The four-step total synthesis of (-)-chaetominine

Article abstract of DOI:10.1039/c3cc48833k

The total synthesis of the alkaloid (-)-chaetominine (1) has been achieved in four steps with an overall yield of 33.4%. Key features of our strategy include a one-pot cascade indole epoxidation-epoxide ring-opening cyclization-lactamization reaction sequence, and the use of a nitro group as a latent amino group for the one-pot construction of the quinazolinone ring. This constitutes a step economical, redox economical and protecting group-free total synthesis.

Full text of DOI:10.1039/c3cc48833k

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
The four-step total synthesis of (À)-chaetominine†
Qi-Long Peng,‡ Shi-Peng Luo,‡ Xiao-Er Xia, Liang-Xian Liu and Pei-Qiang Huang*
Cite this: Chem. Commun., 2014,
50, 1986
Received 19th November 2013,
Accepted 11th December 2013
DOI: 10.1039/c3cc48833k
www.rsc.org/chemcomm
The total synthesis of the alkaloid (À)-chaetominine (1) has been activity against human leukemia K562 (21 nM) and colon cancer
achieved in four steps with an overall yield of 33.4%. Key features of SW1116 (28 nM) cell lines7 made (À)-chaetominine an attractive
our strategy include a one-pot cascade indole epoxidation – epoxide synthetic target.8 Snider and co-workers reported the first total
ring-opening cyclization – lactamization reaction sequence, and the synthesis of (À)-chaetominine soon after its isolation.8a Later
use of a nitro group as a latent amino group for the one-pot construc- on, Evano and Papeo reported the second8b and the third
tion of the quinazolinone ring. This constitutes a step economical, approaches.8c Papeo’s work also clarified that (À)-chaetominine
redox economical and protecting group-free total synthesis.
(1) showed a negligible inhibitory activity on several cancer
cell lines.8c The fourth one disclosed by Evano et al. has so far
Efficiency is a major pursuit in organic synthesis, which is of been the most efficient with nine steps and 14% overall yield
particular importance in the field of the total synthesis of complex from D-tryptophan.8d
natural products.1 With this end in view, the concepts of step
With our interest in the asymmetric synthesis of bioactive
economy,2 pot economy,3 redox economy,4 and protecting group- natural products9 and the development of step economical synthetic
free synthesis5 have been introduced. Recently, a number of quite methodologies,10 we envisaged that (À)-chaetominine (1) is an
concise total syntheses have been achieved.6
ideal molecule for demonstrating the concepts of step economy,
In 2006, Tan and co-workers reported the isolation of a new pot economy, redox economy, and protecting group-free synthesis.
alkaloid (À)-chaetominine (1 in Fig. 1) from the solid-substrate We report herein a four-step total synthesis of (À)-chaetominine (1)
culture of Chaetomium sp. IFB-E015, an endophytic fungus on starting from D-tryptophan.11
apparently healthy Adenophora axilliflora leaves.7 The intriguing
structural feature in combination with the reported potent in Scheme 1. The key feature of our approach resides in the
Our retrosynthetic analysis of (À)-chaetominine (1) is depicted
ambitious one-pot formation of (À)-chaetominine (1) from
Fig. 1 Structure of (À)-chaetominine (1).
Department of Chemistry and Fujian Provincial Key Laboratory for Chemical
Biology, College of Chemistry & Chemical Engineering, Xiamen University, Xiamen,
Fujian 361005, PR China. E-mail: pqhuang@xmu.edu.cn; Fax: +86-592-2189959
† Electronic supplementary information (ESI) available: X-ray structures, experi-
mental procedures and compound characterization data, and 1H and 13C NMR
spectra of new compounds. CCDC 791762–791764 and 884128. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3cc48833k
Scheme 1 Retrosynthetic analysis of (À)-chaetominine (1).
‡ These authors contributed equally to this work.
