Total synthesis of microtubule-stabilizing agent ceratamine A

Article abstract of DOI:10.1021/jo402165n

The total synthesis of ceratamine A, a natural microtubule-stabilizing agent with unusual cellular effects, has been accomplished starting from 5-methoxybenzimidazole in 10 steps in an overall yield of 12.7%. The key steps in the synthesis involved the Schmidt rearrangement to construct the azepine ring, the alkylation of lactam to introduce the C-5 benzylic side chain, and the highly economical S_NAr reaction to install the C-2 methylamine residue.

Full text of DOI:10.1021/jo402165n

Note
pubs.acs.org/joc
Total Synthesis of Microtubule-Stabilizing Agent Ceratamine A
Qiguo Feng, Lulu Tao, and Zhanzhu Liu*
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical
College and Chinese Academy of Medical Sciences, Beijing 100050, P. R. China
S
* Supporting Information
ABSTRACT: The total synthesis of ceratamine A, a natural microtubule-stabilizing
agent with unusual cellular effects, has been accomplished starting from 5-
methoxybenzimidazole in 10 steps in an overall yield of 12.7%. The key steps in the
synthesis involved the Schmidt rearrangement to construct the azepine ring, the
alkylation of lactam to introduce the C-5 benzylic side chain, and the highly
economical SNAr reaction to install the C-2 methylamine residue.
he first promoter of tubulin polymerization ever
discovered was paclitaxel, which arguably represents one
synthesis. Herein, we report the second total synthesis of
ceratamine A, which follows a different strategy.
T
of the major milestones in the history of cancer treatment after
its successful development into an effective anticancer drug.1
The taxanes such as paclitaxel and docetaxel are the most
successful class of anticancer drugs currently used in clinics.
Drug resistance and cross resistance with other chemo-
therapeutic agents are the major common drawbacks of these
drugs. Despite the appearance of many cancer-specific targets
over the past several decades, investigation of new tubulin
inhibitors still represents an important sphere of modern
anticancer drug discovery and development, especially for
multidrug resistance cancer cells.2 So far, a number of
structurally diversified natural products with microtubule-
stabilizing activity have been found, and the epothilone
derivative, ixabepilone, was successfully launched in 2007 for
the treatment of breast cancer.3
We envisioned that, for the synthetic route to be suitable for
the efficient synthesis of ceratamine A derivatives, introduction
of the 2-methylamino group and 5-benzylic side chain at a later
stage would be the best choice. The retrosynthetic analysis of
ceratamine A is shown in Scheme 1. Ceratamine A (1) could be
transformed from compound 12 via dehydrogenation. 2-
Methylaminoimidazole 12 could be accessed from C-2
functionalization of bromide compound 10 with methylamine.
Scheme 1. Retrosynthetic Analysis of Ceratamine A
Ceratamine A (1), originally isolated from marine sponge
Pseudoceratina sp. collected in Papua New Guinea, is an
antimitotic heterocyclic alkaloid with a novel imidazo[4,5-
d]azepine core.4 Structurally, ceratamine A has a novel but
simple chemical structure without chiral centers. Functionally,
mechanistic studies have shown that ceratamine A is a
microtubule-stabilizing agent, which has a tubulin-binding site
totally different from that of paclitaxel.5 While blocking the
cancer cell division cycle by promoting tubulin polymerization,
ceratamine A exhibits an unprecedented mitotic arrest
phenotype that is distinct from those of all the other tubulin-
stabilizing agents described to date. The unique mechanism of
action implies that ceratamine A may show a different spectrum
of toxicity and anticancer activity, particularly against multidrug
resistance cancers. Thus, ceratamine A is a promising anticancer
leading compound. One total synthesis by Coleman and one
synthetic study by Andersen have been reported.6 However,
investigations of systematic structural modification and SAR
have not been reported, because of the limitation of these
synthetic routes. The purpose of this paper is to report a
flexible approach to this natural product suitable for analogue
Received: October 8, 2013
Published: December 4, 2013
© 2013 American Chemical Society
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Note
Compound 10 could in turn be prepared through the α-
benzylation of the carbonyl group of lactam 8 and the ensuing
C-2 bromination. Lactam 8 could be constructed through the
pivotal Schmidt rearrangement of ketone 5. Compound 5 could
be prepared through several steps from 5-methoxybenzimida-
zole (2).
