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Current Organic Synthesis


ISSN (Print): 1570-1794
ISSN (Online): 1875-6271

Letter Article

Short Protecting Group-free Syntheses of CDE Synthon of Racemic Camptothecin

Author(s): Pingxuan Shao, Wei Lu and Lei Wang*

Volume 17, Issue 7, 2020

Page: [588 - 591] Pages: 4

DOI: 10.2174/1570179417666200611125740

Price: $65


A practical and concise total synthesis of tricyclic ketone 7 (CDE ring), a valuable intermediate for the synthesis of racemic camptothecin and analogs, was described (8 chemical steps and 29% overall yield). The synthesis starts with two inexpensive, readily available materials and is operationally simple to perform. It is worth mentioning that the reported protecting group-free synthesis, with advantages of a short route, would be helpful for the future development of industry-scale syntheses of camptothecin-family alkaloids.

Keywords: Natural product, alkaloid, camptothecin, CDE ring, total syntheses, protecting group-free.

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Wall, M.E.; Wani, M.C.; Cook, C.E.; Palmer, K.H.; MacPhail, A.T.; Sim, G.A. J. Am. Chem. Soc., 1966, 88, 3888-3890.
(a)Hsiang, Y.H.; Hertzberg, R.; Hecht, S.; Liu, L.F. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J. Biol. Chem., 1985, 260(27), 14873-14878.
[PMID: 2997227]
(b)Nitiss, J.; Wang, J.C. DNA topoisomerase-targeting antitumor drugs can be studied in yeast. Proc. Natl. Acad. Sci. USA, 1988, 85(20), 7501-7505.
[] [PMID: 2845409]
Huang, Q.; Wang, L.; Lu, W. Evolution in medicinal chemistry of E-ring-modified Camptothecin analogs as anticancer agents. Eur. J. Med. Chem., 2013, 63, 746-757.
[] [PMID: 23578545]
Kacprzak, K.M.; Ramawat, K.G. Springer Berlin Heidelberg; Mérillon, J.M., Ed.; Berlin, Heidelberg, 2013, pp. 643-682.
(a)Takashi, N.; Kiyoshi, S.; Takahiro, J.; Yuki, A.; Toshinori, A. Chem. Pharm. Bull. (Tokyo), 2019, 67, 173-185.
[] [PMID: 30827997]
(b)Takegawa, N.; Nonagase, Y.; Yonesaka, K.; Sakai, K.; Maenishi, O.; Ogitani, Y.; Tamura, T.; Nishio, K.; Nakagawa, K.; Tsurutani, J. DS-8201a, a new HER2-targeting antibody-drug conjugate incorporating a novel DNA topoisomerase I inhibitor, overcomes HER2-positive gastric cancer T-DM1 resistance. Int. J. Cancer, 2017, 141(8), 1682-1689.
[] [PMID: 28677116]
Joto, N.; Ishii, M.; Minami, M.; Kuga, H.; Mitsui, I.; Tohgo, A. DX-8951f, a water-soluble camptothecin analog, exhibits potent antitumor activity against a human lung cancer cell line and its SN-38-resistant variant. Int. J. Cancer, 1997, 72(4), 680-686.
[<680:AID-IJC21>3.0.CO;2-E] [PMID: 9259410]
(a)Du, W. Towards new anticancer drugs: A decade of advances in synthesis of camptothecins and related alkaloids. Tetrahedron, 2003, 59, 8649-8687.
(b)Chen, L.; Chen, F-E. Total synthesis of camptothecins: An update. Synlett, 2017, 28(10), 1134-1150.
(c)Liu, Q.; Huang, G-X.; Liu, M-J.; Chen, F-E. A concise total synthesis of (±)-camptothecin. Synthesis, 2019, 51, 3506-3510.
