Asymmetric Total Syntheses of Colchicine, β-Lumicolchicine, and Allocolchicinoid N-Acetylcolchinol-O-methyl Ether (NCME)

Article abstract of DOI:10.1021/acs.orglett.7b02224

A concise and highly enantioselective synthesis of colchicine (>99% ee) in eight steps and 9.3% overall yield, without the need for protecting groups, was developed. A unique Wacker oxidation was used for enabling regioselective construction of the highly oxidized and synthetic challenging tropolone C-ring. Furthermore, asymmetric syntheses of β-lumicolchicine and N-acetylcolchinol-O-methyl ether (NCME) were achieved. Notably, NCME was synthesized from β-lumicolchicine by an unusual decarbonylation and electrocyclic ring-opening cascade reaction.

Full text of DOI:10.1021/acs.orglett.7b02224

This is an open access article published under an ACS AuthorChoice License, which permits
copying and redistribution of the article or any adaptations for non-commercial purposes.
Letter
pubs.acs.org/OrgLett
Asymmetric Total Syntheses of Colchicine, β‑Lumicolchicine, and
Allocolchicinoid N‑Acetylcolchinol‑O‑methyl Ether (NCME)
Xin Liu,†,‡,∥ Ya-Jian Hu,†,‡,∥ Bo Chen,‡,∥ Long Min,‡ Xiao-Shui Peng,§ Jing Zhao,*,† Shaoping Li,*,†
Henry N. C. Wong,§ and Chuang-Chuang Li*,‡
†Institute of Chinese Medical Sciences, University of Macau, Macao, China
‡Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055, China
§Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
S
* Supporting Information
ABSTRACT: A concise and highly enantioselective synthesis of colchicine (>99% ee) in eight steps and 9.3% overall yield,
without the need for protecting groups, was developed. A unique Wacker oxidation was used for enabling regioselective
construction of the highly oxidized and synthetic challenging tropolone C-ring. Furthermore, asymmetric syntheses of β-
lumicolchicine and N-acetylcolchinol-O-methyl ether (NCME) were achieved. Notably, NCME was synthesized from β-
lumicolchicine by an unusual decarbonylation and electrocyclic ring-opening cascade reaction.
nean fever.1 Colchicine has also been used as a neurotoxin in
olchicine (1), which is an alkaloid natural product, was
Cthe first tubulin-destabilizing agent to be reported in the animal models of Alzheimer’s disease and epilepsy,2 as well as
literature (Figure 1).1 This material has also been investigated
to treat chronic myelocytic leukemia. However, its high toxicity
has precluded its clinical use in cancer chemotherapy.3
against a variety of different indications because of its
Interestingly, some of the allocolchicines including N-
acetylcolchinol-O-methyl ether (NCME) (2), which are
biphenyl analogues of colchicine, have been found to be active
against various cancer cell lines, including drug-resistant ones.
They operate by inhibiting tubulin assembly and polymer-
ization, leading to the arrest of cell mitosis.4
remarkable antimitotic activity. Furthermore, in a similar
manner to many other tubulin-binding natural products (e.g.,
taxol and the epothilones), colchicine has been used to treat
several diseases, including acute gout and familial Mediterra-
Structurally, colchicine (1) possesses an unusual 6−7−7
tricyclic ring system, and NCME (2) possesses a 6−7−6
carbocyclic skeleton. The stereocenter at C-7 and the aR-
configured chiral axis defined by the pivot bond joining the A
and C rings, and the regioselective construction of the highly
oxidized tropolone C-ring, represent formidable synthetic
challenges.5 It is noteworthy that another colchicinoid β-
lumicolchicine (3) has a novel tetracyclic 6−7−4−5 membered
ring system with three stereocenters, and α-lumicolchicine (4)
has a unique nonacyclic 6−7−4−5−4−5−4−7−6 ring skeleton
with ten stereocenters.6
Owing to their unusual structural motifs and promising
pharmacological properties, colchicine (1) and NCME (2)
have attracted considerable attention from synthetic chemists,
which has resulted in several elegant total syntheses of 17,8 and
Received: July 20, 2017
Figure 1. Structures of colchicine, NCME, and β-lumicolchicine.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02224
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2.9 Recently, we developed an enantioselective synthesis of
colchicine (1) from commercially available and inexpensive
2,3,4-trimethoxybenzaldehyde (5).7e The challenging tricyclic
6−7−7 core of colchicinoids was efficiently introduced using an
intramolecular oxidopyrylium-mediated [5 + 2] cycloaddition
reaction.10 In our continuing efforts toward the synthesis of
biologically active natural products,11 we herein describe a
modified concise and highly enantioselective synthesis of
colchicine using the Wacker oxidation for the regioselective
construction of the highly oxidized tropolone C-ring. More-
over, asymmetric total syntheses of β-lumicolchicine and
NCME were also achieved.
