Biomimetic synthesis of (-)-chaetominine epimers via copper-catalyzed radical cyclization

Article abstract of DOI:10.1016/j.tet.2014.09.029

Synthetic endeavors toward (-)-chaetominine via copper-catalyzed radical cyclization are reported. Both of the pyrido[2,3,b]-indole ring (C ring) and imidazolidinone (D ring) are efficiently constructed in one-pot manner. It's unveiled that the newly form

Full text of DOI:10.1016/j.tet.2014.09.029

Tetrahedron xxx (2014) 1e6
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Tetrahedron
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Biomimetic synthesis of (ꢀ)-chaetominine epimers via
copper-catalyzed radical cyclization
,
,
,
,b
Xu Deng a, Kangjiang Liang a b, Xiaogang Tong a b, Ming Ding a b, Dashan Li a
,
,
Chengfeng Xia a
*
a State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming
650201, Yunnan, China
b University of Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 July 2014
Received in revised form 4 September 2014
Accepted 9 September 2014
Available online xxx
Synthetic endeavors toward (ꢀ)-chaetominine via copper-catalyzed radical cyclization are reported. Both
of the pyrido[2,3,b]-indole ring (C ring) and imidazolidinone (D ring) are efficiently constructed in one-
pot manner. It’s unveiled that the newly formed stereo center is controlled by the chiral of alanine, not by
tryptophan. With these synthetic discoveries, highly efficient and diastereoselective synthesis of
(þ)-2,3,14-epi-chaetominine 5 and (ꢀ)-11-epi-chaetominine 11 is achieved.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Indole alkaloids
(ꢀ)-Chaetominine
Total synthesis
Copper-catalyzed
Cyclization
1. Introduction
core along with four stereogenic centers, and the unique quinazo-
linone moiety. (ꢀ)-Chaetominine (1) has been shown potent cy-
Endophytic fungi represent one of the most productive sources
of secondary metabolites with novel architectures and/or broad
biological profiles.1 (ꢀ)-Chaetominine (1) (Fig. 1) was isolated from
the solid culture of an endophytic fungus, Chaetomium sp. IFB-E015,
and found on apparently healthy Adenophora axilliflora leaves.2 Its
structure was fully characterized by spectroscopic analysis and
single crystal X-ray diffraction analysis. The absolute stereochem-
istry was assigned by Marfey’s analysis. The intriguing structural
features of (ꢀ)-chaetominine (1) include the strained tetracyclic
totoxicity against human leukemia K562 (21 nM) and colon cancer
SW1116 (28 nM) cell lines.2 However, Papeo’s assays revealed that
their synthetic (ꢀ)-chaetominine exhibited negligible inhibitory
activities on several cancer cell lines.3
Given the unprecedented architecture and potential biological
profiles, numerous synthetic efforts have been directed to the total
synthesis of (ꢀ)-chaetominine (1).3e9,11 Soon after its isolation,
Snider and co-workers reported the first synthesis of (ꢀ)-chaeto-
minine (1) with the Buchwald palladium-catalyzed cyclization as
the key step.4 Later, Evano described the first generation synthesis
of (ꢀ)-chaetominine (1) through copper-mediated cyclization to
install the ABC tricyclic core,5,6 and the second-generation synthesis
via an oxidative NCS-mediated cyclization.7 Meanwhile, Papeo also
reported a unique NCS-mediated N-acyl cyclization to construct
ABC ring system.3 Recently, Huang and co-workers disclosed the
most efficient route with DMDO-mediated cyclization as the key
transformation.8e10 Moreover, Roche reported a fluorine-mediated
cascade annulation of preactivated tryptophan dipeptide to con-
struct tetracyclic a
-carboline architectures.11 As part of our ongoing
Fig. 1. Structure of (ꢀ)-chaetominine (1).
efforts toward the rapid synthesis of pyrroloindoline alkaloids, we
recently reported a method involving copper-catalyzed radical cy-
clization to access 3-hydroxypyrroloindoline skeleton.12 This report
details the synthetic endeavors toward (ꢀ)-chaetominine via
* Corresponding author. Tel./fax: þ86 871 6522 3354; e-mail address: xia-
chengfeng@mail.kib.ac.cn (C. Xia).
http://dx.doi.org/10.1016/j.tet.2014.09.029
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.
