Chemistry, Nerviano Medical Sciences
Viale Pasteur 10, 20014 Nerviano (MI) (Italy)
Fax : (+39)0331581347
E-mail: gianluca.papeo@nervianoms.com
[c] Prof. Dr. C. Gennari
Dipartimento di Chimica Organica e Industriale
Centro Interdipartimentale C.I.S.I.
Universitꢁ degli Studi di Milano
More recently, a second total synthesis of 1 was reported
by Evano and co-workers.[17] In the isolation and structure
determination manuscript,[11] Tan proposed a plausible bio-
Via G. Venezian 21, 20133 Milano (Italy)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900793.
7922
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Chem. Eur. J. 2009, 15, 7922 – 7929

FULL PAPER
this new route is the a–c tricyclic ring construction via an
unprecedented NCS-mediated tetrahydro-1H-pyrido
b]indole formation (Scheme 2).
ACHTUNGTRENNUNG[2,3-
Results and Discussion
Starting from commercially available d-tryptophan methyl
ester (5), we planned to introduce the quinazolinone moiety
(ring e–f of chaetominine) from the very beginning of the
synthesis (Scheme 3).
Thus reaction of compound 5 with anthranilic acid using
TBTU as activating agent, followed by treatment with
(EtO)3CH in the presence of a catalytic amount of TsOH in
EtOAc at 508C,[20] delivered the tryptophan quinazolinone
À
intermediate 6 in excellent overall yield (90%).[21] Subse-
quent hydrolysis of methyl ester 6 afforded the correspond-
ing acid which, upon coupling with l-alanine methyl ester,[22]
was transformed into compound 7 again in excellent yield
(90%). At this stage, the presence of a minor diastereoiso-
mer (ꢀ10%), originated by partial racemization of the qui-
nazolinone-bearing stereocenter during the LiOH-mediated
Figure 1. Chaetominine (1), tryptoquivalin G (2), fumiquinazoline A (3),
and kapakahine B (4).
synthetic pathway for (À)-chaetominine (1) involving l-ala-
nine, anthranilic acid and d-tryptophan, the last two being
closely linked through the shikimate pathway.[18]
1
hydrolysis of methyl ester 6, was detected by H NMR anal-
According to the biosynthetic proposal, rings c and d of
the tetracyclic core of 1 should simultaneously form through
oxidation[14a] of a putative nine-membered ring cyclic tripep-
tide intermediate (A, Scheme 1). The final assembly of the
quinazolinone moiety (rings e–f) would require a C1 unit in
the formic acid oxidation state.
ysis.[23] The minor diastereoisomer could not be separated,
and the 9:1 mixture was processed further. Intermediate 7
possesses all the nitrogen and carbon atoms present in chae-
tominine, and sets the stage for a stepwise ring c and ring d
construction, according to our retrosynthetic analysis (see
Scheme 2).
N-Acylated and N-carbamoy-
lated derivatives of tryptophan
are known to give tricyclic
dihydropyrroloACTHNUTRGENUGN[2,3-b]indoles by
reaction with NBS, in phos-
phate buffer at pH 9 or with
tert-butyl
hypochlorite
in
CH2Cl2 and Et3N.[24] These cyc-
lizations presumably occur via
3-haloindolenines, which ring
close to 3-haloindolines. On
standing, the dihydropyrrolo-
AHCTUNGTRENGN[UN 2,3-b]indoles arise by sponta-
neous or base-catalyzed dehy-
drohalogenation of the 3-hal-
oindolines.[24a] However, to the
best of our knowledge, no ex-
amples were ever reported
where a six-membered lactam
ring is formed following the
Scheme 1. Proposed biosynthetic pathway for (À)-chaetominine (1).
Although a biomimetic route towards 1 seemed attractive,
a closer inspection of the postulated biosynthetic intermedi-
aforementioned reaction protocol.
After extensive experimental efforts (selected conditions
are reported in Table 1), tricyclic tetrahydro-1H-pyrido[2,3-
b]indole (8) was finally secured in 40–63% yield using a
slight excess of NCS in CH2Cl2 in the presence of Et3N at
À788C (the minor isomer at the quinazolinone-bearing ste-
reocenter was separated at this stage). A variable amount
(15–20%) of the corresponding 3-chloroindolenine (9) was
À
ate A, including two amides and one trans C C double
ACHTUNGTRENNUNG
bond in a nine-membered ring, revealed the potential prob-
lems associated with its preparation and/or stability. There-
fore we envisioned a different approach, where the se-
quence of synthetic events was carefully planned in order to
minimize the use of protective groups.[19] The key step of
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G. Papeo et al.
(Scheme 4). Compound 10,
again processed as a 9:1 mix-
ture of diastereoisomers,[23] cy-
clized on a gram scale to give
the tricyclic tetrahydro-1H-
pyridoACHTNUTRGNE[NUG 2,3-b]indole (11) in an
acceptable 52% isolated yield
as a single diastereoisomer (the
minor isomer at the quinazoli-
none-bearing stereocenter was
separated at this stage). HPLC
analysis of the reaction mixture
revealed the presence of the in-
termediates stereoisomeric 3-
chloroindolines,[24a]
slower dehydrohalogenation
whose
Scheme 2. Retrosynthetic analysis of (À)-chaetominine (1).
(slower in the tert-butyl ester
series compared to the methyl
ester series) seems to protect 2-carbonylamino-indole 11
from further halogenation by excess NCS, thus reducing the
amount of 3-chloroindolenine (12) formed (13%).
TFA-mediated cleavage of tert-butyl ester 11 afforded
acid 13 in quantitative yield, which was subjected to intra-
molecular cyclization via the corresponding acid chloride in
the
presence
of
diisopropylethylamine
(DIPEA)
(Scheme 5). Tetracyclic intermediate 14 was thus obtained
in 75% yield as a single diastereoisomer. Careful HPLC-MS
and NMR analysis of the crude reaction mixture revealed
no presence of epimerized material.