Scheme 3. Construction of the Imidazo[4,5-d]azepine
System
The entire synthesis started from the preparation of key
intermediate 4 and its regioisomer 4′ (Scheme 2), both of
which could be applied for the total synthesis of ceratamine A
by this synthetic approach.
Scheme 2. Synthesis of Key Intermediates 4 and 4′
Compounds 4 and 4′ were thus synthesized in satisfactory
yields through an efficient two-step transformation starting
from the commercially available 5-methoxybenzimidazole (2).
Birch-type reduction of methoxybenzimidazole 2 with lithium
in liquid ammonia yielded methyl enol ether 3 in a fairly good
yield.7 Treatment of 3 with sodium hydride and BOMCl in
DMF provided a mixture of compounds 4 and 4′ in a ratio of
1:1, which was successfully separated to give two pure
compounds. The structures of compounds 4 and 4′ were
identified by NOE correlations.
Acid-promoted hydrolysis of 4 (25 °C, 2 h) gave ketone 5 in
an almost quantitative yield (Scheme 3). Construction of the
azepine ring of lactam 6 is the key step in this synthetic route,
which was realized through the Schmidt rearrangement
reaction.8 First, treatment of 5 with sodium azide in TFA
afforded two isomeric mixtures of lactam 6 and undesired
lactam 7 in a ratio of 3:1 (determined by 1H NMR).
Fortunately, if ketone 5 was treated with 2 equiv of sodium
azide in phosphoric acid, products 6 and 7 were obtained in a
7:1 ratio. Methylation of the nitrogen of lactam 6 with sodium
hydride and iodomethane afforded 8 in an excellent yield. For
the benzylation of lactam 8, LHDMS and LDA were initially
investigated as the bases. However, the desired product 9 was
not observed either in THF or in a THF/DMPU (10:1)
cosolvent. We were pleased to find that deprotonation of N-
methyllactam 8 with n-BuLi in the presence of DMPU and 1,3-
dibromo-5-(iodomethyl)-2-methoxybenzene9 furnished benzy-
lated product 9 in 84% yield, which was subsequently
brominated at C-2 using NBS10 to give bromide compound
10 in 85% yield.
treatment of 10 with methylamine in a mixed solvent of
dioxane and THF with the addition of activated molecular
sieves in a sealed tube yielded the desired compound 12 as the
major product (Scheme 4).13
Then exposure of 12 to anhydrous AlCl3 in CH2Cl2 cleanly
yielded 2-aminoimidazole 13 in an almost quantitative yield.
Finally, oxidation of 13 with IBX afforded ceratamine A
according to the method developed by Coleman’s group.6c The
Scheme 4. Completion of the Total Synthesis of Ceratamine
A
Functionalization of C-2 of compound 10 with the
methylamine group proved to be unexpectedly complicated.
First, the copper(I)- and Pd-catalyzed methods developed for
the synthesis of the 2-aminoimidazole were tested.11,12
Unfortunately, both methods gave only the major byproduct
of phenol 11.13,14 Next, we returned to the SNAr reaction,
which was used in the transformation of 2-bromo-azoles into
diversified 2-aminoimidazoles, for the introduction of the C-2
methylamine group.15 However, treatment of 10 with aqueous
methylamine in a sealed tube also yielded undesired byproduct
11 (Scheme 3). After several conditions had been tested,
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The Journal of Organic Chemistry
Note
2H), 2.70 (t, J = 6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 206.8,
137.9, 136.7, 136.1, 128.8, 128.5, 128.0, 122.5, 73.5, 70.1, 39.5, 35.9,
22.9; HRMS (ESI) m/z calcd for C15H17N2O2 (M + H)+ 257.12845,
found 257.12848.
spectral data (1H and 13C NMR) of the synthetic compound 1
are identical with those reported for the natural ceratamine A.
In summary, we have accomplished an efficient synthesis of
ceratamine A starting from the readily available 5-methox-
ybenzimidazole in 10 steps in an overall yield of 12.7%. Our
synthetic approach features a highly effective Schmidt
rearrangement to form the azepine ring. Other key steps
include the successful isolation of the regioisomeric mixtures of
compound 4 and 4′, the benzylation of lactam 8 to introduce
the C-5 side chain, and a highly economical SNAr reaction to
install the C-2 methylamine group at an advanced stage that
would facilitate the structural modification of ceratamine A to a
great extent. Thus, this synthetic route is amenable to the
synthesis of structural variants of ceratamine A. The further
structural modification and biological studies of ceratamine A
are currently in progress and will be reported in due course.