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2
X. Deng et al. / Tetrahedron xxx (2014) 1e6
copper-catalyzed radical cyclization and the rapid access to
(þ)-2,3,14-epi-chaetominine 5 and (ꢀ)-11-epi-chaetominine 11.
heated with isatoic anhydride in the presence of Et3N, followed by
treatment with triethyl orthoformate in the presence of the cata-
lytic TsOH to furnish the desired tryptophan-quinazolinone 3 in
good overall yield.3,5,26 Subsequently, hydrolysis of compound 3
2. Results and discussion
followed by the coupling with L-alanine methyl ester using EDCI as
the activation agent produced the tripeptide 2 in excellent yield.
However, partial racemization of the quinazolinone-bearing stereo
center was detected by 1H NMR analysis (14%), possibly due to the
LiOH-mediated hydrolysis of the methyl ester 3, giving an in-
separable mixture, which was used without further purifications.
This was also observed by Papeo during the hydrolysis.3
With the tripeptide 2 in hand, we then turned to investigate the
key copper-catalyzed radical cyclization. A base screen revealed
that Et3N was not competent, and NaH was capable to access the C
ring but with only partial conversion. Upon considerable experi-
ments, we were pleased to find that DBU was the optimal choice
(Scheme 2). The double cyclization occurred smoothly and afforded
product 4 in excellent diastereoselectivity.12 At this stage, it’s dif-
2.1. Retrosynthetic analysis
Biosynthetically, (ꢀ)-chaetominine (1) is speculated to originate
from D-tryptophan, L-alanine, and anthranilic acid via oxidative cy-
clization of the tripeptide precursor (Scheme 1).2,13e15 Inspired by
the biosynthetic pathway and in combination with our well-
developed copper-catalyzed radical cyclization,12 we envisaged
a biomimetic strategy of (ꢀ)-chaetominine (1) as illustrated in
Scheme 1. The key feature involves the expeditious copper-catalyzed
radical cyclization to form tetrahydro-1H-pyrido[2,3,b]-indole moi-
ety. The tripeptide 2 would be prepared by the coupling of
with the intermediate 3, which could be obtained by acylation of
-tryptophanwithisatoicanhydride and incorporationof a C-1 unit.4
L-alanine
D
Scheme 1. Key step of plausible biosynthetic pathways and our retrosynthetic analysis of (ꢀ)-chaetominine 1.
As the abundant occurrence of C3-hydroxylpyrroloindoline
ficult to establish the configuration of the newly formed stereo-
centers. Further reductive removal of the 2,2,6,6-tetramethyl-
piperidinyl (TMP) moiety gave the product 5 in excellent yield,
which was assigned to be (þ)-2,3,14-epi-chaetominine by full
matching the data with the reported.8,9 This indicated that the
quinazolinone-bearing stereocenter epimerized during the oxida-
tive cyclization reaction, which has also been observed by Huang.8,9
It was also observed that the C2eH and C3eOH were in the cis-
position with the C11 methyl group of alanine.
There are two possible pathways for the diastereo outcome
during the double cyclization (Scheme 3). In pathway A, the tri-
peptide 2 partially epimerizes at C14 in the presence of base to
provide its epimer 6. Subsequently, compound 6 undergoes ther-
modynamically favored endo cyclization to form (þ)-2,3,14-epi-
chaetominine 5, which drives equilibrium from 2 to 6. Alternatively,
in pathway B, the tripeptide 2 proceeds kinetically exo cyclization
first, giving 2,3-epi-chaetominine 7. Then compound 7 was depro-
tonated followed by thermodynamically favored endo protonation
to afford (þ)-2,3,14-epi-chaetominine 5.