Compound 7 could be synthesized from 5 through several
simple functional group transformations reported previously.7e
Our synthesis began with the preparation of 6 (>99% ee)
from 5 in 5 steps in 21.8% overall yield, as reported previously
(Scheme 1).7e The diastereoselective reduction of the ketone
Scheme 1. Asymmetric Total Synthesis of 1
Retrosynthetically (Figure 2), β-lumicolchicine (3) could be
prepared from colchicine (1) through a 4π-electrocyclization
group in 6, followed by the in situ chemoselective methylation
of the resulting alcohol, afforded 8 in 75% yield (1.0 g scale).
The structure of 8 was unambiguously confirmed using X-ray
crystallography. After extensive experimentation, we found that
the regioselective Wacker oxidation of the substituted olefin
using air as a co-oxidant gave ketone 9 in good yield. We
reasoned that the methoxy group at C10 in 8 was critical for
this regioselective outcome. Finally, the double elimination of
the oxa-bridge in 9 proceeded smoothly using a slightly
modified version of Cha’s procedure7c in the presence of
TMSOTf and Me2EtN in DCM to complete our total synthesis
1
of (−)-1 in 81% yield in >99% ee. The H and 13C NMR
spectra of synthetic 1, as well as its optical rotation, were
identical to those of the natural product.
Figure 2. Retrosynthetic analysis of 1−3.
With colchicine (1) in hand, we proceeded to investigate our
proposed syntheses of β-lumicolchicine (3) and NCME (2)
(Scheme 2). The irradiation of a 10:1 (v/v) CH3CN/acetone
solution of 1 (0.0025 mol/L) with a 125 W high-pressure
mercury arc lamp surrounded by a Pyrex water jacket for 25
min resulted in β-lumicolchicine (3) with a much improved
yield6 of 68%.
Subsequently, the proposed transition-metal-catalyzed de-
carbonylation/electrocyclic ring-opening cascade reaction of 3
was attempted using several different catalysts (Rh, Ni, and Pd)
in a variety of different solvents, as reported previously.12
However, these conditions failed to afford any of the desired
product of 2. To our delight, the irradiation of a solution of β-
reaction.6 We anticipate that NCME (2) would be synthesized
from 3 through a Rh-catalyzed decarbonylation process12 via
intermediate A to give the fused bicyclobutene B, followed by
an electrocyclic ring-opening reaction.13 The formation of the
more stable aromatic ring C is one of the driving forces for this
process. It was envisioned that colchicine (1) could be
generated from 6 through a Wacker oxidation,14 followed by
the regioselective formation of the tropolone C-ring. Tricyclic 6
could itself be synthesized from 7 through the intramolecular
oxidopyrylium-mediated [5 + 2] cycloaddition reaction.
B
DOI: 10.1021/acs.orglett.7b02224
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Asymmetric Synthesis of 2 and 3
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02224.
1
Detailed experimental procedure, and H NMR and 13C
NMR spectra, as well as X-ray data information (PDF)
Crystallographic data (CIF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: ccli@sustc.edu.cn.
