Bio-inspired step-economical, redox-economical and protecting-group-free enantioselective total syntheses of (-)-chaetominine and analogues

Article abstract of DOI:10.1002/cjoc.201400413

Full details of the enantioselective four-step and five-step total syntheses of (-)-chaetominine from D-Trp and L-Trp are described. Featuring an oxidative double cyclization reaction, and tandem C14 epimerization- lactamization reactions as key steps, the method provides a rapid access to (-)-chaetominine (6a) and analogues. The total syntheses of (-)-chaetominine (6a) are so far the most concise and efficient. Through comprehensive investigation, the stereochemical requirements for the double cyclization reaction were revealed, and the confusion regarding physicochemical properties of this natural product was clarified. Moreover, short pathways to complexity generation, a scenarios revealed for the biosynthesis of fungal peptidyl alkaloid multi-cyclic scaffolds, have been validated through the chemical synthesis. On the basis of these findings, a plausible biosynthetic pathway for (-)-chaetominine (6a) was suggested. Copyright

Full text of DOI:10.1002/cjoc.201400413

FULL PAPER
DOI: 10.1002/cjoc.201400413
Bio-inspired Step-Economical, Redox-Economical and
Protecting-Group-Free Enantioselective Total Syntheses
of (−)-Chaetominine and Analogues†
Shi-Peng Luo,‡ Qi-Long Peng,‡ Chu-Pei Xu, Ai-E Wang, and Pei-Qiang Huang*
Department of Chemistry and Fujian Provincial Key Laboratory for Chemical Biology, College of Chemistry and
Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, China
Full details of the enantioselective four-step and five-step total syntheses of (−)-chaetominine from D-Trp and
L-Trp are described. Featuring an oxidative double cyclization reaction, and tandem C14 epimerization-lactamiza-
tion reactions as key steps, the method provides a rapid access to (−)-chaetominine (6a) and analogues. The total
syntheses of (−)-chaetominine (6a) are so far the most concise and efficient. Through comprehensive investigation,
the stereochemical requirements for the double cyclization reaction were revealed, and the confusion regarding
physicochemical properties of this natural product was clarified. Moreover, short pathways to complexity genera-
tion, a scenarios revealed for the biosynthesis of fungal peptidyl alkaloid multi-cyclic scaffolds, have been validated
through the chemical synthesis. On the basis of these findings, a plausible biosynthetic pathway for (−)-chaeto-
minine (6a) was suggested.
Keywords total synthesis, step economy, redox economy, double cyclization, alkaloids, bio-inspired synthesis
Introduction
CCK, and fiscalin C (5). In 2006, (−)-chaetominine (6a),
a hexacyclic quinazolinone alkaloid, was isolated from
the solid-substrate culture of Chaetomium sp. IFB-E015,
an endophytic fungus on apparently healthy Adeno-
phora axilliflora leaves.[5a] Later on, the same alkaloid
was isolated from the metabolites of Aspergillus sp.
HT-2 collected from Guizhou province, China.[5b]
Structurally and biosynthetically, this quinazolinone
alkaloid also belongs to fungal peptidyl indole alka-
loids.[6] The characteristic tetracyclic core structure of
(−)-chaetominine (6a), with different stereochemical
patterns, is also found in kapakahines (e.g. 7 and 8 in
In the late 1940s, anti-malaria alkaloids febrifugine
(1) (Figure 1) and isofebrifugine were isolated from
traditional Chinese medicinal plants Dichroa febrifuga
Lour. (Chang Shan),[1] which opened up chemical and
medicinal studies towards quinazolinone alkaloids.[2]
The related studies have led to the discovery of syn-
thetic quinazolinone drugs such as methaqualone[3] and
halofuginone (2).[4] Up to 2006, more than 150 quina-
zolinone alkaloids have been isolated from natural
sources,[2c] which include anti-fungal fumiquinazoline I
(3), asperlicin (4), an antagonist of the peptide hormone
O
Me
(S)
O
NH
(S)
N
NH
N
O
NHR
O
N
HN
N
O
O
N
N
N
(S) NH
HN
HO
H
N
H
N
O
N
N
O
HO
O
HO
OH
N
X
Y
(S)
(R)
(R)
N
(R)
(S)
(S)
O
O
O
O
N
N
H
HO
O
N
N
O
N
O
N
N
NH
N
O
NH
H
(S)
H
(S)
Ph
O
febrifugine (1, X = Y = H)
O
Me
kapakahine B (7, R = H)
halofuginone hydrobromide salt (2)
fiscalin C (5)
(−)-chaetominine (6a)
asperlicin (4)
kapakahine F (8, R = L-Phe)
(X = Cl; Y = Br)
fumiquinazoline I (3)
Figure 1 Some quinazolinone alkaloids and synthetic drugs.
*
E-mail: pqhuang@xmu.edu.cn; Tel.: 0086-0592-2182240; Fax: 0086-0592-2189959
Received June 24, 2014; accepted August 6, 2014; published online August 25, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400413 or from the author.
These authors contributed equally to this work.
Dedicated to Professor Chengye Yuan and Professor Li-Xin Dai on the occasion of their 90th birthdays.
‡
†
Chin. J. Chem. 2014, 32, 757—770
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Luo et al.
FULL PAPER
Figure 1), a group of seven cyclic peptides isolated
from the marine sponge Cribrochalina olemda.[7] Un-
like kapakahines, (−)-chaetominine contains a non-
proteinogenic D-tryptophan (Trp) residue.
The unique yet diverse structural features of the
fungal peptidyl alkaloids and the reported important
biological activities[7] have attracted the attention of
many chemists and biochemists. On one hand, a num-
ber of elegant enantioselective total syntheses have
been reported.[8,9] On the other hand, biosynthetic path-
ways of several fungal peptidyl alkaloids have been
revealed.[6]
As part of our continuous efforts in the synthesis of
bioactive natural products and analogues[10] and the
development of step-economical synthetic methodolo-
gies,[11] we embarked on the total synthesis of
(−)-chaetominine (6a). The preliminary results, includ-
ing a four-step and a five-step syntheses of (−)-chaeto-
minine from D-Trp[8c,8f] and L-Trp,[8g] respectively, have
been communicated recently. Herein we report full ac-
counts of these studies, which include the syntheses of
five analogues of (−)-chaetominine, the clarification on
the physicochemical properties of (−)-chaetominine
(6a), and a plausible biosynthetic pathway of (−)-chae-
tominine (6a).
gested as the key intermediates in the biosyntheses of
asperlicins C, D, and E,[6c] and fumiquinazolines C and
F,[6c] respectively. Moreover, they also revealed short
pathways to complexity generation in the biosynthesis
of those polycyclic peptidyl alkaloids.[6a-6c]
It is well known that direct formation of medium-
sized rings (8 to 11 atoms) is challenging in organic
synthesis due to unfavorable ring strain.[13] It is thus
risky to plan a total synthesis based on a multiply func-
tionalized key intermediate such as A or D. Thus, a
bio-inspired but non-biomimetic approach to
(−)-chaetominine (6a) from D-Trp bypassing any
nine-membered ring was envisioned. To develop a pro-
tecting-group-free total synthesis,[14] we opted for a ni-
tro group as a latent amino group. Thus, our retrosyn-
thetic analysis of (−)-chaetominine (6a) is outlined in
Scheme 2, which features the one-pot transformation of
intermediate 10a into (−)-chaetominine (6a) via an am-
bitious indole epoxidation – amidative cyclization –
lactamization cascade process as the key step and the
use of o-nitrobenzamide derivative 11a as a precursor of
the quinazolinone ring system. According to this analy-
sis, no extra protection-deprotection steps are required.
Experimental
Strategy for the total synthesis of (−)-chaetominine
General methods
In view of developing a concise total synthesis of
(−)-chaetominine (6a), a biomimetic synthesis[12] was
initially envisaged. Two plausible biosynthesis path-
ways have been suggested by Tan et al. (a in Scheme
1)[5a] and Walsh/Tang (b in Scheme 1),[6a] which feature
D-Trp as the starting material, and the nine-membered
bis-lactam ring-systems A[5a] or D/E[6a] as the key in-
termediates. They also mentioned that D-Trp is likely
formed from L-Trp via inversion of configuration. In the
extensive studies on the biosynthesis of fungal peptidyl
alkaloids by Tang/Walsh and co-workers,[6] eleven-
membered and ten-membered ring systems were sug-
Melting points were uncorrected. Infrared spectra
were measured using film KBr pellet techniques. H
1
NMR spectra were recorded in CDCl3 or DMSO-d6 with
tetramethylsilane as an internal standard. Chemical
shifts (δ) are expressed in ppm downfield from TMS.
Silica gel (300－400 mesh) was used for flash column
chromatography, eluting (unless otherwise stated) with
ethyl acetate/petroleum ether (PE) (60－90 ℃) mixture.
DMSO was pre-dried over calcium hydride. Ether and
THF were distilled over sodium benzophenone ketyl
under N2. Dichloromethane was distilled over calcium
Scheme 1 Plausible biosynthetic pathways to (−)-chaetominine (6a) suggested by Tan (a) and Walsh/Tang (b)
NH2
CO2H
O
O
COOH
NH2
NH2
OH
NH2
NH
O
NH
O
N
H
OH
N
O
N
D-Trp
N
O
N
NH2
H
H
O
Me
a. Plausible biosynthetic
pathway proposed by Tan
Me
Me
A
B
SEnz
O
H
O
O
Me
O
O
N
HN
N
OH
N
N
N
N
N
O
(R)
O
O
N
N
O
N
N
O
N
N
O
HN
Me
H
H
O
N
O
Me
Me
D
C
E
(−)-chaetominine (6a)
b. Plausible biosynthetic pathway proposed by Walsh/ Tang
758
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 757—770