alkaloids in nature,16 plenty of efficient methods are available in
our toolbox, including iodine(III)-mediated intramolecular annu-
lation,17,18 selenocyclization/oxidative deselenation sequence,19,20
Danishefsky’s DMDO oxidation,21 and photosensitized oxygen-
ation.22e24 Whereas, the direct method leading to the fused tetra-
hydro-1H-pyrido[2,3,b]-indole ring system remains scarce.8,9 We
presumed that there are two main challenges during the total
synthesis of (ꢀ)chaetominine (1): (1) whether the copper-
catalyzed radical cyclization could access tetrahydro-1H-pyrido
[2,3,b]-indole core, which has not been testified previously; (2)
whether the diastereoselectivity would be correct and sufficiently
high as expected. Thus it is worthwhile to engage in this adventure.
2.2. Synthesis of (D)-2,3,14-epi-chaetominine
Our first synthetic route to (ꢀ)-chaetominine (1) commenced
with the installation of the exocyclic quinazolinone moiety
(Scheme 2).3,8,25 In this event,
D-tryptophan methyl ester was
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X. Deng et al. / Tetrahedron xxx (2014) 1e6
3
Scheme 2. TEMPO-mediated double cyclization to access (þ)-2,3,14-epi-chaetominine.
Scheme 3. Possible mechanism for the diastereo outcome of the double cyclization.
To investigate whether the substrate epimerized completely
before the cyclization, we performed a control experiment. The
tripeptide 2 was stirred with DBU under argon at room tempera-
ture, followed by analysis of the isolated tripeptide with 1H NMR. It
was revealed that tripeptide 2 epimerized in a time dependent
manner (the epimerization ratio was 20% after 1.0 h and 32% after
12 h, respectively). It is likely that there is equilibration between
two diastereoisomers (Scheme 3).
L-tryptophan methyl ester according to the above-mentioned route.
Interestingly, compound 6 was not epimerized even by treating
with DBU for several days.
When the tripeptide 6 was subjected to the cyclization condi-
tion, the same product 4 was obtained (Scheme 4), which indicated
that the cyclization favors antiecis product. No epimerization was
detected during this process. We reasoned that the C11 methyl
group plays a critical role in the epimerization of C14 stereocenter,
whereas the C14 quinazolinone moiety is not the dominant con-
trolling factor in cyclization.
To determine the cyclization favors the antiecis product or the
synecis product, we prepared the 14-epi-tripeptide 6 starting from
Scheme 4. TEMPO-mediated double cyclization to access compound 4.
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X. Deng et al. / Tetrahedron xxx (2014) 1e6
The isomerization of C14 might be due to the existence of bulky
alanine. Both of the C ring and D ring were formed in one-pot
procedures. With this method, two of the (ꢀ)-chaetominine epi-
mers 5 and 11 were efficiently generated. This is the first example of
copper-catalyzed radical cyclization to rapid access tetrahydro-1H-
pyrido[2,3,b]-indole skeleton.
TMP group. In our previous report, we also noticed that different
radical trapping reagents gave different stereoselectivities.12 We
proposed that switch the trapping reagent from TEMPO to dioxy-
gen might enable the desired configuration. To test this hypothesis,
a dioxygen-mediated oxidative cyclization reaction was conducted
using dipeptide 2 as the substrate. However, only the same
(þ)-2,3,14-epimer 5 was isolated (Scheme 5). The high diaster-
eoselectivity control of the cyclization is probably due to the chiral
center forming event takes places during the amide addition and is
nearby the chiral quinazolinone moiety. This is different from the
previous reports that the chiral center forming at the dearomative
step is far from the chiral quinazolinone moiety.8,9,11
4. Experimental section
4.1. General information
All reactions were performed under argon atmosphere using
oven-dried glassware unless otherwise stated. Acetonitrile (CH3CN),
dichloromethane (CH2Cl2), and N,N-dimethylformamide (DMF)
weredistilled overCaH2 underN2. Tolueneandtetrahydrofuranwere
distilled over sodium benzophenone under N2. All reagents were
commercially available and used without further purification unless
otherwise indicated. Thin layer chromatographies were carried out
on GF254 plates (0.25 mm layer thickness). Flash chromatography
was performed with 300e400 mesh silica gels. Visualization of the
developed chromatogram was performed by fluorescence quench-
ing or by ceric ammonium molybdate, or KMnO4 stain. Yields re-
ported were for isolated, spectroscopically pure compounds. Zinc
powder was activated by washing sequentially with 3 M HCl, water,
acetone, and ether and dried under reduced pressure.