*E-mail: spli@umac.mo.
*E-mail: jingzhao@umac.mo.
ORCID
Chuang-Chuang Li: 0000-0003-4344-0498
Author Contributions
∥X.L., Y.-J.H., and B.C. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Natural Science Foundation of
China (Grant Nos. 21402083, 21502087, 21522204, 21472081,
and 21672095), Guangdong Science and Technology Depart-
ment (2016A050503011), the Shenzhen Science and Technol-
ogy Innovation Committee (Grant Nos. JCYJ20170412152-
454807, JSGG20160301103446375, and KQTD20150717-
10315717), and Innovation and Technology Fund (GHP/
004/16GD) from Innovation and Technology Commission,
HKSAR.
lumicolchicine (3) in 10:1 (v/v) CH3CN/acetone (0.0024
mol/L) with a 125 W high-pressure mercury arc lamp
surrounded by a Pyrex water jacket for 20 min gave 2 in 54%
yield instead of α-lumicolchicine (4)6 and colchicine. The
outcome of this transformation suggested that under the
irradiation compound 3 had probably undergone a decarbon-
ylation process to generate the intermediate B, followed by the
anticipated retro-4π-electrocyclization reaction to give 2, which
has been reported to exhibit greater inhibitory activity toward
REFERENCES
■
(1) (a) Boye, O.; Brossi, A. In The Alkaloids; Brossi, A., Cordell, G.
A., Eds.; Academic Press: San Diego, 1992; Vol. 41, p 125. (b) Le
Hello, C. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: San
Diego, 2000; Vol. 53, p 287. (c) Bhattacharyya, B.; Panda, D.; Gupta,
S.; Banerjee, M. Med. Res. Rev. 2008, 28, 155. (d) Jordan, M. A.;
Wilson, L. Nat. Rev. Cancer 2004, 4, 253. (e) Ravelli, R. B. G.; Gigant,
B.; Curmi, P. A.; Jourdain, I.; Lachkar, S.; Sobel, A.; Knossow, M.
Nature 2004, 428, 198.
(2) Weiner, J. L.; Buhler, A. V.; Whatley, V. J.; Harris, R. A.;
Dunwiddie, T. V. J. Pharmacol. Exp. Ther. 1998, 284, 95.
(3) Finkelstein, Y.; Aks, S. E.; Hutson, J. R.; Juurlink, D. N.; Nguyen,
P.; Dubnov-Raz, G.; Pollak, U.; Koren, G.; Bentur, Y. Clin. Toxicol.
2010, 48, 407.
tubulin than colchicine.4d The H and 13C NMR spectra of
1
synthetic 2 and 3, as well as their optical rotation, were identical
to those of the natural products. We also have tried to extend
the time of irradiation for one-pot synthesis of compound 2
from 1, but a trace of 2 was detected. Probably, other
unidentified compounds made the reaction more complex, with
the time extended and the temperature of the solution
increased. So, after many attempts, we found that 25 min is
the best time length for the first irradiation and the two-step
sequence is more efficient than the one-pot procedure for the
preparation of 2 from 1.
In summary, we developed a concise and highly
enantioselective synthesis of colchicine (>99% ee) in eight
steps in 9.3% overall yield without the need for protecting
groups.15 An unusual Wacker oxidation was used for enabling
the regioselective construction of the highly oxidized tropolone
C-ring. β-Lumicolchicine was prepared through a 4π-electro-
cyclization reaction with a much-improved yield compared with
existing procedures, and the allocolchicinoid NCME was
synthesized from β-lumicolchicine through a novel decarbon-
ylation/electrocyclic ring-opening cascade reaction.
(4) (a) Perez-Ramirez, B.; Gorbunoff, M. J.; Timasheff, S. N.