Enantioselective Total Syntheses of (−)-Chaetominine and Analogues
Scheme 2 Retrosynthetic analysis of (−)-chaetominine (6a)
NH2
N
COOH
D-Trp
O
N
O
NO2
O
N
OH
N
one-pot from 10a
N
NH
N
O
(R)
(S)
(S)
N
O
H
O
epoxidation triggered
cascade bis-cyclization
reactions
O
N
N
O
O
1 O
+
O
H
(S)
2 N
H
HN
MeO
11a
HCl
NH2
HN
MeO
10a
O
Cl
N
H
3
N
N
Me
O
Me
Me
Me
H
H
MeO
O
(−)-chaetominine (6a)
NO2
OMe
O
Me
L-Ala-OMe
9
mL, 0.85 mmol) at –78 ℃. After being stirred for 1 h,
K2CO3/MeOH (94 mg/10 mL) was added and the mix-
ture was warmed up to –10 ℃ over 30 min. To the
resulting mixture was added 10 mL of NH4Cl (sat.).
After removal of the solvent under reduced pressure, to
the residue was added H2O (100 mL), and the resulting
mixture was extracted with EtOAc (10 mL×3). The
combined organic layers were washed with brine (2 mL),
dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The residue was purified by
column chromatography on silica gel (eluent: EtOAc∶
PE＝3∶2 then CH2Cl2∶CH3OH＝30∶1) to give
chaetominine (6a)[8f] (73 mg, yield: 38%) and com-
pound 17a[8f] (98 mg, yield: 47%).
hydride under N2.
For the experimental procedures, spectral data, and
1H and 13C NMR spectra regarding compounds 6a, 10a,
11a, (R)-12, 17a, 18a and 19, and cif files regarding the
single crystal X-ray diffraction analyses of compounds
6a, 16, 18a and 19 (deposited to the Cambridge Crys-
tallographic Data Centre: CCDC 791762; CDCC
791763; CCDC 791764; CCDC 884128), please see the
electronic supplementary information (ESI) of reference
8f. For the experimental procedures regarding com-
1
pounds (S)-12, 20, 21, 22 and 23, and spectral data, H
and 13C NMR spectra of compounds (S)-12, 20, 21, and
22, please see the electronic supplementary information
(ESI) of reference 8g.
Methyl
(S)-2-((R)-3-(1H-indol-3-yl)-2-(2-nitroben-
Methyl (S)-[(R)-2-(2-aminobenzamido)-3-(1H-indol-
3-yl)propanamido]propanoate (13)
zamido)propanamido)-4-methylpentanoate (11b)
To a solution of compound (R)-12 (1.97 g, 5.58
mmol) in THF (20 mL) at −20 ℃ were added succes-
sively N-methylmorpholine (NMM, 0.74 mL, 6.69
To a suspension of Pd/C (0.260 g, 10% Pd) in etha-
nol (10 mL) was added a solution of 11a (1.29 g, 2.94
mmol) in methanol (20 mL). The mixture was stirred at
r.t. under an atmosphere of H2 for 12 h. The resulting
mixture was filtered through Celite and the filtrate was
concentrated. The residue was purified by flash chro-
matography on silica gel (eluent: EtOAc∶PE＝1∶1)
to provide compound 13 (1.16 g, 2.85 mmol, yield: 97%)
i
mmol) and BuOCOC1 (0.80 mL, 6.13 mmol). After
being stirred at −20 ℃ under N2 for 15 min, the resul-
tant suspension was added dropwise to a solution of
L-leucine methyl ester hydrochloride (2.02 g, 11.16
mmol) and N-methylmorpholine (1.84 mL, 16.74 mmol)
in THF (36 mL) at −20 ℃, and the reaction mixture
was stirred at −20 ℃ for 12 h. The reaction was
quenched with a saturated aqueous NH4Cl (20 mL) and
diluted with water (100 mL). The aqueous phase was
separated and extracted with EtOAc (20 mL×3). The
combined organic phases were dried over anhydrous
Na2SO4, filtered, concentrated under reduced pressure.
The residue was purified by flash chromatography on
silica gel (eluent: EtOAc∶PE＝3∶2) to give com-
pound 11b in 91% yield as a yellow solid. M.p. 73－75
20
as a white solid. M.p. 172－173 ℃ (EtOAc); [α]D
＋36.8 (c 1.0, CHCl3); IR (film) νmax: 3349, 1738, 1633,
1513, 1454, 1217, 1159, 744 cm−1; 1H NMR (400 MHz,
CDCl3) δ: 8.24 (br s, 1H), 7.73 (m, 1H), 7.36 (m, 1H),
7.23－7.08 (m, 5H), 6.84 (d, J＝7.2 Hz, 1H), 6.65 (m,
1H), 6.57 (m, 1H), 6.28 (d, J＝7.3 Hz, 1H), 5.52 (br s,
2H), 4.91 (m, 1H), 4.46 (dq, J＝7.3, 7.2 Hz, 1H), 3.65
(s, 3H), 3.45 (dd, J＝14.6, 5.6 Hz, 1H), 3.24 (dd, J＝
14.6, 8.0 Hz, 1H), 1.11 (d, J＝7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ: 172.9, 170.9, 169.1, 148.9, 136.2,
132.6, 127.53, 127.46, 123.1, 122.4, 119.9, 118.9, 117.3,
116.7, 115.2, 111.3, 110.8, 53.9, 52.4, 48.0, 28.1, 17.8;
MS (ESI) m/z: 431 (M＋Na＋, 100%), 409 (M＋H＋,
17%), 477 (M＋K＋, 7%). Anal. calcd for C22H24N4O4:
C 64.69, H 5.92, N 13.72; found C 64.55, H 5.95, N
13.32.
℃ (EtOAc); [α]D20 –42.3 (c 1.0, CHCl3); IR (film) νmax
:
3294, 2957, 1738, 1646, 1531, 1457, 1349, 745 cm−1;
1H NMR (500 MHz, CDCl3) δ: 8.45 (s, 1H), 7.98－7.95
(m, 1H), 7.68－7.63 (m, 1H), 7.53－7.46 (m, 2H), 7.35
－7.31 (m, 1H), 7.18－7.13 (m, 2H), 7.10－7.05 (m,
2H), 6.68 (d, J＝8.0 Hz, 1H), 6.58 (d, J＝7.8 Hz, 1H),
5.05 (ddd, J＝7.8, 7.1, 6.5 Hz, 1H), 4.53－4.47 (m, 1H),
3.66 (s, 3H), 3.44 (dd, J＝14.8, 6.5 Hz, 1H), 3.32 (dd,
J＝14.8, 7.1 Hz, 1H), 1.50－1.36 (m, 3H), 0.84 (d, J＝
6.3 Hz, 3H), 0.82 (d, J＝6.3 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ: 173.2, 170.7, 166.4, 146.2, 136.1,
133.7, 132.2, 130.5, 128.5, 127.5, 124.5, 123.2, 122.2,
General procedure for the synthesis of (−)-chaeto-
minine (6a)
To a solution of compound 10a (200 mg, 0.48 mmol)
in anhydrous acetone (2 mL) was added a solution of
0.05 mol/L dimethyldioxirane (DMDO) in acetone (17
Chin. J. Chem. 2014, 32, 757—770
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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759

Luo et al.
FULL PAPER
119.7, 118.5, 111.3, 110.2, 54.2, 52.2, 51.0, 40.7, 27.3,
24.5, 22.6, 21.6; MS (ESI) m/z: 481 (M＋H＋, 100%).
Anal. calcd for C25H28N4O6: C 62.49, H 5.87, N 11.66;
found C 62.58, H 5.95, N 11.58.
(film) νmax: 3292, 1747, 1649, 1530, 1348, 1213, 744
cm−1; 1H NMR (400 MHz, CDCl3) δ: 8.55 (s, 1H), 7.93
－7.87 (m, 1H), 7.58 (d, J＝7.7 Hz, 1H), 7.47－7.39 (m,
2H), 7.29－7.24 (m, 1H), 7.17－7.07 (m, 5H), 6.81 (dd,
J＝5.3, 5.3 Hz, 1H), 4.97 (ddd, J＝7.0, 6.8, 6.3 Hz, 1H),
3.89 (dd, J＝17.9, 5.3 Hz, 1H), 3.89 (dd, J＝17.9, 5.3
Hz, 1H), 3.62 (s, 3H), 3.37 (dd, J＝14.7, 6.3 Hz, 1H),
3.28 (dd, J＝14.7, 6.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ: 171.2, 169.8, 166.4, 146.2, 136.1, 133.6,
132.1, 130.5, 128.6, 127.5, 124.3, 123.5, 122.0, 119.5,
Methyl
(S)-2-((R)-3-(1H-indol-3-yl)-2-(2-nitroben-
zamido)propanamido)-3-phenylpropanoate (11c)
Following the procedure described for the synthesis
of compound 11b, except for using L-phenylalanine
methyl ester hydrochloride salt (2.40 g, 11.16 mmol)
other than L-alanine methyl ester hydrochloride salt,
compound 11c was synthesized in 85% yield as a
118.5, 111.3, 110.0, 54.1, 52.2, 41.2, 27.5; MS (ESI) m/z:
＋
447 (M ＋ Na , 100%); HRMS-ESI calcd for
20
C21H20N4O6: (M＋Na)＋ 447.1281, found 447.1271.
yellow solid. M.p. 176－179 ℃ (EtOAc); [α]D –42.3
(c 1.0, THF); IR (film) νmax: 3291, 2959, 1742, 1654,
1531, 1456, 1349, 1214, 744 cm−1; 1H NMR (400 MHz,
DMSO-d6) δ: 10.85－10.82 (m, 1H), 8.88 (d, J＝8.4 Hz,
1H), 8.61 (d, J＝8.0 Hz, 1H), 8.02－7.98 (m, 1H), 7.77
－7.64 (m, 2H), 7.59 (d, J＝7.8 Hz, 1H), 7.40－7.32 (m,
2H), 7.29－7.20 (m, 5H), 7.12－7.05 (m, 2H), 7.03－
6.98 (m, 1H), 4.77 (m, 1H), 4.55 (m, 1H), 3.65 (s, 3H),
3.05 (dd, J＝13.6, 5.4 Hz, 1H) 2.95 (dd, J＝14.8, 5.0
Hz, 1H), 2.91－2.82 (m, 2H); 13C NMR (100 MHz,
DMSO-d6) δ: 172.3, 171.6, 165.5, 147.6, 137.6, 136.5,
133.7, 132.5, 131.2, 129.7 (2C), 129.6, 128.7 (2C),
127.8, 127.1, 124.4, 124.0, 121.3, 118.9, 118.7, 111.7,
110.4, 54.01, 53.96, 52.4, 37.4, 28.2; MS (ESI) m/z: 537
(M＋Na＋, 100%); HRMS-ESI calcd for C28H26N4O6:
(M＋Na)＋ 537.1750, found 537.1734.
Methyl (S)-2-((R)-3-(1H-indol-3-yl)-2-(4-oxoquina-
zolin-3(4H)-yl)propanamido)-4-methylpentanoate
(10b)
To a suspension of zinc powder (200 mg, 3.05 mmol)
in THF (5 mL) was added TiCl4 (0.22 mL, 2.59 mmol).
The resulting mixture was stirred at 50 ℃ for 1 h. Af-
ter being cooled to 0 ℃, a solution of compound 11b
(186 mg, 0.42 mmol) in THF (2 mL) and trimethyl or-
thoformate (0.20 mL, 1.82 mmol) were added dropwise.
The reaction mixture was stirred at 0 ℃ for 24 h and
then quenched with brine (5 mL) and stirred for another
2 h. The phases were separated, and the aqueous phase
was extracted with EtOAc (2 mL×3). The combined
organic phases were dried over anhydrous Na2SO4, fil-
tered, and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica
gel (eluent: EtOAc∶PE＝3∶2) to give compound 10b
in 99% yield as a white solid. M.p. 201－203 ℃
Methyl (R)-2-(3-(1H-indol-3-yl)-2-(2-nitrobenzamido)-
propanamido)-2-methylpropanoate (11d)
According to procedure for the synthesis of com-
pound 11b, except for the use of 2,2-dimythylalanine
methyl ester hydrochloride (1.31 g, 11.16 mmol), com-
pound 11d was synthesized in 91% yield as a yellow
(EtOAc); [α]D20＋52.8 (c 1.0, CHCl3); IR (film) νmax
:
3315, 2956, 1744, 1661, 1610, 1476, 1241, 742 cm−1;
1H NMR (400 MHz, CDCl3) δ: 8.43 (s, 1H), 8.28 (br s,
1H), 8.21－8.17 (m, 1H), 7.72－7.63 (m, 3H), 7.45－
7.39 (m, 1H), 7.32－7.28 (m, 1H), 7.17－7.12 (m, 1H),
7.08－7.01 (m, 2H), 6.90 (d, J＝8.1 Hz, 1H), 5.94 (dd,
J＝8.9, 6.8 Hz, 1H), 4.50 (td, J＝8.1, 5.4 Hz, 1H), 3.73
(dd, J＝14.4, 8.9 Hz, 1H), 3.54 (s, 3H), 3.41 (dd, J＝
14.4, 6.8 Hz, 1H), 1.51－1.43 (m, 1H), 1.38－1.29 (m,
2H), 0.78 (d, J＝6.3 Hz, 3H), 0.77 (d, J＝6.3 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ: 172.5, 168.7, 161.2,
147.4, 144.2, 136.2, 134.5, 127.4, 127.2, 126.9, 126.8,
123.3, 122.3, 121.3, 119.8, 118.4, 111.3, 109.5, 56.2,
52.2, 51.1, 40.8, 27.3, 24.5, 22.6, 21.6; MS (ESI) m/z:
461 (M＋H＋, 100%); HRMS-ESI calcd for C26H28N4O4:
(M＋H)＋ 461.2189, found 461.2172.
20
solid. M.p. 91－93 ℃ (EtOAc); [α]D –30.0 (c 1.0,
CHCl3); IR (film) νmax: 3319, 2959, 1737, 1651, 1530,
1349, 1285, 1152, 747 cm−1; 1H NMR (400 MHz,
CDCl3) δ: 8.67－8.64 (m, 1H), 7.95－7.91 (m, 1H),
7.67 (d, J＝8.0 Hz, 1H), 7.49－7.42 (m, 2H), 7.32 (d,
J＝8.0 Hz, 1H), 7.16－7.02 (m, 4H), 6.81 (d, J＝7.6 Hz,
1H), 6.65 (s, 1H), 4.93 (ddd, J＝7.6, 6.8. 6.0 Hz, 1H),
3.66 (s, 3H), 3.37 (dd, J＝14.8, 6.0 Hz, 1H), 3.24 (dd,
J＝14.8, 6.8 Hz, 1H), 1.41 (s, 3H), 1.39 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ: 174.5, 169.9, 166.3, 146.2,
136.1, 133.7, 132.1, 130.5, 128.5, 127.4, 124.4, 123.5,
122.0, 119.5, 118.6, 111.4, 110.1, 56.3, 54.0, 52.4, 27.1,
24.7, 24.5; MS (ESI) m/z: 475 (M＋Na＋ , 100%);
HRMS-ESI calcd for C23H24N4O6: (M＋Na)＋ 475.1594,
found 475.1587.
Methyl (S)-2-((R)-2-oxo-3-(4-oxoquinazolin-3(4H)-yl)-
3,4-dihydro-2H-pyrido[2,3]indol-1(9H)-yl)-3-phenyl-
propanoate (10c)
Methyl
(R)-2-(3-(1H-indol-3-yl)-2-(2-nitrobenza-
mido)propanamido)acetate (11e)
Following the procedure described for the synthesis
of compound 10b, compound 10c was synthesized in
93% yield as a white solid. M.p. 172－174 ℃ (EtOAc);
Following the procedure described for the synthesis
of compound 11b, except for using glycine methyl ester
hydrochloride salt (2.40 g, 11.16 mmol) other than
L-alanine methyl ester hydrochloride salt, compound
11e was synthesized in 87% yield as a yellow solid. M.p.
20
[α]D –10.5 (c 1.0, THF); IR (film) νmax: 3306, 2950,
1743, 1671, 1608, 1475, 1217, 743 cm−1; 1H NMR (400
MHz, CDCl3) δ: 8.38 (s, 1H), 8.32 (br s, 1H), 8.21－
8.17 (m, 1H), 7. 73－7.63 (m, 3H), 7.44－7.38 (m, 1H),
20
193－195 ℃ (EtOAc); [α]D –9.0 (c 1.0, THF); IR
760
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Chin. J. Chem. 2014, 32, 757—770

