First enantioselective total synthesis of (-)-heliannuol C

Article abstract of DOI:10.1016/j.tetlet.2003.09.086

The first, efficient total synthesis of (-)-heliannuol C (1) was accomplished enantioselectively, using a chemoenzymatic desymmetrization of the σ-symmetrical diol, a ring closing metathesis, a diastereoselective epoxidation, and a regioselective reductiv

Full text of DOI:10.1016/j.tetlet.2003.09.086

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8505–8507
First enantioselective total synthesis of (−)-heliannuol Cꢀ
Tomoyo Kamei, Mitsuru Shindo and Kozo Shishido*
Institute for Medicinal Resources, University of Tokushima, 1-78 Sho-machi, Tokushima 770-8505, Japan
Received 25 August 2003; revised 5 September 2003; accepted 5 September 2003
Abstract—The first, efficient total synthesis of (−)-heliannuol C (1) was accomplished enantioselectively, using a chemoenzymatic
desymmetrization of the s-symmetrical diol, a ring closing metathesis, a diastereoselective epoxidation, and a regioselective
reductive cleavage of epoxide as the key reaction steps.
© 2003 Elsevier Ltd. All rights reserved.
Heliannuol C (1) has been isolated from the aqueous
leaf extracts of Helianthus annuus L. var. SH-222 and
VYP by Macias.1 Allelopathic activity bioassays of 1
suggested that this new type of sesquiterpene may be
involved in the cultivar sunflower defense against
dicotyledon species. Although the structure of 1 was
determined mainly by NMR techniques, the absolute
structure has never been established. A recent commu-
nication on the enantioselective synthesis2 of heliannuol
E (2)3 suggested that the absolute structure of 1 would
be (8R,10S) from the biogenetic parallelism. The
promising biological profiles of this compound coupled
with its intriguing structural features inspired us to
develop an efficient and enantioselective strategy for the
synthesis of the natural product. We report here the
first, efficient total synthesis of (−)-heliannuol C,
thereby establishing its absolute stereochemistry (Fig.
1).
We anticipated that heliannuol C (1) would be derived
from 3 by regioselective cleavage4 of the epoxide ring
followed by dehydration to provide the C-8 vinyl func-
tionality. Consideration of the molecular model of 4,
which can be prepared by ring-closing metathesis
(RCM)5 of 5, suggested that the epoxidation would
occur from the sterically less congested bottom face of
the double bond to give 3 diastereoselectively.4 The
diene 5 might be obtained from the optically active
alcohol 6, previously prepared from the s-symmetrical
3-aryl-1,5-pentanediol 7 by lipase mediated desym-
metrization,3 with the R configuration at the benzylic
stereogenic center (Scheme 1).
Treatment of the prochiral diol 8 with immobilized
lipase PS on diatomite6 in the presence of vinyl acetate
in Et2O at room temperature for 13 h produced the
monoacetate 9, [h]D26 +2.38 (c 0.29, CHCl3), and the
corresponding diacetate, which can be converted into 8
by basic hydrolysis (K2CO3 in aq. MeOH) in 24 and
76% yield, respectively. The enantiomeric excess of 9
was >99% as determined by HPLC on a Chiralcel OD
column. The absolute configuration of the stereogenic
center was elucidated by the following chemical conver-
sion. Dehydration7 of the primary alcohol moiety in 9
gave 10, which was ozonized and reduced with NaBH4
to provide the alcohol 11. Tosylation, followed by
reduction of the resulting 12 with NaBH4 in hot
DMSO, afforded the alcohol 13 after basic hydrolysis.
Sequential oxidation of 13 with Dess–Martin periodi-
nane and PDC provided the carboxylic acid 14, whose
spectral properties are identical with those of the
known carboxylic acid 144 having the R configuration,
which, except for the sign of its optical rotation, has
been prepared by our laboratory. Thus, the absolute
configuration of 9 was established to be S8 (Scheme 2).
Figure 1.
Keywords: lipase; ring-closing metathesis; diastereoselective epoxida-
tion; cleavage of epoxide; sesquiterpene.
ꢀ This work was presented at the 123rd Annual Meeting of the
Pharmaceutical Society of Japan, Nagasaki, March 2003 (Abstract
paper: 28[P1]I-113).
* Corresponding author. Tel.: +81 88 633 7287; fax: +81 88 633 9575;
e-mail: shishido@ph2.tokushima-u.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.086

