The complete absolute stereochemistry of two new cytotoxic marine polyproniates isolated from the saponified extract of the pulmonate mollusc #Onchidium sp.$, onchitriol 1 and 2 (4,5), was established using Mosher-Trost's methodollogy. (Résumé d'auteur

Debitus, Cécile

Riguera, R.

Rodriguez, J.

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m 
NEW MARINE CYTOTOXIC BISPYRONES. ABSOLUTE 
STEREOCHEMISTRY OF ONCHITRIOLS I AND II 
~ -~ 
I . Tetrah&on let ter^. Vol. 33. NO. 8. pp. 1089-1092, 1992 00404039/p2 $3.00 + .00 
Pergmon Press plc 
i 
' 
mu Printed in Great Briwn 
Jaime Rodriguez, Ricardo Riguera* 
Depan de Química Organica, Fac. de Química, Univ. de Santiago de Compostela, Santiago de Compostela. 15706. Espa?ia 
M e  Debitus 
Centre ORSTOM. B. P. A5. Not" Cedex. Nouvelle CalMonie. 
Key Words: Onchidim sp., onchitriols, polypmpionates, Mosher-Trost's method, antitumour activity. 
Abstract: The complete absolute stereochemistry of two new cytotoxic marine polypropionaies isolated from the saponified 
emact of the pulmonate mollusc Onchidiwn sp., onchitriol I and II (4$5). was established using Mosher-TrostS methodology. 
In the last few years a number of propionate derivatives with interesting biological properties have 
been isolated from m a h e  molluscs. They include the polyhydmxylated compounds, peroniatriol I and II (1,2) 
and ilikonapymne (3) (isolated from the saponified extracts of Peroniu peronii and Onchidim verruculatm 2 
respectively), which have a linear structure containing two pyrone rings, three hydroxyl groups and seven 
asymmetric centers. Although an X-ray crystallographic analysis of the acetonide of3, established its general 
structure and relative stereochemistry, its absolute stereochemistry could not be deduced. The structure and 
relative stereochemistry of 1 and 2 was originally inferred essentially from comparison of their NMR data with 
those of 3, though a synthesis of the optically active left wing CI-CIO has recently allowed correction at (2-43; 
the absolute stereochemistry of 1 and 2 remains unknown too. 
In the course of a study of the cytotoxic components of New Caledonian marine organisms, we 
isolated from Onchidim sp., a pulmonate mollusc, a mixture of eight acetates and propionates that inhibited the 
growth of several cell lines in virro. The components were separated by hplc and individually saponified to give 
two new bis-pyrone polypropionate triols we named onchitriol I (4) and onchitriol JI (5). We report here their 
structure and absolute stereochemistry, as deduced by Mosher-Trost's NMR method. 
The skeletons of 4 and 5 and the positions of their functional groups, were deduced by extensive 
NMR studies. Inverse NMR COSY and 13C-lH correlated (HMQC and HMBC) spectra showed, in addition to 
the two pyrone rings, the presence of four relevant spin systems (a-d) that could be arranged either as in 
ilikonapyrone (a-c-b-d) or as in peroniatriol (a-b-c-d). The exact arrangement was deduced from the high 
resolution mass spectrum (€REIMS), which showed peaks at m/z 365.2333 and m/z 180.1154 due to the loss 
of the pyrone ring bonded to fragments c and d, and a peak at m/z 307.1928 due to C13-Cl4 cleavage giving a 
particularly stable allylic oxonium ion (see Figure 1). 
1089 
b4 JUIL. 1992 
OR STOk Fonds Documentaire 
, 
24 27 30 
1 
O 
3 Ilikonapyrone 1 %=Me, Rz=H, R 3 4 H .  %=H, Peroniatrio1 I 
2 RFH. R2=Me. R3=H. R 4 4 H .  Peroniatrio1 II 
4 R=H, Onchiuiol I 5 Onchitriol II O 
6 R=Ac 
a b C d 
- .  -r--h-q - 
,w.!+"'""1- 
s. Exp 347.2215 Eip 365.2333 
ö 
a p  180.1154 
Figure 1. HREIMS of onchitriols I and II. 
- 
The relative stereochemistry of 4 and 5 was obtained by comparison of the NMR data with those of 1- 