Compound 6. To a solution of compound 5 (1.43 g, 5.58 mmol)
in THF (5 mL) and phosphoric acid (85% solution in water, 35 mL)
was added portionwise sodium azide (0.73 g, 11.23 mmol) over a
period of 1 h. The reaction mixture was stirred for 3 h at 60 °C and
carefully neutralized by the addition of ammonium hydroxide (28−
30% solution in water) under vigorous stirring and cooling with an
ice/water bath. The mixture was extracted with DCM (3 × 50 mL),
and the combined organic layers were washed with brine (50 mL),
dried over Na2SO4, and concentrated. The crude product was purified
by column chromatography to yield compound 6 (0.82 g, 2.99 mmol,
1
54%) as a foam: H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.38−
7.27 (m, 5H), 6.36 (t, J = 6.6 Hz, 1H), 5.39 (s, 2H), 4.51 (s, 2H), 3.72
(s, 2H), 3.56 (dt, J = 6.6, 5.0 Hz, 2H), 2.92 (t, J = 5.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 172.4, 136.6, 136.1, 135.6, 128.9, 128.6,
128.2, 119.5, 74.3, 70.7, 39.7, 31.2, 28.9; HRMS (ESI) m/z calcd for
C15H18N3O2 (M + H)+ 272.13935, found 272.13934.
EXPERIMENTAL SECTION
■
Compound 8. NaH (0.20 g, 60% in oil, 5.00 mmol) was added to
a solution of compound 6 (1.19 g, 4.39 mmol) in DMF (40 mL) at −5
°C. The resulting solution was stirred for 30 min at this temperature,
and iodomethane (0.33 mL, 5.27 mmol) was added dropwise. The
mixture was stirred at room temperature for 2 h. The reaction was
quenched by the addition of MeOH (5 mL) and H2O (30 mL) and
the mixture extracted with EtOAc (3 × 50 mL), and the combined
organic layers were washed with brine (50 mL), dried over Na2SO4,
and concentrated. The crude product was purified by column
chromatography to yield compound 8 (1.18 g, 4.14 mmol, 94%) as
Compound 3. A solution of compound 2 (3.4 g, 22.9 mmol) in
THF (30 mL) and MeOH (10 mL) was added dropwise to liquid
ammonia (200 mL) at −78 °C. The resulting solution was treated
portionwise with lithium (1.4 g, 201.7 mmol). The mixture was stirred
at −78 °C for 6 h and treated dropwise with MeOH. After evaporation
of the ammonia and removal of the MeOH and THF under reduced
pressure, the residue was treated with DCM (100 mL) and H2O (50
mL). The organic layer was separated and the aqueous phase extracted
with DCM (3 × 50 mL), and the combined organic layers were
washed with brine (50 mL), dried over Na2SO4, and concentrated.
The crude product was purified by column chromatography to yield
compound 3 (2.6 g, 17.3 mmol, 76%) as a brown solid: 1H NMR (400
MHz, CDCl3) δ 8.73 (br s, NH), 7.66 (s, 1H), 4.81 (br s, 1H), 3.61 (s,
3H), 3.35 (br s, 4H); 13C NMR (100 MHz, CDCl3) δ 153.4, 133.8,
127.2, 126.6, 90.9, 54.8, 27.3, 22.5; HRMS (ESI) m/z calcd for
C8H11N2O (M + H)+ 151.08659, found 151.08606.
1
a foam: H NMR (500 MHz, CDCl3) δ 7.43 (s, 1H), 7.37−7.28 (m,
5H), 5.25 (s, 2H), 4.44 (s, 2H), 3.73 (s, 2H), 3.68 (m, 2H), 3.05 (s,
3H), 2.87 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 170.7, 137.7,
137.0, 136.3, 128.8, 128.4, 128.1, 119.5, 73.3, 69.9, 48.3, 34.6, 31.9,
27.2; HRMS (ESI) m/z calcd for C16H20N3O2 (M + H)+ 286.15500,
found 286.15507.
