Anthony Melvin crasto Brevetoxin synthesis

1. BREVETOXIN CHEMISTRY, With a
spectroscopy section
BY
DR ANTHONY MELVIN CRASTO
A SHORT PRESENTATION FOR
ACADEMICS
MAR 2012

2. Dedicated to my son Lionel
Crasto,
He was only in first standard in school (dec2007)
when I was Paralysed head to toe.
His smiling face sees me through day in and day out.
Vast readership from academia and industry motivates me, and keeps me
going.
I am helping millions with free advertisement free websites and has million
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Thanks for helping me to keep lionel smiling

3. Shore
• Your own will power and determination which
reach you to the shore even if you are drowned
in the middle of a storm

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

5. Brevetoxin A [2] Brevetoxin B [3]

6. 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]

8. • 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]

9. 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.

10. 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 six-
membered 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 six-
membered product that is formed.

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

13. Total synthesis of brevetoxin A
K. C. Nicolaou, Zhen Yang, Guo-qiang Shi,
Janet L. Gunzner, Konstantinos A. Agrios
and Peter Gärtner
Nature 392, 264-269(19 March 1998)
doi:10.1038/32623

15. • 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)

16. 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-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,

17. Me
Me H Me
O H O
H O
B C D
TBDPSO
O O E
P iv O H H
H
H 26
Compound 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.

18. 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
43
Compound 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.

20. 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

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

27. 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）。

28. Total Synthesis of Brevetoxin-B

37. NMR

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57. amcrasto@gmail.com
DR ANTHONY CRASTO
chemistry sites
https://sites.google.com/site/anthonycrastoorganicchemistry/sites---my-own-on-the-net

58. Thanks
DR ANTHONY MELVIN CRASTO Ph.D
amcrasto@gmail.com
MBILE-+91 9323115463
GLENMARK SCIENTIST , NAVIMUMBAI,
INDIA
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