Scheme 5. O2-Mediated double cyclization to access (þ)-2,3,14-epi-chaetominine.
2.3. Synthesis of (L)-11-epi-chaetominine
1H and 13C NMR experiments were performed on a Bruker AM-
400 and DRX-600 NMR spectrometers at ambient temperature. The
residual solvent protons (1H) or the solvent carbons (13C) were used
as internal standards. 1H NMR data are presented as follows:
chemical shift in parts per million (ppm) downfield from tetra-
methylsilane (multiplicity, coupling constant, integration). The
following abbreviations are used in reporting NMR data: s, singlet;
br s, broad singlet; d, doublet; t, triplet; q, quartet; qt, quartet of
triplets; dd, doublet of doublets; dt, doublet of triplets; AB, AB
quartet; m, multiplet. Mass spectra (MS) and high-resolution mass
spectra (HRMS) were taken on API STAR Pulsar.
On basis of the above experimental results, we noticed that the
C2eH and C3eOH were in the cis-position with the C11 methyl
group, while the C14 quinazolinone in the anti-position of C11. We
postulated that if a D-alanine instead of L-alanine was incorporated
into the tripeptide, all of the C2, C3, C14 chiral configurations would
be same as (ꢀ)-chaetominine (1) after copper-catalyzed cyclization.
Then isomerization of the C11 methyl group with base would afford
(ꢀ)-chaetominine (1). Thus we prepared the C11(R),C14(S) sub-
strate 9 using L-tryptophan methyl ester and D-alanine methyl ester
as the starting material. Subsequently, applying the substrate 9 to
the standard cyclization reaction condition produced product 10
with the requisite stereochemistry at C2,C3,C14 as expected. Re-
ductive removal of TMP moiety delivered (ꢀ)-11-epi-chaetominine
11 in good yield, which is characterized as an enantiomer of
(þ)-2,3,14-epi-chaetominine 5 by full match of spectra data to that
of the previous report.9 Subsequently, extensive efforts have been
directed to epimerize the C11 stereocenter, such as deprotonation
of H11 by LHMDS followed by trapping with t-BuOH, whereas no
desired isomerization occurred (Scheme 6).
4.2. R-3-(1H-Indol-3-yl)-2-(4-oxo-4H-quinazolin-3-yl)-pro-
pionic acid methyl ester (3)
To a solution of
D-tryptophan methyl ester hydrochloride
(1020 mg, 5.0 mmol) in dry toluene (100 mL) were added isatoic
anhydride (1222 mg, 7.5 mmol) and Et3N (5050 mg, 50 mmol)
successively. The resulting suspension was heated to 90 ꢁC for 24 h.
Then the solvent was removed under reduced pressure. The crude
Scheme 6. TEMPO-mediated double cyclization to access (ꢀ)-11-epi-chaetominine 11.
3. Conclusion
residue was purified by flash chromatography over silica gel
(dichloromethane/methanol¼30:1) to give the product as a yellow
solid (1240 mg, 79%).
The crude product (674 mg, 2.0 mmol) was dissolved in AcOEt
(20 mL) under argon. Then p-TsOH (69 mg, 0.4 mmol) and triethyl
In summary, copper-catalyzed cyclization was utilized for the
biomimetic synthesis of (ꢀ)-chaetominine epimers. It is discovered
that the newly formed stereo center is controlled by the chiral of
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X. Deng et al. / Tetrahedron xxx (2014) 1e6
5
orthoformate (1480 mg, 10.0 mmol) were added to the mixture
successively. The resulting mixture was heated to 50 ꢁC overnight.