3. Thus the ClO-Cl6 segment of onchitriol I (4) must be identical to the same segment of peroniatriol I (1) 
because of the agreementin carbon and proton chemical shifts and vicinal J values.5 Similarly, the C13-CI 66 
fragment of onchitriol II (5) has NMR parametem identical to those of C13-Cl6 in peroniatriol II (2); and the 
C3-C4 fragment of both onchitriols, has the same relative stèreochemistry as in peroniatriol II (2). Finally, the 
MM calculations for the acetonides of4  and 5 afforded vicinal J values for the C13-CI6 fragment that agreed 
with those observed experimentally by NMR. - L -  . 
In view of the presence of three secondary alcohol groups in the onchitriol molecules, we investigated 
absolute stereochemistry by analysis of the *H NMR spectra.of the corresponding R- and S- 
methoxyphenylacetic estersi This approach is based on Mosher-Trost's assumption that the NMR behavior of 
O-methoxymandelates (RO-MPA) is dominated by the conformation in which the carbinyl proton, the C=O 
carbonyl bond and the methoxy group are in the same plane.4 With this premise, the R/S configuration of the 
hydroxyl-bearing carbons C3, CI3 and CI5 can be inferred from the NMR spectra of mono, di and/or tri 
mandelates of selected natural esters and of the triols 4 and 5 by comparison of the chemical shifts produced by 
the benzene rings of the R and S mandelates on directly bonded groups. Smaller but significant shifts are also 
observed for near"oy groups, and this information, coupled with the relative orientation, affords the complete 
absolute stereochemistry of the molecule. 
6 
1 
I 
1091 
R: 0.80 
~ 0 . 7 6  R:533 
Z4.49 I . 3 5 ' 9  R: 456 
Figure 2. Selected 6 values of he S and R trimandelates of onchitriol I (4). and absolute configuration. 
Figure 2 shows 1H NMR chemical shifts of representative signals of the R and S-trimandelates of 
onchitriol I (4). The C1 methyl group resonates at lower field in the S trimandelate than in the R form, and 
viceversa for H13 and H15. This indicates that the absolute configuration of 4 at these centers is 3S, 13R and 
15R. Those of C4, C10, C14 and C16 now follow from the relative orientation of their substituents with 
respect to the hydroxylated carbons, and proves to be 4S, los, 14R, 16R. 
. .  
R 0.85 
. so.91 u.2 
I ss.30 
Figure 3. Selected 6 values of S and R trimandelates of onchitriol II (3, and absolue configuration. 
Similarly, the natural monoacetafte 6 was converted to the corresponding R and S dimandelates. Figure 
3'shows selected chemical shifts indicating that onchiGolII (5) has the configuration 3 S ,  4S,13S, 14R. 15R 
and 16R. The configuration as C10 follows from noting that compounds 2 and 5 have either the same or the 
opposite configuration at C3; C4, C13, C14, C15 and C16, and that the only way for 2 and 5 to be 
diastereoisomers (as they are: compound 2 [a]~=+224.8 and [a]~=-33 .0  for 5 )  is for the absolute 
configuration of the remaining assynietric cenire to be IOR. 
Compounds 4 and 5.showed antitumour activity (ICs0 10 and 20 pdml respectively) when tested in 
vitro against cell hnes P388, A-549 and HT-29. Both compounds were also found to posses moderate antiviral 
activity against cell lines HSV-1 and VSV at 20 pg/ml. 
ACKNOWLEDGEMENTS 
This work was supported by the Plan Nacional de Investigación (FAR 88-0512). J. R. acknowledges 
fellowship from the Xunta de Galicia. 
REFERENCES. 
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Biskupiak. J. E.; and Ireland, C. M. Terruhedron Left. 1985,26,4307. 
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Arimoto H. Nishiyama S., and Yamamura. S .Tpahedron Len. 1990.31.5491. 
Tmst, B. M.; Belletire. J. L.; Godleski. S.: McDougal, P.G; and Balkovec. I. M. J. Org. Chem. 1986,51,2370. 