Compound 9. To a stirred solution of compound 8 (0.88 g, 3.08
mmol) in THF (45 mL) and DMPU (3 mL) cooled to −78 °C was
added dropwise a solution of n-BuLi (2.5 M in hexane, 1.36 mL, 3.39
mmol) via syringe. The resulting solution was stirred at −78 °C for
100 min. A solution of 1,3-dibromo-5-(iodomethyl)-2-methoxyben-
zene (1.50 g, 3.70 mmol) in THF (10 mL) was added dropwise via
syringe. The reaction mixture was warmed to −18 °C and stirred at
this temperature for 3 h, 0 °C for 2 h, room temperature for 2 h, and
70 °C for 2 h, diluted with DCM (400 mL), washed with H2O (3 ×
200 mL), dried over Na2SO4, and concentrated. The crude product
was purified by column chromatography to afford compound 9 (1.46
g, 2.59 mmol, 84%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ
7.51 (s, 1H), 7.39−7.29 (m, 5H), 7.25 (s, 2H), 5.16 (d, J = 11.2 Hz,
1H), 4.81 (d, J = 11.2 Hz, 1H), 4.47 (d, J = 12.1 Hz, 1H), 4.43 (d, J =
12.1 Hz, 1H), 4.17 (ddd, J = 15.0, 12.7, 1.9 Hz, 1H), 4.08 (m, 1H),
3.85 (s, 3H), 3.48 (dt, J = 15.0, 3.0 Hz, 1H), 3.12 (m, 2H), 3.09 (s,
3H), 2.99 (ddd, J = 16.2, 12.7, 3.0 Hz, 1H), 2.89 (d, J = 16.2 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 170.7, 153.2, 138.8, 137.9, 137.0,
135.9, 133.2, 128.9, 128.6, 128.1, 123.1, 118.2, 73.3, 70.0, 60.8, 47.5,
47.3, 39.5, 36.6, 27.7; HRMS (ESI) m/z calcd for C24H26Br2N3O3 (M
+ H)+ 562.03354, found 562.03253.
Compound 4 and Compound 4′. NaH (0.68 g, 60% in oil, 17.00
mmol) was added to a solution of compound 3 (2.05 g, 13.65 mmol)
in DMF (60 mL) at −18 °C. The resulting solution was stirred for 1 h
at 0 °C, and BOM-Cl (2.18 mL, 15.70 mmol) was added dropwise at
−18 °C. The mixture was stirred at 0 °C for 2 h and at room
temperature for 2 h. The reaction was quenched by the addition of
H2O (100 mL) and the mixture extracted with EtOAc (3 × 100 mL),
and the combined organic layers were washed with brine (100 mL),
dried over Na2SO4, and concentrated. The crude product was purified
by column chromatography to yield compound 4′ (1.72 g, 6.36 mmol,
1
47.4%) as a colorless oil: H NMR (600 MHz, DMSO-d6) δ 7.72 (s,
1H), 7.35−7.27 (m, 5H), 5.37 (s, 2H), 4.86 (t, J = 3.3 Hz, 1H), 4.43
(s, 2H), 3.55 (s, 3H), 3.29 (m, 2H), 3.19 (d, J = 6.5 Hz, 1H), 3.18 (d, J
= 6.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 154.8, 137.1, 136.5,
134.8, 128.8, 128.4, 128.1, 123.5, 89.5, 73.6, 69.8, 54.8, 29.1, 21.1;
HRMS (ESI) m/z calcd for C16H19N2O2 (M + H)+ 271.14410, found
271.14412. Compound 4 (1.79 g, 6.62 mmol, 47.6%) was obtained as
a colorless oil: 1H NMR (600 MHz, DMSO-d6) δ 7.71 (s, 1H), 7.35−
7.27 (m, 5H), 5.37 (s, 2H), 4.89 (m, 1H), 4.43 (s, 2H), 3.55 (s, 3H),
3.32 (d, J = 6.5 Hz, 1H), 3.31 (d, J = 6.5 Hz, 1H), 3.19 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 152.0, 137.1, 136.5, 135.5, 128.8, 128.4,
128.0, 122.8, 92.4, 73.5, 69.8, 54.9, 25.6, 24.6; HRMS (ESI) m/z calcd
for C16H19N2O2 (M + H)+ 271.14410, found 271.14304.
Compound 5. To a solution of compound 4 (1.61 g, 5.95 mmol)
in 1,4-dioxane (200 mL) was added hydrochloric acid (1 M, 20 mL).