Enantioselective Total Syntheses of (−)-Chaetominine and Analogues
7.31 (d, J＝8.0 Hz, 1H), 7.21－7.16 (m, 1H), 7.15－
7.03 (m, 4H), 6.94－6.88 (m, 2H), 6.77－6.73 (m, 2H),
5.84 (dd, J＝8.8, 7.0 Hz, 1H), 4,81 (dt, J＝7.6, 6.0 Hz,
1H), 3.67 (dd, J＝14.5, 8.8 Hz, 1H), 3.55 (s, 3H), 3.37
(dd, J＝14.5, 7.0 Hz, 1H), 2.9 (d, J＝6.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ: 171.0, 168.4, 161.0, 147.4,
144.2, 136.2, 135.4, 134.5, 129.0 (2C), 128.4 (2C),
127.4, 127.2, 127.0, 126.9, 126.8, 123.2, 122.4, 121.4,
119.9, 118.4, 111.3, 109.4, 56.4, 53.4, 52.3, 37.4, 27.3;
MS (ESI) m/z: 495 (M＋H＋, 100%); HRMS-ESI calcd
for C29H26N4O4: (M＋H)＋ 495.2032, found 495.2026.
Following the General Procedure, the tandem
reaction of compound 10b (200 mg, 0.43 mmol)
produced, after column chromatographic purification on
silica gel (eluent: EtOA∶PE＝1∶1 to EtOAc∶PE＝
3 ∶ 1), compound 6b (60 mg, yield: 31%) and
compound 17b (93 mg, yield: 45%).
Compound 6b: White solid, m.p. 171－175 ℃
20
(EtOAc); [α]D −52.2 (c 0.9, CHCl3); IR (film) νmax
:
3371, 2926, 1737, 1682, 1610, 1479, 1292, 759 cm−1;
1H NMR (500 MHz, CDCl3) δ: 8.17－8.15 (m, 1H),
7.81 (s, 1H), 7.76－7.71 (m, 1H), 7.49 (d, J＝8.1 Hz,
1H), 7.61－7.57 (m, 1H), 7.48－7.43 (m, 1H), 7.41－
7.36 (m, 2H), 7.20－7.16 (m, 1H), 5.80 (br s, 1H), 5.46
(s, 1H), 4.61 (br s, 1H), 4.34 (dd, J＝5.5, 4.2 Hz, 1H),
2.83－2.48 (m, 2H), 2.22－2.13 (m, 1H), 2.05－1.95
(m, 2H), 0.89 (d, J＝6.5 Hz, 3H), 0.77 (d, J＝6.5 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ: 172.1, 165.5,
161.1, 147.5, 144.9, 139.7, 134.7, 134.3, 131.1, 127.6,
127.5, 126.9, 125.9, 124.3, 121.7, 115.4, 83.0, 77.6,
62.8, 39.2, 35.8, 25.3, 22.9, 22.2 (one amide carbonyl
carbon was not observed due to slow rotation at the
C9－N bond);[8a] MS (ESI) m/z: 445 (M＋H＋, 100%);
HRMS-ESI calcd for C25H24N4O4: (M＋H)＋ 445.1876,
found 445.1870.
Methyl (R)-2-(3-(1H-indol-3-yl)-2-(4-oxoquinazolin-
3(4H)-yl)propanamido)-2-methylpropanoate (10d)
Following the procedure described for the synthesis
of compound 10b, compound 10d was synthesized in
96% yield as a white solid. M.p. 145－147 ℃ (EtOAc);
20
[α]D –66.1 (c 1.0, CHCl3); IR (film) νmax: 3324, 3011,
1740, 1659, 1610, 1547, 1475, 1286, 1157, 748 cm−1;
1H NMR (400 MHz, CDCl3) δ: 8.60 (s, 1H), 8.52 (s,
1H), 8.20 (d, J＝7.6 Hz, 1H), 7.72－7.60 (m, 2H), 7.50
(d, J＝7.6 Hz, 1H), 7.46 (s, 1H), 7.38－7.32 (m, 1H),
7.21 (d, J＝8.0 Hz, 1H), 7.07－6.98 (m, 2H), 6.88 (t,
J＝7.6 Hz, 1H), 5.88 (dd, J＝8.4, 7.2 Hz, 1H), 3.68 (dd,
J＝14.4, 8.4 Hz, 1H), 3.60 (s, 3H), 3.37 (dd, J＝14.4,
7.2 Hz, 1H), 1.42 (s, 3H), 1.36 (s, 3H); 13C NMR (100
MHz, CDCl3) δ: 174.2, 168.2, 160.9, 146.9, 145.0,
136.1, 134.6, 127.2, 127.1, 126.8, 126.5, 123.7, 122.0,
121.1, 119.4, 118.2, 111.3, 109.0, 56.6, 56.4, 52.4, 27.1,
24.7, 24.5; MS (ESI) m/z: 433 (M ＋ H ＋ , 100%);
HRMS-ESI calcd for C24H25N4O4: (M＋H)＋ 433.1876,
found 433.1867.
Compound 17b: White solid, m.p. 175－177 ℃
20
(EtOAc); [α]D –125.2 (c 1.0, THF); IR (film) νmax
:
3391, 2956, 1738, 1681, 1612, 1471, 1322, 1227, 1176,
1
752 cm−1; H NMR (500 MHz, CDCl3) δ: 8.22－8.18
(m, 1H), 7.74－7.69 (m, 1H), 7.65 (d, J＝8.0 Hz, 1H),
7.60 (br s, 1H), 7.44 (t, J＝8.0 Hz, 1H), 7.29 (d, J＝7.4
Hz, 1H), 7.21－7.16 (m, 1H), 6.82 (t, J＝7.4 Hz, 1H),
6.78 (d, J＝8.0 Hz, 1H), 5.39 (dd, J＝10.6, 5.2 Hz, 1H),
5.37 (d, J＝4.0 Hz, 1H), 5.36 (br s, 1H), 5.33 (d, J＝4.0
Hz, 1H), 3.75 (s, 3H), 3.33 (br s, 1H), 2.85 (br s, 1H),
2.50 (dd, J＝12.1, 4.0 Hz, 1H), 1.92－1.78 (m, 2H),
1.77－1.70 (m, 1H), 1.01 (d, J＝6.5 Hz, 3H), 1.00 (d,
J＝6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ: 174.0,
170.3, 160.5, 148.3, 147.3, 145.2, 134.4, 130.9, 129.0,
127.23, 127.19, 127.0, 123.6, 121.8, 120.1, 110.1, 80.0,
79.6, 53.4, 52.5, 51.7, 41.2, 39.2, 24.4, 23.1, 21.2; MS
(ESI) m/z: 499 (M＋Na＋, 100%); HRMS-ESI calcd for
C26H28N4O5: (M＋H)＋ 476.2138, found 476.2143.
(R)-Methyl 2-(3-(1H-indol-3-yl)-2-(4-oxoquinazolin-
3(4H)-yl)propanamido) acetate (10e)
Following the procedure described for the syn-
thesis of compound 10b, compound 10e was synthe-
sized in 91% yield as a white solid. M.p. 142－145 ℃
20
(EtOAc); [α]D –58.7 (c 1.0, MeOH); IR (film) νmax
:
1
3395, 1737, 1666, 1611, 1220, 1097, 738 cm−1; H
NMR (400 MHz, CDCl3) δ: 8.35 (s, 1H), 8.32 (br s, 1H),
8.20－8.15 (m, 1H), 7.73－7.63 (m, 2H), 7.61－7.56
(m, 1H), 7.45－7.40 (m, 1H), 7.29－7.25 (m, 1H), 7.15
－7.01 (m, 3H), 7.00－6.97 (m, 1H), 5.87 (dd, J＝8.2,
7.4 Hz, 1H), 3.96 (dd, J＝18.2, 5.5 Hz, 1H), 3.91 (dd,
J＝18.2, 5.5 Hz, 1H), 3.73 (dd, J＝14.7, 8.2 Hz, 1H),
3.62 (s, 3H), 3.45 (dd, J＝14.7, 7.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ: 169.6, 169.3, 161.2, 147.4, 144.4,
136.2, 134.5, 127.4, 127.2, 126.84, 126.78, 123.3, 122.3,
121.4, 119.7, 118.3, 111.3, 109.4, 56.5, 52.3, 41.4, 27.0;
MS (ESI) m/z: 405 (M＋H＋, 100%); HRMS-ESI calcd
for C22H20N4O4: (M＋H)＋ 405.1563, found 405.1562.
(2S,4R,5aS,9cS)-4,5,5a,9c-Tetrahydro-5a-hydroxy-2-
benzyl-4-(4-oxo-3(4H)-quinazolinyl)-3H-2a,9b-diaza-
cyclopenta[jk]fluorene-1,3(2H)-dione (6c) and methyl
(αS,3S,4aR,9aS)-2,3,4,4a,9,9a-hexahydro-4a-hy-
droxy-α-methyl-2-oxo-3-(4-oxo-3(4H)-quinazolinyl)-
1H-pyrido[2,3]indole-1-ethanoate (17c)
Following the General Procedure, the tandem reac-
tion of compound 10c (200 mg, 0.40 mmol) produced,
after column chromatographic purification on silica gel
(eluent: EtOAc∶PE＝1∶1 to EtOAc∶PE＝3∶1),
compound 6c (62 mg, yield: 32%) and compound 17c
(105 mg, yield: 51%).
(2S,4R,5aS,9cS)-4,5,5a,9c-Tetrahydro-5a-hydroxy-2-
isobutyl-4-(4-oxo-3(4H)-quinazolinyl)-3H-2a,9b-
diazacyclopenta[jk]fluorene-1,3(2H)-dione (6b) and
methyl (αS,3S,4aR,9aS)-2,3,4,4a,9,9a-hexahydro-4a-
hydroxy-α-methyl-2-oxo-3-(4-oxo-3(4H)-quinazolinyl)-
1H-pyrido[2,3]indole-1-ethanoate (17b)
Compound 6c: White solid, m.p. 155－ 157 ℃
20
(EtOAc); [α]D −70.0 (c 0.4, CHCl3); IR (film) νmax
:
3370, 2925, 1736, 1677, 1610, 1478, 1286, 760 cm−1;
Chin. J. Chem. 2014, 32, 757—770
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
761