The mixture was quenched with triethyl amine and then washed
with water (50 mLꢂ2), dried over Na2SO4, filtered and then con-
centrated in vacuo. The resulting crude product was purified by
flash chromatography (petrol ether/ethyl acetate¼3:1) to give
compound 3 (617 mg, 89%) as yellow solid. 1H NMR (400 MHz,
1H), 3.73 (d, J¼7.5 Hz, 1H), 3.69 (s, 3H), 3.49e3.41 (m, 1H), 1.33 (d,
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 172.9, 169.0, 161.1, 146.9,
144.9, 136.3, 134.6, 127.2, 126.8, 126.6, 123.5, 121.8, 121.1, 119.2, 117.9,
111.3, 108.4, 56.0, 52.2, 48.9, 27.4, 17.1; ESIMS (m/z): 419 [MþH]þ.
4.6. (2S,4S,5aR,9cR)-4,5,5a,9c-Tetrahydro-2-methyl-4-(4-oxo-
3(4H)-quinazolinyl)-5a-[(2,2,6,6-tetramethyl-1-piperidinyl)
oxy]-3H-2a,9b-diazacyclopenta[jk]fluorene-1,3(2H)-dione (4)
CDCl3)
d
10.87 (s, 1H), 8.58 (d, J¼8.3 Hz, 1H), 8.38 (d, J¼1.6 Hz, 1H),
8.32 (s, 1H), 7.54 (d, J¼7.8 Hz, 1H), 7.42 (dd, J¼11.5, 4.1 Hz, 1H), 7.35
(d, J¼8.1 Hz, 1H), 7.29 (d, J¼8.1 Hz, 1H), 7.19 (t, J¼7.4 Hz, 1H), 7.09 (t,
J¼7.3 Hz, 1H), 7.02e6.97 (m, 2H), 6.81 (d, J¼7.3 Hz, 1H), 5.06 (dd,
J¼12.9, 5.5 Hz, 1H), 3.76 (s, 3H), 3.44 (qd, J¼14.8, 5.5 Hz, 2H); 13C
To a solution of compound 2 (104 mg, 0.25 mmol) in CH3CN
(2.5 mL) under argon was added DBU (114 mg 0.75 mmol). The
mixture was stirred at room temperature for 0.5 h. Then TEMPO
(117 mg, 0.75 mmol) and CuCl2 (3.5 mg, 0.025 mmol) were added to
the mixture successively. The resulting suspension was stirred at
room temperature for 24 h until no starting material was detected
by TLC. The reaction was quenched with HCl solution (2 N). The
aqueous phase was extracted with EtOAc (25 mLꢂ3). The combined
organic layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated. The crude product was subjected to flash
NMR (100 MHz, CDCl3)
d 172.1, 168.3, 159.6, 138.4, 136.2, 132.8,
127.4,126.9,123.4,123.0,122.4,122.0,119.9,119.8,118.4,111.5,109.5,
53.5, 52.6, 27.5; ESIMS (m/z): 370 [MþNa]þ.
4.3. S-3-(1H-Indol-3-yl)-2-(4-oxo-4H-quinazolin-3-yl)-pro-
pionic acid methyl ester (8)
The protocol for preparation of compound 8 follows that of
chromatography on silica gel to afford compound 4 (petrol ether/
25
compound 3 by using
L-tryptophan methyl ester hydrochloride as
acetone¼6:1, 108 mg, 0.20 mmol, 80% yield). [
a
]
þ65.8 (c 0.27,
D
thesubstrate instead. Theoptimizedyieldforcompound 8is76%. The
spectral data for compound 8 are the same to that of compound 3.
