Login Register Cart 0
Generic placeholder image

Current Organic Chemistry

Editor-in-Chief

ISSN (Print): 1385-2728
ISSN (Online): 1875-5348

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Advances in the Total Synthesis of Gelsemine

Author(s): Liyan Yang and Zhonglei Wang*

Volume 26, Issue 4, 2022

Published on: 25 February, 2022

Page: [356 - 368] Pages: 13

DOI: 10.2174/1385272826666220210124835

Price: $65

Abstract

Gelsemine is a remarkable indole alkaloid isolated from the medicinal plant Gelsemium elegans (Carolina or yellow jasmine) and demonstrates effectiveness in alleviating cognitive impairment, suggesting it could treat Alzheimer's disease. Gelsemine comprises seven adjoining chiral carbon centres and hexacyclic cage structures, making it an oddly difficult synthetic target. The unique structure and potential bio-pharmacological properties of gelsemine have led to the publication of nine interesting total syntheses of gelsemine (including three asymmetric syntheses) in the near past three decades by eight distinguished research groups. Several strategies are brimming with modern concepts of synthesis, such as highly enantioselective organocatalytic Diels–Alder reaction and the biomimetic enol–oxonium cyclization reaction. To better explore the therapeutic effects of gelsemine, this review summarizes the progress in the total synthesis tactics and strategies of the fascinating natural product gelsemine.

Keywords: Gelsemine, indole alkaloid, Alzheimer's disease, total synthesis, asymmetric synthesis, hexacyclic cage structures.