Luo et al.
FULL PAPER
1H NMR (400 MHz, acetone-d6) δ: 8.13－8.09 (m, 1H),
7.74－7.70 (m, 1H), 7.58 (d, J＝7.7 Hz, 1H), 7.49 (d,
J＝8.0 Hz, 1H), 7.46－7.42 (m, 1H), 7.38－7.32 (m,
1H), 7.31－7.24 (m, 2H), 7.12－7.08 (m, 1H), 6.99－
6.95 (m, 1H), 6.91－6.83 (m, 4H), 5.87－5.76 (m, 1H),
5.57 (s, 1H), 5.56 (br s, 1H), 4.73 (dd, J＝6.2, 2.2 Hz,
1H), 3.55 (dd, J＝14.6, 6.2 Hz, 1H), 3.37 (dd, J＝14.6,
2.2 Hz, 1H), 2.66 (br s, 1H), 2.40 (dd, J＝12.5, 3.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ: 173.5, 166.2,
161.2, 147.6, 144.0, 140.5, 135.5, 134.7, 133.8, 131.1,
130.0 (2C), 127.8 (2C), 127.6, 127.5, 127.2, 127.0,
126.0, 124.1, 121.4, 115.2, 83.3, 78.2, 63.2, 51.0, 38.8,
33.7; MS (ESI) m/z: 479 (M＋H＋, 100%); HRMS-ESI
calcd for C28H22N4O4: (M ＋ K) ＋ 479.1719, found
479.1716.
Methyl (αS,3S,4aR,9aS)-2,3,4,4a,9,9a-hexahydro-4a-
hydroxy-2-oxo-3-(4-oxo-3(4H)-quinazolinyl)-1H-py-
rido[2,3-b]indole-1-ethanoate (16a and 17e)
Following the General Procedure, the tandem reac-
tion of compound 10e (200 mg, 0.49 mmol) (EtOAc∶
PE＝3∶1) gave two inseparable compound 17e and
compound 16a as a mixture of two inseparable di-
astereomers (168 mg, 0.40 mmol, yield: 81%, ratio＝
2∶1) as a white solid. IR (film) νmax: 3341, 2949, 1741,
1678, 1610, 1476, 1241, 1158, 756 cm−1; minor∶major
＝1∶2. 1H NMR (500 MHz, CD3CN): major isomer δ:
8.15－8.12 (m, 1H), 2.93 (s, 1H), 7.82－7.76 (m, 1H),
7.67－7.63 (m, 1H), 7.54－7.46 (m, 1H), 7.31(d, J＝7.4
Hz, 1H), 7.24－7.13 (m, 1H), 6.87－6.79 (m, 1H), 6.74
(d, J＝7.9 Hz, 1H), 5.53 (d, J＝3.3 Hz, 1H), 5.22 (br s,
1H), 5.14 (d, J＝3.3 Hz, 1H), 4.33 (s, 1H), 4.24 (d, J＝
17.4 Hz, 1H), 4.20 (d, J＝17.4 Hz, 1H), 3.72 (s, 3H),
3.01－2.92 (m, 1H), 2.68 (dd, J＝12.3, 4.1 Hz, 1H); 13C
NMR (100 MHz, CD3CN) δ: 170.4, 169.5, 161.1, 150.1,
148.4, 146.6, 135.2, 133.0, 131.3, 130.2, 128.1, 127.2,
124.5, 122.3, 120.3, 111.0, 84.7, 79.6, 52.6, 51.7, 48.5,
38.9; minor isomer δ: 8.20－8.12 (m, 1H), 7.97 (s, 1H),
7.82－7.76 (m, 1H), 7.67－7.63 (m, 1H), 7.54－7.46
(m, 1H), 7.24－7.19 (m, 1H), 7.17－7.13 (m, 1H), 6.87
－6.79 (m, 1H), 6.71 (d, J＝7.9 Hz, 1H), 5.43 (d, J＝
4.8 Hz, 1H), 5.22 (br s, 1H), 5.13 (d, J＝4.8 Hz, 1H),
4.51 (br s, 1H), 4.45 (d, J＝17.4 Hz, 1H), 4.41 (d, J＝
17.4 Hz, 1H), 3.69 (s, 1H), 2.73－2.66 (m, 1H), 2.46－
2.37 (m, 1H); 13C NMR (100 MHz, CD3CN) δ: 170.0,
168.2, 161.2, 148.6, 147.8, 147.3, 135.2, 133.0, 131.2,
130.5, 127.9, 127.1, 123.5, 122.7, 120.8, 111.6, 83.1,
78.4, 52.5, 49.6, 46.4, 36.6; MS (ESI) m/z: 443 (M＋
Na＋, 100%); HRMS-ESI calcd for C22H20N4O5: (M＋
Na)＋ 443.1331, found 443.1334.
Compound 17c: Colorless crystal, m.p. 251－253
℃ (EtOAc); [α]D20 −210.5 (c 1.0, THF); IR (film) νmax
:
3374, 2954, 1740, 1679, 1612, 1473, 1234, 745 cm−1;
1H NMR (500 MHz, DMSO-d6) δ: 8.04 (dd, J＝8.0, 1.2
Hz, 1H), 7.85－7.81 (m, 1H), 7.67 (d, J＝7.9 Hz, 1H),
7.57－7.50 (m, 2H), 7.42－7.23 (m, 6H), 7.17－1.12
(m, 1H), 6.79－6.74 (m, 1H), 6.68 (d, J＝7.9 Hz, 1H),
6.22 (s, 1H), 5.86 (d, J＝4.0 Hz, 1H), 5.33 (d, J＝4.0
Hz, 1H), 5.27 (dd, J＝8.9, 6.4 Hz, 1H), 5.25－5.17 (m,
1H), 3.73 (s, 3H), 3.37 (dd, J＝14.0, 6.4 Hz, 1H), 3.04
(dd, J＝14.0, 8.9 Hz, 1H), 2.53 (br s, 1H), 2.44 (dd, J＝
11.9, 4.1 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ:
171.3, 169.8, 160.1, 149.4, 147.6, 145.8, 137.6, 135.1,
130.7, 130.1 (3C), 128.6 (2C), 127.7, 127.6, 127.1,
126.8, 124.3, 121.4, 119.3, 110.4, 81.2, 79.1, 58.2, 52.9,
50.0, 40.3, 36.0; MS (ESI) m/z: 533 (M＋Na＋, 100%);
HRMS-ESI calcd for C29H26N4O5: (M＋H)＋ 511.1981,
found 511.1975.
(2R,4R,5aS,9cR)-4,5,5a,9c-Tetrahydro-5a-hydroxy-2-
isobutyl-4-(4-oxo-3(4H)-quinazolinyl)-3H-2a,9b-di-
azacyclopenta[jk]fluorene-1,3(2H)-dione (18b)
Methyl (αS,3S,4aR,9aS)-2,3,4,4a,9,9a-hexahydro-4a-
hydroxy-α,α-dimethyl-2-oxo-3-(4-oxo-3(4H)-quinazo-
linyl)-1H-pyrido[2,3-b]indole-1-ethanoate (17d)
To a solution of compound 17b (48 mg, 0.1 mmol)
in MeOH (1 mL) was added a solution of freshly pre-
pared CH3ONa (14 mg, 0.254 mmol) in CH3OH (3.5
mL) at −10 ℃. After being stirred for 24 h, the reaction
mixture was acidified with 10% HCOOH until pH 7.
The solvent was evaporated under reduced pressure, and
the residue was extracted with EtOAc (2 mL×3). The
combined organic layers were washed with brine (1 mL),
dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The residue was purified by
flash chromatography on silica gel (eluent: EtOAc∶PE
＝3∶2) to give compound 18b (39 mg, yield: 88%) as
a white solid. M.p. 192－195 ℃ (EtOAc); [α]D20＋89.9
(c 1.0, THF); IR (film) νmax: 3363, 2956, 1682, 1611,
1481, 1326, 1293, 756 cm−1; 1H NMR (500 MHz,
CDCl3) δ: 8.19－8.16 (m, 1H), 7.77 (s, 1H), 7.76－7.72
(m, 1H), 7.66 (d, J＝8.0 Hz, 1H), 7.54 (d, J＝8.0 Hz,
1H), 7.48－7.44 (m, 1H), 7.41－7.37 (m, 1H), 7.34－
7.30 (m, 1H), 7.14 (t, J＝7.6 Hz, 1H), 5.95 (br s, 1H),
5.77 (s, 1H), 4.86 (dd, J＝10.2, 4.5 Hz, 1H), 4.79 (br s,
Following the General Procedure, the tandem reac-
tion of compound 10d (200 mg, 0.44 mmol) produced,
after column chromatographic purification on silica gel
(eluent: EtOAc∶PE＝1∶1), compound 17d (93 mg,
0.21 mmol, yield: 45%) as a white solid. M.p. 164－166
20
℃ (EtOAc); [α]D –195.0 (c 1.0, THF); IR (film) νmax
:
3340, 2955, 1740, 1678, 1611, 1474, 1244, 1157, 754
1
cm−1; H NMR (500 MHz, CDCl3) δ: 8.18－8.15 (m,
1H), 7.73－7.68 (m, 1H), 7.63－7.60 (m, 1H), 7.46－
7.42 (m, 1H), 7.31－7.28 (m, 1H), 7.18－7.13 (m, 1H),
6.85－6.81 (m, 1H), 6.67 (d, J＝7.9 Hz, 1H), 5.33 (s,
1H), 5.00 (br s, 1H), 4.90 (s, 1H), 4.24 (br s, 1H), 3.69
(s, 3H), 2.99 (br s, 1H), 2.45 (dd, J＝12.0, 3.6 Hz, 1H),
1.49 (s, 3H), 1.48 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ: 174.9, 170.0, 160.4, 148.6, 147.2, 145.7, 134.5, 131.0,
129.0, 127.3, 127.1, 126.9, 123.8, 121.8, 120.6, 110.4,
79.8, 79.7, 61.6, 52.7 (2C), 39.6, 24.43, 24.39; MS (ESI)
m/z: 471 (M＋Na＋ , 100%); HRMS-ESI calcd for
C24H25N4O4: (M＋K)＋ 487.1384, found 487.1378.
762
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 757—770