Admczeski. M.; Quifio& E.; and Crews, P. J. Org. Chem. 1990.55.240. Kustemi,.T; Ohtami, I; Inouye, Y.; and 
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Chenr. 1991.56, 1296. Ohtani, I.; Kusumi. T.; Kashman, Y.; and Kakisawa, H. J. Am. Chem. Soc. 1991,113, 
4092. Finamore, E.; Minale, L.; Riccio, R.; Rinaldo G.: and Zollo, F. J. Org. Chem.; 1991.56, 1146. 
Onchitriol I 4: [ a ~ 1 = - 2 0 . 0 ~  (C12CH2. c=O.Ol); UV (MeOH) 260 nm: lR V m a  (cm-l): 1665. 1620. 
HREIMS: C32Q807: Calc 544.3395; Exp.: 544.3400. EIMS m/z (W): 544 (7). 515 (2). 486 (6). 459 (4). 365 (IO), 319 
(7). 307 (U), 248 (34). 219 (13). 191 (16). 180 (100): 179 (54). 151 (20), 123 (16). 97 (17), 83 (34). NMR 1H (250.13 
MHZ,  Cl3CD): 0.95 (t. 3H, J=7.3 Hz,:Hl); 1.43, 1.40 (m, 2H. H2); 3.55 (dd$ 1H. h72.8.3 and 3.5 Hz, H3): 2.97 (dq, 
1H. J=7.2 and 7.0 Hz. H4); 3.90 (dq, 1H. J=9.2 and 6.9 Hz,  H10); 5.59 (dq, IH, J=92 and 1.1 Hz, Hll), 4.05 (d, IH, 
J=7.4 Hz,  H13); 1.92 (ddq,'IH: J=7.4,7.0 and 1.9 &, H14); 4.12 (dd. 1H,'J=9.6 and 1.9 Hz, HIS); 3.13 (dq, 9.6.6.9 Hz, 
H16); 2.56 (m. 2H, H22); 1.15 (t. 3H; J=7.5 Hz, H23); 1.26 (d. 3H. J=7.0 Hz,  H24); 1.98 (s, 3H, H25); 1.97 (s. 3H, 
H26); 1.26 (d, 3H, J=7.0 Hz, H27); 1.70 (d. 3H, J=l.l Hz, H28): 0.92 (d, 3H.'J=7.0 Hz, H29); 1.14 (d. 3H, Jz6.9 Hz, 
, 
... . .-. . .  
9 
H30); 1.95 (s. 3H, H31); 1.92 (s, 3H, H32). NMR I3C (62.83 MHz, C13CD): 9.6 (q, CI). 27.9 (t. a), 75.4 (d, C3), 
41.4 (d, C4), 164.7 (s, CS), 119.8 (s, C6), 179.8 (s. C7), 118.8 (s. C8), 164.4 (s, C9). 39.1 (d, CIO), 127.3 (d, C11). 
137.6 (S, C12). 79.8 (d, C13), 34.4 (d, C14),-72.4 (d, C15). 36.4 (d. C16), 16p.3 (s, C17). 118.0 (s, C18). 179.8 (s. 
C19h 117.4 (s, c20). 164.3 (S, a l ) ,  24.7 (t. ai), 11.4 (9. C23), 13.9 (q, C24), 10.1 (q, (2.5). 9.3 (q, C26). 18.7 (4. 
a 7 ) .  14.4 (q. a 8 ) .  9A.(q, C29); 12.0 (q, C29). 12.0 (q. C30). 9.1 (4, C31). 9.2 (q, C32). 
In contrast lo the perfect agreement of NMR data for the ClO-Cl6 fragments of 1 and 4, there is small difference betwcen 
lhe CIO 13C chemical shifts of 2 and 5. Qnchitriol115 [ a~]=-33 .0~  (CI2CH2, e0.01); W (MeOH) Xma: 260 nm; IR 
vmax'(Cm-1):'l$80,1610. HREIMS: U44 (5) c32m807: Calc 544.3395, Exp: 544.33991; 1486 (5) C2gH@6: Calc 
486.2981, Exp: 486.29811; i365 (IO) C21H3305: Calc 365.2328, Exp: 365.23331; [347 (3) C21H3104: Calc 3472222, 
Exp: 347.22151; 1307 (15) C18H2704: Calc 307.1909, Exp: 307.19281; [289 (5) C18H2503: Calc 289.1804, Exp: 
289.18611, E48 (10) C15H2003: Calc 248.1412, Exp: 248.14131; '[I80 (100) C11H1602: Calc 180.1150, Exp: 
180.11541. NMR IH (250.13 MHz, C13CD): 0.87 (ti 3H. J=7.3 H z ,  HI); 1.60, 1.40 (m. 2H, H2); 3.55 (ddd, 1H. J=7.9, 
8.3 and 3.0 Hz, H3); 2.79 (dq, IH, 1=8.3 and 6.9 Hz, H4); 3.95 (dq, IH, J=9.6 and 6.8 Hz, H10); 5.84 (dq. IH, J=9.6 and 
1.2 Hz. HII), 4.03 (d, IH, J=3.3 Hz, H13); 1.90 (ddq, IH, Js7.0.3.3 and 2.0 Hz, H14); 3.68 (dd, lH, J=9.7 and 2.0 Hz, 
HIS); 3.08 (dq, lH, J=9.7 and 7.1 Hz, H16); 2.55, 2.24 (m, 2H, H22); 0.98 (t. 3H, J=7.5 Hz, H23); 1.14 (d, 3H, J=76.9 
. .  , . . .  . ~ . , .  . . . .  . 
HZ, m); 1.85 (S, 3H, H25); 1.87 (S. 3H. H26); 1.31 (d, 3H, Jz7.1 Hz. H27); 1.63 (d, 3H, J=1.2 Hz, H28): 1;15 (d, 3H, 
Jz7.1 Hz,  H29); 1.02 (d, 3H, J27.1 Hz, H30); 1.93 (S, 3H, H31); 2.04 (s, 3H, H33). NMR I3C (62.83 MHz,  C13CD): 
9.7 (q, Cl), 27.6 (t. a), 75.2 (d, C3), 41.8 (d, C4). 165.6 (s, CS), 120.2 (s, C6). 179.8 (s, C7), 118.5 (s, C8), 164.9 (s, 
C9), 39.1 (d. CIO), 125.5 (d, Cll) ,  137.3 (s, C12), 79.9 (d, '213). 34.3 (d, C14). 73.1 (d, CIS), 34.0 (d, Cl@, 164.5 (s. 
117-4 (s. C W ,  180.0 6, c19). 116.0 6, CZO), 164.1 (s, C21), 24.5 (t. C22), 10.5 (q, C23), 13.7 (4, (24). 9.5 (q, 
(Received in UK 6 December 1991) 


New marine cytotoxic bispyrones : absolute sterochemistry of onchitriols I and II

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