1986 | Chem. Commun., 2014, 50, 1986--1988
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
quinazolinonetripeptide
2
via
a
one-pot cascade indole gave the aroylated product 4 in 90% yield (Scheme 2). Successive
epoxidation – epoxide ring-opening cyclization – lactamization treatment of compound 4 with i-BuOCOCl/N-methylmorpholine
reaction sequence. The formation of the pyrrolo[2,3-b]indole (NMM, THF, À20 1C, 15 min) and the L-alanine methyl ester
ring system through b-oxygenation of tryptophan derivatives hydrochloride salt (THF, NMM, À20 1C, 8 h) produced the desired
followed by nucleophilic addition at the a-position has been dipeptide derivative 3 in 91% yield. The quinazolinone ring system18
known for a long time, which includes the photosensitized was constructed by a modification of Shi’s method.19 In the event, 3
oxygenation,12 and Witkop’s stepwise oxidative transposition.13 was treated with HC(OMe)3 and low valent titanium generated in situ
Recently, much attention has been paid to the oxidative cyclization from TiCl4 and Zn powders in THF at 0–5 1C, which gave the desired
of tryptophan derivatives,14–16 due to the presence of the pyrrolo- quinazolinone 2 in 97% yield without observable epimerization.
[2,3-b]indole ring system in many bioactive alkaloids.17 Nevertheless, Higher temperature reported by Shi and co-workers19 led to
to the best of our knowledge, no redox and protecting group-free substantial epimerization.
oxidative cyclization leading to the fused six-membered ring system
With compound 2 in hand, we then focused on the key
(piperidino[2,3-b]indole) has ever been reported.12–17 Even in the epoxidation-initiated cascade reaction to construct the tricyclic
cases where formation of both five or six-membered rings was core of (À)-chaetominine (1). Although treatment of dipeptide 2
possible, the five-membered ring product (pyrrolo[2,3-b]indole) with a solution of DMDO in acetone at À78 1C for up to 1 h led
always dominated over the six-membered ring.14b,d In the first to complex products, the results implied that the epoxidation might
total synthesis of kapakahines B and F,14b,c Baran and co-workers have occurred, but the unstable epoxide intermediate failed to
have developed an elegant method for the access to the cyclize to give the desired product 1. So, basic conditions were
tetrahydro-1H-pyrido[2,3-b]indole ring system of kapakahines envisaged to be necessary to realize the cascade epoxidation-bis-
by in situ kinetic trapping of a dynamic mixture.
cyclization reactions (Scheme 2). In view of the easy epimerization of
Thus construction of the tricyclic core of (À)-chaetominine our substrate (vide supra), weak basic conditions are preferred to
(1) from the tryptophan derived dipeptide 2 via epoxidative avoid any epimerization during the cyclization. After considerable
cyclization appeared to be quite challenging. Nevertheless, experimentation, it was found that a combination of DMDO with
considering the high efficiency of this approach, it was worth- DMSO gave optimal results. In the event, dipeptide 2 was first
while to be engaged in this adventure.
treated with DMDO in acetone at À78 1C for 1 h, and then DMSO
As regards the quinazolinone ring system, a number of methods (CaH2 dried) was added, and the mixture was stirred at rt for 2 days
have been reported.18 In view of developing a protecting group-free to give the desired chaetominine (1) in 42% yield, along with a small
total synthesis of (À)-chaetominine (1), the nitro group was envisioned portion of its lactamization precursor 5 (3% yield) and an epimer of
as a latent amino group for the construction of the quinazolinone the latter (6) in 51% yield. The structure of (À)-chaetominine (1) was
ring. Thus o-nitrobenzoyl dipeptide derivative 3 was envisaged as confirmed by single crystal X-ray analysis.20 The physical {[a]D20 À49.7
the intermediate of our synthesis, which is readily accessible from (c 0.48, MeOH) lit. À48 (c 0.45, MeOH);8a À49.4 (c 0.26, MeOH);8b,c
commercially available D-tryptophan, o-nitrobenzoyl chloride, and À47.9 (c 0.25, MeOH);8d À70 (c 0.48, MeOH)7} and spectral data of
L-alanine methyl ester hydrochloride salt.