The solution was stirred overnight at room temperature and carefully
neutralized by the addition of 2 M sodium hydroxide under vigorous
stirring and cooling with an ice/water bath. The mixture was extracted
with EtOAc (3 × 100 mL), and the combined organic layers were
washed with water (100 mL) and brine (100 mL), dried over Na2SO4,
and concentrated. The crude product was purified by column
chromatography to yield compound 5 (1.52 g, 5.93 mmol, 100%) as
a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.38−7.26
(m, 5H), 5.21 (s, 2H), 4.45 (s, 2H), 3.46 (s, 2H), 2.98 (t, J = 6.8 Hz,
Compound 10. To a solution of compound 9 (1.30 g, 2.31 mmol)
in THF (50 mL) was added NBS (0.62 g, 3.48 mmol) at 0 °C. The
reaction mixture was stirred overnight at this temperature, and
saturated aqueous Na2SO3 (20 mL) and H2O (20 mL) were added.
The mixture was extracted with EtOAc (3 × 50 mL), and the
combined organic layers were washed with brine (60 mL), dried over
Na2SO4, and concentrated. The crude product was purified by column
chromatography to yield compound 10 (1.26 g, 1.96 mmol, 85%) as a
1
foam: H NMR (400 MHz, CDCl3) δ 7.38−7.30 (m, 5H), 7.22 (s,
2H), 5.22 (d, J = 11.2 Hz, 1H), 4.93 (d, J = 11.2 Hz, 1H), 4.56 (d, J =
11.6 Hz, 1H), 4.52 (d, J = 11.6 Hz, 1H), 4.13 (t, J = 13.0 Hz, 1H), 4.06
(t, J = 7.6 Hz, 1H), 3.85 (s, 3H), 3.45 (d, J = 13.0 Hz, 1H), 3.08 (brs,
5H), 2.97−2.83 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 170.4,
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The Journal of Organic Chemistry
Note
153.4, 139.3, 136.7, 136.2, 133.2, 128.9, 128.6, 128.0, 126.3, 120.6,
118.3, 73.8, 70.9, 60.9, 48.1, 47.3, 39.5, 36.8, 27.8; HRMS (ESI) m/z
calcd for C24H25Br3N3O3 (M + H)+ 639.94406, found 639.94348.
Compound 11. A mixture of compound 10 (102 mg, 0.160 mmol)
and methylamine [40% (w/w) aqueous, 5 mL] was heated for 36 h at
120 °C in a sealed tube. The reaction mixture was concentrated, and
the residue was purified by column chromatography (C-18 reverse-
phase silica, 60% MeOH/H2O mixture) to afford compound 11 (71
mg, 0.123 mmol, 77%) as a colorless oil: 1H NMR (400 MHz, DMSO-
d6) δ 7.37−7.28 (m, 5H), 7.28 (s, 2H), 5.85 (m, NH), 5.17 (d, J = 11.6
Hz, 1H), 4.95 (d, J = 11.6 Hz, 1H), 4.47 (d, J = 12.2 Hz, 1H), 4.44 (d,
J = 12.2 Hz, 1H), 4.12 (t, J = 13.5 Hz, 1H), 3.77 (dd, J = 9.9, 6.7 Hz,
1H), 3.40 (dt, J = 15.2, 3 Hz, 1H), 2.99 (m, 2H), 2.88 (s, 3H), 2.74 (d,
J = 4.2 Hz, 3H), 2.66 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ
170.2, 150.6, 149.6, 137.4, 132.7, 132.6, 132.4, 128.3, 127.6, 127.5,
116.8, 111.8, 70.3, 69.1, 46.8, 46.5, 38.2, 35.5, 29.6, 27.1; HRMS (ESI)
m/z calcd for C24H27Br2N4O3 (M + H)+ 577.04444, found 577.04453.
Compound 12. A mixture of compound 10 (150 mg, 0.234
mmol), methylamine (2 M in THF, 3 mL, 6.000 mmol), 1,4-dioxane
(20 mL), and activated molecular sieves (3A, powder, 5 g) was heated
for 12 h at 120 °C in a sealed tube. The reaction mixture was filtered,
the filtrate concentrated, and the residue purified by column
chromatography (C-18 reverse-phase silica, 70% MeOH/H2O
mixture) to afford compound 12 (112 mg, 0.189 mmol, 81%) as a
ASSOCIATED CONTENT
■
S
* Supporting Information
Full experimental details and copies of NMR spectral data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*liuzhanzhu@imm.ac.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support of the Specialized
Research Fund for the Doctoral Program of Higher Education
(20131106110029) and the Beijing Key Laboratory of Active
Substance Discovery and Druggability Evaluation.
