BREVETOXIN CHEMISTRY, With a spectroscopy section

BY DR ANTHONY MELVIN CRASTO

A SHORT PRESENTATION FOR ACADEMICS MAR 2012

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This is a vast topic and a short overview is given and in no way complete justice can be done for this

Brevetoxin A [2]

Brevetoxin B [3]

Brevetoxin (PbTx), or brevetoxins, are a suite of cyclic polyether compounds produced naturally by a species of dinoflagellate known asKarenia brevis. Brevetoxins are neurotoxins that bind to voltage-gated sodium channels in nerve cells, leading to disruption of normal neurological processes and causing the illness clinically described as neurotoxic shellfish poisoning (NSP).[1] Although brevetoxins are most well-studied in K. brevis, they are also found in other species of Karenia and at least one large fish kill has been traced to brevetoxins 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, Grtner P.". Nature 392 (6673): 2649. 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: 1025210263. ^ 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 of the most complex structures ever isolated from nature. But their structure of repeating oxygen-containing rings suggests a fairly simple biosynthesis, involving zipping up a long chain molecule. Koji Nakanishi, who isolated brevetoxin B in 1981, proposed in 1985 that a cascade of epoxide-opening reactions could explain how these seemingly complex structures are made2. But until now, attempts to recreate this cascade in the lab have predominantly yielded the wrong product - producing five-membered rings, rather than the sixmembered rings of the natural product. However, Tim Jamison and Ivan Vilotijevic at the Massachusetts Institute of Technology, US, have now found that the solvent used in the reaction is crucial. When the reaction is done in water - as it is in nature - rather than in organic solvents, it is almost exclusively the sixmembered product that is formed.

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

Total synthesis of brevetoxin A K. C. Nicolaou, Zhen Yang, Guo-qiang Shi, Janet L. Gunzner, Konstantinos A. Agrios and Peter Grtner Nature 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- 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 (4.0 equiv.), CH2Cl2, 0 C, 15 min, 99%; (m) Ph2PLi (3.0 equiv.), HMPA (3.0 equiv.), THF, 0 C, 30 min; then 5% aq. H2O2 (excess), 93%: DIBAL, diisobutylaluminium hydride, 4-DMAP, 4-Ndimethylaminopyridine; HMPA, hexamethylphosphoramide; KHMDS, potassium hexamethyldisilazide; MS, molecular sieves; NMO, 4methylmorpholine-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 O H O H B C D TBDPSO E OH HO PivO H H 26

Me

Compound 26: Rf = 0.58 (silica, 1:1 ethyl acetate:hexane); [a]22D + 14.4 (c 1.0, CHCl3); IR (neat) nmax 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) d 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) d 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 HO Me O H C O H H D HO H B E

Me H OH OTBS H O Me H O H HO H I J H G O O H H H 43 F

OTBDPS

Compound 43: Rf = 0.40 (silica, 2:8 ethyl acetate:hexane); [a]22D +107.0 (c 1.0, CH2Cl2); IR (neat) nmax 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) d 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) d 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.

Crimmins synthesis of brevetoxin

REFERENCE http://www.unc.edu/depts/mtcgroup/pap ers/ol2009489.pdf

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

 (Ciguatoxin) (Brevetoxin)

Toxicon, 1985, 23, 473.

Total Synthesis of Brevetoxin-B

NMR

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