Scheme 3. Synthesis of intermediate 7. a) Anthranilic acid, TBTU,
DIPEA, DMF, RT; b) (EtO)3CH, TsOH (cat.), AcOEt, 508C (90% over-
all yield); c) 0.2n LiOH, THF, RT (100%); d) H-l-Ala-OMe·HCl,
EDC·HCl, DhBtOH, DIPEA, DMF, RT (90%).
At this point, completion of the synthesis required the ste-
reoselective manipulation of the indole double bond via an
oxidation–reduction sequence. Hydroxylation at C-3 of the
indole ring in compound 14 was performed using the classi-
cal Davis (Æ)-oxaziridine 15.[25] As desired and expected,
the reaction turned out to be highly stereoselective, under
substrate control governed by the two stereogenic centers of
the rigid tetracycle 14. Also the addition of methanol to the
postulated acyliminium intermediate occurred with com-
plete stereocontrol in favor of the cis-diastereoisomer (16).
The excellent stereoselectivity of this entire process marks
the difference with the results reported by Snider on less
rigid substrates, where mixtures of diastereoisomers were
obtained in various ratios.[15,16]
Table 1. Optimization of the cyclization conditions to tricyclic tetrahy-
dro-1H-pyridoACHTUNGTRENNUNG[2,3-b]indole (8).
Entry
Conditions
T [8C]
8 [%][a]
Isolated
Isolated
yield 8 [%]
yield 9 [%]
a
b
c
d
e
f
tBuOCl
RT
RT
RT
À78
À78
RT
53
50
27
[d]
[d]
Hydroxyl-directed reduction of 16 with sodium borohy-
1.2 equiv NCS
1.5 equiv NCS
1.2 equiv NCS
1.3 equiv NCS
40
dride in acetic acid[26] did not afford any desired product.
[c]
[d]
[d]
70
55–75
30
51
16
Also attempts to reduce 16 with either NaBHACTHNUGTRENUNG(OAc)3 or
40–63
20–15
NaBH3CN/HCl failed. Pleasingly, chaetominine (1) was se-
cured in a reasonable yield (65%) using Et3SiH as reducing
agent,[15,27] in CH2Cl2/TFA at room temperature (Scheme 6).
The observed complete stereocontrol of the reduction,
probably involving a N-acyliminium ion, can be attributed
to ring constrain, which forces the ring b–c junction in the
more favorable cis-orientation. Synthetic (À)-chaetominine
(1) was fully characterized by spectroscopic and analytical
methods and proved to be identical to the natural prod-
uct.[11] In gloomy contrast to the results reported by Tan,[11]
(À)-chaetominine (1) proved to possess, in our hands, a neg-
[b]
[d]
[d]
XeF2
[a] Measured by integration of the HPLC trace at 254 nm. [b] See ref.
[19b]. [c] Complex mixture. [d] Not determined.
also produced, probably due to a competing electrophilic
halogenation of the more electron-rich 2-carbonylaminoin-
dole 8. However, despite repeated attempts, this reaction
proved capricious and not reproducible on a larger scale.
For this reason, we turned our attention to the correspond-
ing tert-butyl ester 10, rapidly available from methyl ester 6
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Chem. Eur. J. 2009, 15, 7922 – 7929

Total Synthesis of (À)-Chaetominine
FULL PAPER
straightforward synthetic se-
quence, starting from commer-
cially available d-tryptophan
methyl ester. Compared to the
previously published total syn-
theses,[16,17] the early stage in-
troduction (first step) of the
quinazolinone moiety and the
late stage introduction (penulti-
mate step) of the hydroxy
group allow a synthetic strategy
characterized by a minimal use
of protective groups.
Scheme 4. Synthesis of tricyclic tetrahydro-1H-pyridoACTHNUGTRNEUNG[2,3-b]indole 11. a) 0.2n LiOH, THF, RT (100%); b) H-
l-Ala-OtBu·HCl, EDC·HCl, DhBtOH, DIPEA, DMF, RT (80%); c) NCS, Et3N, CH2Cl2, À788C (52% 11,
13% 12).
In this paper, we also document the first example of tricy-
clic tetrahydro-1H-pyrido[2,3-b]indole synthesis via NCS
AHCTUNGTRENNUNG
mediated N-acyl cyclization on an indole ring. In the penul-
timate step, oxidation of the tetracyclic intermediate 14 with
oxaziridine 15 gave only one of the four possible diastereo-
isomers, the cis-diastereoisomer 16 resulting from the attack
of the oxaziridine to the double bond face opposite to the
c–d ring substituents. In the last step, the complete stereo-
control of the Et3SiH/TFA reduction of compound 16, prob-
ably involving a N-acyliminium ion, can be attributed to
ring constrain, which forces the b–c ring junction in the
more stable cis-orientation.
Scheme 5. Synthesis of tetracyclic intermediate 16. a) 20% TFA in
CH2Cl2, RT (100%); b) (COCl)2, DIPEA, DMF cat., CH2Cl2, RT
(75%); c) CH2Cl2/MeOH 2:1, RT (50%).
Experimental Section
All solvents were reagent grade and all reagents were used as supplied.
