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Review
. 2008 Jun;108(6):1982-2014.
doi: 10.1021/cr078198u. Epub 2008 May 20.

Chemistry, biology, and medicinal potential of narciclasine and its congeners

Alexander Kornienko  1 , Antonio Evidente
Affiliations
Review

Chemistry, biology, and medicinal potential of narciclasine and its congeners

Alexander Kornienko et al. Chem Rev. 2008 Jun.
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1
Ring types and representative Amaryllidaceae alkaloids (see Table 1).
Figure 2
Figure 2
Alkaloids from Amaryllis belladonna L.: hippeastrine (10), pancracine (11), vittatine (12), 11-hydroxyvittatine (13) and amarbellisine (14).
Figure 3
Figure 3
Alkaloids from Clivia spp.: clivonine (15), clivatine (16), clivimine (18), nobilisine (19), nobilisitine A (20) and B (17), and (+)-8-demethylmaritidine (21).
Figure 4
Figure 4
Selected alkaloids from Crinum spp.: crinamine (22), hyamine (23), pratorimine (24) and pratosine (25).
Figure 5
Figure 5
Alkaloids from Narcissus tazetta L.: homolycorine (26), its 9-O-demethyl derivative (27) and tazettine (28).
Figure 6
Figure 6
Alkaloids from Leucojum aestivum, N. tazetta ssp. tazetta and Pancratium maritimum exhibiting antimalarial activity: crinine (29), 3-epi-hydroxybulbospermine (30), 6-hydroxyhaemanthamine (31), galanthamine (32) and 3-epi-galanthamine (33).
Figure 7
Figure 7
Phenanthridiunium betaine alkaloids from Pancratium and Zephyranthes: ungeremine (34), zeflabetaine (35), zefbetaine (36), iso-zefbetaine (37), pseudolycorine (38), α-dihydrolycorine (39), maritidine (40) and (+)-epi-maritidine (41), as well as lycorine oxidation derivatives anhydrolycorinium chloride (42) and anhydrolycorine lactam (=crinasiadine, 43).
Figure 8
Figure 8
Representative amaryllidaceae plants used in traditional medicine. Reprinted with with permission of Springer Science and Business Media (Reference 28).
Figure 9
Figure 9
Narciclasine (44), pancratistatin (51) and their corresponding naturally occurring analogues (45–50) and (52–56).
Figure 10
Figure 10
Biosynthesis of O-methylnorbelladine (59).
Figure 11
Figure 11
Biosynthesis of Amaryllidaceae alkaloids by para-ortho oxidative coupling of O-methylnorbelladine.
Figure 12
Figure 12
Biosynthesis of Amaryllidaceae alkaloids by para-para oxidative coupling of O-methylnorbelladine.
Figure 13
Figure 13
Biosynthesis of Amaryllidaceae alkaloids by a third mode of oxidative coupling of O-methylnorbelladine.
Figure 14
Figure 14
Biosynthesis of narciclasine (44).
Figure 15
Figure 15
Incorrect original structure assignment of narciclasine (A) and narciprimine (B).
Figure 16
Figure 16
Structures of anisomycin and trichodermin.
Figure 17
Figure 17
Ring A analogues.
Figure 18
Figure 18
Ring B analogues.
Figure 19
Figure 19
Ring C analogues.
Figure 20
Figure 20
Structures of ent-7-deoxynarciclasine and ent-7-deoxypancratistatin.
Figure 21
Figure 21
Structures of 3,4-cyclic phosphate prodrugs.
Figure 22
Figure 22
Chemoenzymatic strategy to (+)-pancratistatin, (+)-7-deoxypancratistatin and (+)-7-deoxynarciclasine.
Figure 23
Figure 23
Radical cyclization strategy to (+)-narciclasine and (+)-7-deoxynarciclasine.
Figure 24
Figure 24