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T. Kamei et al. / Tetrahedron Letters 44 (2003) 8505–8507
Scheme 1. Retrosynthetic analysis.
Scheme 2. Reagents and conditions: (a) o-nitrophenyl selenocyanate, n-Bu3P, THF, rt, 50 min; (b) 35% H2O2, THF, rt, 10 h, 48%
for the two steps; (c) O3, MeOH then NaBH4, MeOH, −78 to 0°C, 1.5 h, 50%; (d) TsCl, Et3N, 4-DMAP, CH2Cl2, rt, 16 h; (e)
NaBH4, DMSO, 60°C then K2CO3, MeOH, H2O, rt, 15 h, 54% for the two steps; (f) Dess–Martin periodinane, CH2Cl2, rt, 3 h;
(g) PDC, DMF, rt, 19 h, 35% for the two steps.
For the synthesis of the natural heliannuol C, the
acetoxyethyl moiety in 9 must be transformed to the
vinyl group. Protection of the hydroxyl function as the
methoxymethyl (MOM) ether followed by reduction
with LiAlH4 provided the alcohol 15, which was dehy-
drated to give the alkene 16. Sequential oxidation with
CAN and reduction of the resulting quinone with
Na2S2O4 gave the hydroquinone 17,9 whose sterically
less congested hydroxyl moiety (C-5) was selectively
protected as the t-butyldiphenylsilyl ether to furnish 18
in 80% yield, accompanied by the bissilyl ether in 16%
yield. With the desired phenolic compound 18 in hand,
we next examined the key conversions in our strategy.
The substrate diene 20 for the RCM was obtained in
85% yield as a single product by the reaction of 18 with
i-butyl-2-methyl-3-buten-2-yl carbonate in the presence
of tetrakis(triphenylphosphine)palladium in THF.10
Treatment of 20 with 10 mol% of (tricyclohexyl)-phos-
phine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimida-
zol-2-ylidene][benzylidene]ruthenium (IV) dichloride 21
in CH2Cl2 at room temperature provided the desired
seven-membered heterocycle 22 in 98% yield. Epoxida-
tion of 22 with methyl(trifluoromethyl) dioxirane, gen-
erated in situ from methyl trifluoromethyl ketone and
Oxone® in acetonitrile,11 produced 78% yield of a 10:1
inseparable diastereomeric mixture of the epoxide 23.
Although the stereochemistry of the major diastereoiso-
mer could not be determined at this stage, its confirma-
tion was made in the next step. When a mixture of the
epoxide was treated with LiAlH4 in THF at 40°C, the
reaction proceeded smoothly and regioselectively to
give a chromatographically separable mixture of the
alcohol 24 in 89% yield. The absolute configuration at
C-10 of the major diastereoisomer was determined to
be the requisite S12 by the Kusumi–Mosher ester
method,13 and this result indicated that the epoxidation
had occurred from the bottom face of the double bond
in 22, as we predicted. Removal of the MOM protect-
ing group, dehydration of the resulting alcohol 25,
followed by desilylation produced (−)-heliannuol C (1),
[h]D25 −60 (c 0.29, MeOH) {lit.1 [h]2D5 −38 (c 0.10,
MeOH)}, the spectral data of which were in agreement
with those reported for the natural heliannuol C
(Scheme 3).
In summary, we have completed the first enantioselec-
tive total synthesis of the optically pure, natural enan-
tiomer of (−)-heliannuol C. The key steps of the
synthesis include the enantioselective construction of
the two remote tertiary stereogenic centers by a com-
bined use of the chemoenzymatic desymmetrization of

T. Kamei et al. / Tetrahedron Letters 44 (2003) 8505–8507
8507
Scheme 3. Reagents and conditions: (a) MOMCl, i-Pr2NEt, rt, 18 h, 95%; (b) LiAlH4, THF, rt, 10 min, 96%; (c) o-nitrophenyl
selenocyanate, n-Bu3P, THF, rt, 15 min; (d) 35% H2O2, THF, rt, 3.5 h, 91% for the two steps; (e) (NH4)2Ce(NO3)6, CH3CN, H2O,
rt, 20 min; (f) Na2S2O4, THF, H2O, rt, 10 min, 95% for the two steps; (g) t-BuPh2SiCl, imidazole, 4-DMAP, CH2Cl2, rt, 1 h, 80%;
(h) i-BuOCO2C(Me)2CHꢀCH2, (Ph3P)4Pd, THF, rt, 14 h, 85%; (i) 21, CH2Cl2, rt, 16.5 h, 98%; (j) CH3COCF3, Oxone®, CH3CN,
rt, 2.5 h, 78%; (k) LiAlH4, THF, 40°C, 20 min, 89%; (l) 6N-HCl, THF, rt, 3 h, 84%; (m) o-nitrophenyl selenocyanate, n-Bu3P,
THF, rt, 20 min; (n) 35% H2O2, THF, rt, 3.5 h, 88% for the two steps; (o) n-Bu4NF, THF, rt, 15 min, quant.
the s-symmetrical diol and a substrate controlled
diastereoselective epoxidation of the double bond in the
seven-membered heterocycle followed by regioselective
hydride reduction of the epoxide. In addition, the abso-
lute configurations were established to be (8R,10S) by
the present total synthesis. The synthetic route devel-
oped here is not only general and efficient but also can
be applied to the synthesis of the enantiomer and other
related natural products.
4. Kishuku, H.; Shindo, M.; Shishido, K. Chem. Commun.
2003, 350–351.
5. For a review, see: Trnka, T. M.; Grubbs, R. H. Acc.
Chem. Res. 2001, 34, 18–29.
6. In a previous report,3 we used lipase AK to obtain the
optically active monoacetate 9. Further screening of
enzymes revealed that the immobilized lipase PS on
diatomite was the best choice for the desired transforma-
tion.
7. Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem.
1976, 41, 1485–1486.
Acknowledgements
8. Our previous assignment3 of the R-configuration for the
(+)-monoacetate was incorrect and we herewith correct it
to the opposite configuration.
We thank Mr. T. Mase (Amano Enzyme, Co.) for
kindly providing us with immobilized lipase PS on
diatomite.
9. Takabatake, K.; Nishi, I.; Shindo, M.; Shishido, K. J.
Chem. Soc., Perkin Trans. 1 2000, 1807–1808.
10. Kaiho, T.; Yokoyama, T.; Mori, H.; Fujiwara, J.;
Nobori, T.; Odaka, H.; Kamiya, J.; Maruyama, M.;
Sugawara, T. JP 06128238, 1994; [C.A., 1995, 123,
55900].
11. Yang, D.; Wong, M. K.; Yip, Y. C. J. Org. Chem. 1995,
60, 3887–3889.
12. Selected Dl values (Dl=l(S)−l(R)) for the MTPA ester of
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