Our synthesis started with the aroylation of D-tryptophan The structure of compound 6 was tentatively deduced from its
with o-nitrobenzoyl chloride (THF, 1 M NaOH, 0 1C, 2 h), which cyclized product 7 and the bromo derivative 8, both determined
our synthetic (À)-chaetominine (1) are identical to those reported.
i
Scheme 2 Reagents and conditions: (i) o-nitrobenzoyl chloride, 1 M NaOH, THF, 0 1C, 2 h; (ii) H-L-Ala-OMeÁHCl, ClCO2 Bu, NMM, THF, À20 1C, 8 h; (iii)
HC(OMe)3, Zn/TiCl4, THF, 0 1C, 1 day; (iv) DMDO, acetone, À78 1C, 1 h; then, DMSO (CaH2 dried), rt, 48 h. Syntheses of compounds 7 and 8 for single
crystal X-ray diffraction analysis: (v) NaOMe, MeOH, À10 1C, 90%; (vi) NBS, rt; NaOMe, MeOH, À10 1C, 40% (unoptimized).
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 1986--1988 | 1987

View Article Online
ChemComm
Communication
by single crystal X-ray analysis.20 The direct formation of
chaetominine (1) from 2 implied that an anti–cis disposition
between the hydroxyl group at C3 and the quinazolinonyl group
favors the lactamization. For diastereomer 6, the fact that only
in the presence of a base can the lactamization occur implied a
syn-disposition between the substituents at C3 and C14.
It is worth mentioning that although the yield of chaetomi-
nine (1) from 2 via the epoxidation-trigged cascade reaction was
modest, the strategy is highly efficient. In this cascade reaction
sequence, three reactions have been accomplished in one-pot,
which also avoided the use of any protecting group. In the
previous syntheses,8a–d the highest diastereoselectivity (95% de)
has been achieved with DMDO in Evano’s first generation total
synthesis of (À)-chaetominine (1).8b However, five steps were
required to build the tricyclic ring system, which let them to
abandon that route and develop a more efficient one.8d
In summary, we have disclosed a very concise and efficient
strategy for the total synthesis of (À)-chaetominine (1) starting
from D-Trp. This four-step total synthesis of (À)-chaetominine
(1) has so far been the shortest one, with the highest overall
yield of 33.4%.
10886–10887; ( f ) eight-step total synthesis of (Æ)-stemoamide:
Y. Wang, L. Zhu, Y. Zhang and R. Hong, Angew. Chem., Int. Ed.,
2011, 50, 2787–2790.
7 R.-H. Jiao, S. Xu, J.-Y. Liu, H.-M. Ge, H. Ding, C. Xu, H.-L. Zhu and
R.-X. Tan, Org. Lett., 2006, 8, 5709–5712.
8 (a) B. B. Snider and X.-X. Wu, Org. Lett., 2007, 9, 4913–4915;
(b) M. Toumi, F. Couty, J. Marrot and G. Evano, Org. Lett., 2008,
10, 5027–5030; (c) B. Malgesini, B. Forte, D. Borghi, F. Quartieri,
C. Gennari and G. Papeo, Chem.–Eur. J., 2009, 15, 7922–7929;
(d) A. Coste, G. Karthikeyan, F. Couty and G. Evano, Synthesis,
2009, 2927–2934.
9 (a) S.-P. Luo, L.-D. Guo, L.-H. Gao, S. Li and P.-Q. Huang, Chem.–Eur. J.,
2013, 19, 87–91; (b) H.-H. Huo, X.-E. Xia, H.-K. Zhang and P.-Q. Huang,
J. Org. Chem., 2013, 78, 455–465.
10 (a) K.-J. Xiao, J.-M. Luo, K.-Y. Ye, Y. Wang and P.-Q. Huang, Angew.
Chem., Int. Ed., 2010, 49, 3037–3040; (b) S.-H. Xiang, J. Xu,
H.-Q. Yuan and P.-Q. Huang, Synlett, 2010, 1829–1832; (c) K.-J.