Enantioselective Total Syntheses of (−)-Chaetominine and Analogues
1H), 2.63 (dd, J＝13.1, 3.5 Hz, 1H), 2.60－2.50 (m,
1H), 1.82－1.76 (m, 2H), 1.74－1.67 (m, 1H), 1.03 (d,
J＝6.3 Hz, 3H), 0.9 (d, J＝6.3 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ: 170.4, 166.2, 160.9, 147.1, 144.9,
137.4, 135.8, 134.7, 130.6, 127.5, 127.2, 126.9, 126.0,
124.1, 121.4, 115.5, 83.8, 77.5, 63.1, 50.9, 39.4, 38.8,
25.2, 23.0, 21.5; MS (ESI) m/z: 445 (M＋H＋, 100);
HRMS-ESI calcd for C25H24N4O4: (M＋H)＋ 445.1876,
found 445.1879.
aroylation of D-Trp with o-nitrobenzoyl chloride (THF,
0.4 N NaHCO3, 0 ℃, 4 h), prepared in situ from
o-nitrobenzoic acid (SOCl2, reflux, 20 min), to give the
20
aroylated product (R)-12 {[α]D −7.8 (c 1.1, CH3OH)}
20
in 80% yield (Scheme 3). The yield of (R)-12 {[α]D
−7.7 (c 1.1, CH3OH)} was improved to 90% by the use
of 1 N NaOH (H2O, THF, 0 ℃, 2 h). Successive treat-
ment of compound (R)-12 with i-BuOCOCl/N-methyl-
morpholine (NMM, THF, −20 ℃, 15 min), and L-Ala
methyl ester hydrochloride salt (THF, NMM, −20 ℃, 8
h) produced the desired dipeptide derivative 11a in 91%
yield.
(2S,4S,5aR,9cR)-4,5,5a,9c-Tetrahydro-5a-hydroxy-2-
benzyl-4-(4-oxo-3(4H)-quinazolinyl)-3H-2a,9b-diaza-
cyclopenta[jk]fluorene-1,3(2H)-dione (18c)
Following the procedure described for the synthesis
of compound 18b, reaction of 17c (51 mg, 0.10 mmol)
gave compound 18c (31 mg, yield: 60%) as a white
solid, and 15 mg of recovered 17c. Compound 18c: M.p.
150－152 ℃ (EtOAc); [α]D20＋122.0 (c 0.2, CHCl3);
IR (film) νmax: 3357, 2925, 1679, 1611, 1480, 1327,
Scheme 3 Synthesis of quinazolinone derivative 10a
O
OH
NH2
O
NO2
NO2
NH
COOH
(R)-12
COOH
1
1293, 758 cm−1; H NMR (500 MHz, CDCl3) δ: 8.16－
SOCl2, refl. 20 min;
1 mol/L NaOH, H2O
THF, 0 οC, 2 h
90%
N
H
N
8.13 (m, 1H), 7.76－7.70 (m, 2H), 7.61 (d, J＝7.9 Hz,
1H), 7.58－7.54 (m, 1H), 7.48－7.44 (m, 1H), 7.34－
7.30 (m, 2H), 7.29－7.25 (m, 2H), 7.23－7.28 (m, 2H),
7.15－7.09 (m, 2H), 5.9 (br s, 1H), 5.04 (dd, J＝5.6, 4.5
Hz, 1H), 4.82 (s, 1H), 4.5 (s, 1H), 3.29 (dd, J＝14.1, 4.5
Hz, 1H), 3.23 (dd, J＝14.1, 5.6 Hz, 1H), 2.57 (dd, J＝
12.0, 3.6 Hz, 1H), 2.54－2.45 (m, 1H); 13C NMR (125
MHz, CDCl3) δ: 169.8, 166.3, 160.9, 147.2, 144.8,
137.8, 135.3, 135.2, 134.7, 130.8, 129.6 (2C), 128.8
(2C), 127.5, 127.39, 127.35, 126.9, 126.2, 124.1, 121.5,
115.6, 85.0, 77.5, 65.6, 50.8, 39.5, 36.5; MS (ESI) m/z:
479 (M＋H＋, 100%); HRMS-ESI calcd for C28H22N4O4:
(M＋H)＋ 479.1719, found 479.1713.
D-Trp
H
O
O
NO2
NH2 HCl
Me
MeO
NH
O
i
ClCO2 Bu, NMM, THF
HN
H2
−20 οC, 8 h
N
Me
97% 10% Pd/C
r.t., 12 h
H
91%
MeO
O
97%
11a
Zn/TiCl4
HC(OMe)3
THF, 0 to 5 οC
O
N
O
NH2
N
NH
HC(OEt)3
p-TsOH
(4S,5aR,9cR)-4,5,5a,9c-Tetrahydro-5a-hydroxy-2,2-
dimethyl-4-(4-oxo-3(4H)-quinazolinyl)-3H-2a,9b-di-
azacyclopenta[jk]fluorene-1,3(2H)-dione (18d)
O
O
HN
MeO
10a
HN
MeO
13
THF, 0 to 20 οC
94%
N
N
Me
Me
H
H
Following the procedure described for the synthesis
of compound 18b, reaction of 17d (47 mg, 0.1 mmol)
gave compound 18d (38 mg, 0.092 mmol, yield: 92%)
O
O
20
To construct the quinazolinone ring system,[15]
a
as a white solid. M.p. 164－167 ℃ (EtOAc); [α]D
＋121.0 (c 1.0, THF); IR (film) νmax: 3450, 2976, 1734,
two-step procedure was first investigated. The nitro
group in 11a was first reduced by catalytic hydrogena-
tion (H2, 1 atm, 10% Pd/C, EtOH, r.t., 12 h) to give ani-
line derivative 13 in 97% yield. The latter was then
treated with HC(OEt)3 in the presence of p-TsOH in
THF[16] at 40 ℃ to yield the desired quinazolinone 10a.
However, partial epimerization was observed. To our
delight, when the reaction was run at 0－20 ℃, epim-
erization could be avoided and quinazolinone 10a was
obtained in 94% yield. With the aim to develop a redox-
economical total synthesis,[17] we next examined the
possibility to undertake a direct synthesis of 10a from
11a. A one-pot reductive cyclization of o-nitrobenza-
mide and triethyl orthoformate to construct the quina-
zolinone ring has been developed by Shi and
co-workers.[18] Following Shi’s procedure, the mixture
of 11a and HC(OMe)3 was treated with low-valent tita-
nium,[19] generated in situ from TiCl4 and Zn powder, in
1
1681, 1610, 1478, 1325, 1292, 1050, 762 cm−1; H
NMR (400 MHz, CDCl3) δ: 8.16－8.11 (m, 1H), 7.77 (s,
1H), 7.75－7.69 (m, 1H), 7.65－7.60 (m, 1H), 7.57－
7.53 (m, 1H), 7.47－7.42 (m, 1H), 7.38－7.33 (m, 2H),
7.17－7.12 (m, 1H), 5.50 (s, 1H), 4.99 (br s, 1H), 2.85
－2.40 (m, 2H), 1.68 (s, 3H), 1.56 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ: 174.2, 165.0, 161.0, 147.3, 145.1,
139.0, 134.8, 134.7, 130.9, 127.6, 127.3, 126.8, 126.0,
124.3, 121.7, 115.6, 81.6, 77.5, 67.7, 38.8, 22.5, 21.1;
MS (ESI) m/z: 455 (M＋K＋, 100%). HRMS-ESI calcd
for C23H21N4O4: (M＋H)＋ 417.1563, found 417.1563.
Results and Discussion
Total synthesis of (−)-chaetominine (6a) from D-Trp
We first investigated the synthesis of (−)-chaeto-
minine (6a) from D-Trp. The synthesis started with the
Chin. J. Chem. 2014, 32, 757—770
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763

Luo et al.
FULL PAPER
refluxing THF. The desired quinazolinone 10a was
formed, however, with considerable epimerization
observed. The epimerization occurred even if the reac-
tion temperature was lowered to r.t. Further studies
showed that when running the reaction at 0－5 ℃, the
desired product 10a could be obtained in 97% yield
without epimerization.
promising and it was selected for the cascade reaction.
Dipeptide 10a was first treated with a freshly prepared
solution of DMDO in acetone at −78 ℃ for up to 1 h
(Scheme 4). However, no desired epoxidative cycliza-
tion product was obtained. It was recognized that basic
conditions would be necessary to realize the tandem
epoxidation-bis-cyclization reactions. In view of the
easy epimerization of our substrates (vide supra),
weakly basic conditions are preferred to avoid any
epimerization during the cyclization. After considerable
trials, it was found that a combination of DMDO with
DMSO gave optimal results. In the event, dipeptide 10a
was treated with DMDO in acetone at −78 ℃ for 1 h,
and then with CaH2 dried DMSO, and the mixture was
stirred at r.t. for 2 d to produce directly the desired
(−)-chaetominine (6a) in 42% yield, along with a small
amount of its precursor 16 (3 % yield) and an epimer of
the latter (17a) in 51% yield.
Besides the DMDO-DMSO (CaH2-dried) combina-
tion, many weak bases were examined. A combination
of DMDO with K2CO3/MeOH was also effective for
this tandem epoxidation-bis-cyclization reaction, which
yielded (−)-chaetominine (6a) and compound 17a in
38% and 47% yields, respectively. Moreover, treatment
of the presumed epoxide intermediates with a saturated
aqueous solution of Na2SO3 also yielded chaetominine
(6a, 22% yield), its precursor 16 (9% yield) and 17a
(42% yield). The structures of (−)-chaetominine (6a)
and its precursor 16 were confirmed by single crystal
X-ray analyses (Scheme 4).[8f] The spectral data of our
synthetic (−)-chaetominine (6a) are identical with those
reported (vide infra for a discussion on the physical
properties).[5a,8a] It is interesting that the two carbonyl
groups have a syn-disposition in the single crystal of
(−)-chaetominine (6a) we obtained, while they are in a
anti-disposition in the single crystal of (−)-chaeto-
With compound 10a in hand, we next investigated
the key epoxidation-triggered tandem reaction to con-
struct the tricyclic core of (−)-chaetominine (6a) (cf.
Scheme 2). The oxidative cyclization of tryptophan de-
rivatives leading to β-oxygenated pyrrolo[2,3-b]indole
ring systems has been known for a long time.[20,21] This
strategy has been used extensively in the total synthesis
of hexahydropyrrolo[2,3-b]indole alkaloids.[22] However,
to the best of our knowledge, no direct oxidative cycli-
zation leading to the fused six-membered ring system
(oxygenated piperidino[2,3-b]indoline) has ever been
reported. Even when the formation of both five and
six-membered rings were possible, five-membered ring
product (pyrrolo[2,3-b]indole) always dominated over
six-membered ring.[9,20k,23] The only solution was found
in Baran’s total synthesis of kapakahines,[9a,9b] where the
piperidino[2,3-b]indoline ring system was formed in-
geniously via a shift of topology by dynamic equilibra-
tion of the corresponding pyrroloindoline. In Rainier’s
total synthesis of kapakahines E and F,[9c,9d] the trans-
formation of pyrroloindoline derivative to piperidino-
[2,3-b]indoline ring system was proven to be much
more challenging. In Evano’s and Papeo’s total synthe-
ses of chaetominine,[8b,8d,8e] while piperidino[2,3-b]-
indoline ring systems were built stereoselectively, sev-
eral steps were required for further transform into the
target molecules.
For the oxidation of indole,[20] the mild and green
oxidant dimethyldioxirane (DMDO)[24] appeared to be
Scheme 4 Epoxidation-triggered cascade reaction leading to (−)-chaetominine (6a)
O
O
N
O
N
O
N
O
N
O
N
N
acetone
−78 οC, 1 h;
O
O
O
+
O
O
additive
HN
MeO
10a
HN
HN
Me
Me
N
Me
N
H
N
H
H
MeO
14
MeO
O
O
(47: 53)
15
6a
O
O
N
N
N
+
N
N
N
HO
N
OH
HO
+
14
O
O
O
N
O
N
H
N
N
N
H
H
H
11
H
Me
Me
MeO
MeO
O
Me
O
O
(−)-chaetominine (6a)
additives
DMSO
16
(3%)
(not observed)
(9%)
17a
(42%)
(51%)
(47%)
(42%)
K2CO3/MeOH
Na2SO3 (aq.)
(38%)
(22%)
16
764
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Chin. J. Chem. 2014, 32, 757—770

Enantioselective Total Syntheses of (−)-Chaetominine and Analogues
minine•MeOH that Tan reported.
15 were thus deduced as those shown in Scheme 4 and
the diastereoselectivity in the epoxidation of 10a with
DMDO was determined to be 53∶47 in favor of
β-epoxide. To improve the diastereoselectivity of the
key tandem reaction, several other oxidants were exam-
ined, including Oxone, mCPBA, TBTH/VO(acac)2,[26]
NaClO,[27] as well as Salen (Mn)/DMDO[28] and Shi
oxidation.[29] However, the starting material 10a was
either destroyed or remained intact in most cases. Only
the latter two conditions gave 6a and 17a in disappoint-
ing 20%/25% yields, and 10%/13% yields, respectively.
The formation of compound 17a in substantial
amount led us to carry out its cyclization for the synthe-
sis of a diastereomer of (−)-chaetominine (6a). Com-
pound 17a was thus treated with NaOMe/MeOH at −10
℃ to produce 2,3,14-triepi-chaetominine 18a in 90%
yield (Scheme 5). The relative stereochemistry of 18a
was confirmed by X-ray analysis of a single crystal of
18a•H2O (Scheme 5, cf. Supporting Information, p.
22).[8f]
To determine the absolute stereochemistries of com-
pounds 17a and 18a, compound 17a was converted to
its bromo derivative and further cyclized to give 19.
X-ray analysis of a single crystal of 19•H2O[8f] con-
firmed its absolute stereochemical structure as displayed
in Scheme 5. In addition, using Marfey’s method,[25,5a]
the absolute configuration of the Ala residue in 17a was
determined to be S, identical to that in 10a.
Moreover, the comparison of the optical rotation
data of the precursor 16 and its lactamization product 6a
(minor difference) with those of 17a and 18a (signifi-
cant difference in value with opposite sense) implicated
that compound 18a is a concomitantly epimerized lac-
tamization product, instead of a simple lactamization
product from 17a (Scheme 5).
On the basis of these results, the absolute stereo-
chemistry of 17a was deduced as 2R,3R,11S,14S. The
stereochemistries of the epoxide intermediates 14 and
Enantioselective syntheses of homologues and ana-
logues of (−)-chaetominine from D-Trp
To demonstrate the flexibility of the method, the
syntheses of homologues/analogues of (−)-chaetominine
with different substituents at C-11 were envisioned, in
view of the presence of different alkyl groups in struc-
turally related quinazolinone-containing indole alka-
loids.[2] The synthesis of (−)-chaetominine analogue
incorporating an L-Leu, the residue presenting in both
fumiquinazoline I (3) and asperlicin (4), was first un-
dertaken. Following the procedures developed for the
synthesis of (−)-chaetominine (6a), C11-iso-butyl ana-
logue (6b) of (−)-chaetominine and its diastereomer 17b
were obtained in three and four steps, respectively, start-
ing from D-Trp derivative (R)-12 and L-leucine methyl
ester hydrochloride salt (Scheme 6). The yield of each
Scheme 5 Syntheses of diastereomer and analogue of chaetominine and comparison of specific optical rotation values
N
OH
N
NaOMe, MeOH
N
O
14
O
N
O
−10 οC
O
N
N
11
HO
H
14
3
90%
O
O
Me
N
C14 epimerization
triggered cyclization
N
18a
(+)-2,3,14-triepi-chaetominine (
[α]D20 +98.0 (c 0.50, MeOH)
)
H
Me
H
MeO
17a
[α]D20 −184.2 (c 1.0, CHCl3)
H O
2 O
2
i) NBS, r.t.
40%
ii) NaOMe, MeOH
(un-optimized)
−
10
οC
Br
6
N
HO
•
18a H2O
N
O
3
14
O
1N
H
N
11
O
Me
19
N
O
N
H O
H O
2
2
N
O
OH
N
HO
14
O
O
O
N
H
N
O
N
11
H
N
H
Me
Me
MeO
16
6a
(−)-chaetominine (
)
20
20
[α]D
=
[α]D
=
•
19 H2O
−62.5 (c 0.36, CHCl3)
−49.7 (c 0.45, MeOH)
(carbon numbered according to the ring system of chaetominine)
Chin. J. Chem. 2014, 32, 757—770
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765

Luo et al.
FULL PAPER
step is comparable to that of (−)-chaetominine (6a) and
its diastereomer 17a. It is worth mentioning that
DMDO-K2CO3/MeOH combination gave more repro-
ducible results for the cascade reaction and it was used
for the synthesis of (−)-chaetominine analogues. Treat-
ment of 17b with NaOMe led to 18b in 88% yield.
Considering the presence of a benzyl group in ka-
pakahines B and F,[7] the synthesis of C-11 benzyl ana-
logue of (−)-chaetominine was next undertaken
(Scheme 6). Starting from (R)-12 and L-phenylalanine
methyl ester hydrochloride salt, 11-benzyl analogue (6c)
of (−)-chaetominine and its diastereomer 17c were syn-
thesized in four and five steps, respectively. The
final NaOMe-mediated cyclization of 17c afforded 18c
in 60% yield (90% based on the recovered 17c).
The incorporation of non-proteinogenic amino acid
as gem-dimethyl group in several quinazoline-contain-
ing indole alkaloids such as tryptoquialanine, deoxy-
tryptoquivaline, and fiscalin C (5) prompted us to syn-
thesize 11-methylchaetominine (6d) (Scheme 6). Start-
ing from (R)-12 and α-methylglycine methyl ester hy-
drochloride salt, compound 10d was obtained in 87%
overall yield over two steps. Treatment of 10d with
DMDO and K2CO3/MeOH produced only 17d in 45%
yield. The expected tandem cyclization product
11-methylchaetominine (6d) was not observed. Treat-
ment of 17d with NaOMe in MeOH afforded the lac-
tamization product 18d in 92% yield.
Scheme 6 Syntheses of homologues/analogues of (−)-chaeto-
minine (6a)
Enantioselective synthesis of (−)-chaetominine from
L-Trp
O
NO2
ClCO2Bus, NMM
During the synthesis of (−)-chaetominine from D-Trp,
the β-epoxide 15 (and thus the diastereomer 17a) was
formed predominately from 10a (Scheme 4). And the
complete epimerization at C14 was observed during the
transformations of compounds 17a (Scheme 5) and 17b
－17d (Scheme 6) to 18a and 18b－18d. Taking advan-
tages of these two results, we assumed that it is possible
to develop a second generation total synthesis of
(−)-chaetominine (6a) starting from L-Trp. To test the
feasibility of our assumption, we needed to figure out
which stereogenic center between C11 and C14 is
determinant in the preferred β-epoxidation of 10a. For
this purpose, tripeptide derivative 10e was synthesized
(Scheme 6). Treatment of 10e with DMDO and K2CO3/
MeOH produced diastereomers 17e and 16a as an in-
separable diastereomeric mixture (dr＝2∶1, combined
yield: 81%). Although the stereochemistries of 17e and
16a could not be determined, a comparison of this result
with those from the epoxidation reactions of 10a－10d
(dr＝53∶47) indicated that the asymmetric inductions
of C14 and C11 are mismatch and the chirality at C14 is
slightly dominant over C11 to give β-diastereoselective
epoxidation products. The predominant asymmetric in-
duction of C14 over C11 could be readily understood
since the larger quinazolinonyl group at C14 situates
closer to the indole ring than the methyl, isobutyl or
benzyl group at C11.
In order to get further insight into the asymmetric in-
duction of the C14, we next undertook a conformational
analysis (Scheme 7). From the observed low diastereo-
selectivity in the epoxidation of 10x, we assumed that
the reaction passed through a product-like transition
state to give the more stable β-epoxide 15x as the major
product. With the quinazolinonyl group at the axial po-
sition of the chair-like conformation, the α-epoxide 14x
is less stable, and formed as the minor product. Epox-
ides 15x and 14x are probably in equilibrium with their
iminol tautomers 14xa and 15xa, which upon treatment
with a weak base, yielded lactams 16x and 17x, respec-
Zn/TiCl4
HC(OMe)3
NH
THF, −20 ο
C
(R)-12
O
R2
R1
THF, 0 ο
C
O
HN
MeO
NH2 HCl
R2
N
MeO
H
R1
O
11b: R1 = iBu, R2 = H (91%)
11c: R1 = Bn, R2 = H (85%)
11d: R1 = R2 = Me (91%)
11e: R1 = R2 = H (87%)
O
N
N
O
DMDO, THF
−78 ο
N
HO
C
N
O
O
HN
MeO
K2CO3/MeOH
R2
R1
N
H
N
N
H
R2
R1
O
O
6b: R1 = iBu, R2 = H (31%)
6c: R1 = Bn, R2 = H (32%)
6d: R1 = R2 = Me (0%)
6e: R1 = R2 = H (0%)
10b: R1 = iBu, R2= H (99%)
10c: R1 = Bn, R2 = H (93%)
10d: R1 = R2 = Me (96%)
10e: R1 = R2 = H (91%)
+
N
O
N
N
HO
N
HO
MeONa, MeOH
−10 ο
O
O
R2
R1
N
N
O
N
H
C
N
R2
H
H
R1
O
MeO
O
18b: R1 = iBu, R2 = H (88%)
17b: R1 = iBu, R2 = H (45%)
17c: R1 = Bn, R2 = H (51%)
17d: R1 = R2 = Me (45%)
18c: R1= Bn, R2 = H (60%; 90% BRSM)
18d: R1 = R2 = Me (92%)
17e: R1 = R2 = H
(BRSM = based on the
recovered starting material)
+
O
N
N
HO
O
N
N
H
H
MeO
combined yield of 17e and 16a = 81%, dr = 2: 1
O
16a
(stereochemistry not determined)
766
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Chin. J. Chem. 2014, 32, 757—770

Enantioselective Total Syntheses of (−)-Chaetominine and Analogues
Scheme 7 Conformational analysis of the diastereoselective oxidative double cyclization of tripeptide derivative 10x
tively. Inspection of conformer 16x and the single crys-
tal structure of 16 (Scheme 4) revealed the indoline ni-
trogen is quite close to the ester carbonyl. This explains
why the amino ester 16, once formed, is prone to un-
dergo second lactamization to give spontaneously
(−)-chaetominine (6a). In fact, it is difficult to obtain
amino ester 16 in a pure form. The equilibrium between
amino ester 16 and its tautomer (−)-chaetominine (6a)
has been investigated by Snider and Wu.[8a]
Scheme 8 Synthesis of compound 22 from L-Trp
O
Cl
NH2
O
NO2
NO2
NH
COOH
(S)-12
COOH
1 mol/L NaOH, H2O
THF, 0 οC, 2 h
91%
N
H
N
H
L-Trp
In contrast, the indoline nitrogen is far away from
the ester carbonyl in 17x (Scheme 7), which prevents a
direct cyclization. A base-promoted epimerization at
C14 is thus necessary for the next cyclization to 18x.
With the asymmetric induction of the C14 confirmed,
the total synthesis of (−)-chaetominine (6a) from L-Trp
was conducted. Following the procedure described for
the synthesis of quinazolinone 10a, compound 21 was
synthesized from L-Trp in three steps as shown in
Scheme 8. Treatment of 21 with DMDO in THF at −78
℃ followed by work-up with an aqueous solution of
Na2SO3 produced the mono-cyclized product 22 in 48%
yield, along with 2,3,14-triepi-chaetominine (18a) in
32% yield.
Next the selective C14 epimerization-induced lacta-
mization of compound 22 was conducted. To our dis-
appointment, treatment of 22 with NaOMe in methanol
at −10 ℃ yielded the bis-epimerized product (−)-11-
epi-chaetominine 23, the antipode of 18a, in 82% yield
(Scheme 9). Treatment of 22 with t-BuOK at −70 ℃
gave 23 in 50% yield. After tremendous trials, it was
discovered that a 60% yield of (−)-chaetominine (to-
gether with 19% of 23) could be obtained by treating 22
with 0.1 equiv. of DMAP in refluxing toluene for 168 h.
O
O
NO2
NH2 HCl
Me
MeO
Zn/TiCl4
HC(OMe)3
NH
O
THF, 0 οC
95%
i
ClCO2 Bu, NMM, THF
HN
−20 οC, 8 h
N
H
Me
93%
MeO
O
20
O
N
N
HO
O
N
N
O
N
Me
H
H
N
O
MeO
DMDO, THF
−78 οC, 1 h;
Na2SO3 (aq.), 0 ο
O
22 (48%)
O
+
HN
MeO
21
C
N
Me
N
H
HO
N
O
N
N
O
H
O
Me
18a (32%)
About the physical properties of (−)-chaetominine
in agreement with those of the synthetic ones {–49.4 (c
0.26, MeOH);[8a] –48 (c 0.45, MeOH);[8b,8e] –47.9 (c
0.25, MeOH)[8d]}. However all the optical rotation val-
ues of above-mentioned synthetic samples of (−)-chae-
tominine are different from that reported for the natural
(6a)
With the rapid access to (−)-chaetominine (6a) se-
cured, we were in a position to clarify the issues of its
physical properties.
20
The optical rotation value of our synthetic
product {[α]D –70 (c 0.48, MeOH)}.[5a] The higher
(−)-chaetominine (6a) {[α]D20 –49.7 (c 0.45, MeOH)} is
optical rotation value of the natural product
Chin. J. Chem. 2014, 32, 757—770
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
767

Luo et al.
FULL PAPER
Scheme 9 C14-Epimerization-triggered lactamization leading
to (−)-chaetominine (6a) or (−)-11-epi-chaetominine (23)
clear that only such a trans-disposition favors the tan-
dem lactamization of its precursor (e.g. 16). For those
having a cis-disposition between the substituents at C3
and C14 (e.g. 17a and 22), a base-promoted epimeriza-
tion is necessary for establishing the required C3/C14
trans-disposition for the lactamization.
bis-epimerization
at C11 and C14
NaOMe, MeOH
N
O
HO
N
N
O
N
HO
14
−10 οC
14
O
N
N
11
O
82%
On the plausible biogenetic pathway of (−)-chaeto-
minine (6a)
H
N
N
H
H
O
Me
Me
11
MeO
DMAP
23
The successful syntheses of (−)-chaetominine (6a)
from D-Trp and L-Trp in four and five steps, respectively,
also chemically validate the short pathways to complex-
ity generation revealed for the biosynthesis of fungal
peptidyl alkaloids.[6a-6c] This led us to consider a plausi-
ble biosynthetic pathway of (−)-chaetominine (6a) on
the basis of purely chemical principles. Our hypothesis
is outlined in Scheme 10, which involves three key ele-
ments: (1) the direct use of L-Trp as a staring material
for the formation of the tripeptide derivative F; (2) the
epoxidation-triggered lactamization for the conversion
of intermediate F to G, then to H; (3) the selective
epimerization at C14 of the intermediate H for the sub-
sequent tandem lactamization to produce (−)-chaeto-
minine (6a). Although the epoxidation proceeded with
low diastereoselectivity in our synthesis, it is reasonable
to assume that this biogenetic route could run with high
stereoselectivity with the sophisticated enzyme sys-
tem.[30]
tol., reflux
O
(−)-11-epi-chaetominine
selective
epimerization
at C14
22
N
(carbon numbered
according to the ring
system of chaetominine)
OH
N
+ 23
14
O
O
N
N
H
O
Me
23
(−)-chaetominine (6a)
43% (81% BRSM)
48% (63% BRSM)
60%
10%
28%
19%
DMAP (1.0 equiv), 22 h
DMAP (0.5 equiv), 38.5 h
DMAP (0.1 equiv), 168 h
(BRSM = based on the recovered starting material)
might be ascribed to a contamination with some
ring-opening product 16. The interconversion between
(−)-chaetominine (6a) and 16 in refluxing methanol has
been described by Snider.[8a] To test this assumption, our
synthetic (−)-chaetominine (6a) was dissolved in MeOH
under ultrasonic conditions for 4 h then allowed stand-
ing at room temperature for 7 d. A 1.2∶1 mixture of 6a
and its ring-opening amino ester 16 is formed, which
Scheme 10 A plausible biosynthetic pathway of (−)-chaeto-
minine suggested on the basis of chemical syntheses
20
displayed an optical rotation of {[α] D –68.0 (c 0.45,
MeOH)}, consisting with that reported for the natural
20
product {[α]D –70 (c 0.48, MeOH)[5a]}. It is thus rea-
L-Trp
sonable to assume that the reported higher optical rota-
tion value for the natural (−)-chaetominine (6a) is
caused by a contamination with the ring-opening methyl
ester 16 formed during the isolation and purification.[5a]
On the other hand, our synthetic chaetominine, when
collected from column chromatographic purification,
exhibited a melting point of 165－167 ℃, which is
comparable with those reported for the natural product
(m.p.＝161－163 ℃)[5a] and for the synthetic ones (162
－165 ℃;[8a] 164 ℃;[8b,8e] 160－162 ℃[8d]). However,
after recrystallization from EtOAc/hexane, a much
higher melting point of 196－198 ℃ was recorded.
More surprisingly, a sample recrystallized from MeOH
gave an even higher melting point of 288－290 ℃.
anthranilic acid
L-Ala
O
O
N
N
N
14
N
(S)
(S)
epoxidation
O
O
N
H
EnzS
HN
O
:
N
H
N
H
Me
EnzSC
O
Me
O
F
G
epoxidation-triggered
cascade reaction
epoxide-opening
lactamization
6a
On the lactamization endgame of the total synthesis
tadem
lactamization
As outlined in Schemes 4 and 8, only (−)-chaeto-
minine (6a) and its diastereomer 18a were formed from
10a and 21 via the cascade reaction, while the sponta-
neous lactamization could not occur for 17a and 22,
which, after epimerization at C14, could be lactamized
to give (−)-chaetominine (6a) and its diastereomers 23
and 18a, respectively (Schemes 9 and 5). All the syn-
thetic (−)-chaetominine (6a), its diastereomers and ana-
logues possess a trans-disposition between the hydroxyl
group at C3 and the quinazolinonyl group at C14. It is
selective
epimerization
at C14
O
O
N
N
N
(S)
N
(R)
HO
HO
14
14
3
3
O
O
N
N
N
H
N
H
H
H
Me
Me
EnzS
EnzS
O
O
H
I
(carbon numbered according to the ring system of chaetominine)
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Chin. J. Chem. 2014, 32, 757—770
768
www.cjc.wiley-vch.de

Enantioselective Total Syntheses of (−)-Chaetominine and Analogues
Y.; Walsh, C. T. ACS Chem. Biol. 2013, 8, 741; (c) Haynes, S. W.;
Gao, X.; Tang, Y.; Walsh, C. T. J. Am. Chem. Soc. 2012, 134, 17444;
(d) Gao, X.; Chooi, Y.-H.; Ames, B. D.; Wang, P.; Walsh, C. T.;
Tang, Y. J. Am. Chem. Soc. 2011, 133, 2729; (e) Walsh, C. T.;
Haynes, S. W.; Ames, B. D. Nat. Prod. Rep. 2012, 29, 37; (f) Gao,
X.; Haynes, S. W.; Ames, B. D.; Wang, P.; Vien, L. P.; Walsh, C. T.;
Tang, Y. Nat. Chem. Biol. 2012, 8, 823; For an early study, see: (g)
Houck, D. R.; Ondeyka, J.; Zink, D. L.; Inamine, E.; Goetz, M. A.;
Hensens, O. D. J. Antibiot. 1988, 41, 882.
Conclusions
In summary, we have disclosed two bio-inspired but
non-biomimetic concise total syntheses of (−)-chaeto-
minine (6a), its analogues and diastereomers. The first
one, starting from D-Trp, L-alanine methyl ester and
o-nitrobenzoic acid, has been achieved in four steps
with an overall yield of 31.5%. The second approach
used, for the first time, L-Trp as a starting material,
which led to (−)-chaetominine (6a) with an overall yield
of 23.2% in five steps. Using these efficient routes, sev-
eral analogues and diastereomers of chaetominine have
been synthesized. Through this work, the ambiguity
about the optical rotation value and the melting point of
(−)-chaetominine (6a) have been clarified. More impor-
tantly, our synthetic routes, which feature a cascade ep-
oxidation-double cyclization reaction as the key step,
provide a new example of step-economical, redox-
economical and protecting-group-free syntheses of
complex natural products. The synthesis also serves as a
good example of complexity generation in short path-
ways by chemical synthesis. On the basis of chemical
evidences gained during our investigations, a more
plausible biosynthetic approach to (−)-chaetominine (6a)
has been proposed, which is also significant for under-
standing the biosyntheses of other fungal peptidyl alka-
loids.
[7] (a) Nakao, Y.; Yeung, B. K. S.; Yoshida, Y. W.; Scheuer, P. J. J. Am.
Chem. Soc. 1995, 117, 8271; (b) Yeung, B. K. S.; Nakao, Y.; Kinnel,
R. B.; Carney, J. R.; Yoshida, W. Y.; Scheuer, P. J.; Kelly-Borges,
M. J. Org. Chem. 1996, 61, 7168; (c) Nakao, Y.; Kuo, J.; Yoshida,
W. Y.; Kelly, M.; Scheuer, P. J. Org. Lett. 2003, 5, 1387.
[8] For enantioselective syntheses of chaetominine, see: (a) Snider, B.
B.; Wu, X. X. Org. Lett. 2007, 9, 4913; (b) Toumi, M.; Couty, F.;
Marrot, J.; Evano, G. Org. Lett. 2008, 10, 5027; (c) Huang, P.-Q.;
Liu, L.-X.; Peng, Q.-L. ZL 200910110953.2, 2009 (in Chinese)
[Chem. Abstr. CN20091110953 20090122]; (d) Malgesini, B.; Forte,
B.; Borghi, D.; Quartieri, F.; Gennari, C.; Papeo, G. Chem.-Eur. J.
2009, 15, 7922; (e) Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G.
Synthesis 2009, 2927; (f) Peng, Q.-L.; Luo, S.-P.; Xia, X.-E.; Liu,
L.-X.; Huang, P.-Q. Chem. Commun. 2014, 50, 1986; (g) Xu, C.-P.;
Luo, S.-P.; Wang, A.-E; Huang, P.-Q. Org. Biomol. Chem. 2014, 12,
2859.
[9] For enantioselective syntheses of kapakahines B, E and F, see: (a)
Newhouse, T.; Lewis, C. A.; Baran, P. S. J. Am. Chem. Soc. 2009,
131, 6360; (b) Newhouse, T.; Lewis, C. A.; Eastman, K. J.; Baran, P.
S. J. Am. Chem. Soc. 2010, 132, 7119; (c) Espejo, V. R.; Rainier, J.
D. Org. Lett. 2010, 12, 2154; (d) Rainier, J. D.; Espejo, V. R. Isr. J.
Chem. 2011, 51, 473.
[10] (a) Guo, L.-D.; Liang, P.; Zheng, J.-F.; Huang, P.-Q. Eur. J. Org.
Chem. 2013, 2230; (b) Tuo, S.-C.; Liu, X.-K.; Huang, P.-Q. Chin. J.
Chem. 2013, 31, 55; (c) Zheng, J.-F.; Lan, H.-Q.; Yang, R.-F.; Peng,
Q.-L.; Xiao, Z.-H.; Tuo, S.-C.; Hu, K.-Z.; Xiang, Y.-G.; Wei, Z.;
Zhang, Z.; Huang, P.-Q. Helv. Chim. Acta 2012, 95, 1799; (d) Chen,
J.; Wang, A.-E; Huo, H.-H.; Huang, P.-Q. Sci. China-Chem. 2012,
55, 1175; (e) Dai, X.-J.; Huang, P.-Q. Chin. J. Chem. 2012, 30,
1953.
Acknowledgement
The authors are grateful for financial support from
the National Basic Research Program (973 Program) of
China (Grant No. 2010CB833200), the NSF of China
(21332007), the Program for Changjiang Scholars and
Innovative Research Team in University (PCSIRT) of
Ministry of Education, and the Natural Science Founda-
tion of Fujian Province of China (No. 2014J01062). We
thank Dr. Jian-Liang Ye, Ms. Yan-Jiao Gao and Ms.
Jing-Wei Chen for technical assistance.
[11] (a) Xiao, K.-J.; Wang, A.-E; Huang, Y.-H.; Huang, P.-Q. Acta Chim.
Sinica 2012, 70, 1917 (in Chinese); (b) Xiao, K.-J.; Wang, A.-E;
Huang, P.-Q. Angew. Chem., Int. Ed. 2012, 51, 8314.
[12] For recent reviews on biomimetic synthesis, see: (a) Poupon, E.;
Nay, B. Biomimetic Organic Synthesis, Wiley-VCH, Weinheim,
2011; (b) Razzak, M.; De Brabander, J. K. Nat. Chem. Biol. 2011, 7,
865; (c) Gravel, E.; Poupon, E. Nat. Prod. Rep. 2010, 27, 32; (d)
Bulger, P. G.; Bagal, S. K.; Marquez, R. Nat. Prod. Rep. 2008, 25,
254; (e) Gravel, E.; Poupon, E. Eur. J. Org. Chem. 2008, 27; (f)
Torre De la, M. C.; Sierra, M. A. Angew. Chem., Int. Ed. 2004, 43,
160; For selected recent examples, see: (g) Dong, J.-Q.; Wong, H. N.
C. Angew. Chem., Int. Ed. 2009, 48, 2351; (h) Wang, Y.; Zhu, L.;
Zhang, Y.; Hong, R. Angew. Chem., Int. Ed. 2011, 50, 2787; (i)
Zhang, X.-M.; Tu, Y.-Q.; Zhang, F.-M.; Shao, H.; Meng, X. Angew.
Chem., Int. Ed. 2011, 50, 3916; (j) Yin, J.; Wang, C.; Kong, L.-L.;
Cai, S.-J.; Gao, S.-H. Angew. Chem., Int. Ed. 2012, 51, 7786; (k)
Yang, H.-Z.; Feng, J.; Tang, Y.-F. Chem. Commun. 2013, 49, 6442.
[13] For reviews, see: (a) Nubbemeyer, U. Eur. J. Org. Chem. 2001,
1801; (b) Yet, L. Chem. Rev. 2000, 100, 2963; (c) Molander, G. A.
Acc. Chem. Res. 1998, 31, 603; (d) Illuminati, G.; Mandolini, L. Acc.
Chem. Res. 1981, 14, 95; For a recent example, see: (e) Cheng, Y.
A.; Chen, T.; Tan, C. K.; Heng, J. J.; Yeung, Y. Y. J. Am. Chem. Soc.
2012, 134, 16492.
References
[1] (a) Chou, T. Q.; Jang, C. S.; Fu, F. Y.; Kao, Y. S.; Huang, K. C.
Science (Chinese) 1947, 29, 49; (b) Koepfli, J. B.; Mead, J. F.;
Brockman, Jr. J. A. J. Am. Chem. Soc. 1949, 71, 1048.
[2] For recent reviews on the quinazolinone alkaloids, see: (a) Khan, I.;
Ibrar, I.; Abbas, N.; Saeed, A. Eur. J. Med. Chem. 2014, 76, 193; (b)
Michael, J. P. Nat. Prod. Rep. 2008, 25, 166 and references cited
therein; (c) Mhaske, S. B.; Argade, N. P. Tetrahedron 2006, 62,
9787.
[3] Amin, A. H.; Mehta, D. R.; Samarth, S. S. Prog. Drug. Res. 1970,
14, 218.
[4] (a) Waletzky, E.; Berkelhammer, G.; Kantor, S. U. S. Patent
3320124, 1967; (b) Elkin, M.; Reich, R.; Nagler, A.; Aingorn, E.;
Pines, M.; De Groot, N.; Hochberg, A.; Vlodavsky, I. Clin. Cancer
Res. 1999, 5, 1982.
[5] (a) Jiao, R. H.; Xu, S.; Liu, J. Y.; Ge, H. M.; Ding, H.; Xu, C.; Zhu,
H. L.; Tan, R. X. Org. Lett. 2006, 8, 5709; (b) Zhang, L.-M.; Li,
Z.-L.; Bai, J.; Wu, X.; Wang, Y.; Hua, H.-M. Chin. Pharm. J. 2011,
46, 1154.
[14] For reviews, see: (a) Hoffmann, R. W. Synthesis 2006, 3531; (b)
Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193; (c) Andrei, K.;
Yudin, R. H. Chem.-Eur. J. 2007, 13, 6538.
[6] (a) Walsh, C. T.; Haynes, S. W.; Ames, B. D.; Gao, X.; Tang, Y.
ACS Chem. Biol. 2013, 8, 1366; (b) Haynes, S. W.; Gao, X.; Tang,
[15] For a recent review on the synthesis of quinazolinones and quina-
zolines, see: (a) Connolly, D. J.; Cusack, D.; O'Sullivan, T. P.; Guiry,
Chin. J. Chem. 2014, 32, 757—770
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
769