Biochemistry 1998, 37, 1646. (b) Guan, J.; Zhu, X.; Brossi, A.;
Tachibana, Y.; Bastow, K. F.; Verdier-Pinard, P.; Hamel, E.; McPhail,
A. T.; Lee, K. Collect. Czech. Chem. Commun. 1999, 64, 217.
́
(c) Buttner, F.; Bergemann, S.; Guenard, D.; Gust, R.; Seitz, G.;
̈
Thoret, S. Bioorg. Med. Chem. 2005, 13, 3497. (d) Nakagawa-Goto, K.;
Jung, M. K.; Hamel, E.; Wu, C.-C.; Bastow, K. F.; Brossi, A.; Ohta, S.;
Lee, K.-H. Heterocycles 2005, 65, 541.
(5) (a) Graening, T.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2004, 43,
3230. (b) Liu, N.; Song, W.; Schienebeck, C. M.; Zhang, M.; Tang, W.
Tetrahedron 2014, 70, 9281.
(6) (a) Grewe, R.; Wulf, W. Chem. Ber. 1951, 84, 621. (b) Chapman,
O. L.; Smith, H. G. J. Am. Chem. Soc. 1961, 83, 3914. (c) Chapman, O.
L.; Smith, H. G.; King, R. W. J. Am. Chem. Soc. 1963, 85, 803. For the
references above, different from our conditions, irradiation of
C
DOI: 10.1021/acs.orglett.7b02224
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
colchicine utilized sunlight in H2O solution for 2 months to give α,β,γ-
lumicolchicines together.
5785. (h) Mercer, J. A. M.; Cohen, C. M.; Shuken, S. R.; Wagner, A.
M.; Smith, M. W.; Moss, F. R.; Smith, M. D.; Vahala, R.; Gonzalez-
Martinez, A.; Boxer, S. G.; Burns, N. Z. J. Am. Chem. Soc. 2016, 138,
15845. (i) Boon, B. A.; Green, A. G.; Liu, P.; Houk, K. N.; Merlic, C.
A. J. Org. Chem. 2017, 82, 4613. For a review on biomimetic
electrocyclization, see: (j) Beaudry, C. M.; Malerich, J. P.; Trauner, D.
Chem. Rev. 2005, 105, 4757. For the application of cyclobutane
derivatives in organic synthesis, see: (k) Namyslo, J. C.; Kaufmann, D.
E. Chem. Rev. 2003, 103, 1485.
(7) (a) Schreiber, J.; Leimgruber, W.; Pesaro, M.; Schudel, P.;
Eschenmoser, A. Angew. Chem. 1959, 71, 637. (b) Banwell, M. G. Pure
Appl. Chem. 1996, 68, 539. (c) Lee, J. C.; Jin, S. J.; Cha, J. K. J. Org.
Chem. 1998, 63, 2804. (d) Graening, T.; Bette, V.; Neudorfl, J.; Lex, J.;
Schmalz, H. G. Org. Lett. 2005, 7, 4317. (e) Chen, B.; Liu, X.; Hu, Y.;
Zhang, D.; Deng, L.; Lu, J.; Min, L.; Ye, W.; Li, C.-C. Chem. Sci. 2017,
8, 4961.
(8) For selected synthesis, see: (a) Van Tamelen, E. E.; Spencer, T.
A., Jr; Allen, D. S., Jr; Orvis, R. L. J. Am. Chem. Soc. 1959, 81, 6341.
(b) Woodward, R. B. Harvey Lect. 1963, 59, 31. (c) Evans, D.; Tanis,
S.; Hart, D. J. Am. Chem. Soc. 1981, 103, 5813. (d) Boger, D. L.;
Brotherton, C. E. J. Am. Chem. Soc. 1986, 108, 6713. (e) Graening, T.;
Friedrichsen, W.; Lex, J.; Schmalz, H. G. Angew. Chem., Int. Ed. 2002,
41, 1524. (f) Boyer, F.-D.; Hanna, I. Org. Lett. 2007, 9, 2293. (g) For a
summary of colchicinoid synthesis, see refs 5a and 7e (Table S4 in
Supporting Information) for details.
