Asymmetric synthesis of the new marine epoxy lipid, (6S,7S,9S,10S)-6,9-epoxynonadec-18-ene-7,10-diol

Article abstract of DOI:10.1016/S0957-4166(01)00244-0

An efficient and stereocontrolled process is described for the preparation of (6S,7S,9S,10S)-6,9-epoxynonadec-18-ene-7,10-diol, a marine epoxy lipid isolated from the brown alga, Notheia anomala. The key 2,3,5-trisubstituted tetrahydrofuran ring was const

Full text of DOI:10.1016/S0957-4166(01)00244-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1403–1406
Asymmetric synthesis of the new marine epoxy lipid,
(6S,7S,9S,10S)-6,9-epoxynonadec-18-ene-7,10-diol
Hidemi Yoda,* Kazuhide Maruyama and Kunihiko Takabe
Department of Molecular Science, Faculty of Engineering, Shizuoka University, Hamamatsu 432-8561, Japan
Received 1 May 2001; accepted 23 May 2001
Abstract—An efficient and stereocontrolled process is described for the preparation of (6S,7S,9S,10S)-6,9-epoxynonadec-18-ene-
7,10-diol, a marine epoxy lipid isolated from the brown alga, Notheia anomala. The key 2,3,5-trisubstituted tetrahydrofuran ring
was constructed by stereoselective hydrogenation of the hemiketal derivative elaborated through nucleophilic addition of Grignard
reagent in the presence of CeCl3 to the highly functionalized lactone derived from L-galactono-1,4-lactone. © 2001 Elsevier
Science Ltd. All rights reserved.
The tetrahydrofuran backbone is among the most com-
mon heterocyclic units found in natural products.
Structurally complex substituted tetrahydrofurans fea-
ture in many biologically potent compounds such as
pheromones,1 polyether antibiotics2 and marine epoxy
lipids.3 Due to their interesting activity and unique
structural characteristics, they have been the subject of
extensive synthetic efforts which have culminated in
numerous syntheses.4 Noteworthy members among this
class of compounds are optically active tri- and tetra-
substituted tetrahydrofuran derivatives. They serve as
good templates for the construction of pharmacologi-
cally important furanoid groups and exhibit various
degrees of potency and specificity.5 In connection with
this we have recently accomplished the asymmetric total
syntheses of (−)-sesaminone (trisubstituted tetra-
hydrofuran lignan)6 and (−)-virgatusin (tetrasubstituted
tetrahydrofuran lignan),7 employing Lewis acid-induced
deoxygenation of the lactol precursors (Fig. 1).
On the other hand, new trisubstituted tetrahydrofuran-
type marine epoxy lipids, (6S,7S,9S,10S)-6,9-epoxy-
nonadec-18-ene-7,10-diol 18 and its stereoisomer,
(6S,7S,9R,10R)-6,9-epoxynonadec-18-ene-7,10-diol 2,9
possessing a characteristic substitution pattern in their
ring system have recently been isolated from the south-
ern Australian brown alga Notheia anomala, a member
of the Notheiaceae family. These are considered to be
biosynthesized via a cyclization of a natural methylene-
interrupted bisepoxide and within this context a
Figure 1.
* Corresponding author. Tel.: +81-53-478-1150; fax: +81-53-478-1150; e-mail: yoda@mat.eng.shizuoka.ac.jp
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00244-0

