Anthony crasto brevetoxin synthesis

BREVETOXIN CHEMISTRY, With aspectroscopy sectionBYDR ANTHONY MELVIN CRASTOA SHORT PRESENTATION FORACADEMICSMAR 2012

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This is a vast topic and a shortoverview is givenandin no way complete justice can bedone for this

Brevetoxin A [2] Brevetoxin B [3]

Brevetoxin (PbTx), or brevetoxins, are a suite of cyclic polyether compoundsproduced naturally by a species of dinoflagellate known asKarenia brevis.Brevetoxins are neurotoxins that bind to voltage-gated sodium channels in nervecells, leading to disruption of normal neurological processes and causing theillness clinically described as neurotoxic shellfish poisoning (NSP).[1]Although brevetoxins are most well-studied in K. brevis, they are also found inother species of Karenia and at least one large fish kill has been traced tobrevetoxins in Chattonella.[1]

• Biosynthesis• A proposed biosynthetic route includes a novel polyketide formation involving Claisen condensation of a dicarboxylic acid with the alpha-position of the second carboxylic function with a loss of a carboxyl group.[7]

References References ^ a b Watkins, Sm; Reich, A; Fleming, Le; Hammond, R (2008), "Neurotoxic shellfish poisoning" (Free full text), Marine drugs 6 (3): 431– 55,doi:10.3390/md20080021, PMC 2579735, PMID 19005578 ^ "Total synthesis of brevetoxin A. Nicolaou KC, Yang Z, Shi G, Gunzner JL, Agrios KA, Gärtner P.". Nature 392 (6673): 264–9. 1998 Mar 19. ^ a b Goh Matsuo, Koji Kawamura, Nobuyuki Hori, Hiroko Matsukura, and Tadashi Nakata (2004). "Total Synthesis of Brevetoxin-B". J. Am. Chem. Soc. 126: 14374-1437. ^ K.C. Nicolaou, F.P.J.T. Rutjes, E.A. Theodorakis, J. Tiebes, M. Sato, E. Untersteller (1995). "Total Synthesis of Brevetoxin B 3. The Final Strategy and Completion". J. Am. Chem. Soc. 117: 10252–10263. ^ Nature 1998, 392, 264-269 ^ Org. Lett. 2009, 11 (2), 489-492 ^ Hong-Nong Chou and Yuzuru Shimizu (1987). "Biosynthesis of Brevetoxins. Evidence for the Mixed Origin of the Backbone Carbon Chain and the Possible Involvement of Dicarboxylic Acids". J Am Chem Soc 109: 2184– 218. doi:10.1021/ja00241a048.

1 I Vilotijevic and T F Jamison, Science, 2007 (DOI: 10.1126/science.1146421)Brevetoxin B, gymnocin B and related toxic marine natural products are some ofthe most complex structures ever isolated from nature. But their structure ofrepeating oxygen-containing rings suggests a fairly simple biosynthesis, involvingzipping up a long chain molecule. Koji Nakanishi, who isolated brevetoxin B in1981, proposed in 1985 that a cascade of epoxide-opening reactions could explainhow these seemingly complex structures are made2.But until now, attempts to recreate this cascade in the lab have predominantlyyielded the wrong product - producing five-membered rings, rather than the six-membered rings of the natural product. However, Tim Jamison and IvanVilotijevic at the Massachusetts Institute of Technology, US, have now found thatthe solvent used in the reaction is crucial. When the reaction is done in water - asit is in nature - rather than in organic solvents, it is almost exclusively the six-membered product that is formed.

Gymnocin B and related ladder polyether toxins could be biosynthesised via an epoxide-opening cascade

Total synthesis of brevetoxin AK. C. Nicolaou, Zhen Yang, Guo-qiang Shi, Janet L. Gunzner, Konstantinos A. Agriosand Peter GärtnerNature 392, 264-269(19 March 1998)doi:10.1038/32623