REFERENCES
■
(1) (a) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail,
A. T. J. Am. Chem. Soc. 1971, 93, 2325−2327. (b) Schiff, P. B.; Fant, J.;
Horwitz, S. B. Nature 1979, 277, 665−667. (c) Rowinsky, E. K. Annu.
Rev. Med. 1997, 48, 353−374.
(2) Jordan, M. A.; Wilson, L. Nat. Rev. Cancer 2004, 4, 253−265.
(3) (a) Kuppens, I. E. L. M. Curr. Clin. Pharmacol. 2006, 1, 57−70.
(b) Donovan, D.; Vahdat, L. T. Oncology 2008, 22, 408−416.
(4) Manzo, E.; van Soest, R.; Matainaho, L.; Roberge, M.; Andersen,
R. J. Org. Lett. 2003, 5, 4591−4594.
(5) Karjala, G.; Chan, Q.; Manzo, E.; Andersen, R. J.; Roberge, M.
Cancer Res. 2005, 65, 3040−3043.
1
pale yellow oil: H NMR (400 MHz, CDCl3) δ 7.42−7.34 (m, 3H),
7.30 (d, J = 6.8 Hz, 2H), 7.13 (s, 2H), 4.64 (d, J = 11.3 Hz, 1H), 4.45
(d, J = 12.2 Hz, 1H), 4.36 (d, J = 12.2 Hz, 1H), 4.30 (d, J = 11.3 Hz,
1H), 4.11 (m, 2H), 3.85 (s, 3H), 3.73 (t, J = 7.7 Hz, 1H), 3.42 (dt, J =
15.2, 3.3 Hz, 1H), 3.08 (s, 3H), 3.03 (t, J = 7.7 Hz, 1H), 2.95 (d, J =
5.2 Hz, 3H), 2.90 (m, 2H), 2.79 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 171.2, 153.2, 151.5, 137.1, 136.2, 133.2, 133.0, 129.0, 128.7,
128.2, 118.3, 117.2, 70.1, 69.6, 60.8, 47.6, 47.5, 40.1, 36.5, 30.3, 27.7;
HRMS (ESI) m/z calcd for C25H29Br2N4O3 (M + H)+ 591.06009,
found 591.06110.
(6) (a) Nodwell, M.; Riffell, J. L.; Roberge, M.; Andersen, R. J. Org.
Lett. 2008, 10, 1051−1054. (b) Nodwell, M.; Pereira, A.; Riffell, J. L.;
Zimmerman, C.; Patrick, B. O.; Roberge, M.; Andersen, R. J. J. Org.
Chem. 2009, 74, 995−1006. (c) Coleman, R. S.; Campbell, E. L.;
Carper, D. J. Org. Lett. 2009, 11, 2133−2136. (d) Nodwell, M.;
Zimmerman, C.; Roberge, M.; Andersen, R. J. J. Med. Chem. 2010, 53,
7843−7851.
Compound 13. To compound 12 (90 mg, 0.152 mmol) in DCM
(5 mL) was added anhydrous AlCl3 (203 mg, 1.52 mmol) in one
portion, and the reaction mixture was stirred for 1 h at room
temperature. The resulting blood red slurry was quenched by the
addition of methanol and filtered, and the filtrate was concentrated.
The residue was purified by column chromatography (C-18 reverse-
phase silica, 60% MeOH/H2O mixture) to afford compound 13 (72
(7) Scarponi, U.; Cimaschi, R.; Rusconi, L.; Santangelo, F.; Arcari, G.
Farmaco, Ed. Sci. 1985, 40, 818−832.
(8) (a) Zlotos, D. P.; Meise, W. Heterocycles 1997, 45, 2137−2157.
(b) Dalence-Guzman, M. F.; Berglund, M.; Skogvall, S.; Sterner, O.
Bioorg. Med. Chem. 2008, 16, 2499−2512.