CHCl3); 1H NMR (600 MHz, CDCl3)
d
8.34 (d, J¼7.8 Hz, 1H), 7.84 (s,
1H), 7.80e7.76 (m, 1H), 7.72 (d, J¼8.0 Hz, 1H), 7.60 (d, J¼8.0 Hz, 1H),
7.52 (dd, J¼13.0, 7.3 Hz, 2H), 7.38 (t, J¼7.8 Hz, 1H), 7.15 (t, J¼7.6 Hz,
1H), 6.12 (s, 1H), 4.86 (q, J¼7.2 Hz, 1H), 3.15 (dd, J¼13.6, 2.5 Hz, 1H),
1.65 (d, J¼7.2 Hz, 3H), 1.63e1.56 (m, 3H), 1.54 (m, 2H), 1.42 (d,
4.4. (S)-2-[(R)-3-(1H-Indol-3-yl)-2-(4-oxo-4H-quinazolin-3-
yl)-proprionylamino]propionic acid methyl ester (2)
J¼13.1 Hz, 1H), 1.31 (s, 3H), 1.25 (s, 3H), 1.23 (s, 3H), 1.16 (s, 3H); 13
C
To a solution of compound 3 (155 mg, 0.447 mmol) dissolved in
THF (4 mL) was added an aqueous solution of LiOH (2 N, 0.224 mL)
dropwise. The mixture was stirred at room temperature for 2 h
until the reaction was deemed complete by TLC. The mixture was
neutralized by 1 N HCl aqueous solution and was extracted with
EtOAc (20 mLꢂ3). The combined the organic layers were washed
with saturated NaHCO3, and brine, followed by drying over Na2SO4.
Filtration and concentration in vacuo yielded the crude product,
which was used for the next step without further purifications.
The crude product (149 mg, 0.447 mmol) was dissolved in dry
DMF (4 mL) at 0 ꢁC. HOBT (102 mg, 0.67 mmol), DIPEA (213 mg,
NMR (150 MHz, CDCl3) d 171.5,160.6,147.4,144.8,139.8,134.5,133.4,
130.4, 128.4, 127.5, 127.3, 127.1, 124.7, 121.7, 115.0, 86.4, 82.5, 61.1,
59.9, 59.4, 40.9, 40.4, 35.6, 33.4, 29.6, 21.2, 21.2, 16.9, 15.3; HRESIMS
(m/z): calcd for C31H35N5O4Na [MþNa]þ, 564.2587, found 564.2588.
4.7. (2R,4R,5aS,9cS)-4,5,5a,9c-Tetrahydro-2-methyl-4-(4-oxo-
3(4H)-quinazolinyl)-5a-[(2,2,6,6-tetramethyl-1-piperidinyl)
oxy]-3H-2a,9b-diazacyclopenta[jk]fluorene-1,3(2H)-dione (10)
The protocol for preparation of compound 10 follows that of
compound 4 by using compound 6 as the substrate instead. The
1.34 mmol), and
L-alanine (74 mg, 0.53 mmol) were subsequently
optimized yield for compound 10 is 68%. [
a
]
25 ꢀ99.4 (c 0.69, CHCl3);
D
added under argon atmosphere. EDC-HCl (128 mg, 0.67 mmol) was
then added. After 24 h until no starting material was detected by TLC,
the reaction mixture was poured into water and extracted with DCM
(15 mLꢂ3). The combined the organic layers were washed with
saturated NaHCO3, brine, and dried over Na2SO4, followed by filtra-
tion and concentration in vacuo to give the crude material, which
was subjected to chromatography to afford compound 2 as white
solid (petrol ether/acetone¼3:1, 173 mg, 93% yield). 1H NMR
1H NMR (600 MHz, CDCl3)
d
8.30 (d, J¼7.9 Hz, 1H), 7.84 (s, 1H), 7.76
(t, J¼7.6 Hz, 1H), 7.68 (d, J¼8.1 Hz, 1H), 7.56 (d, J¼8.0 Hz, 1H), 7.50 (t,
J¼7.4 Hz, 2H), 7.35 (t, J¼7.8 Hz,1H), 7.13 (t, J¼7.6 Hz,1H), 6.10 (s, 1H),
4.81 (q, J¼7.1 Hz, 1H), 4.09 (q, J¼7.1 Hz, 1H), 1.62 (d, J¼7.2 Hz, 3H),
1.52e1.57 (m, 2H), 1.40 (d, J¼13.1 Hz, 1H), 1.29 (s, 3H), 1.24 (d,
J¼7.2 Hz, 2H), 1.20 (s, 3H), 1.12 (s, 3H), 0.46 (s, 3H); 13C NMR
(150 MHz, CDCl3) d 171.6,165.6,147.2,147.1,139.7,134.7,133.5,130.4,
128.3, 127.5, 127.3, 127.1, 124.7, 115.0, 86.3, 82.4, 61.1, 60.4, 59.9, 59.5,
40.9, 40.4, 35.6, 33.4, 21.2, 21.1, 20.9, 16.9, 15.2, 14.1; HREIMS (m/z):
calcd for C31H35N5O4 [M]þ, 541.2689, found 541.2691.