Radical cyclization strategy in the first generation synthesis of (+)-7-deoxypancratistatin of Keck and coworkers.
Figure 25
Figure 25
Kim cascade radical cyclization strategy in the second generation synthesis of (+)-7-deoxypancratistatin of Keck and coworkers.
Figure 26
Figure 26
Strategy to (+)-narciclasine based on intramolecular arene-epoxide ring opening.
Figure 27
Figure 27
Strategy to (+)-pancratistatin based on intramolecular ring opening of a cyclic sulfate moiety.
Scheme 1.<sup>a</sup>
Scheme 1.a
a Reagents and conditions: (a) CH2N2 (excess), EtOH, 48 h; (b) KMnO4, H2O, 0 °C, 48 h; (c) Ac2O, py, 48 h, rt; (d) Ba(OH)2, MeOH, reflux; (e) acetone, HC(OEt)3, TsOH, reflux, 15 h; (f) conc. HCl; (g) H2, Pd/CaCO3, EtOH, 3 h.
Scheme 2.<sup>a</sup>
Scheme 2.a
a Reagents and conditions: (a) Ac2O, py, 3 h; (b) Ac2O, py, 3 d; (c) MnO2, THF, 2.5 h; (d) silica gel, THF; (e) NaBH4, EtOH, 0.5 h, rt.
Scheme 3.<sup>a</sup>
Scheme 3.a
a Reagents and conditions: (a) Ac2O, py; (b) OsO4 (cat.), NMO, HQ, DMF/H2O; (c) NH3/MeOH, CH2Cl2.
Scheme 4.<sup>a</sup>
Scheme 4.a
a Reagents and conditions: (a) OsO4 (cat.), NMO, (DHQD)2PHAL, DMF/H2O; (b) H2SO4, THF/H2O; (c) SOCl2, Et3N, THF; RuCl3·3H2O/NaIO4, MeCN/CCl4/H2O; (d) PhCO2H, Cs2CO3, DMF; H2SO4, THF/H2O, 60 °C; K2CO3, MeOH.
Scheme 5.<sup>a</sup>
Scheme 5.a
a Reagents and conditions: (a) Ac2O (3.25 equiv.), py; (b) OsO4 (cat.), NMO, (DHQ)2PHAL, DMF/H2O; (c) N,N’-thiocarbonyldiimidazole, 2-butanone; (d) Bu3SnH, AIBN, PhCH3, 80 °C, 16 h; (e) K2CO3, H2O/MeOH/CH2Cl2.
Scheme 6.<sup>a</sup>
Scheme 6.a
a Reagents and conditions: (a) MCPBA, phosphate buffer; (b) H2, 10% Pd/C; K2CO3, MeOH/H2O (c) SOCl2, Et3N, THF; RuCl3·3H2O/NaIO4, MeCN/CCl4/H2O; (d) PhCO2H, Cs2CO3, DMF; H2SO4, THF/H2O, 70 °C; (e) K2CO3, MeOH.
Scheme 7.<sup>a</sup>
Scheme 7.a
a Reagents and conditions: (a) Me2CH(OMe)2, p-TsOH, DMF; (b) TBSCl, imidazole, DMF; LiAlH4, ether; TBAF, THF; (c) aq. H2SO4, THF/CH2Cl2; NaHCO3; HCl, MeOH (d) HCl, MeOH.
Scheme 8.<sup>a</sup>
Scheme 8.a
a Reagents and conditions: (a) 3H2O, Pd/C, 60 °C, 23 h, sealed ampoule; co-evaporation with ethanol (5 times).
Scheme 9.<sup>a</sup>
Scheme 9.a
a Reagents and conditions: (a) Ac2O, DMAP, py; (b) H2O, py, reflux; (c) i-Pr2NP(OBn)2, tetrazole, CH2Cl2; MCPBA, CH2Cl2; (d) (BnO)2P(O)H, DIPEA, DMAP, CCl4/MeCN; (e) H2, 10% Pd/C, ethanol; NaOH, H2O; (f) NaOMe, HOMe; H2, 10% Pd/C, ethanol; NaOMe, HOMe.
Scheme 10.<sup>a</sup>
Scheme 10.a
a Reagents and conditions: (a) Me2C(OMe)2, p-TsOH, CH2Cl2; (b) PhI=NTs, Cu(acac)2, MeCN; (c) Bu3SnH, AIBN, THF; (d) THF, −78 °C to rt; (e) s-BuLi, THF, (Boc)2O; (f) Na/anthracene, DME, −78 °C; (g) TBAF, THF; (h) NaAl(MeOCH2CH2O)2H2, morpholine, −45 °C, THF; (i) BnBr, K2CO3, DMF; (j) NaClO2, KH2PO4, 2-methyl-2-butene, t-BuOH, H2O; (k) CH2N2; (l) AcOH, THF, H2O, 60 °C; (m) t-BuOOH, VO(acac)2, PhH, 60 °C; (n) BzONa (cat.), H2O, 100 °C.
Scheme 11.<sup>a</sup>
Scheme 11.a
a Reagents and conditions: (a) MnO2, NaCN, Me2NH, i-PrOH; (b) n-BuLi, TMEDA, −104 °C; B(OMe)3, THF; AcOH, H2O2; (c) TBSCl, imidazole; (d) n-BuLi, TMEDA, −104 °C, Et2O, I2; (e) Me3OBF4, Na2HPO4, MeCN; (f) TsCl, py; (g) i. s-BuLi, TMEDA, THF, −90 °C; ii. CuCN, −90 to −20 °C.
Scheme 12.<sup>a</sup>
Scheme 12.a
