Scheme 3 Reagents and conditions: i, tBu(Me)2SiCl, imidazole, 4-DMAP, CH2Cl2, rt (quant.); ii, AD-mix-α, MeSO2NH2, tBuOH, H2O, 0 ЊC (99%,
i
94% de); iii, MsCl, pyridine, CH2Cl2, rt (86%); iv, K2CO3, MeOH, rt (quant.); v, MOMCl, Pr2NEt, 4-DMAP, CH2Cl2, rt (81%); vi, CsF, DMF,
rt (93%); vii, 5% NaOH (aq.), rt (54% for 22, 4% for 23); viii, 6 M HCl, THF, rt (quant. for 1, 75% for 2).
For the preparation of the key epoxide 3, the di-tert-
butyldimethylsilyl (TBS) ether of (S)-13 was subjected to
asymmetric dihydroxylation employing AD-mix-α14 to give the
diol 14 in 99% yield (Scheme 3). The diastereomeric excess was
Mr Hidetoshi Shimizu, Novo Nordisk Bioindustry Ltd., for
providing CAL.
1
Notes and references
94% as determined by H NMR analysis of its (R)-MTPA [α-
methoxy-α-(trifluoromethyl)phenylacetic acid] ester derivative.
The absolute configuration of the newly formed stereogenic
centre was confirmed to be S by means of the modified Mosher
method.15 Mesylation followed by basic treatment provided an
inseparable 4:1 mixture of the monophenolic epoxides, 16 and
17, along with the di-TBS epoxide 15 in 71% and 4% yield,
respectively. It was postulated that the major isomer would be
16, which should be generated from the hydrolysis of the steric-
ally less hindered TBS ether. The confirmation was made by
NOE experiments of the corresponding MOM ethers, 18 and
19. Desilylation of a mixture of 16 and 17 with tetra-n-butyl-
ammonium fluoride did not give the expected epoxide 3 but
instead the corresponding quinone. Therefore, the phenolic
hydroxy moiety was protected as the methoxymethyl (MOM)
ether and the resulting mixture of 18 and 19 was reacted with
caesium fluoride to give the MOM protected phenolic epoxides,
20 and 21, in 75% yield for the two steps. The crucial cyclisation
was realized by treatment of a mixture of 20 and 21§ with 5%
aqueous NaOH solution at room temperature to give an easily
separable mixture of the 7- and 8-membered cyclic ethers, 22
and 23, in 54% and 4% yield, respectively. Finally, acidic
hydrolysis of each produced heliannuol D 1, [α]D Ϫ20.1 (c 2.27,
CHCl3), and heliannuol A 2, [α]D ϩ61.0 (c 0.38, MeOH), whose
spectral properties were identical with those of the natural
products except for the sign of the optical rotations: for natural
1,1 [α]D ϩ16 (c 0.16, CHCl3); for natural 2,2 [α]D Ϫ55.4 (c 0.3,
MeOH).
‡ In order to prepare the enantiomeric series, (S)-6 was converted into
(S)-7 by the following 5-step sequence: i) MOMCl, iPr2NEt, 4-DMAP,
CH2Cl2 (95%); ii) K2CO3, MeOH (98%); iii) TsCl, Et3N, 4-DMAP,
CH2Cl2 (94%); iv) NaBH4, DMSO (87%); v) cؒHCl, MeOH (98%). The
enantiomeric alcohol (S)-7 was also successfully converted into the
natural (ϩ)-heliannuol D and (Ϫ)-heliannuol A by the same sequence
of reactions. Details will be reported in due course.
§ Unreacted 21 was not recovered from the reaction mixture.
1 F. A. Macías, J. M. G. Molinillo, R. M. Varela, A. Torres and
F. R. Fronczek, J. Org. Chem., 1994, 59, 8261.
2 F. A. Macías, R. M. Varela, A. Torres, J. M. G. Molinillo and
F. R. Fronczek, Tetrahedron Lett., 1993, 34, 1999.
3 Recent Advances in Allelopathy. Vol. I. A Science for the Future, ed.
F. A. Macías, J. C. G. Galindo, J. M. G. Molinillo and H. G. Cutler,
Servico de Publicaciones-Universidad de Cádiz, Spain, 1999.
4 For ( )-heliannuol D: J. R. Vyvyan and R. E. Looper, Tetrahedron
Lett., 2000, 41, 1151.
5 For ( )-heliannuol A: E. L. Grimm, S. Levac and L. A. Trimble,
Tetrahedron Lett., 1994, 35, 6847.
6 (a) S. Takano, K. Samizu and K. Ogasawara, Synlett, 1993, 393; (b)
T. Sakamoto, Y. Kondo and H. Yamanaka, Heterocycles, 1993, 36,
2437; (c) Y. Koga, M. Sodeoka and M. Shibasaki, Tetrahedron Lett.,
1994, 35, 1227.
7 S. M. Hubig, W. Jung and J. K. Kochi, J. Org. Chem., 1994, 59, 6233.
8 H. Frauenrath, Synthesis, 1989, 721.
9 For an example of the use of this lipase: I. Yamamura, Y. Fujiwara,
Y. Yamato, O. Irie and K. Shishido, Tetrahedron Lett., 1997, 38,
4121.
10 F. McEnroe and W. Fenical, Tetrahedron, 1978, 34, 1661.
11 G. Guanti, E. Narisano, T. Podgorski, S. Thea and A. Williams,
Tetrahedron, 1990, 46, 7081.
12 I. Nakagawa, K. Aki and T. Hata, J. Chem. Soc., Perkin Trans. 1,
1983, 1315.
In summary, the first enantiocontrolled total syntheses of
two allelopathic sesquiterpenoids, heliannuol D and heliannuol
A, have been accomplished and the absolute configurations
were found to be the enantiomers of those shown in Fig. 1.
13 E. Schrötter, E. Landmann, H. Schick, B. Schönecker, U. Hasuchild
and P. Droescher, J. Prakt. Chem., 1988, 330, 501.
14 K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino,
J. Hartung, K. S. Jeong, H. L. Kwong, K. Morikawa, Z. M. Wang,
D. Xu and X. Zhang, J. Org. Chem., 1992, 57, 2768.
15 I. Ohtani, T. Kusumi, Y. Kashman and H. Kakisawa, J. Am. Chem.
Soc., 1991, 113, 4092.
Acknowledgements
We are grateful to Professor Francisco Macías, University of
Cádiz, for providing spectral data of the natural heliannuols
D and A and for valuable discussions. We also thank
1808
J. Chem. Soc., Perkin Trans. 1, 2000, 1807–1808