1
mg, 0.152 mmol, 100%) as a pale yellow solid: H NMR (400 MHz,
DMSO-d6) δ 12.08 (m, NH), 7.74 (m, NH), 7.61 (s, 2H), 4.11 (m,
1H), 3.78 (br s, 5H), 3.14 (m, 2H), 2.89 (s, 3H), 2.85 (d, J = 4.6 Hz,
3H), 2.67 (m, 2H); 13C NMR for 13·HCl (75 MHz, DMSO-d6) δ
169.6, 151.7, 146.9, 138.4, 133.4, 121.2, 117.7, 116.9, 60.3, 45.6, 40.2,
38.8, 34.9, 29.5, 23.0; HRMS (ESI) m/z calcd for C17H21Br2N4O2 (M
+ H)+ 471.00258, found 471.00278.
(9) Zuev, D.; Michne, J. A.; Huang, H.; Beno, B. R.; Wu, D.; Gao, Q.;
Torrente, J. R.; Xu, C.; Conway, C. M.; Macor, J. E.; Dubowchik, G.
M. Org. Lett. 2005, 7, 2465−2468.
(10) (a) Sun, C.; Lin, X.; Weinreb, S. M. J. Org. Chem. 2006, 71,
3159−3166. (b) Plante, J. P.; Glass, T. E. Org. Lett. 2006, 8, 2163−
2166.
Ceratamine A (1). Compound 13 (68 mg, 0.144 mmol) was
dissolved in DMSO (0.6 mL). Pyridine (58 μL, 0.720 mmol) and IBX
(162 mg, 0.576 mmol) were added, and the mixture was stirred for 1 h
at 35 °C. The resulting dark yellow solution was quenched by the
addition of saturated aqueous Na2S2O4 (9 mL) and saturated
NaHCO3 (5 mL). The reaction mixture was extracted with EtOAc
(2 × 50 mL), and the combined organic layers were washed with brine
(30 mL), dried over Na2SO4, and concentrated. The crude product
was purified by column chromatography to yield ceratamine A (1) (56
mg, 0.120 mmol, 85%) as a yellow solid: 1H NMR (400 MHz, DMSO-
d6) δ 8.68 (m, NH), 7.74 (d, J = 9.9 Hz, 1H), 7.66 (s, 2H), 6.42 (d, J =
9.9 Hz, 1H), 4.23 (s, 2H), 3.72 (s, 3H), 3.55 (s, 3H), 3.07 (d, J = 4.9
Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ 175.6, 169.7, 164.1,
160.5, 151.4, 142.9, 140.2, 133.1, 121.3, 116.6, 100.4, 60.3, 43.7, 35.0,
29.2; HRMS (ESI) m/z calcd for C17H17Br2N4O2 (M + H)+ 466.9713,
found 466.9716.
(11) (a) Verma, S. K.; Acharya, B. N.; Kaushik, M. P. Org. Biomol.
Chem. 2011, 9, 1324−1327. (b) Ognyanov, V. I.; Balan, C.; Bannon, A.
W.; Bo, Y.; Dominguez, C.; Fotsch, C.; Gore, V. K.; Klionsky, L.; Ma,
Vu. V.; Qian, Y. X.; Tamir, R. J. Med. Chem. 2006, 49, 3719−3742.
(c) Whittle, C. P. Aust. J. Chem. 1980, 33, 1545−1551.
(12) (a) Hartwig, J. F.; Hooper, M. W.; Utaunomiya, M. J. Org.
Chem. 2003, 68, 2861−2873. (b) Hong, Y.; Tanoury, G. J.; Wilkinson,
H. S.; Bakale, R. P.; Wald, S. A.; Senanayake, C. H. Tetrahedron Lett.
1997, 38, 5607−5610. (c) Rosenberg, A. J.; Clark, D. A. Org. Lett.
2012, 14, 4678−4681.
(13) Beccalli, E. M.; Clerici, F.; Marchesini, A. Tertahedron 2000, 56,
2699−2702.
(14) Huffman, J. W.; Wu, M. J.; Lu, J. J. Org. Chem. 1998, 63, 4510−
4514.
(15) (a) Rosenberg, A. J.; Zhao, J.; Clark, D. A. Org. Lett. 2012, 14,
1764−1767. (b) Clark, D. A.; Rosenberg, A. J.; Williams, T. M.;
Jordan, A. J. Org. Biomol. Chem. 2013, 11, 3064−3072. (c) Robins, M.
12817
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The Journal of Organic Chemistry
Note
J.; Hatfield, P. W.; Balzarini, J.; Clercq, E. D. J. Med. Chem. 1984, 27,
1486−1492.
12818
dx.doi.org/10.1021/jo402165n | J. Org. Chem. 2013, 78, 12814−12818