Tetrahedron Letters Vol. 21, pp 4043 - 4044 OOAO-4Oj9/80/1008-4043$02.

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OPergamon Press Ltd. 1980. Printed in Great Britain

GADUSOL, A METABOLITE FROM FISH EGGS

Patrick T. Grant and Peter A. Plack

N.E.R.C. Institute of Marine Biochemistry,
St. Fittick's Road, Aberdeen, AB1 3RA
and
Ronald H. Thomson*
Department of Chemistry, University of Aberdeen,
Meston Walk, Old Aberdeen, AB9 ZUE, Scotland

Abstract: Gadusol, a metabolite from the eggs of cod and other fishes, has been
identified as 1,4,5-trihydroxy-2-methoxy-5-hydroxymethylcyclohex-l-en-3-one,
related to the mycosporines and analogous compounds.

In the course of work' on the constituents of cod eggs (&z&s morhzua)we have isolated a
new acidic compound, gadusol, first recognised by its UV absorption during gel filtration of a
saline extract. It was isolated by extraction of cod eggs with 80% aq. ethanol; after
removal of ethanol, lipids were extracted with chloroform, and amino acids and related
compounds were removed by passage through Dowex 50 (H+ form)(eluent, H20). It was purified by
chromatography on Dowex 1 (acetate form)(eluent, 0.511acetic acid), and finally obtained as an
amorphous white powder, m.p. 178-9", from ethanol.
Gadusol (l), CaH120s (Found: M+, 204.0633; required 204.0633), [&I<” + 100' (HzO), is
monobasic (pK, 4.25) and has reducing properties (Tollen's reagent, Cu(II) ions, Ia/KI) similar
to those of cyclohexane-1,3-dione. It shows Xmax_ (&O/H+) 269 nm (E 12,400), Xmax (H20/HO-)
296 nm (E 22,200); vmax (KBr) 3700-2400, 1664 and 1611 cm-'; 'H &(CD,,~D)4.10 (1;1,s, XHOH),
3.69 and 3.48 (each lH, dd, J. 12H2, CH20H), 3.60 (3H, s, OMe), 2.78 and 2.38 (each lA, dd, L
18Hz, ring CHz), and 13c 6(CDBOD) 179.3 (s, C-l), 134.68 (s, C-Z and C-3), 75.15 (6, C-5),
74.83 (d, C-6), 65.48 (t, C-7), 60.23 (q, CHa), and 39.18 (t, C-4). These data are fully
consistent with the enolised @-diketone structure (1) as is the mass spectrum, m/e
-- 204, 186,
173, 168, 156, 141.
Confirmation was obtained by refluxing gadusol with acetic anhydride-sodium acetate when it
aromatised to give the tetra-acetate (2), m.p. 92-3" (Found: M+, 354.0954; C1sHlsOg requires
M, 354.0950), 6 'H (CDCRa) 7.08 (lH, s, ArH), 5.00 (2H, s, CHz), 3.82 (3H, s, OMe), 2.30 (3H, s,
OAC), 2.27 (6H, s, 2 OAc), and 2.03 (3H, s, OAc), which we have synthesised. Reduction of the
 4044

triester (3)' with LiARH+ to the benzyl alcohol (4) [M+, 170.0581. CaHloOt, requires H,
170.0579; 'H S(CDsOD) 6.38 (2H, s, ArH), 4.41 (ZH, 6, CH20H) and 3.77 (3H, s, OMe!lfollowed
by oxidation with Fremy's salt afforded the quinone (5) which was immediately subjected to
reductive acetylation to give (2) identical with the product derived from gadusol.
Gadusol is isomeric with "spinulosin quinol-hydrate" (6),3 a metabolic product of
AspergiZh fmtigatus, and closely related to the mycosporines, e.g., (7) found in various fung
and in the zoanthid PaZythoa tuberculosa,5 and to the analogous cyclohexenimines, e.g., (8)

OAc bMe bMe

OH (1) (2) (3) (4 1

0
HO OMe

I
HO OH
Me
OMe OH

(5) (61

isolated from zoanthids,6the alga Ci2ondrus yand~i,~ and the mussel Myfilus guZ2opravinciaZis.a
The metabolite (6) is known3 to be acetate-derived; while this is also possible for gadusol
biogenesis from shikimate is equally plausible.
The concentration of gadusol in ripe cod eggs from various geographical locations is
q 4 mg/g dry wt. Similar amounts are present in the eggs of haddock, common dab, and flounder,
and much smaller quantities were detected in the eggs of several other fishes and crabs.
Traces of substances absorbing at 300-310 nm are consistent with the presence of mycosporine-
type compounds.
REFERENCES
1 P.A. Plack, D.J. Pritchard, and N.W. Fraser, Bio&om. J., 1971,121, 847.
2 E. Fischer, M. Bergmann and W. Lipschitz, Ber., 1918, 52, 45.
3 Y. Yamamoto, M. Shinya, and Y. Oohata, C&m. Phamn. Bull., 1970, 18, 561.
4 J. Favre-Bonvin, N. Arpin, and C. Brevard, Can. J. Chem., 1976, 54, 1105; N. Arpin,
J. Favre-Bonvin, and S. Thivend, Tet. ktt., 1977, 819; J. Favre-Bonvin, M.L. Bouillant,
M.C. Lunel, J. Bernillon, J.L. Pittet, and N. Arpin, PZanta Med., 1980, 39, 196.
5 S. Ito and Y. Hirata, let. Lett., 1977, 2429.
6 S. Takano, D. Uemura, and Y. Hirata, Tet. Lett., 1978, 2299, 4909.
7 I. Tsujino, K. Yabe, I. Sekikawa, and N. Hamanaka, Tet. Lett., 1978, 1401.
8 F, Chioccara, G. Misuraca, E. Novellino, and G. Prota, Te'et.Lett., 1979, 3181.

(Received fn UK 6 Angust 1980)