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H. Yoda et al. / Tetrahedron: Asymmetry 12 (2001) 1403–1406
biomimetic synthesis of ( )-2 has been reported.10 In
addition, since it became apparent that these com-
pounds are potent and selective inhibitors of the larval
development of parasitic nematodes,8 considerable
efforts have been directed toward the synthesis of 2,11
some of which require multi-step reactions or are non-
stereoselective. Herein we communicate a novel and
efficient asymmetric synthesis of 1 based on Lewis
acid-promoted deoxygenation of the hemiketal interme-
determined by 13C NMR). Enhancement of the selectiv-
ity was not observed under any conditions.
Next, we turned our attention and researched an alter-
native synthetic strategy towards 1. When the lactone 7
obtained from the TBS-protection of 4 was treated with
n-pentyl Grignard reagent also in the presence of
CeCl3, followed by subsequent hydrogenation with
Et3SiH under the same conditions as above, it rapidly
yielded the cis-tetrasubstituted tetrahydrofuran 8 with
the desired stereochemistry16 as a sole product (deter-
mined by 13C NMR and HPLC analysis). Highly sub-
stituted five-membered ring oxocarbenium ions
sometimes exhibit opposite stereoselectivities to what
would be expected based upon a consideration of sim-
ple steric effects alone. In this case, steric destabiliza-
tion of the transition state leading to the
trans-2,3-stereochemistry is presumably being observed
due to the presence of the b-OTBS group (Fig. 2).15a
Consequently it could proceed through the exclusive
attack of Et3SiH to the oxocarbenium ion intermediate
from the opposite side of the large a-OBn and g-sub-
stituent.7,14b With the above stereochemical outcome in
hand, deprotection of 8 and thiocarbonate formation
followed by radical elimination were performed again,
smoothly providing the optically pure tetrahydrofuran
6a in three steps (56% yield).
diate elaborated from
L-galactono-1,4-lactone with
complete stereoselectivity. To the best of our knowl-
edge, only one approach to the synthesis of 1 has been
reported12 recently based on Sharpless asymmetric
dihydroxylation during the course of our studies.
As shown in Scheme 1, commercially available and
conveniently functionalized -(+)-galactono-1,4-lactone
L
3 was selected as a starting material. Acetonide forma-
tion of 3 and successively regioselective benzylation
with Ag2O–BnBr was performed to give the mono-pro-
tected hydroxylactone 4 in moderate yield. To begin
with, we attempted the direct conversion of the lactone
5 derived from 4 to the corresponding trisubstituted
tetrahydrofuran framework via Lewis acid-induced
reductive deoxygenation. Thus, 4 was subjected to reac-
tion with phenyl chlorothionoformate followed by radi-
cal elimination with Bu3SnH, leading to the desired
compound 5.13 Treatment of 5 with pentylmagnesium
7,14
bromide in the presence of CeCl3
at low temperature
The remaining C(8) side unit was then easily introduced
as follows: acetonide deprotection of 6a afforded the
diol 9, which was in turn subjected to regioselective
tosylation in the presence of Bu2SnO17 and subsequent
cyclization under mildly basic conditions, leading to
epoxide 10 ([h]2D5=+44.9 (c 0.97, CHCl3)) in high yield.
Exchange of the benzyl ether protecting group in 10 to
provided the labile hemiketal intermediate, which was
readily effected by BF3·OEt2-promoted hydrogenation
with Et3SiH15 at −78°C to afford the trisubstituted
tetrahydrofuran 6 in moderate yield. However, the
reaction occurred with unsatisfactory selectivity (the
ratio of the stereoisomers 6a and 6b was almost 1:1 as
Scheme 1. Reagents and conditions: (a) 1, (CH3)2C(OCH3)2, CH3COCH3, cat. p-TsOH; 92%; 2, BnBr, Ag2O, CH3COOEt; 50%;
(b) 1, ClC(S)OC6H5, pyridine, DMAP, CH3CN; 2, Bu3SnH, cat. AIBN, toluene, 90°C; 45% (5) (two steps yield from 4); 57% (6a)
(two steps yield from 8); (c) 1, C5H11MgBr, CeCl3, −78°C, THF; 2, Et3SiH, BF3·OEt2, CH2Cl2, −78°C; 36% (6a and 6b) (two steps
yield from 5); 41% (8) (two steps yield from 7); (d) TBSCl, imidazole, CH2Cl2; 92%; (e) Bu4NF, THF; 98%.
Figure 2. Mechanistic origin of the stereoselective reduction with Et3SiH.