Luo et al.
FULL PAPER
P. J. Tetrahedron 2005, 61, 10153; For recent methods, see: (b) Wu,
X. F.; He, N.; Neumann, H.; Beller, M. Chem.–Eur. J. 2013, 19,
12635; (c) Cheng, R.; Guo, T.; Zhang-Negrerie, D.; Du, Y.; Zhao, K.
Synthesis 2013, 45, 2998; (d) Xu, L.; Jiang, Y.; Ma, D. Org. Lett.
2012, 14, 1150; (e) Liu, X.-W.; Fu, H.; Jiang, Y.-Y.; Zhao, Y.-F.
Angew. Chem., Int. Ed. 2009, 48, 348; (f) Zhichkin, P.; Kesicki, E.;
Treiberg, J.; Bourdon, L.; Ronsheim, M.; Ooi, H. C.; White, S.; Jud-
kins, A.; Fairfax, D. Org. Lett. 2007, 9, 1415.
[21] For a related review, see: (a) Zhuo, C.-X.; Zhang, W.; You, S.-L.
Angew. Chem., Int. Ed. 2012, 51, 12662; For related methods, see: (b)
Crich, D.; Huang, X. H. J. Org. Chem. 1999, 64, 7218; (c) Depew,
K. M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.; Bornmann, W. G.;
Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11953; (d) Galli, R.;
Dobler, M.; Güller, R.; Stahl, R.; Borschberg, H. J. Helv. Chim. Acta
2002, 85, 3400; (e) Ley, S. V.; Cleator, E.; Hewitt, P. R. Org. Bio-
mol. Chem. 2003, 1, 3492; (f) Iwasa, E.; Hamashima, Y.; Fujishiro,
S.; Higuchi, E.; Ito, A.; Yoshida, M.; Sodeoka, M. J. Am. Chem. Soc.
2010, 132, 4078; (g) Cai, Q.; Yin, Q.; You, S.-L. Asian J. Org.
Chem. 2014, 3, 408.
[22] For recent reviews, see: (a) Xie, W.; Zuo, Z.; Zi, W.; Ma, D. Chin. J.
Org. Chem. 2013, 33, 869; (b) Ruiz-Sanchis, P.; Savina, S. A.; Al-
bericio, F.; Álvarez, M. Chem.−Eur. J. 2011, 17, 1388; (c) Schmidt,
M. A.; Movassaghi, M. Synlett 2008, 313.
[23] For related cyclization reactions, see: (a) Tréguier, B.; Roche, S. P.
Org. Lett. 2014, 16, 278; (b) Kumar, N. N. B.; Mukhina, O. A.; Ku-
tateladze, A. G. J. Am. Chem. Soc. 2013, 135, 9608; (c) Gahtory, D.;
Chouhan, M.; Sharma, R.; Nair, V. A. Org. Lett. 2013, 15, 3942; (d)
Xiao, J.; Loh, T. P. Tetrahedron Lett. 2008, 49, 7184; (e) Gon-
zalez-Vera, J. A.; Garcia-Lopez, M. T.; Herranz, R. Tetrahedron
2007, 63, 9229; (f) Gonzalez-Vera, J. A.; Garcia-Lopez, M. T.; Her-
ranz, R. J. Org. Chem. 2007, 72, 5395.
[24] (a) Murray, R. W. Chem. Rev. 1989, 89, 1187; (b) Adam, W.; Curci,
R.; Edward, J. O. Acc. Chem. Res. 1989, 22, 205; (c) Adam, W.;
Hadjiarapoglou, L. Top. Curr. Chem. 1993, 164, 45.
[25] Marfey, P. Carlsberg Res. Commun. 1984, 49, 591.
[26] Lattanzi, A.; Senatore, A.; Massa, A.; Scettri, A. J. Org. Chem. 2003,
68, 3691.
[27] (a) Zhang, W.; Loebach, J.; Wilson, S. R.; Jacobsen, E. N. J. Am.
Chem. Soc. 1990, 112, 2801; (b) Lee, N. H.; Muci, A. R.; Jacobsen,
E. N. Tetrahedron Lett. 1991, 32, 5055.
[28] Adam, W.; Fell, R. T.; Levai, A.; Patonay, T.; Simon, A.
Tetrahedron: Asymmetry 1998, 9, 1121.
[16] Priego, J.; Flores, P.; Claudia, O. N.; Escalante, J. Tetrahedron:
Asymmetry 2004, 15, 3545.
[17] Burn, N. Z.; Hoffmann, P. S.; Baran, R. W. Angew. Chem., Int. Ed.
Engl. 2009, 48, 2854.
[18] (a) Shi, D. Q.; Rong, L. C.; Wang, J. X.; Zhuang, Q. Y.; Wang, X. S.;
Hu, H. W. Tetrahedron Lett. 2004, 45, 3199; (b) Shi, D. Q.; Wang,
X. S.; Tu, S. J.; Hu, H. W. Chin. J. Struct. Chem. 2003, 22, 581; (c)
Shi, D. Q.; Wang, J. X.; Rong, L. C.; Zhuang, Q. Y.; Hu, H. W.
Chem. J. Chin. Univ. 2004, 25, 462.
[19] (a) McMurry, J. E. Acc. Chem. Res. 1974, 7, 281; (b) Wong, H. N. C.
Acc. Chem. Res. 1989, 22, 145; (c) McMurry, J. E. Chem. Rev. 1989,
89, 1513.
[20] (a) Kamenecka, T. M.; Danishefsky, S. J. Angew. Chem., Int. Ed.
1998, 37, 2993; (b) Kamenecka, T. M.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 1998, 37, 2995; (c) Schkeryantz, J. M.; Woo, J. C.
G.; Siliphaivanh, P.; Depew, K. M.; Danishefsky, S. J. J. Am. Chem.
Soc. 1999, 121, 11964; (d) Kamenecka, T. M.; Danishefsky, S. J.
Chem.−Eur. J. 2001, 7, 41; (e) Snider, B. B.; Zeng, H. B. Org. Lett.
2002, 4, 1087; (f) Galli, R.; Dobler, M.; Güller, R.; Stahl, R.;
Borschberg, H. J. Helv. Chim. Acta 2002, 85, 3400; (g) Éles, J.;
Kalaus, G.; Greiner, I.; Mária, K. P.; Szabó, P.; Keserû, G. M.;
Szabó, L.; Szántay, C. J. Org. Chem. 2002, 67, 7255; (h) Kim, Y. A.;
Han, S. Y. Synth. Commun. 2004, 34, 2931; (i) Schwaebisch, D.;
Tchabanenko, K.; Adlington, R. M.; Cowley, A. M.; Baldwin, J. E.
Chem. Commun. 2004, 2552; (j) Didier, C.; Critcher, D. J.; Walshe,
N. D.; Kojima, Y.; Yamauchi, Y.; Barrett, A. G. M. J. Org. Chem.
2004, 69, 7875; (k) May, J. P.; Fournier, P.; Pellicelli, J.; Patrick, B.
O.; Perrin, D. M. J. Org. Chem. 2005, 70, 8424; (l) May, J. P.; Pat-
rick, B. O.; Perrin, D. M. Synlett 2006, 3403; (m) Rege, P. D.; Tian,
Y.; Corey, E. J. Org. Lett. 2006, 8, 3117.
[29] Shi, Y. Acc. Chem. Res. 2004, 37, 488.
[30] For a review on the biosynthetic oxidative cascade strategy, see:
Dorrestein, P.; Begley, T. P. Bioorg. Chem. 2005, 33, 136.
(Pan, B.)
770
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Chin. J. Chem. 2014, 32, 757—770