(9) (a) Seganish, W. M.; DeShong, P. Org. Lett. 2006, 8, 3951.
(b) Djurdjevic, S.; Green, J. R. Org. Lett. 2007, 9, 5505. For other
allocolchicine syntheses, see: (c) Sawyer, J. S.; Macdonald, T. L.
Tetrahedron Lett. 1988, 29, 4839. (d) Vorogushin, A. V.; Predeus, A.
V.; Wulff, W. D.; Hansen, H.-J. J. Org. Chem. 2003, 68, 5826.
(e) Leblanc, M.; Fagnou, K. Org. Lett. 2005, 7, 2849. (f) Wu, T. R.;
Chong, J. M. Org. Lett. 2006, 8, 15. (g) Besong, G.; Jarowicki, K.;
Kocienski, P. J.; Sliwinski, E.; Boyle, F. T. Org. Biomol. Chem. 2006, 4,
2193. (h) Broady, S. D.; Golden, M. D.; Leonard, J.; Muir, J. C.;
Maudet, M. Tetrahedron Lett. 2007, 48, 4627. For oxidative
degradation method, see: (i) Iorio, M. A. Heterocycles 1984, 22,
2207. (j) Brecht, R.; Haenel, F.; Seitz, G. Liebigs Ann./Recl. 1997, 1997,
2275. (k) Dilger, U.; Franz, B.; Roettele, H.; Schroeder, G.; Herges, R.
J. Prakt. Chem./Chem.-Ztg. 1998, 340, 468.
(14) (a) Smidt, J.; Hafner, W.; Jira, R.; Sedlmeier, J.; Sieber, R.;
Ruttinger, R.; Kojer, H. Angew. Chem. 1959, 71, 176. (b) Tsuji, J.
̈
Synthesis 1984, 1984, 369. (c) Takacs, J. M.; Jiang, X. Curr. Org. Chem.
2003, 7, 369. (d) Tsuji, J. Palladium Reagents and Catalysts: New
Perspectives for the 21st Century, 2nd ed.; John Wiley & Sons, Ltd:
Chichester, U.K., 2004. (e) Sigman, M. S.; Jensen, D. R. Acc. Chem.
Res. 2006, 39, 221. (f) Jira, R. Angew. Chem., Int. Ed. 2009, 48, 9034.
(g) Sigman, M. S.; Werner, E. W. Acc. Chem. Res. 2012, 45, 874.
(h) Michel, B. W.; Steffens, L. D.; Sigman, M. S. Org. React. 2014, 84,
75. (i) Mann, S. E.; Benhamou, L.; Sheppard, T. D. Synthesis 2015, 47,
3079. (j) Baiju, T. V.; Gravel, E.; Doris, E.; Namboothiri, I. N. N.
Tetrahedron Lett. 2016, 57, 3993.
(15) (a) Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev.
2009, 38, 3010. (b) Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193.
For selected recent syntheses using a protecting-group-free strategy,
see: (c) Zhao, Y.-M.; Maimone, T. J. Angew. Chem., Int. Ed. 2015, 54,
1223. (d) Jansen, D. J.; Shenvi, R. A. J. Am. Chem. Soc. 2013, 135,
1209. (e) Ge, H. M.; Zhang, L.-D.; Tan, R. X.; Yao, Z.-J. J. Am. Chem.
Soc. 2012, 134, 12323. (f) Zhou, Q.; Chen, X.; Ma, D.-W. Angew.
Chem., Int. Ed. 2010, 49, 3513. (g) Baran, P. S.; Maimone, T. J.;
Richter, J. M. Nature 2007, 446, 404. (h) McFadden, R. M.; Stoltz, B.
M. J. Am. Chem. Soc. 2006, 128, 7738.
(10) For related studies of [5 + 2] cycloaddition reaction from our
group, see: (a) Mei, G.; Liu, X.; Qiao, C.; Chen, W.; Li, C.-C Angew.