Flash chromatography was performed with silica gel 60 ꢃ (particle size
230–400 mesh) supplied by Aldrich. Melting points were recorded on a
Buchi 535 instrument. NMR spectra were performed at 25, 50 and 808C
in [D6]DMSO on a Varian Inova 500 spectrometer equipped with 5 mm
1H
Inova 400 spectrometer equipped with 5 mm 1H
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
rect detection probe. Residual solvent signal was used as reference (d=
2.50 ppm for 1H and d=39.5 for 13C). Standard two-dimensional sequen-
ces provided by Varian (gradient-enhanced HSQC, HMBC and T-roesy)
were used to assign carbons and stereochemistry. Electrospray (ESI)
mass spectra were obtained on a LCQ Deca XP (Thermo) ion trap mass
spectrometer. HPLC-UV-MS analyses, used to assess compound purity,
were carried out combining the ion trap MS instrument with a Surveyor
HPLC system (Thermo) equipped with an autosampler and UV6000
diode array detector (UV detection 215–400 nm). Instrument control,
data acquisition and processing were performed by using Xcalibur 1.4
software (Thermo). HPLC chromatography was run at room tempera-
ture, and 1 mLminÀ1 flow rate, using a Phenomenex Gemini C18 column
(4.6ꢀ50 mm; 3.0 mm). Mobile layer A was ammonium acetate 5 mm
buffer (pH 5.5 with acetic acid): acetonitrile 95:5, and mobile layer B was
ammonium acetate 5 mm buffer (pH 5.5 with acetic acid): acetonitrile
5:95; the gradient was from 0 to 100% B in 7 min then hold 100% B for
2 min before re-equilibration. Exact mass data ESI(+) were obtained on
a Waters Q-Tof Ultima directly connected with micro HPLC 1100 Agi-
lent as previously described.[28] Optical rotation measurements were per-
formed on a Perkin–Elmer 241 polarimeter.
Scheme 6. Synthesis of (À)-chaetominine (1). a) Et3SiH, CH2Cl2, TFA,
RT (65%).
ligible (2%) inhibitory activity at 72 h on human leukaemia
cell line K562 at 10 mm. The growth of other cancer cell lines
(A2780 and MCF7) was similarly unaffected by 1 (see Ex-
perimental Section, Table 2).
Table 2. Inhibitory activity of (À)-chaetominine (1) at 10 mm concentra-
tion on selected cell lines.
Cancer cell lines
A2780
2.89
K562
1.70
MCF7
9.61
% inhibition in the presence of 10 mm 1
(R)-3-(1H-Indol-3-yl)-2-(4-oxo-4H-quinazolin-3-yl)-propionic acid methyl
ester (6): To a solution of d-triphtophane methyl ester hydrochloride
(2 g, 7.89 mmol) in dry DMF (100 mL) kept at 08C, TBTU (3.8 g,
11 mmol) and DIPEA (5.40 mL, 32 mmol) were subsequently added
under argon atmosphere. Anthranilic acid (1.62 g, 11 mmol) was then
added portionwise in 1 h. After 5 h, the reaction mixture was poured into
Conclusions
In conclusion, a new total synthesis of (À)-chaetominine (1)
was achieved. The natural product was obtained in 9.3%
overall yield, by capitalizing on a concise (nine steps) and
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7925

G. Papeo et al.
water and extracted with AcOEt (2ꢀ100 mL). The combined organic
layers were washed with brine (100 mL) and saturated NaHCO3
(100 mL) then dried over Na2SO4, filtered and eventually concentrated in
vacuo. The crude light yellow solid (2.4 g, 7.1 mmol) was dissolved under
an inert atmosphere in AcOEt (65 mL) at room temperature and p-
TsOH (120 mg, 0.63 mmol) and triethyl orthoformate (1.3 mL, 7.8 mmol)
were added. The solution was warmed at 508C for 5 h. The reaction mix-
ture was then washed with water (2ꢀ100 mL), dried over Na2SO4, fil-
tered and eventually concentrated in vacuo. The crude light yellow solid
was purified by flash chromatography (EtOAc/CH2Cl2 1:9–2:8) affording
then poured into water at 08C, extracted with CH2Cl2 (2ꢀ100 mL), and
then washed with brine (3ꢀ50 mL). The combined organic layers were
dried over Na2SO4 and concentrated in vacuo, delivering a light brown
solid which was purified by flash chromatography (EtOAc/CH2Cl2 1:9–
3:7). Product 8 (0.513 g, 1.235 mmol, 63%) was obtained along with side-
product 9 (0.185 g, 0.412 mmol, 21%). 8: m.p. 235–2378C (decomp); [a]D20
(c=0.7, CHCl3)=+248; 1H NMR (500 MHz, [D6]DMSO, 258C): d=1.59
(d, 3J
DMSO, 2J
14.0, 3J(H,H)=14.0 Hz, 1H; CHH), 3.68 (s, 3H; OCH3), 5.06 (q, 3J-
(H,H)=6.9 Hz, 1H; CHCH3), 5.70–5.75 (m, 1H; CHCH2), 6.99–7.08 (m,
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
6 (2.46 g, 7.1 mmol, 90% over two steps) (6). M.p. 98–1018C; [a]D20
(c=0.99, MeOH)=+3758; 1H NMR (500 MHz, [D6]DMSO, 258C): d=
3.61 (dd, 2J(H,H)=15.1, 3J(H,H)=5.4 Hz, 1H; CHH), 3.66 (dd, 2J-
(H,H)=15.1, 3J
(H,H)=10.4 Hz, 1H; CHH), 3.73 (s, 3H, OCH3), 5.53
(H,H)=10.4, 5.4 Hz, 1H; CHCH2), 6.84–6.90 (m, 1H; ArH of ring
a), 6.97–7.03 (m, 2H; ArH of ring b and ArH of ring a), 7.26 (d, 3J-
(H,H)=8.1 Hz, 1H; ArH of ring a), 7.45 (d, 3J
(H,H)=7.7 Hz, 1H; ArH
of ring a), 7.51–7.55 (m, 1H; ArH of ring f), 7.55–7.58 (m, 1H; ArH of
ring f), 7.80 (ddd, 3J(H,H)=8.3, 7.0, 4J
(H,H)=1.6 Hz, 1H; ArH of ring
f), 7.99 (s, 1H; ArH of ring e), 8.11 (ddd, 3J(H,H)=8.0, 1.6, 4J
(H,H)=
=
ACHTUNGTRENNUNG
3
2H; ArH of ring a), 7.31–7.40 (m, 2H; ArH of ring a), 7.60 (t, JACHTUNGTRENNUNG
7.5 Hz, 1H; ArH of ring f), 7.74 (d, JACHUTNGTRENNUNG
3
A
U
A
E
ACHTUNGTRENNUNG
3
(dd, J
N
ring f), 8.35 (s, 1H; ArH of ring e), 11.42 ppm (brs, 1H; NH); 13C NMR
(125 MHz, [D6]DMSO, 258C): d=14.6 (CH3CH), 21.6 (CH2), 52.1
(OCH3), 52.3 (CHCH3), 56.1 (CHCH2), 90.6 (ArC of ring b), 111.0
(ArCH of ring a), 116.5 (ArCH of ring a), 119.6 (2ꢀArCH of ring a),
121.7 (ArC of ring f), 125.9 (ArC of ring a), 126.0 (ArCH of ring f), 127.2
(2ꢀArCH of ring f), 133.6 (ArC of ring a), 134.6 (ArCH of ring f), 135.0
(ArC of ring b), 147.1 (ArCH of ring e), 147.8 (ArC of ring f), 160.3
(NCO of ring e), 166.2 (CHCON of ring c), 170.6 ppm (COOCH3);
HRMS (ESI+): m/z: calcd for C23H20N4O4 +H 417.1558, found 417.1556.