« Previous Next »
Graphical Abstract

[1]
Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J. Nat. Prod., 2020, 83(3), 770-803.
[http://dx.doi.org/10.1021/acs.jnatprod.9b01285] [PMID: 32162523]
[2]
Sun, J.; Yang, H.; Tang, W. Recent advances in total syntheses of complex dimeric natural products. Chem. Soc. Rev., 2021, 50(4), 2320-2336.
[http://dx.doi.org/10.1039/D0CS00220H] [PMID: 33470268]
[3]
Fernandes, R.A.; Kumar, P.; Choudhary, P. Advances in catalytic and protecting-group-free total synthesis of natural products: A recent update. Chem. Commun. (Camb.), 2020, 56(61), 8569-8590.
[http://dx.doi.org/10.1039/D0CC02659J] [PMID: 32537619]
[4]
Trost, B.M. The atom economy--a search for synthetic efficiency. Science, 1991, 254(5037), 1471-1477.
[http://dx.doi.org/10.1126/science.1962206] [PMID: 1962206]
[5]
Yang, L.; Wang, Z. Advances in the total synthesis of aflatoxins. Front Chem., 2021, 9, 779765.
[http://dx.doi.org/10.3389/fchem.2021.779765] [PMID: 34917589]
[6]
Shoaib, R.M.; Zhang, J.Y.; Mao, X.F.; Wang, Y.X. Gelsemine and koumine, principal active ingredients of Gelsemium, exhibit mechanical antiallodynia via spinal gly-cine receptor activation-induced allopregnanolone biosynthesis. Biochem. Pharmacol., 2019, 161, 136-148.
[http://dx.doi.org/10.1016/j.bcp.2019.01.014] [PMID: 30668937]
[7]
Zhang, J.Y.; Gong, N.; Huang, J.L.; Guo, L.C.; Wang, Y.X. Gelsemine, a principal alkaloid from Gelsemium sempervirens Ait., exhibits potent and specific antinocicep-tion in chronic pain by acting at spinal α3 glycine receptors. Pain, 2013, 154(11), 2452-2462.
[http://dx.doi.org/10.1016/j.pain.2013.07.027] [PMID: 23886522]
[8]
Chen, L.; Pan, H.; Bai, Y.; Li, H.; Yang, W.; Lin, Z.X.; Cui, W.; Xian, Y.F. Gelsemine, a natural alkaloid extracted from Gelsemium elegans Benth. alleviates neuroin-flammation and cognitive impairments in Aβ oligomer-treated mice. Psychopharmacology (Berl.), 2020, 237(7), 2111-2124.
[http://dx.doi.org/10.1007/s00213-020-05522-y] [PMID: 32363440]
[9]
Ye, Q.; Feng, Y.; Wang, Z.; Jiang, W.; Qu, Y.; Zhang, C.; Zhou, A.; Xie, S.; Zou, J. Effects of gelsemine on oxidative stress and DNA damage responses of Tetrahymena thermophila. PeerJ, 2018, 6, e6093.
[http://dx.doi.org/10.7717/peerj.6093] [PMID: 30581679]
[10]
Lara, C.O.; Murath, P.; Muñoz, B.; Marileo, A.M.; Martín, L.S.; San Martín, V.P.; Burgos, C.F.; Mariqueo, T.A.; Aguayo, L.G.; Fuentealba, J.; Godoy, P.; Guzman, L.; Yévenes, G.E. Functional modulation of glycine receptors by the alkaloid gelsemine. Br. J. Pharmacol., 2016, 173(14), 2263-2277.
[http://dx.doi.org/10.1111/bph.13507] [PMID: 27128379]
[11]
Lin, L.; Zheng, J.; Zhu, W.; Jia, N. Nephroprotective effect of gelsemine against cisplatin-induced toxicity is mediated via attenuation of oxidative stress. Cell Biochem. Biophys., 2015, 71(2), 535-541.
[http://dx.doi.org/10.1007/s12013-014-0231-y] [PMID: 25343941]
[12]
Maftei, C.V.; Fodor, E.; Jones, P.G.; Daniliuc, C.G.; Franz, M.H.; Kelter, G.; Fiebig, H-H.; Tamm, M.; Neda, I. Novel 1,2,4-oxadiazoles and trifluoromethylpyridines related to natural products: Synthesis, structural analysis and investigation of their antitumor activity. Tetrahedron, 2016, 72(9), 1185-1199.
[http://dx.doi.org/10.1016/j.tet.2016.01.011]
[13]
Ott, I. On the medicinal chemistry of gold complexes as anticancer drugs. Coord. Chem. Rev., 2009, 253(11-12), 1670-1681.
[http://dx.doi.org/10.1016/j.ccr.2009.02.019]
[14]
Gasser, G.; Ott, I.; Metzler-Nolte, N. Organometallic anticancer compounds. J. Med. Chem., 2011, 54(1), 3-25.
[http://dx.doi.org/10.1021/jm100020w] [PMID: 21077686]
[15]
Maftei, C.V.; Fodor, E.; Jones, P.G.; Freytag, M.; Franz, M.H.; Kelter, G.; Fiebig, H.H.; Tamm, M.; Neda, I. N-heterocyclic carbenes (NHC) with 1,2,4-oxadiazole-substituents related to natural products: synthesis, structure and potential antitumor activity of some corresponding gold(I) and silver(I) complexes. Eur. J. Med. Chem., 2015, 101, 431-441.
[http://dx.doi.org/10.1016/j.ejmech.2015.06.053] [PMID: 26185007]