a Reagents and conditions: (a) Me2C(OMe)2, p-TsOH, CH2Cl2; (b) p-O2NPhSO3NHCO2Me, K2CO3, CH2Cl2; (c) Bu3SnH, AIBN, THF; (d) BF3·Et2O, THF, −78 °C to −30 °C; (e) AcOH, THF, H2O, 65 °C; (f) t-BuOOH, VO(acac)2, PhH, 60 °C; (g) BzONa (cat.), H2O, 100 °C; (h) Ac2O, DMAP, py; (i) Tf2O, DMAP, CH2Cl2, 5 °C; (j) MeONa, MeOH.
Scheme 13.<sup>a</sup>
Scheme 13.a
a Reagents and conditions: (a) Bu4NIO4, CH2Cl2; (b) Al(Hg), THF; (c) i-PrMe2SiCl, imidazole, CH2Cl2; (d) BuLi, THF, −78 °C; (e) Pd(OAc)2, Tl(OAc), DIPHOS, anisole; (f) Pd/C, cyclohexene, EtOH; (g) CF3CO2H, 0 °C.
Scheme 14.<sup>a</sup>
Scheme 14.a
a Reagents and conditions: (a) Me2C(OMe)2, p-TsOH; (b) AcOH, H2O; (c) NaIO4, CH2Cl2; (d) CBr4, PPh3, NEt3; (e) L-selectride, Et2O, −78 °C; (f) HCl·H2NOBn, py; (g) n-BuLi, Et2O, −90 °C.
Scheme 15.<sup>a</sup>
Scheme 15.a
a Reagents and conditions: (a) 166, Pd(OAc)2, CuI, NEt3, PPh3, THF; (b) PhSH, hν, PhMe, 27 °C; (c) SmI2, THF, H2O, 0 °C; (d) MeI, K2CO3, DMF; (e) Me3Al, THF; (f) SmI2, MeOH, THF, 0 °C; (g) TFA, 0 °C.
Scheme 16.<sup>a</sup>
Scheme 16.a
a Reagents and conditions: (a) Pd(OAc)2, CuI, NEt3, PPh3, THF; (b) PhSH, hν, PhMe, 27 °C; (c) SmI2, THF; (d) TFA, 0 °C.
Scheme 17.<sup>a</sup>
Scheme 17.a
a Reagents and conditions: (a) TBSCl, imidazole; (b) 192, NaH, Cl3CCN, 0 °C; (c) TfOH, THF, 0 °C; (d) L-selectride, CH2Cl2, −78 °C; (e) HCl·H2NOBn, py; (f) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C; (g) HF·py, THF; (h) TPAP, NMO, 4Å MS; (i) 1-amino-2-phenylaziridine, EtOH, 0 °C; (j) Ph3SnH, AIBN, PhH, 78 °C; (k) SmI2, THF, then TFAA; (l) PCC, CH2Cl2, 55 °C; (m) BF3·Et2O, CH2Cl2; (n) K2CO3, MeOH.
Scheme 18.<sup>a</sup>
Scheme 18.a
a Reagents and conditions: (a) SOCl2, MeOH; (b) HCl·NH2OH, MeOH, AcONa; (c) t-BuOCl, CH2Cl2; (d) CH2Cl2, 0 °C, 12 h; (e) Al-Hg, H2O/MeCN; (f) p-O2NPhSO2Cl, MeCN, NEt3; (g) TBSCl, DBU; (h) NBS, H2O/acetone; (i) MeCN, K2CO3, 60 °C, then 208; (j) 20 mol% SnCl4, CH2Cl2; (k) Ac2O, K2CO3; (l) HSCH2CO2H, LiOH, DMF; (m) Boc2O, MeCN; (n) RuCl3, NaIO4, H2O; (o) DBU, PhH, 70 °C; (p) HCO2H, THF, 60 °C; (q) LiAlH4, THF.
Scheme 19.<sup>a</sup>
Scheme 19.a
a Reagents and conditions: (a) TIPDSCl2, imidazole, DMAP; (b) Me2C(OMe)2, p-TsOH; (c) PPh3, DEAD, MeSO3H, CH2Cl2; (d) NaN3, DMF, 60 °C; (e) TBAF, THF; (f) SOCl2, Et3N, CH2Cl2; (g) NaIO4, RuCl3, aq. MeCN; (h) PPh3, aq. THF.
Scheme 20.<sup>a</sup>
Scheme 20.a
a Reagents and conditions: (a) AcOH, 100 °C; (b) MgBr2·OEt2, COCl2, ether, 219; (c) K2CO3, MOMCl, DMF; (d) t-BuLi, CeCl3, ultrasound, THF, −78 °C to rt; (e) BBr3, CH2Cl2, −78 °C, then MeOH, −78 °C to rt.
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References

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    1. Gardeil JB, translator. Traduction des Oeuvres Médicales d’Hippocrate. 4 vols. Toulouse: Fages, Meilhec et Cie; 1801.
    1. Aetios of Amida. The gynaecology and obsterics of the VI century, A.D. Philadelphia: Blakiston Co.; 1950. 215 pp. (transl. by J. V. Ricci)
    1. Leclerc L Ibn al-Baitar. Traité des Simples par Ibn el-Beïthar. I. Vol. 23. Paris: Notices et Extraits des Manuscrits de la Bibl. Nat.; 1877. 476 pp. 1881, 25(I), 489 pp.; 1883, 26(I), 483 pp.
    1. Martin SF. The Alkaloids. New York: Academic Press; 1987. p. 251.

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