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
0.5 Hz, 1H; ArH of ring f), 10.78 ppm (brs, 1H; NH); 13C NMR
(125 MHz, [D6]DMSO, 258C): d=24.1 (CH2), 52.5 (COOCH3), 59.6
(CHCH2), 108.5 (ArC of ring b), 111.7 (ArCH of ring a), 118.0 (ArCH of
ring a), 118.6 (ArCH of ring a), 121.3 (ArC of ring f), 121.4 (ArCH of
ring a), 124.0 (ArCH of ring b), 126.4 (ArCH of ring f), 126.8 (ArC of
ring a), 127.3 (2ꢀArCH of ring f), 134.8 (ArCH of ring f), 136.2 (ArC of
ring a), 147.2 (ArCH of ring e), 147.4 (ArC of ring f), 160.0 (NCO of ring
e), 169.7 ppm (COOCH3); HRMS (ESI+): m/z: calcd for C20H17N3O3 +
H 348.1343, found 348.1328.
Compound 9: 1H NMR (500 MHz, [D6]DMSO, 258C): d=1.61 (d, 3J-
(H,H)=6.9 Hz, 3H; CH3CH), 2.67 (dd, 2J(H,H)=14.1, 3J
AHCTUNGTREUNNGN ACHTUNGTRENNUNG ACHTUNGTRENNUNG
10.7 Hz, 1H; CHH), 3.39 (dd, 2J(H,H)=14.1, 3J
ACTHNUGTRENNUGN ACHTUNGTRENNNUG
3
CHH), 3.61 (s, 3H; OCH3), 5.57 (q, JACTHUNGTRENNNUG
3
(dd, JACHTNUGTRENNUNG
(S)-2-[(R)-3-(1H-Indol-3-yl)-2-(4-oxo-4H-quinazolin-3-yl)-proprionylami-
no]propionic acid methyl ester (7): To a solution of 6 (2 g, 5.7 mmol) in
THF (77 mL), aqueous 0.2n LiOH (28.5 mL, 5.7 mmol) was added. The
reaction was stirred for 3h at room temperature, then poured into water,
neutralized with 1n HCl (5.7 mL) and extracted with AcOEt (2ꢀ
100 mL). The combined organic layers were washed with brine, dried
over Na2SO4, filtered and concentrated in vacuo affording the product as
a white solid (1.89 g, 5.7 mmol). The product thus obtained was dissolved
in dry DMF (78 mL) at 08C. DhBtOH (1.022 g, 6.3 mmol), DIPEA
(3.9 mL, 23 mmol) and l-alanine methyl ester (0.8 g, 5.7 mmol) were sub-
sequently added under argon atmosphere. EDC·HCl (1.22 g, 6.3 mmol)
was then added portionwise in 30 min. After 12 h, the reaction mixture
was poured into water and extracted with CH2Cl2 (2ꢀ100 mL), saturated
NaHCO3 (2ꢀ100 mL), 0.3n KHSO4 (2ꢀ100 mL) and eventually with
brine. The combined organic layers were filtered and concentrated in
vacuo to give a light yellow solid which was purified through flash chro-
matography (AcOEt/CH2Cl2 5:95–20:80) affording 7 (2.14 g, 5 mmol,
N
ACHTUNGTRENNUNG
3
ACHTUNGTRENNUNG(H,H)=
of
90%). 1H NMR (400 MHz, [D6]DMSO, 258C): d=1.33 (d, 3J
7.3 Hz, 3H; CH3CH), 3.51–3.58 (m, 2H; CH2), 3.61 (s, 3H; OCH3), 4.35
(dq, 3J
(H,H)=7.3, 7.0 Hz, 1H; CHCH3), 5.98- 6.00 (m, 1H; CHCH2),
6.93–6.97 (m, 1H; ArH of ring a), 7.00–7.04 (m, 1H; ArH of ring a), 7.09
(d, 3J(H,H)=2.3 Hz, 1H; ArH of ring b), 7.24 (d, 3J
(H,H)=7.9 Hz, 1H;
ArH of ring a), 7.45–7.49 (m, 1H; ArH of ring f), 7.60 (d, 3J
(H,H)=
7.7 Hz, 1H; ArH of ring f), 7.74–7.80 (m, 2H; ArH of ring f and ArH of
ring a), 8.01 (dd, 3J(H,H)=8.2, 4J
(H,H)=1.3 Hz, 1H; ArH of ring f),
8.46 (s, 1H; ArH of ring e), 9.09 (d, 3J
(H,H)=7.0 Hz, 1H; CONH),
ACHTUNGTRNE(NUNG H,H)=
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
1
3
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
10.73 ppm (brs, 1H; NH); 13C NMR (125 MHz, [D6]DMSO, 258C): d=
16.5 (CH3CH), 26.4 (CH2), 47.7 (CHCH3), 51.9 (OCH3), 55.0 (CHCH2),
108.7 (ArC of ring b), 111.3 (ArCH of ring a), 118.5 (ArCH of ring a),
118.7 (ArCH of ring a), 121.1 (ArCH of ring a), 121.2 (ArC of ring f),
124.0 (ArCH of ring b), 126.1 (ArCH of ring f), 126.8 (2ꢀArCH of ring
f), 127.1 (ArC of ring a), 134.5 (ArCH of rinf f), 136.1 (ArC of ring a),
146.7 (ArCH of ring e), 147.5 (ArC of ring f), 160.3 (NCO of ring e),
169.5 (CHCONH), 173.2 ppm (COOCH3); HRMS (ESI+): m/z: calcd
for C23H22N4O4 +H 419.1714, found 419.1719.