(400 MHz, CDCl3)
d
8.39 (s, 1H), 8.30 (s, 1H), 8.16 (dd, J¼8.0, 1.0 Hz,
1H), 7.70e7.60 (m, 3H), 7.43e7.37 (m, 1H), 7.29 (d, J¼8.1 Hz, 1H),
7.18e7.11 (m, 1H), 7.06 (dd, J¼10.9, 3.9 Hz, 2H), 7.00 (d, J¼2.3 Hz, 1H),
5.87 (dd, J¼8.4, 7.2 Hz, 1H), 4.47 (t, J¼7.2 Hz, 1H), 3.72 (dd, J¼14.5,
8.7 Hz,1H), 3.58 (s, 3H), 3.40 (dd, J¼14.6, 6.9 Hz,1H),1.20 (d, J¼7.2 Hz,
4.8. (D)-2,3,14-epi-Chaetominine (5)
3H); 13C NMR (100 MHz, CDCl3)
d
172.6, 168.4, 161.1, 147.4, 144.3,
To a solution of compound 4 (68 mg, 0.125 mmol) in THF
(2.5 mL) under argon were added activated zinc dust (65 mg,
1.0 mmol) and HOAc (60 mg, 1.0 mmol) successively. The mixture
was heated to 50 ꢁC. When the reaction was complete as indicated
by TLC, the mixture was quenched with saturated NaHCO3 aqueous
solution. The aqueous phase was extracted with DCM (15 mLꢂ3).
The combined organic phase was washed with brine, dried over
anhydrous Na2SO4, and concentrated. The crude product was sub-
jected to flash chromatography on silica gel to afford 2,3,14-tri-epi-
chaetominine 5 (petrol ether/acetone¼3:1, 45 mg, 0.112 mmol, 90%
136.1, 134.5, 127.4, 127.2, 126.9, 126.8, 123.3, 122.3, 121.3, 119.8, 118.4,
111.3, 109.6, 56.3, 52.4, 48.4, 27.2, 17.5; ESIMS (m/z): 419 [MþH]þ.
4.5. (S)-2-[(S)-3-(1H-Indol-3-yl)-2-(4-oxo-4H-quinazolin-3-
yl)-proprionylamino]propionic acid methyl ester (6)
The protocol for preparation of compound 6 follows that of
compound 2 by using compound 8 as the substrate instead. The
optimized yield for compound 6 is 86%. 1H NMR (400 MHz, CDCl3)
d
9.34 (s, 1H), 8.44 (s, 1H), 8.20 (d, J¼7.9 Hz, 1H), 7.84 (d, J¼6.9 Hz,
yield). [
a
]
25 þ55.2 (c 1.08, CHCl3) {lit. [
a
]
20 þ98.0 (c 0.5, MeOH)8,9};
D
D
1H), 7.74 (t, J¼7.6 Hz, 1H), 7.66 (d, J¼8.1 Hz, 1H), 7.61 (d, J¼7.9 Hz,
1H), 7.47 (t, J¼7.5 Hz, 1H), 7.32 (d, J¼12.8 Hz, 1H), 7.12 (t, J¼7.5 Hz,
1H), 7.03 (d, J¼8.8 Hz, 2H), 5.89 (t, J¼7.8 Hz, 1H), 4.47 (p, J¼7.0 Hz,
1H NMR (600 MHz, DMSO-d6)
d
8.22 (s, 1H), 8.19 (d, J¼7.2 Hz, 1H),
7.89e7.83 (m, 1H), 7.69 (d, J¼8.0 Hz, 1H), 7.60e7.54 (m, 1H),
7.48e7.44 (m, 2H), 7.42e7.38 (m, 1H), 7.23 (td, J¼7.5, 0.9 Hz, 1H),
Please cite this article in press as: Deng, X.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.029

6
X. Deng et al. / Tetrahedron xxx (2014) 1e6
6.76 (s, 1H), 5.90 (d, J¼11.2 Hz, 1H), 5.84 (s, 1H), 4.63 (q, J¼7.2 Hz,
1H), 3.43 (ddd, J¼14.0, 7.0, 5.1 Hz, 1H), 2.91 (t, J¼13.0 Hz, 1H), 2.46
(d, J¼3.3 Hz, 1H), 1.48 (d, J¼7.3 Hz, 3H); 13C NMR (150 MHz, DMSO-
Technology Professionals Introduction Program (2010CI117), the
West Doctor Foundation of Chinese Academy of Sciences
(292014312D11016), and National Basic Research Program of China
(2011CB915500).
d6)
d 170.9, 166.2, 159.9, 147.3, 146.7, 137.7, 137.5, 134.7, 129.7, 127.3,
127.2, 126.4, 125.5, 124.6, 121.0, 114.5, 82.9, 82.5, 76.6, 59.7, 56.0,
38.3, 18.5, 15.1; HRESIMS (m/z): calcd for C22H18N4O4Na [MþNa]þ,
425.1226, found 425.1222.
Supplementary data
Copies of 1H and 13C NMR spectra associated with this article.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.09.029.
4.9. Alternative synthesis of (D)-2,3,14-epi-chaetominine (5)
To a solution of compound 2 (42 mg) in CH3CN (1.0 mL) under
argon was added DBU (76 mg) dropwise. The mixture was stirred at
room temperature for 15 min. Then the atmosphere was replaced
with O2. And CuCl2 (2 mg) was added to the mixture in one portion.
The resulting mixture was stirred at room temperature. When the
reaction was complete as indicated by TLC, the mixture was
quenched with HCl solution (2 M). The aqueous phase was
extracted with EtOAc (15 mLꢂ3). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, and concen-
trated. The crude product was subjected to flash chromatography
on silica gel to afford 2,3,14-tri-epi-chaetominine (5) (petrol ether/
acetone¼3:1, 25 mg, 62% yield).
References and notes
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25
20
nine 11 is 94%. [
a
]
ꢀ33.6 (c 0.57, CHCl3); {lit. [
a
]
ꢀ98.0 (c 0.5,
D
D
MeOH)8}; 1H NMR (600 MHz, DMSO-d6)
d
8.33 (s, 1H), 8.23 (s, 1H),
ꢀ
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(dd, J¼11.6, 4.4 Hz, 1H), 7.48 (d, J¼8.6 Hz, 2H), 7.42 (d, J¼7.8 Hz, 1H),
7.25 (td, J¼7.5, 0.9 Hz, 1H), 6.79 (s, 1H), 5.86 (s, 1H), 4.64 (q, J¼7.2 Hz,
1H), 2.93 (t, J¼13.0 Hz,1H),1.49 (d, J¼7.3 Hz, 3H); 13C NMR (150 MHz,
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DMSO-d6)
d 171.3, 166.6, 160.4, 147.7, 147.1, 138.1, 138.0, 135.2, 130.2,
127.7, 127.7,126.9,125.9,125.1,121.4,114.9, 83.3, 77.0, 60.1, 39.9,15.5;
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Acknowledgements
This work was financially supported by National Natural Science
Foundation of China (21272242 and 21302193), Yunnan High-End
Please cite this article in press as: Deng, X.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.029