I. S. Marcos et al. / Tetrahedron Letters 44 (2003) 5419–5422
5421
Synthesis of chrysolic acid and isofregenedol from ketone
G. Synlett 2002, 458; (b) Urones, J. G.; Marcos, I. S.;
Go´mez-Pe´rez, B.; Lithgow, A. M.; D´ıez, D.; Basabe, P.;
Go´mez, P. M. Tetrahedron Lett. 1994, 35, 3781; (c)
Urones, J. G.; Marcos, I. S.; Go´mez-Pe´rez, B.; Lithgow,
A. M.; D´ıez, D.; Go´mez, P. M.; Basabe, P.; Garrido, N.
M. Tetrahedron 1995, 51, 1845.
8 (Scheme 2)
Horner–Emmons reaction of 8 with excess of the phos-
phonate (EtO)2POCH2COOMe9 gave a mixture E/Z
9:1 of the esters in good yield. DIBAL-H10 reduction of
the mixture led to the corresponding mixture of allylic
alcohols, from which 12 was isolated in an 81% yield.
Sharpless epoxidation of 12 gives the corresponding
7. Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 20, 399.
8. Leite, M. A. F.; Sarragiotto, M. H.; Imamuna, P.; Mar-
saidi, A. J. J. Org. Chem. 1986, 51, 5409.
enantiomeric epoxides 13 or 14 using
D
-(−)-DET or
9. (a) Etemad-Moghadam, G.; Seiden-Peine, J. Tetrahedron
1984, 5153; (b) Still, W. C.; Gennan, C. Tetrahedron Lett.
1983, 4405; (c) Boutagy, J.; Thomas, R. Chem. Rev. 1974,
74, 87; (d) Wadsworth, W. S. Org. Reactions 1978, 25, 73;
(e) For a review, see: Kelly, S. E. In Comprehensive
Organic Synthesis; Trost, B. M.; Fleming, I., Eds. Alkene
Synthesis. Pergamon Press: Oxford, 1991; Vol. 1, pp. 755.
10. (a) Winterfeldt, E. Synthesis 1975, 617; (b) Yoon, N. M.;
Gyoung, Y. S. J. Org. Chem. 1985, 50, 2443; (c) For a
review, see: Keinan, E.; Greenspoon, N. In Comprehen-
sive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.
Partial reduction of Enones, Styrenes and Related Sys-
tems. Pergamon Press: Oxford, 1991; Vol. 8, pp. 543.
11. (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980,
102, 5974; (b) Pfenninger, A. Synthesis 1986, 89; (c)
Toshiro, I.; Shinya, N.; Takashi, T. J. Chem. Soc., Chem.
Comm. 1994, 2353.
12
L
-(+)-DET11, respectively.
Reduction of 13 with LAH gave a diol that by oxida-
tion with PDC in DMF, followed by esterification with
diazomethane lead to 15 [h]D=−7 (c 0.78, CHCl3). The
same sequence with 14 gave the enantiomer of 15, 16
[h]D=+7 (c 1.25, CHCl3).
Spectroscopic properties for 1513 and 16 are identical to
the ones described for chrysolic acid methyl ester. The
[h]D=−12 (c 2.39, CHCl3) described, for the last com-
pound implies that the absolute configuration is 13R,
the one of 15, opposite to the described one.4
The hydroxy derivative 17 was synthesised starting
from 14 in three steps, tosylation,14 iodide sustitution15
and Zn/AcOH reduction,16 in a good overall yield.
12. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem.
1969, 34, 2543 The e.e. of epoxides was controlled by
comparison of Mosher’s ester of the Sharpless products
with those of the racemic epoxides obtained with m-
CPBA. The e.e. for 13 was 86% and 87%, for 14.
13. Methyl 13R-hydroxy-15-isofregenedanoate, 15 Rf (Hex/
AcOEt 8/2)=0.40; [h]D=−7 (c 0.78, CHCl3); IR (film):
The physical properties for 1717 [h]D=+16 (c 1.28,
CHCl3) agree with those described for the natural
product ([h]D=+20), establishing the absolute configu-
ration as 13S for the natural product (+) isofregenedol,
opposite to the one proposed on the base of biogenetic
hypotheses.
3522, 1738, 1678, 1593, 1456, 1383, 1362 and 1209 cm−1
.
1
The assignments for the spectra, H NMR and 13C NMR
for 15 and 16 were done by bidimensional experiments
HMQC and HMBC. H NMR (CDCl3, 400 MHz) l 7.04
Acknowledgements
1
(1H, s, H-6), 3.73 (3H, s, COOMe), 3.64 (1H, s, OH),
2.70–2.60 (4H, m, H-1 and H-11), 2.61 (1H, d, J=15.0
Hz, H-14), 2.53 (1H, d, J=15.0 Hz, H-14), 2.21 (3H, s,
Me-17), 2.15 (3H, s, Me-20), 1.90–1.70 (4H, m, H-2 and
H-12), 1.36 (3H, s, Me-16), 1.29 (6H, s, Me-18 and
Me-19); 13C NMR (CDCl3, 100 MHz) l 28.5 (C1), 19.8
(C2), 38.9 (C3), 33.8 (C4), 143.4 (C5), 125.0 (C6), 137.4
(C7), 132.4 (C8), 134.8 (C9), 131.3 (C10), 29.8 (C11), 43.4
(C12), 71.0 (C13), 45.1 (C14), 171.5 (C15), 26.7 (C16), 15.3
(C17), 32.0 (C18), 32.0 (C19), 15.6 (C20), 51.5 (COOMe).
EIMS (rel. intensity): m/z 332 (7) [M+], 314 (10), 299 (82),
258 (6), 243 (35), 225 (14), 201 (30), 185 (100). EIHRMS
calcd. for C21H32O3: 332.2351, found: 332.2344.
The authors thank the CYCIT for financial support
(BQU 2002-02049).
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