H. Yoda et al. / Tetrahedron: Asymmetry 12 (2001) 1403–1406
1405
Scheme 2. Reagents and conditions: (a) cat. p-TsOH, MeOH; 50%; (b) 1, TsCl, Bu2SnO, Et3N, CH2Cl2; 90%; 2, K2CO3, MeOH;
90%; (c) 1, Pd (black), 4.4% HCOOH–MeOH; 87%; 2, DPSCl, imidazole, CH2Cl2; quant.; (d) CH2CH(CH2)6MgBr, cat. CuI,
THF, −50°C; 2, Bu4NF, THF; 68% (two steps).
a tert-butyldiphenylsilyl (DPS) ether18 was necessary to
avoid the use of hydrogenation conditions after intro-
duction of the octenyl chain. The was carried out to
give the furan 11 in 87% yield. Finally, 11 was subjected
to a coupling reaction in the presence of CuI with
octenylmagnesium bromide reagent followed by desilyl-
ation to complete the total synthesis of the marine
epoxy lipid 1 ([h]D23.2=+23.7 (c 0.42, CHCl3))19 in high
yield. The spectral data of synthesized 1 were com-
pletely identical with those of the reported natural
compound8 (Scheme 2).
4. (a) Mihelich, E. D. J. Am. Chem. Soc. 1990, 112, 8995;
(b) Kang, S. H.; Hwang, T. S.; Kim, W. J.; Lim, J. K.
Tetrahedron Lett. 1990, 31, 5917; (c) Harmange, J.-C.;
Figade`re, B. Tetrahedron: Asymmetry 1993, 4, 1711; (d)
Koert, U. Synthesis 1995, 115; (e) Li, K.; Vig, S.; Uckun,
F. M. Tetrahedron Lett. 1998, 39, 2063.
5. (a) Yoshida, S.-I.; Ogiku, T.; Ohmizu, H.; Iwasaki, T. J.
Org. Chem. 1997, 62, 1310; (b) Chen, I.-S.; Chen, J.-J.;
Duh, C.-Y.; Tsai, I.-L. Phytochemistry 1997, 45, 991; (c)
Cao, S.-G.; Wu, X.-H.; Sim, K.-Y.; Tan, B. K. T.;
Pereira, J. T.; Goh, S.-H. Tetrahedron 1998, 54, 2143.
6. Yoda, H.; Kimura, K.; Takabe, K. Synlett 2001, 400.
7. Yoda, H.; Mizutani, M.; Takabe, K. Tetrahedron Lett.
1999, 40, 4701.
In summary, this work constitutes an efficient and
straightforward pathway for the asymmetric synthesis
of a marine epoxy lipid based on the stereoselective
Lewis acid-induced hydrogenation of a hemiketal
derivative and will serve for the synthesis of other
polysubstituted tetrahydrofuran natural products.
8. Capon, R. J.; Barrow, R. A.; Rochfort, S.; Jobling, M.;
Skene, C.; Lacey, E.; Gill, J. H.; Friedel, T.; Wadsworth,
D. Tetrahedron 1998, 54, 2227.
9. Warren, R. G.; Wells, R. J.; Blount, J. F. Aust. J. Chem.
1980, 33, 891.
10. (a) Capon, R. J.; Barrow, R. A.; Skene, C.; Rochfort, S.
Tetrahedron Lett. 1997, 38, 7609; (b) Capon, R. J.; Bar-
row, R. A. J. Org. Chem. 1998, 63, 75.
Acknowledgements
11. (a) Williams, D. R.; Harigaya, Y.; Moore, J. L.; D’sa, A.
J. Am. Chem. Soc. 1984, 106, 2641; (b) Hatakeyama, S.;
Sakurai, K.; Saijo, K.; Takano, S. Tetrahedron Lett.
1985, 26, 1333; (c) Gurjar, M. K.; Mainkar, P. S. Hetero-
cycles 1990, 31, 407; (d) Chikashita, H.; Nakamura, Y.;
Uemura, H.; Itoh, K. Chem. Lett. 1993, 477; (e) Wang,
Z.-M.; Shen, M. J. Org. Chem. 1998, 63, 1414; (f) Mori,
Y.; Sawada, T.; Furukawa, H. Tetrahedron Lett. 1999,
40, 731.
This work was supported in part by a Grant-in-Aid for
Scientific Research from Japan Society for the Promo-
tion of Science.
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H. Yoda et al. / Tetrahedron: Asymmetry 12 (2001) 1403–1406
5531; (e) Yoda, H.; Yamazaki, H.; Kawauchi, M.; Tak-
g, 4.730 mmol) was added. After the mixture was stirred
for 5 min, BF3·OEt2 (0.167 g, 1.182 mmol) was slowly
added. The solution was further stirred for 2 h at the
same temperature and quenched by the addition of satu-
rated aqueous NaHCO3 (3 mL). The aqueous layer was
extracted with CH2Cl2 (3×5 mL) and the combined
organic extracts were dried (Na2SO4) followed by the
concentration in vacuo. The residue was chromato-
graphed (10:1 hexane–ethyl acetate) to give the tetra-
substituted furan 8 as a colorless oil (0.091 g, 0.189
mmol, 41%).
abe, K. Tetrahedron: Asymmetry 1995, 6, 2669 and refer-
ences cited therein.
16. The absolute configuration of the generated stereogenic
center was determined based on its spectral data of
synthetic (+)-1 and in this case b-elimination of the
TBSO-group also took place as an accompanying reac-
tion.
Experimental procedure for the synthesis of 8 from 7: To
a suspension of well-dried cerium chloride (0.176 g, 0.473
mmol) in THF (3 mL) was added a solution of lactone 7
(0.200 g, 0.473 mmol) in THF (1 mL) at −20°C and
stirred for 1 h under nitrogen. Then, the reaction mixture
was cooled to −78°C and pentylmagnesium bromide (1.5
M in THF, 1.0 mL, 1.5 mmol) was added. After the
solution was stirred for 2 h at the same temperature, it
was quenched by the addition of water (3 mL) and
filtered through a pad of Celite followed by the extraction
with ether (3×5 mL). The combined organic extracts were
dried (Na2SO4) and concentrated in vacuo to give an oil
of the crude hemiketal. A solution of the product in
CH2Cl2 (2.5 mL) was cooled to −78°C and Et3SiH (0.550
17. Pawlak, J. M.; Vaidyanathan, R. Org. Lett. 1999, 1, 447.
18. The direct coupling reaction between the debenzylated
hydroxyl tetrahydrofuran with octenylmagnesium bro-
mide did not proceed even at room temperature.
19. Although the naturally isolated compound 1 is reported
to be a colorless oil ([h]D=+74.5 (c 0.4, CHCl3)),8 our
synthetic 1 was a waxy oil and has a different specific
rotation in analogy with the product described in the
preceding synthetic report ([h]2D5=+20.5 (c 0.4, CHCl3)).12
This would be due to impurities present in the natural
compound.
.