Xiao, A.-E. Wang and P.-Q. Huang, Angew. Chem., Int. Ed., 2012,
51, 8314–8317; (d) K.-J. Xiao, A.-E. Wang, Y.-H. Huang and
P.-Q. Huang, Asian J. Org. Chem., 2012, 1, 130–132; (e) K.-J. Xiao,
A.-E. Wang, Y.-H. Huang and P.-Q. Huang, Acta Chim. Sin., 2012, 70,
1917–1922; ( f ) S.-Y. Huang, Z. Chang, S.-C. Tuo, L.-H. Gao,
A.-E. Wang and P.-Q. Huang, Chem. Commun., 2013, 49,
7088–7090; (g) K.-J. Xiao, J.-M. Luo, X. E. Xia, Y. Wang and
P.-Q. Huang, Chem.–Eur. J., 2013, 19, 13075–13086.
11 An application for a Chinese patent covering a part of this work was
made by P.-Q. Huang, L.-X. Liu and Q.-L. Peng, ZL 200910110953.2,
2009, in Chinese, Chem. Abstr. CN20091110953 20090122.
12 (a) M. Nakagawa, S. Kato, S. Kataoka and T. Hino, J. Am. Chem. Soc.,
1979, 101, 3136–3137; (b) M. Nakagawa, Y. Yokoyama, S. Kato and
T. Hino, Tetrahedron, 1985, 41, 2125–2132; (c) C. Didier, D. J. Critcher,
N. D. Walshe, Y. Kojima, Y. Yamauchi and A. G. M. Barrett, J. Org.
Chem., 2004, 69, 7875–7879.
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, 21072160), and
the Program for Changjiang Scholars and Innovative Research
Team in University (PCSIRT) of Ministry of Education, China.
We are indebted to Professor Dr Henry N. C. Wong (CUHK) for
valuable discussion.
13 M. Ohno, T. F. Spande and B. Witkop, J. Am. Chem. Soc., 1968, 90,
6521–6522.
14 (a) A. Mendoza, Y. Ishihara and P. S. Baran, Nat. Chem., 2012, 4,
21–25; (b) T. Newhouse, C. A. Lewis, K. J. Eastman and P. S. Baran, J. Am.
Chem. Soc., 2010, 132, 7119–7137; (c) T. Newhouse, C. A. Lewis and
P. S. Baran, J. Am. Chem. Soc., 2009, 131, 6360–6361; (d) T. Newhouse and
P. S. Baran, J. Am. Chem. Soc., 2008, 130, 10886–10887; (e) P. S. Baran and
J. M. Richter, J. Am. Chem. Soc., 2004, 126, 7450–7451.
15 (a) T. M. Kamenecka and S. J. Danishefsky, Angew. Chem., Int. Ed.,
1998, 37, 2993–2995; (b) T. M. Kamenecka and S. J. Danishefsky,
Angew. Chem., Int. Ed., 1998, 37, 2995–2998; (c) T. M. Kamenecka
and S. J. Danishefsky, Chem.–Eur. J., 2001, 7, 41–63; (d) J. P. May,
P. Fournier, J. Pellicelli, B. O. Patrick and D. M. Perrin, J. Org. Chem.,
2005, 70, 8424–8430; (e) J. P. May, B. O. Patrick and D. M. Perrin,
Synlett, 2006, 3403–3406.
Notes and references
1 (a) B. M. Trost, Science, 1991, 254, 1471–1477; (b) C.-J. Li and
B. M. Trost, Proc. Natl. Acad. Sci. U. S. A., 2008, 105, 13197–13202.
2 (a) P. A. Wender, M. P. Croatt and B. Witulski, Tetrahedron, 2006, 62,
7505–7511; (b) P. A. Wender, V. A. Verma, T. J. Paxton and
T. H. Pillow, Acc. Chem. Res., 2008, 41, 40–49.
3 Three-pot total synthesis of prostaglandin PGE1 methyl ester and
PGA1 methyl ester: Y. Hayashi and S. Umemiya, Angew. Chem., Int.
Ed., 2013, 52, 3450–3452.
4 For a review, see: (a) N. Z. Burns, R. W. Hoffmann and P. S. Baran,
Angew. Chem., Int. Ed., 2009, 48, 2854–2867; For an example, see:
(b) J. M. Richter, Y. Ishihara, T. Masuda, B. W. Whitefield, T. Llamas,
A. Pohjakallio and P. S. Baran, J. Am. Chem. Soc., 2008, 130, 17938–17954.
5 For reviews, see: (a) R. W. Hoffmann, Synthesis, 2006, 3531–3541;
(b) I. S. Young and P. S. Baran, Nat. Chem., 2009, 1, 193–205; (c) R. Hili
and A. K. Yudin, Chem.–Eur. J., 2007, 13, 6538–6542; For typical recent
examples, see: (d) P. S. Baran, T. J. Maimone and J. M. Richter, Nature,
2007, 446, 404–408; (e) V. Hickmann, M. Alcarazo and A. Fu¨rstner,
J. Am. Chem. Soc., 2010, 132, 11042–11044.
16 (a) F. He, B. M. Foxman and B. B. Snider, J. Am. Chem. Soc., 1998, 120,
6417–6418; (b) D. Crich and X. H. Huang, J. Org. Chem., 1999, 64,
7218–7223; (c) R. Galli, M. Dobler, R. Gu¨ller, R. Stahl and
H. J. Borschberg, Helv. Chim. Acta, 2002, 85, 3400–3413; (d) S. V. Ley,
E. Cleator and P. R. Hewitt, Org. Biomol. Chem., 2003, 1, 3492–3494.
17 For a recent review on natural products with hexahydropyrrolo-
[2,3-b]indole, see: P. Ruiz-Sanchis, S. A. Savina, F. Albericio and
´
M. Alvarez, Chem.–Eur. J., 2011, 17, 1388–1408.
18 For a review on quinazolinone alkaloids, see: S. B. Mhaske and
N. P. Argade, Tetrahedron, 2006, 62, 9787–9826.
6 For selected examples, see: (a) three-pot total synthesis of
(–)-oseltamivir: H. Ishikawa, T. Suzuki and Y. Hayashi, Angew.
Chem., Int. Ed., 2009, 48, 1304–1307; (b) three-step synthesis of
19 (a) D.-Q. Shi, L.-C. Rong, J.-X. Wang, Q.-Y. Zhuang, X.-S. Wang and
H.-W. Hu, Tetrahedron Lett., 2003, 44, 3199–3201; (b) D.-Q. Shi,
X.-S. Wang, S.-J. Tu and H.-W. Hu, Chin. J. Struct. Chem., 2003, 22,
581–584; (c) D.-Q. Shi, J.-X. Wang, L.-C. Rong, Q.-Y. Zhuang and
H.-W. Hu, Chem. J. Chin. Univ., 2004, 25, 462–465.
20 (a) (À)-chaetominine (1): CCDC 791762; (b) the precursor of
(À)-chaetominine (compound 5): CDCC 791763; (c) compound 7:
CCDC 791764; (d) compound 8: CCDC 884128. For single crystal
X-ray structures, see: ESI†.
¨
(–)-pycnanthuquinone C: F. Lobermann, P. Mayer and D. Trauner,
Angew. Chem., Int. Ed., 2010, 49, 6199–6202; (c) four-step total
synthesis of (Æ)-psychotrimine: A. Mendoza, Y. Ishihara and
P. S. Baran, Nat. Chem., 2012, 4, 21–25; (d) seven-step total synthesis
of prostaglandin PGF2: G. Coulthard, W. Erb and V. Aggarwal,
Nature, 2012, 489, 278–281; (e) seven-step total synthesis of taxanes:
T. Newhouse and P. S. Baran, J. Am. Chem. Soc., 2008, 130,
1988 | Chem. Commun., 2014, 50, 1986--1988
This journal is ©The Royal Society of Chemistry 2014