[16]
Maftei, E.; Maftei, C.V.; Jones, P.G.; Freytag, M.; Franz, M.H.; Kelter, G.; Fiebig, H.H.; Tamm, M.; Neda, I. Trifluoromethylpyridine-substituted N-heterocyclic carbenes (NHC) related to natural products: Synthesis, structure and potential antitumor activity of some corresponding gold(I), rhodium(I) and iridium(I) complexes. Helv. Chim. Acta, 2016, 99(6), 469-481.
[http://dx.doi.org/10.1002/hlca.201500529]
[17]
Sheikh, Z.; Steel, R.W.; Tasker, A.S.; Johnson, A.P. A total synthesis of gelsemine: Synthesis of a key tetracyclic intermediate. J. Chem. Soc. Chem. Commun., 1994, (6), 763-764.
[http://dx.doi.org/10.1039/c39940000763]
[18]
Dutton, J.K.; Steel, R.W.; Tasker, A.S.; Popsavin, V.; Johnson, A.P. A total synthesis of gelsemine: Oxindole spiroannelation. J. Chem. Soc. Chem. Commun., 1994, (6), 765-766.
[http://dx.doi.org/10.1039/c39940000765]
[19]
Newcombe, N.J.; Ya, F.; Vijn, R.J.; Hiemstra, H.; Speckamp, W.N. The total synthesis of (±)-gelsemine. J. Chem. Soc. Chem. Commun., 1994, 0(6), 767-768.
[http://dx.doi.org/10.1039/C39940000767]
[20]
Kuzmich, D.; Wu, S.C.; Ha, D.C.; Lee, C.S.; Ramesh, S.; Atarashi, S.; Choi, J.K.; Hart, D.J. Total synthesis of dL-21-oxogelsemine. J. Am. Chem. Soc., 1994, 116(15), 6943-6944.
[http://dx.doi.org/10.1021/ja00094a062]
[21]
Atarashi, S.; Choi, J.K.; Ha, D.C.; Hart, D.J.; Kuzmich, D.; Lee, C.S.; Ramesh, S.; Wu, S.C. Free radical cyclizations in alkaloid total synthesis: (±)-21-Oxogelsemine and (±)-gelsemine. J. Am. Chem. Soc., 1997, 119(27), 6226-6241.
[http://dx.doi.org/10.1021/ja970089h]
[22]
Fukuyama, T.; Liu, G. Stereocontrolled total synthesis of (±)-gelsemine. J. Am. Chem. Soc., 1996, 118(31), 7426-7427.
[http://dx.doi.org/10.1021/ja961701s]
[23]
Fukuyama, T.; Liu, G. Stereocontrolled total synthesis of (±)-gelsemine. Pure Appl. Chem., 1997, 69(3), 501-505.
[http://dx.doi.org/10.1351/pac199769030501]
[24]
Madin, A.; O’Donnell, C.J.; Oh, T.; Old, D.W.; Overman, L.E.; Sharp, M.J. Total synthesis of (±)-gelsemine. Angew. Chem. Int. Ed., 1999, 38(19), 2934-2936.
[http://dx.doi.org/10.1002/(SICI)1521-3773(19991004)38:19<2934::AIDANIE2934>3.0.CO;2-L]
[25]
Earley, W.G.; Jacobsen, J.E.; Madin, A.; Meier, G.P.; O’Donnell, C.J.; Oh, T.; Old, D.W.; Overman, L.E.; Sharp, M.J. Aza-cope rearrangement-mannich cyclizations for the formation of complex tricyclic amines: stereocontrolled total synthesis of (+/-)-gelsemine. J. Am. Chem. Soc., 2005, 127(51), 18046-18053.
[http://dx.doi.org/10.1021/ja055710p] [PMID: 16366556]
[26]
Earley, W.G.; Oh, T.; Overman, L.E. Synthesis studies directed toward gelsemine. Preparation of an advanced pentacyclic intermediate. Tetrahedron Lett., 1988, 29(31), 3785-3788.
[http://dx.doi.org/10.1016/S0040-4039(00)82114-0]
[27]
Ng, F.W.; Lin, H.; Chiu, P.; Danishefsky, S.J. Explorations in organic chemistry leading to the total synthesis of (+/-)-gelsemine. J. Am. Chem. Soc., 2002, 124(33), 9812-9824.
[http://dx.doi.org/10.1021/ja0204675] [PMID: 12175241]
[28]
Ng, F.W.; Lin, H.; Tan, Q.; Danishefsky, S.J. The synthesis of a key intermediate en route to gelsemine: A program based on intramolecular displacement of the carbon-oxygen bond of a strategic oxetane. Tetrahedron Lett., 2002, 43(4), 545-548.
[http://dx.doi.org/10.1016/S0040-4039(01)02212-2]
[29]
Lin, H.; Ng, F.W.; Danishefsky, S.J. The synthesis of (±)-gelsemine. Tetrahedron Lett., 2002, 43(4), 549-551.
[http://dx.doi.org/10.1016/S0040-4039(01)02213-4]
[30]
Lin, H.; Danishefsky, S.J. Gelsemine: A thought-provoking target for total synthesis. Angew. Chem. Int. Ed., 2003, 42(1), 36-51.
[http://dx.doi.org/10.1002/anie.200390048] [PMID: 19757588]
[31]
Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Enantioselective total synthesis of (+)-gelsemine: Determination of its absolute configuration. Angew. Chem. Int. Ed. Engl., 2000, 39(22), 4073-4075.
[http://dx.doi.org/10.1002/1521-3773(20001117)39:22<4073:AID-ANIE4073>3.0.CO;2-V] [PMID: 11093209]
[32]