G
ACHTUNGTRENNUNG
(H,H)=2.2 Hz, 1H; ArH of ring b), 7.24
3
(d, J
G
(S)-2-[(R)-2-Oxo-3-(4-oxo-4H-quinazolin-3-yl)-2,3,4,9-tetrahydropyrido-
ACHTUGNTRENUN(GN CH3)3), 108.7 (ArC of ring b), 111.1 (ArCH of ring a), 118.4 (ArCH of
A
ring a), 118.8 (ArCH of ring a), 121.1 (ArCH of ring a), 121.2 (ArC of
ring f), 124.0 (ArCH of ring b), 126.1 (ArCH of ring f), 126.7 (2ꢀArCH
of ring f), 127.0 (ArC of ring e), 134.4 (ArCH of ring f), 136.2 (ArC of
ring e), 146.5 (ArCH of ring e), 147.5 (ArC of ring f), 160.3 (NCO), 169.2
(0.820 g, 1.96 mmol) in dry CH2Cl2 (45 mL), kept at À788C and under
argon atmosphere, Et3N (1.09 mL, 7.84 mmol) and NCS (0.348 g,
2.61 mmol) were added. The reaction mixture was kept at À788C for 3 h
7926
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 7922 – 7929

Total Synthesis of (À)-Chaetominine
FULL PAPER
(CHCONH), 171.7 ppm (COOtBu); HRMS (ESI+): m/z: calcd for
C26H28N4O4 +H 461.2184, found 461.219.
ring f), 133.7 (ArC of ring a), 134.6 (ArCH of ring f), 135.2 (ArC of ring
b), 147.3 (ArCH of ring e), 147.9 (ArC of ring f), 160.6 (NCO of ring e),
166.2 (CHCON), 171.7 ppm (COOH); HRMS (ESI+): m/z: calcd for
C22H18N4O4 +H 403.1401, found 403.1396.
(S)-2-[(R)-2-Oxo-3-(4-oxo-4H-quinazolin-3-yl)-2,3,4,9-tetrahydropyrido-
ACHTUNGTRENNUNG[2,3-b]indol-1-yl]-propionic acid tert-butyl ester (11): To a solution of 10
(350 mg, 0.76 mmol) and Et3N (0.42 mL, 3.04 mmol) in dry CH2Cl2
(35 mL) at À788C under argon, NCS (135 mg, 1.01 mmol) was added.
The mixture was kept at À788C and the reaction was monitored by
HPLC. After 4.5 h further NCS was added (90 mg, 0.674 mmol) and the
reaction was stirred at the same temperature for additional 2 h. The reac-
tion was then quenched with water and let rise to room temperature
overnight. The mixture was diluted with CH2Cl2 and washed twice with
water, the organic layer was dried over Na2SO4 and the solvent was re-
moved under vacuum. The crude was purified by flash chromatography
(hexane/AcOEt 70:30–65:35) affording 11 (180 mg, 0.395 mmol, 52%)
and 12 (50 mg, 0.101 mmol, 13%) as side-product. 11: m.p. 176–1788C;
[a]2D0 (c=0.9, MeOH)=+49.58; 1H NMR (500 MHz, [D6]DMSO, 258C):
AHCTUNGTRENNUNG
a
0.077 mmol) in dry CH2Cl2 (3 mL) under argon, DIPEA (0.052 mL,
0.309 mmol), oxalyl chloride (0.010 mL, 0.116 mmol) and catalytic DMF
were added at room temperature. The mixture was stirred for 1 h, than it
was diluted with CH2Cl2 and washed with water (3ꢀ10 mL). The organic
layer was dried over Na2SO4 and taken to dryness under vacuum. The
crude was purified by flash chromatography (CH2Cl2/acetone 9:1) yield-
ing 14 as white solid (22 mg, 0.057 mmol, 75%). M.p. 2568C; [a]2D0 (c=
0.63, CHCl3)=+ 27.68; 1H NMR (500 MHz, [D6]DMSO, 258C): d=1.69
(d, 3J
11.2 Hz, 1H; CHH-b), 3.47 (dd, 2J
CHH-a), 5.06 (q, 3J
(H,H)=7.2 Hz, 1H; CHCH3), 5.61 (brs, 1H;
G
E
ACHTUNGTRENNUNG(H,H)=
R
ACHTUNGTRENNUNG
d =1.40 (s, 9H; tBu), 1.51 (d, 3J
ACTHNUTRGNE(NUG H,H)=7.0 Hz, 3H, CH3CH), 3.31–3.35
AHCTUNGTRENNUNG
(m obscured by water, 1H; CHH-a), 3.59 (t, 2J
(H,H)=14.1, 3J
N
CHCH2), 7.20–7.23 (m, 1H; ArH of ring a), 7.30–7.33 (m, 1H; ArH of
ring a), 7.43 (d, J
ArH of ring f), 7.73–7.77 (m, 2H; ArH of ring a and ArH of ring f),
7.89–7.92 (m, 1H; ArH of ring f), 8.18 (d, 3J
(H,H)=7.9 Hz, 1H; ArH of
3
14.1 Hz, 1H; CHH-b), 4.71 (q, J
G
3
(H,H)=7.6 Hz, 1H; ArH of ring a), 7.59–7.62 (m, 1H;
1H; CHCH2), 7.01–7.06 (m, 2H; ArH of ring a), 7.34–7.38 (m, 2H; ArH
of ring a), 7.58–7.62 (m, 1H; ArH of ring f), 7.74 (d, 3J
(H,H)=8.1 Hz,
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
1H; ArH of ring f), 7.87–7.90 (m, 1H; ArH of ring f), 8.16–8.20 (m, 1H;
ArH of ring f), 8.30 (s, 1H; ArH of ring e), 11.44 ppm (s, 1H; NH);
13C NMR (125 MHz, [D6]DMSO, 258C): d =14.4 (CH3CH), 21.8 (CH2),
ring f), 8.57 ppm (s, 1H; ArH of ring e); 13C NMR (125 MHz,
[D6]DMSO, 258C and 100 MHz, [D6]DMSO, 808C): d=15.7 (CH3CH),
24.7 (CH2), 57.9 (CHCH2), 62.7 (CHCH3), 85.6 (ArC of ring b), 113.6
(ArCH of ring a), 118.9 (ArCH of ring a), 121.8 (ArCH of ring a and
ArC of ring f), 125.1 (ArCH of ring a), 126.5 (ArCH of ring f), 127.5 (2ꢀ
ArCH of ring f), 128.8 (ArC of ring a), 134.1 (ArC of ring a), 135.0
(ArCH of ring f), 143.0 (NCN), 148.1 (ArCH of ring e and ArC of ring
f), 160.1 (NCO of ring e), 163.5 (CHCON), 166.7 ppm (NCO of ring d);
HRMS (ESI+): m/z: calcd for C22H16N4O3 +H 385.1295, found
385.1296.
27.1 (tBu), 53.7 (CHCH3), 55.3 (CHCH2), 81.2 (CACHTNUGTRNEUGN(CH3)3), 89.9 (ArC of
ring b), 111.2 (ArCH of ring a), 116.7 (ArCH of ring a), 120.0 (2ꢀArCH
of ring a), 121.9 (ArC of ring f), 126.1 (ArCH of ring f), 126.4 (ArC of
ring a), 127.4 (2ꢀArCH of ring f), 133.4 (ArC of ring a), 134.8 (ArCH of
ring f), 135.4 (ArC of ring b), 147.4 (ArCH of ring e), 147.7 (ArC of ring
f), 160.0 (NCO), 165.6 (CHCON), 168.9 ppm (COOtBu); HRMS (ESI+):
m/z: calcd for C26H26N4O4 +H 459.2027, found 459.2018.
Compound 12: 1H NMR (500 MHz, [D6]DMSO, 258C): d=1.34 (s, 9H,
(2S,4R,5aS,9cR)-5a-Hydroxy-9c-methoxy-2-methyl-4-(4-oxo-4H-quinazo-
lin-3-yl)-4,5,5a,9c-tetrahydro-2a,9b-diaza-cyclopenta[jk]fluorene-1,3-
dione (16): To a solution of 14 (50 mg, 0.13 mmol) in CH2Cl2/MeOH 2:1
(0.5:0.25 mL) and (Æ)-trans-2-(phenylsulfonyl)-3-phenyloxaziridine 15
(0.373 g, 0.143 mmol) was added. The resulting mixture was stirred at
room temperature for 2 h. After removal of the solvent under reduced
pressure, the mixture was purified by flash chromatography on silica gel
(CH2Cl2/acetone 8:2) giving 16 (28.1 mg, 0.065 mmol, 50%) as a white
solid. M.p. 163–1648C; [a]2D0 (c=0.77, CHCl3)=À30.18; 1H NMR
(500 MHz, [D6]DMSO, 258C): d=1.61 (brs, 3H; CH3CH), 2.49–2.57 (m
obscured by DMSO, 1H; CHH-a), 2.97–3.09 (brs, 1H; CHH-b), 3.49 (s,
3
2
3
tBu), 1.55 (d, J
(H,H)=10.9 Hz, 1H; CHH-b), 3.39 (dd, J
1H; CHH-a), 5.39 (q, 3J(H,H)=7.1 Hz, 1H; CHCH3), 5.68 (dd, 3J-
(H,H)=10.9, 6.5 Hz, 1H; CHCH2), 7.27–7.30 (m, 1H; ArH of ring a),
7.45–7.50 (m, 2H; ArH of ring a), 7.57 (t, 3J
(H,H)=7.3 Hz, 1H; ArH of
ring a), 7.63 (d, 3J(H,H)=7.3 Hz, 1H; ArH of ring a), 7.75 (d, 3J
(H,H)=
8.0 Hz; 1H; ArH of ring f), 7.90 (t, J(H,H)=7.3 Hz, 1H; ArH of ring f),
8.06 (d, 3J
ACHTUNGTRENNUNG(H,H)=7.1 Hz, 3H; CH3CH), 2.67 (dd, JACHTUNGTNER(NUGN H,H)=14.1, J-
2
3
U
ACHUTNGTRENNUG(H,H)=14.1, JCAHTUNGTREN(NNGU H,H)=6.5 Hz,
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
3
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG(H,H)=8.05 Hz, 1H; ArH of ring f), 8.74 ppm (s, 1H; ArH of
ring e); 13C NMR (125 MHz, [D6]DMSO, 258C): d=13.9 (CH3CH), 27.4
(tBu), 31.8 (CH2), 52.3 (CHCH3), 56.2 (CHCH2), 65.6 (CCl), 81.3 (C-
ACHTUNGTRENNUNG(CH3)3), 120.0 (ArCH of ring a), 121.6 (ArC of ring f), 123.2 (ArCH of
3H; OCH3), 4.87 (q, 3J
ACTHNUTRGNENU(G H,H)=6.9 Hz, 1H; CHCH3), 6.07 (brs, 1H;
CHCH2), 6.66 (s, 1H; OH), 7.24–7.30 (m, 1H; ArH of ring a), 7.41–7.45
(m, 1H; ArH of ring a), 7.45–7.48 (m, 1H; ArH of ring a), 7.50–7.53 (m,
1H; ArH of ring a), 7.55–7.63 (brs, 1H; ArH of ring f), 7.69 (d, 3J-
ring a), 126.0 (ArCH of ring a), 126.2 (ArCH of ring f), 127.7 (ArCH of
ring f), 128.0 (ArCH of ring f), 131.6 (ArCH of ring a), 135.5 (ArCH of
ring f), 136.2 (ArC of ring a), 147.9 (ArC of ring f), 148.7 (ArCH of ring
e), 151.9 (ArC of ring a), 160.3 (NCO of ring e), 166.6 (CHCON of ring
c), 167.0 (ArC of ring b), 168.1 ppm (COOtBu); HRMS (ESI+): m/z:
calcd for C26H25ClN4O4 +H 493.1637, found 493.1635.
AHCTUNGTRENNUNG
f
d
ACHTUNGTRENNUNG
(S)-2-[(R)-2-Oxo-3-(4-oxo-4H-quinazolin-3-yl)-2,3,4,9-tetrahydropyrido-
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG[2,3-b]indol-1-yl]-propionic acid (13): A solution of 11 (104 mg,
AHCTUNGTRENNUNG
0.227 mmol) in TFA/CH2Cl2 (20%; 3 mL) was stirred at room tempera-
ture for 5 h. The solvent was then removed under reduced pressure and
the residue was triturated with Et2O affording 13 as a light yellow solid
that was used in the next reaction, without any further purification
(90 mg, 0.224 mmol, quantitative yield). 1H NMR (500 MHz, [D6]DMSO,
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
OH), 7.24–7.30 (m, 1H; ArH of ring a), 7.41–7.45 (m, 1H; ArH of ring
a), 7.45–7.48 (m, 1H; ArH of ring a), 7.50–7.53 (m, 1H; ArH of ring a),
7.55–7.63 (m, 1H; ArH of ring f), 7.69 (d, 3J
ACHTUNGTRENNUNG
258C): d=1.58 (d, 3J
14.4, 3J(H,H)=7.8 Hz, 1H; CHH-a), 3.55 (dd, 2J
G
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
E
G
ACHTUNGTRENNUNG
ArH of ring f), 8.25 ppm (s, 1H; ArH of ring e); 13C NMR (125 MHz,
[D6]DMSO, 258C): d=13.9 (CH3CH), 39.5 (CH2), 51.5 (OCH3), 59.7
(CHCH3), 77.7 (C-OH), 105.2 (NCN), 114.2 (ArCH of ring a), 120.9
(ArC of ring f), 124.7 (ArCH of ring a), 125.6 (ArCH of ring a), 126.5
(ArCH of ring f), 127.4 (2ꢀArCH of ring f), 130.1 (ArCH of ring a),
134.8 (ArCH of ring f), 136.1 (2ꢀArC of ring a), 146.2 (ArCH of ring e),
147.3 (ArC of ring f), 160.0 (NCO of ring e), 167.1 (CHCON), 171.6 ppm
(NCO of ring d); CHCH2 not seen because the 1H signal is too broad to
detect the 1H-13C correlations in gHSQC and gHMBC spectra; HRMS
(ESI+): m/z: calcd for C23H20N4O5 +H 433.1507, found 433.1509.
14.1 Hz, 1H; CHH-b), 5.02 (brs, 1H; CHCH3), 5.74 (brs, 1H; CHCH2),
7.00–7.06 (m, 2H; ArH of ring a), 7.33–7.39 (m, 2H; ArH of ring a),
7.58–7.61 (m, 1H; ArH of ring f), 7.74 (d, 3J
ACTHNUTRGNEUNG(H,H)=8.0 Hz, 1H; ArH of
ring f), 7.86–7.92 (m, 1H; ArH of ring f), 8.16–8.21 (m, 1H; ArH of ring
f), 8.35 (s, 1H; ArH of ring e), 11.33 (brs, 1H; NH), 12.95 ppm (brs, 1H;
COOH); 13C NMR (125 MHz, [D6]DMSO, 258C and 100 MHz,
[D6]DMSO, 808C): d=14.2 (CH3CH), 21.9 (CH2), 52.3 (CHCH3), 54.9
(CHCH2), 90.3 (ArC of ring b), 110.9 (ArCH of ring a), 116.5 (ArCH of
ring a), 119.6 (2ꢀArCH of ring a), 121.8 (ArC of ring f), 126.1 (ArCH of
ring f), 126.2 (ArC of ring a), 127.1 (ArCH of ring f), 127.3 (ArCH of
Chem. Eur. J. 2009, 15, 7922 – 7929
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7927

G. Papeo et al.
(À)-Chaetominine (1): To a solution of 16 (20 mg, 0.0463 mmol) in
CH2Cl2/TFA 2:1 (0.4:0.2 mL) Et3SiH (0.011 mL, 0.069 mmol) was added.
The resulting mixture was stirred at room temperature for 2 h. After re-
moval of the solvent under reduced pressure, the crude material was
treated with HF (49%wt. in H2O)/CH3CN at room temperature over-
night to deprotect TES-derived chaetominine[16,17] formed in a variable
amount under reaction conditions. The reaction mixture was then diluted
with AcOEt, washed with saturated NaHCO3 solution and brine, the or-
ganic layer dried over Na2SO4 and concentrated. The crude residue was
purified through flash chromatography on silica gel (CH2Cl2/acetone 8:2).
1 was recovered as a white solid (12 mg, 0.03 mmol, 65%). M.p. 160–
1628C; [a]2D0 (c=0.25, MeOH)=À47.98 in agreement with literature
[1] H. W. Zhang, Y. C. Song, R. X. Tan, Nat. Prod. Rep. 2006, 23, 753–
771.
[2] B. P. Bashyal, E. M. K. Wijeratne, S. H. Faeth, A. A. L. Gunatilaka,
J. Nat. Prod. 2005, 68, 724–728.
[3] G. A. Strobel, A. Stierle, D. Stierle, W. M. Hess, Mycotoxins 1993,
47, 71–78.
[4] R. X. Tan, P. R. Jensen, P. G. Williams, W. Fenical, J. Nat. Prod.
2004, 67, 1374–1382.
[5] S. Safe, A. Taylor, J. Chem. Soc. Perkin Trans. 1 1972, 472–479.
[6] D. Hauser, H. P. Weber, H. P. Sigg, Helv. Chim. Acta 1970, 53, 1061–
1073.
data;[16,17] 1H NMR (500 MHz, [D6]DMSO, 258C): d=1.60 (d, 3J
ACHTUNGTRENNUNG
[7] a) S. Sekita, K. Yoshihira, S. Natori, H. Kuwano, Tetrahedron Lett.
1973, 14, 2109–2112; b) S. Sekita, K. Yoshihira, S. Natori, H.
Kuwano, Tetrahedron Lett. 1976, 17, 1351–1354; c) S. Sekita, K.
Yoshihira, S. Natori, H. Kuwano, Tetrahedron Lett. 1977, 18, 2771–
2774; d) W. Jiao, Y. Feng, J. W. Blunt, A. L. J. Cole, M. H. G. Munro,
J. Nat. Prod. 2004, 67, 1722–1725; e) G. Ding, Y. C. Song, J. R.
Chen, C. Xu, H. M. Ge, X. T. Wang, R. X. Tan, J. Nat. Prod. 2006,
69, 302–304.
[8] Y. Itoh, K. Kodama, K. Furuya, S. Takahashi, T. Haneishi, Y. Taki-
guchi, M. Arai, J. Antibiot. 1980, 33, 468–473.
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Sakamoto, M. Hashimoto, A. Fujie, M. Hino, Y. Hori, Biosci. Bio-
technol. Biochem. 2005, 69, 515–521.
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
3
AHCTUNGTRENNUNG
7.83–7.89 (m, 1H; ArH of ring f), 8.19 (brs, 1H; ArH of ring f), 8.28 ppm
(brs, 1H; ArH of ring e); 1H NMR (500 MHz, [D6]DMSO, 508C): d
=1.60 (d, 3J
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[10] O. Schlçrke, A. Zeeck, Eur. J. Org. Chem. 2006, 1043–1049.
[11] R. H. Jiao, S. Xu, J. Y. Liu, H. M. Ge, H. Ding, C. Xu, H. L. Zhu,
R. X. Tan, Org. Lett. 2006, 8, 5709–5712.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
[12] a) M. Yamazaki, H. Fujimoto, E. Okuyama, Chem. Pharm. Bull.
1978, 26, 111–117; b) J. Clardy, J. P. Springer, G. Bꢆchi, K. Matsuo,
R. Wightman, J. Am. Chem. Soc. 1975, 97, 663–665; c) M. R. Ariza,
T. O. Larsen, B. O. Peterson, J. O. Duus, A. F. Barrero, J. Agric.
Food Chem. 2002, 50, 6361–6365.
[13] a) A. Numata, C. Takahashi, T. Matsushita, T. Miyamoto; K. Kawai,
Y. Usami, E. Matsumura, M. Inoue, H. Ohishi, T. Shingu, Tetrahe-
dron Lett. 1992, 33, 1621–1624; K. Kawai, Y. Usami, E. Matsumura,
M. Inoue, H. Ohishi, T. Shingu, Tetrahedron Lett. 1992, 33, 1621–
1624; b) C. Takahashi, T. Matsushita, M. Doi, K. Minoura, T.
Shingu, Y. Kumeda, A. Numata, J. Chem. Soc. Perkin Trans. 1 1995,
2345–2353; c) G. N. Belofsky, M. Anguera, P. R. Jensen, W. Fenical,
M. Kçck, Chem. Eur. J. 2000, 6, 1355–1360; d) S.-M. Wong, L. L.
Musza, G. C. Kydd, R. Kullnig, A. M. Gillum, R. Cooper, J. Antibiot.
1993, 46, 545–553.
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5030.
AHCTUNGTRENNUNG
ring f), 8.26 ppm (brs, 1H; ArH of ring e); 13C NMR (125 MHz,
[D6]DMSO, 508C): d =13.4 (CH3CH), 37.8 (CH2), 59.4 (CHCH3), 76.0
(C-OH), 82.3 (NCHN), 114.2 (ArCH of ring a), 121.2 (ArC of ring f),
124.7 (ArCH of ring a), 125.3 (ArCH of ring a), 126.3 (ArCH of ring f),
126.9 (2ꢀArCH of ring f), 129.5 (ArCH of ring a), 134.5 (ArCH of ring
f), 136.5 (ArC of ring a), 138.6 (ArC of ring a), 147.0 (ArC of ring f),
160.0 (NCO of ring e), 165.2 (CHCON), 172.0 ppm (NCO of ring d);
CHCH2 and ArCH of ring e not seen because the 1H signal is too broad
to detect the H-13C correlations in gHSQC and gHMBC spectra; HRMS
(ESI+): m/z: calcd for C22H18N4O4 +H 403.1401, found 403.1402.
1
Antiproliferative assay: K-562 human myelogenous leukemia, A2780
human ovarian and MCF7 human breast cancer cells (1250 cells/well)
were seeded in white 384well-plates in complete medium (RPMI1640 or
EMEM plus 10% fetal bovine serum) and treated with 1 dissolved in
0.1% DMSO, 24 h after seeding. The cells were then incubated at 378C
in the presence of 5% CO2. At the end of treatment time the plates were
processed using CellTiter-Glo assay (Promega) following the manufactur-
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This work was supported by the Italian Grant FIRB RBNE03LF7X of
the Ministero dell’Istruzione, dell’Universitꢅ e della Ricerca. Authors
would like to acknowledge Dario Ballinari for performing cellular assays.
7928
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ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 7922 – 7929

Total Synthesis of (À)-Chaetominine
FULL PAPER
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Received: March 26, 2009
Published online: June 27, 2009
Chem. Eur. J. 2009, 15, 7922 – 7929
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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