(d)Liu, Q.; Huang, G-X.; Liu, M-J.; Chen, F-E. A formal synthesis of camptothecin via a photocatalytic decarboxylative radical addition. Eur. J. Org. Chem., 2019, 25, 6024-6027.
(e)Liu, Q.; Huang, G-X.; Liu, M-J.; Chen, F-E. Asymmetric total synthesis of (20S)-Camptothecin using a chiral auxiliary strategy. Tetrahedron, 2019, 75, 2647-2651.
(f)Wei, C-Q.; Jiang, Z-H.; Tian, S-J.; Zhang, D-Z. Highly facile approach to the formal total synthesis of camptothecin. Tetrahedron Lett., 2013, 54, 4515-4517.
(g)Liu, G-S.; Dong, Q-L.; Yao, Y-S.; Yao, Z-J. Expeditious total syntheses of camptothecin and 10-hydroxycamptothecin. Org. Lett., 2008, 10(23), 5393-5396.
[] [PMID: 18991442]
(h)Xu, P.D-S. Chen.; Xi, J.; Yao, Z.-J. Short protecting group‐free syntheses of camptothecin and 10‐hydroxycamptothecin using cascade methodologies. Chem. Asian J., 2015, 10, 976-981.
[]] [PMID: 25431030]
(i)Cenal, J.P.; Carreras, C.R.; Tonn, C.E.; Padron, J.I.; Ramirez, M.A.; Diaz, D.D.; Garcia-Tellado, F.; Martin, V.S. (E)-2-((4R,5R)-5-((Benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-ene-1,4-diol. Synlett, 2005, 1575-1578.
(j)Zhao, L.; Xiong, F-J.; Chen, W-X. Chen. F.-E. A novel and enantioselective total synthesis of (20S)-camptothecin via a sharpless asymmetric dihydroxylation strategy. Synthesis, 2011, 4045-4049.
(k)Li, K.; Ou, J-J. Gao. S.-H. Total synthesis of camptothecin and related natural products by a flexible strategy. Angew. Chem. Int. Ed., 2016, 55, 14778-14783.
(l)Chavan, S.P.; Pathak, A.B. Kalkote; U. R. Total synthesis of (+)-camptothecin via an intramolecular palladium-catalyzed cyclization strategy. Synlett, 2007, 2635-2638.
(m)Yuan, Y.; Xie, X-X.; Curran, D.P. Zhang. Z.-G. Visible‐light‐induced radical cascade cyclization: Synthesis of (20s)‐camptothecin, sn‐38 and irinotecan. Chin. J. Chem., 2018, 36, 1035-1040.
(n)Zhou, H-B.; Liu, G-S. Yao. Z.-J. Highly efficient and mild cascade reactions triggered by bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate and a concise total synthesis of camptothecin. Org. Lett., 2007, 9, 2003-2006.
[] [PMID: 17432868]
(o)Chavan, S.P. Sivappa. R. A synthesis of camptothecin. Tetrahedron Lett., 2004, 45, 3113-3115.
(p)Chavan, S.P.; Pasupathy, K.; Venkatraman, M.S.; Kale, R.R. Formal total synthesis of camptothecin via ring-closing metathesis strategy. Tetrahedron Lett., 2004, 45, 6879-6882.
(q)Twin, H. Batey. R.A. Intramolecular hetero diels−alder (povarov) approach to the synthesis of the alkaloids luotonin a and camptothecin. Org. Lett., 2004, 6, 4913-4916.
(r)Grillet, F.; Sabot, C.; Anderson, R.; Babjak, M.; Greene, A.E.; Kanazawa, A. Intramolecular isomünchnone cycloaddition approach to the antitumor agent camptothecin. Tetrahedron, 2011, 67, 2579-2584.
(s)Stanovnik, B.; Svete, J. Synthesis of heterocycles from alkyl 3-(dimethylamino)propenoates and related enaminones. Chem. Rev., 2004, 104, 2433-2480.
(t)Anderson, R.J.; Raolji, G.B.; Kanazawa, A.; Greene, A.E. A novel, expeditious synthesis of racemic camptothecin. Org. Lett., 2005, 7(14), 2989-2991.