• Reagents and conditions as follows. (a) KHMDS (3.0 equiv.), (PhO)2P(O)Cl (5.0 equiv.), THF, -78 °C, 1 h; (b) (n- Bu)3SnCH = CH2 (3.0 equiv.), LiCl (5.0 equiv.), Pd(Ph3P)4 (0.1 equiv.), THF, 75 °C, 2 h, 81% for two steps; (c) O2, TPP (0.01 equiv.), CCl4, 25 °C, 0.3 h; (d) Al(Hg) (excess), H2O:THF (1:29), 25 °C, 2 h, 58% for two steps; (e) t-Bu2SiCl (1.5 equiv.), imidazole (10.0 equiv.), CH2Cl2, 25 °C, 1 h, 91%; (f) TPAP (0.1 equiv.), NMO (2.0 equiv.), 4-Å MS, CH2Cl2, 25 °C, 1 h, 82%; (g) [(Ph3P)CuH]6 (2.0 equiv.), benzene, 25 °C, 72 h, 70%; (h) DIBAL (2.5 equiv.), CH2Cl2, -78 °C, 30 min, 95%, 5:1 ratio; (i) TrCl4-DMAP (15.0 equiv.), CH2Cl2, 40 °C, 24 h, 75% pure trityl ether after silica- gel chromatography; (j) POCl3 (0.01 equiv.), CH2 = CMe(OMe) (solvent), 25 °C, 6 h, 95%; (k)

neutral alumina-1% H2O activated by heating(excess), hexane, 25 °C, 2 h, 96%; (l) MsCl (2.0 equiv.), Et3N (4.0equiv.), CH2Cl2, 0 °C, 15 min, 99%; (m) Ph2PLi (3.0 equiv.), HMPA (3.0equiv.), THF, 0 °C, 30 min; then 5% aq. H2O2 (excess), 93%:DIBAL, diisobutylaluminium hydride, 4-DMAP, 4-N-dimethylaminopyridine; HMPA, hexamethylphosphoramide;KHMDS, potassium hexamethyldisilazide; MS, molecular sieves; NMO, 4-methylmorpholine-N-oxide; TBDPS, t-BuPh2Si, TBS, t-BuMe2Si;THF, tetrahydrofuran; TPAP, tetra-n-propylammonium perruthenate;TPP, tetraphenylporphyrin; Tr, trityl. Ms, CH3SO2 or methanesulphonyl;imid., imidazole. For selected physical data for compound 2,

Me Me H Me O H O H O B C D TBDPSO O O E P iv O H H H H 26Compound 26: Rf = 0.58 (silica, 1:1 ethyl acetate:hexane); [ ]22D + 14.4 (c 1.0, CHCl3);IR (neat) max 2955.9, 2872.3, 1731.0, 1460.5, 1333.6, 1282.3, 1246.4, 1155.0, 1097.1, 1036.2, 1000.3, 913.1, 820.8, 757.4, 705.5 cm -1 1H NMR (CDCl3, 500 MHz) 7.67-7.63 (m, 4 H), 7.45-7.34 (m, 6 H), 5.68 (ddd, J = 10.5, 8.0, 8.0 Hz, 1 H),5.59 (ddd, J = 10.5, 8.5, 8.5 Hz, 1 H), 4.55 (dd, J = 8.5, 8.5 Hz, 1 H), 4.26 (ddd, J = 10.5, 6.5, 3.5 Hz, 1 H),4.06 (ddd, J = 10.5, 10.0, 5.0 Hz, 1 H), 4.09-4.03 (m, 1 H), 3.70-3.64 (m, 1 H), 3.49 (dd, J = 11.5, 5.0 Hz, 1 H),3.47-3.40 (m, 1 H), 3.37 (dd, J = 9.5, 9.5 Hz, 1 H), 3.33 (dd, J = 9.5, 9.5 Hz, 1 H), 3.00 (ddd, J = 12.0, 9.0, 4.5 Hz, 1 H), 2.49-2.38 (m, 1 H), 2.38-2.18 (m, 6 H), 2.10 (ddd, J = 12.5, 4.5, 4.5 Hz, 1 H), 2.04-1.89 (m, 2 H), 1.72-1.64 (m, 1 H),1.68 (ddd, J = 14.5, 10.5, 5.0 Hz, 1 H), 1.57-1.47 (m, 3 H), 1.47-1.33 (m, 3 H), 1.23 (s, 9 H), 1.06 (s, 3 H), 1.05 (d, J = 7.5 Hz, 3 H),1.01 (s, 9 H), 0.47 (d, J = 7.0 Hz, 3 H); 13C NMR (CDCl3, 125 MHz) 178.1, 174.3, 135.8, 134.2, 133.5, 129.7, 129.6, 129.5,127.6, 127.4, 84.0, 82.9, 81.7, 80.6, 80.5, 77.5, 75.5, 68.7, 61.0, 53.9, 46.8, 38.7, 38.1, 34.2, 33.9, 33.4, 33.2, 33.0, 27.3,27.2, 26.9, 26.4, 23.7, 19.9, 19.3, 16.2; HRMS calcd. for C46H66O8Si (M + Cs+) 907.3581, found 907.3540.