Chem., Int. Ed. 2015, 54, 1754. (b) Mei, G.; Yuan, H.; Gu, Y.; Chen,
W.; Chung, L. W.; Li, C.-C. Angew. Chem., Int. Ed. 2014, 53, 11051.
(c) Liu, X.; Liu, J.-Y.; Zhao, J.; Li, S.; Li, C.-C. Org. Lett. 2017, 19,
2742. For review and selected application of [5 + 2] cycloaddition
reaction in natural product synthesis, see: (d) Ylijoki, K. E. O.; Stryker,
J. M. Chem. Rev. 2013, 113, 2244. (e) Zhang, M.; Liu, N.; Tang, W. J.
Am. Chem. Soc. 2013, 135, 12434. (f) He, C.; Hu, J.; Wu, Y.; Ding, H.
J. Am. Chem. Soc. 2017, 139, 6098.
(11) (a) Qiao, C.; Zhang, W.; Han, J.; Li, C.-C. Org. Lett. 2016, 18,
4932. (b) Han, J. C.; Li, F.; Li, C.-C. J. Am. Chem. Soc. 2014, 136,
13610. (c) Liu, G.; Mei, G. J.; Chen, R.; Yuan, H.; Yang, Z.; Li, C.-C.
Org. Lett. 2014, 16, 4380. (d) Wei, H.; Qiao, C.; Liu, G.; Yang, Z.; Li,
C.-C. Angew. Chem., Int. Ed. 2013, 52, 620.
(12) For seminal reports on the decarbonylation process of ketones
using a transition metal, see: (a) Rusina, A.; Vlcek, A. A. Nature 1965,
206, 295. (b) Murakami, M.; Amii, H.; Ito, Y. Nature 1994, 370, 540.
(c) Murakami, M.; Amii, H.; Shigeto, K.; Ito, Y. J. Am. Chem. Soc.
1996, 118, 8285. For selected recent examples, see: (d) Lei, Z.-Q.; Li,
H.; Li, Y.; Zhang, X.-S.; Chen, K.; Wang, X.; Sun, J.; Shi, Z.-J. Angew.
Chem., Int. Ed. 2012, 51, 2690. (e) Dermenci, A.; Whittaker, R.; Dong,
G. Org. Lett. 2013, 15, 2242. (f) Whittaker, R.; Dong, G. Org. Lett.
2015, 17, 5504. Theoretical study: (g) Dermenci, A.; Whittaker, R. E.;
Gao, Y.; Cruz, F. A.; Yu, Z.-X.; Dong, G. Chem. Sci. 2015, 6, 3201.
(h) Morioka, T.; Nishizawa, A.; Furukawa, T.; Tobisu, M.; Chatani, N.
J. Am. Chem. Soc. 2017, 139, 1416. (i) Somerville, R. J.; Martin, R.
Angew. Chem., Int. Ed. 2017, 56, 6708.
(13) (a) Wingert, H.; Regitz, M. Chem. Ber. 1986, 119, 244.
(b) Wingert, H.; Irngartinger, H.; Kallfass, D.; Regitz, M. Chem. Ber.
1987, 120, 825. (c) Maier, G.; Fleischer, F.; Kalinowski, H.-O. Liebigs
Ann. 1995, 1995, 173. For related studies, see: (d) Dolbier, W. R.;
Koroniak, H.; Burton, D. J.; Bailey, A. R.; Shaw, G. S.; Hansen, S. W. J.
Am. Chem. Soc. 1984, 106, 1871. (e) Kirmse, W.; Rondan, N. G.;
Houk, K. N. J. Am. Chem. Soc. 1984, 106, 7989. (f) Tallarico, J. A.;
Randall, M. L.; Snapper, M. L. J. Am. Chem. Soc. 1996, 118, 9196.
(g) Deak, H. L.; Williams, M. J.; Snapper, M. L. Org. Lett. 2005, 7,
D
DOI: 10.1021/acs.orglett.7b02224
Org. Lett. XXXX, XXX, XXX−XXX