[] [PMID: 15987187]
(u)Dong, W.; Yuan, Y.; Hu, B.; Gao, X.; Gao, H.; Xie, X.; Zhang, Z. Combining visible-light-photoredox and lewis acid catalysis for the synthesis of indolizino[1,2-b]quinolin-9(11h)-ones and irinotecan precursor. Org. Lett., 2018, 20(1), 80-83.
[] [PMID: 29215891]
(v)Yuan, Y.; Dong, W.; Gao, X.; Gao, H.; Xie, X.; Zhang, Z. Visible-light-induced radical cascade cyclization: Synthesis of the abcd ring cores of camptothecins. J. Org. Chem., 2018, 83(5), 2840-2846.
[] [PMID: 29411608]
(w)Peters, R.; Althaus, M.; Nagy, A.L. Practical formal total synthesis of (rac)- and (S)-camptothecin. Org. Biomol. Chem., 2006, 4(3), 498-509.
[] [PMID: 16446808]
(x)Hiroya, K.; Kawamoto, K.; Sakamoto, T. Introduction of the acetate unit to the 2-pyridinone ring system and its application to the synthesis of (20s)-camptothecin de ring system. Synlett, 2006, 16, 2636-2640.
(a)Wani, M.C.; Ronman, P.E.; Lindley, J.T.; Wall, M.E. Plant antitumor agents. 18. Synthesis and biological activity of camptothecin analogues. J. Med. Chem., 1980, 23(5), 554-560.
[] [PMID: 7381856]
(b)Wall, M.E.; Wani, M.C.; Natschke, S.M.; Nicholas, A.W. Plant antitumor agents. 22. Isolation of 11-hydroxycamptothecin from Camptotheca acuminata Decne: Total synthesis and biological activity. J. Med. Chem., 1986, 29(8), 1553-1555.
[] [PMID: 3735324 ]
(c)Wani, M.C.; Nicholas, A.W.; Wall, M.E. Plant antitumor agents. 28. Resolution of a key tricyclic synthon, 5‘(RS)-1,5-dioxo-5’-ethyl-5′-hydroxy-2‘H,5’H,6‘H-6’-oxopyrano[3′, 4′- f]delta 6,8-tetrahydro-indolizine: Total synthesis and antitumor activity of 20(S)- and 20(R)-camptothecin. J. Med. Chem., 1987, 30(12), 2317-2319.
[] [PMID: 3681902]
Henegar, K.E.; Ashford, S.W.; Baughman, T.A.; Sih, J.C.; Gu, R-L. Practical asymmetric synthesis of (s)-4-ethyl-7,8-dihydro-4-hydroxy-1h-pyrano[3,4-f]indolizine- 3,6,10(4h)-trione, a key intermediate for the synthesis of irinotecan and other camptothecin analogs. J. Org. Chem., 1997, 62, 6588-6597.
Chavan, S.P.; Dhawane, A.N.; Kalkote, U.R. Formal synthesis of (±)-camptothecin via tricyclic lactone as key synthon. Tetrahedron Lett., 2010, 51, 3099-3101.
(a)Wang, S.; Coburn, C.A.; Bornmann, W.G.; Danishefsky, S.J. Concise total syntheses of dl-camptothecin and related anticancer drugs. J. Org. Chem., 1993, 58, 611-617.
(b)Yu, J.; DePue, J.; Kronenthal, D. Synthesis of (±)-camptothecin using a [3+2] nitrone cycloaddition to construct the CDE ring moiety. Tetrahedron Lett., 2004, 45, 7247-7250.
(c)Anderson, R.J.; Raolji, G.B.; Kanazawa, A.; Greene, A.E. Increased structural complexity leads to higher activity: Peptides as efficient and versatile catalysts for asymmetric aldol reactions. Org. Lett., 2005, 7, 2990-2991.
Yu, S.; Huang, Q-Q.; Luo, Y.; Lu, W. Total synthesis of camptothecin and SN-38. J. Org. Chem., 2012, 77(1), 713-717.
[] [PMID: 22165912]

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