Me H TBDPSO Me B O H HO O C H H Me D H H O OH H H OTBS E F OMe H O H HO G H I J H OTBDPS O O H H H 43Compound 43: Rf = 0.40 (silica, 2:8 ethyl acetate:hexane); [ ]22D +107.0 (c 1.0, CH2Cl2); IR (neat) max 3474.3, 2929.2, 2862.5, 1457.8, 1424.4, 1385.5, 1252.0, 1082.5, 823.7, 704.3, 606.7, 505.5 cm -1;1H NMR (CDCl3, 600 MHz) 7.68-7.64 (m, 8 H), 7.45-7.34 (m, 12 H), 5.78-5.48 (m, 3 H), 5.70 (dd, J = 11.0, 5.0 Hz, 1 H), 4.48-4.39 (m, 1 H), 4.16-4.08 (m, 1 H), 3.96-3.62 (m, 8 H), 3.59 (dd, J = 11.5, 4.9 Hz, 1 H), 3.56-3.50 (m, 2 H), 3.44-3.36 (m, 1 H),3.33-3.08 (m, 5 H), 3.03-2.91 (m, 3 H), 2.63 (dd, J = 11.0, 11.0 Hz, 1 H), 2.38-2.18 (m, 4 H), 2.18-2.05 (m, 4 H), 2.02-1.82 (m, 6 H), 1.98-1.45 (m, 17 H), 1.44-1.35 (m, 3 H), 1.23 (bs, 3 H), 1.21 (s, 3 H), 1.07 (s, 3 H), 1.04 (s, 9 H),1.01 (s, 9 H), 0.86 (s, 9 H), 0.48 (d, J = 7.1 Hz, 3 H), 0.03 (s, 3 H), 0.02 (s, 3 H); 13C NMR (CDCl3, 150 MHz) 138.4, 135.8, 135.5, 134.2, 134.1, 134.1, 133.5, 129.8, 129.6, 129.5, 127.7, 127.6, 127.5, 124.4,85.8, 83.2, 81.9, 81.2, 80.2, 78.5, 77.1, 76.7, 76.0, 75.5, 72.7, 71.1, 68.8, 67.0, 63.8, 62.0, 60.2, 53.7, 46.5, 44.9, 37.5, 36.4, 36.2,35.7, 35.7, 34.5, 30.9, 30.1, 29.1, 27.2, 27.0, 26.9, 26.5, 25.9, 21.2, 19.4, 19.2, 18.2, 16.6, 16.3, 14.1, -4.3, -5.2;MS (FAB) calcd. for C86H126O13Si3 (M + Na+) 1474, found 1474.

Isobe, Hamajima. ACIEE, 2009, EarlyView.DOI: 10.1002/anie.200805996.Also: 10.1055/s-2004-817769 , 10.1021/jo980088n , 10.1021/jo034021y, 10.1021/ol0600741 ,10.1016/j.tet.2007.03.012 , 10.1016/S0040-4020(03)00873-1, 10.1016/S0040-4020(02)00044-3… and many more. Crimmin’s synthesis of brevetoxin REFERENCE http://www.unc.edu/depts/mtcgroup/pap ers/ol2009489.pdf

READ MORE AThttp://www.unc.edu/depts/mtcgroup/papers/ol2009489.pdf

シガテラ食中毒の原因成分のシガトキシン (Ciguatoxin) や、赤潮が発生させる神経毒のブレベトキシン (Brevetoxin) などの海産毒は「環状ポリエーテル類」と呼ば（Toxicon, 1985, 23, 473.）れ、その構造の複雑さから全合成の良いターゲットとされてきました（構造はリンク先参照）。

Total Synthesis of Brevetoxin-B

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Anthony crasto brevetoxin synthesis

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