Grieco, P.A.; Gilman, S.; Nishizawa, M. Organoselenium chemistry. A facile one-step synthesis of alkyl aryl selenides from alcohols. J. Org. Chem., 1976, 41(8), 1485-1486.
[http://dx.doi.org/10.1021/jo00870a052]
[33]
Zhou, X.; Xiao, T.; Iwama, Y.; Qin, Y. Biomimetic total synthesis of (+)-gelsemine. Angew. Chem. Int. Ed. Engl., 2012, 51(20), 4909-4912.
[http://dx.doi.org/10.1002/anie.201201736] [PMID: 22489097]
[34]
Hili, R.; Yudin, A.K. Readily available unprotected amino aldehydes. J. Am. Chem. Soc., 2006, 128(46), 14772-14773.
[http://dx.doi.org/10.1021/ja065898s] [PMID: 17105264]
[35]
Chen, X.; Duan, S.; Tao, C.; Zhai, H.; Qiu, F.G. Total synthesis of (+)-gelsemine via an organocatalytic Diels-Alder approach. Nat. Commun., 2015, 6(1), 7204.
[http://dx.doi.org/10.1038/ncomms8204] [PMID: 25995149]
[36]
Kohari, Y.; Okuyama, Y.; Kwon, E.; Furuyama, T.; Kobayashi, N.; Otuki, T.; Kumagai, J.; Seki, C.; Uwai, K.; Dai, G.; Iwasa, T.; Nakano, H. Enantioselective Diels-Alder reaction of 1,2-dihydropyridines with aldehydes using β-amino alcohol organocatalyst. J. Org. Chem., 2014, 79(20), 9500-9511.
[http://dx.doi.org/10.1021/jo501433c] [PMID: 25259961]
[37]
Ghosh, A.; Carter, R.G. Recent syntheses and strategies toward polycyclic gelsemium alkaloids. Angew. Chem. Int. Ed. Engl., 2019, 58(3), 681-694.
[http://dx.doi.org/10.1002/anie.201807509] [PMID: 30378226]
[38]
Wang, Z. Advances in the asymmetric total synthesis of natural products using chiral secondary amine catalyzed reactions of α, β-unsaturated aldehydes. Molecules, 2019, 24(18), 3412.
[http://dx.doi.org/10.3390/molecules24183412] [PMID: 31546876]
[39]
Avent, A.G.; Byrne, P.W.; Penkett, C.S. A photochemical approach to the gelsemine skeleton. Org. Lett., 1999, 1(13), 2073-2075.
[http://dx.doi.org/10.1021/ol991119j]
[40]
Pearson, A.J.; Wang, X. A convenient one-pot procedure to afford bicyclic molecules by stereospecific iron carbonyl mediated [6 + 2] ene-type cyclization: A possible approach to gelsemine. J. Am. Chem. Soc., 2003, 125(44), 13326-13327.
[http://dx.doi.org/10.1021/ja030407e] [PMID: 14583006]
[41]
Mao, Z.; Baldwin, S.W. New spirocyclic oxindole synthesis based on a hetero Claisen rearrangement. Org. Lett., 2004, 6(14), 2425-2428.
[http://dx.doi.org/10.1021/ol0491888] [PMID: 15228295]
[42]
Ozturk, C.; Aviyente, V.; Houk, K.N. Modeling the stereoselectivity of the Johnson-Claisen rearrangements in the Danishefsky synthesis of gelsemine. J. Org. Chem., 2005, 70(18), 7028-7034.
[http://dx.doi.org/10.1021/jo050055p] [PMID: 16122220]
[43]
Grecian, S.; Aubé, J. Double conjugate addition of a nitropropionate ester to a quinone monoketal: Synthesis of an advanced intermediate to (+/-)-gelsemine. Org. Lett., 2007, 9(16), 3153-3156.
[http://dx.doi.org/10.1021/ol071174p] [PMID: 17628069]
[44]
Tchabanenko, K.; Simpkins, N.S.; Male, L. A concise approach to a gelsemine core structure using an oxygen to carbon bridge swapping strategy. Org. Lett., 2008, 10(21), 4747-4750.
[http://dx.doi.org/10.1021/ol801835q] [PMID: 18837555]
[45]
Stang, E.M.; White, M.C. Molecular complexity via C-H activation: a dehydrogenative Diels-Alder reaction. J. Am. Chem. Soc., 2011, 133(38), 14892-14895.
[http://dx.doi.org/10.1021/ja2059704] [PMID: 21842902]
[46]
Zhou, S.; Xiao, T.; Song, H.; Zhou, X. Studies toward the total synthesis of (+)-gelsemine and synthesis of spirocyclopentaneoxindole through intramolecular Michael cyclization. Tetrahedron Lett., 2012, 53(42), 5684-5687.
[http://dx.doi.org/10.1016/j.tetlet.2012.08.048]
[47]
Moulia, A.; Teo, J.; Johannes, C.W.; Richard, J.A. Expedient synthesis of bicyclo[3.2.1]octanes and bicyclo[3.3.1]nonanes via the double Michael addition to cyclic dienones. RSC Adv., 2013, 3(45), 22882-22886.
[http://dx.doi.org/10.1039/c3ra43923b]
[48]
Lam, J.K.; Joseph, S.B.; Vanderwal, C.D. A Zincke aldehyde approach to gelsemine. Tetrahedron Lett., 2015, 56(23), 3165-3168.
[http://dx.doi.org/10.1016/j.tetlet.2014.12.089]

Rights & Permissions Print Cite
Article Metrics
56
1
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy