Asymmetric total syntheses of heliannuol e and epi-heliannuol e

Article abstract of DOI:10.1016/j.tetlet.2011.08.131

Asymmetric total syntheses of heliannuol E and epi-heliannuol E were achieved in 10 and 13 steps, respectively, from the commercially available starting materials. The syntheses feature an intramolecular attacking on the sulfate to form the dihydropyran ring of heliannuol E and an acyl transfer-secondary carbocation capture sequence to construct the dihydropyran ring of epi-heliannuol E.

Full text of DOI:10.1016/j.tetlet.2011.08.131

Tetrahedron Letters 52 (2011) 5802–5804
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric total syntheses of heliannuol E and epi-heliannuol E
Yongjiang Liu b, Chong Huang a, Bo Liu a,c,
⇑
a Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China
b College of Chemical Engineering, Sichuan University, Chengdu 610065, China
c Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric total syntheses of heliannuol E and epi-heliannuol E were achieved in 10 and 13 steps,
respectively, from the commercially available starting materials. The syntheses feature an intramolecular
attacking on the sulfate to form the dihydropyran ring of heliannuol E and an acyl transfer-secondary car-
bocation capture sequence to construct the dihydropyran ring of epi-heliannuol E.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 15 July 2011
Revised 16 August 2011
Accepted 23 August 2011
Available online 6 September 2011
Keywords:
Heliannuol E
Total synthesis
Natural product
Sesquiterpene
Helianthus annuus is a rich source of bioactive natural products,
from which Macias and co-workers have already isolated a number
of sesquiterpenes, including structurally related heliannuols A–L1
and heliespirones A–C (Fig. 1).2 Most of these sesquiterpenes exhi-
bit interesting allelopathic activity, which makes them alluring tar-
get molecules for synthetic chemists. Involved in such a synthetic
endeavor, our group reported the first asymmetric total synthesis
of ent-heliespirones A and C recently,3 laying the foundation for
enantioselective construction of other members in this heliannane
family. Considering the structural similarity to heliespirones A and
C, we selected heliannuol E and epi-heliannuol E as our further syn-
thetic targets. While two racemic syntheses4 have been developed,
there are four enantioselective syntheses5 of heliannuol E reported
till now. The third generation enantioselective synthesis of helia-
nnuol E by Shishido group counted only nine steps,5d superior to
the former synthetic routes with approximate 20 overall synthetic
steps5a–c; however, it is discounted by the required HPLC isolation
and low selectivity. Accordingly, a new, concise, and efficient syn-
thetic strategy is still worth exploring. Herein we would like to
present our efforts on the asymmetric total synthesis of heliannuol
E and the first asymmetric total synthesis of epi-heliannuol E.
Our asymmetric total synthesis of heliannuol E commenced
with compound 1, facilely prepared in seven steps from ethyl pro-
piolate and prenyl bromide, according to our synthetic strategy to-
ward ent-heliespirones A and C.3 The treatment with sulfonyl
chloride converted compound 1 to sulfate 2,6 by changing the sec-
ondary hydroxyl to a labile leaving group. Then compound 2 was
subjected to CAN oxidation and subsequent reduction to form phe-
nol 3. Finally, a base-promoted intramolecular ring closure pro-
duced heliannuol E in good yield.7 Notably, no trace amount of
epi-heliannuol E could be detected (Scheme 1). The spectra of our
synthetic heliannuol E were in accordance with those of other syn-
thetic samples (see Supplementary data).
Total synthesis of epi-heliannuol E was initiated with com-
pound 4, another intermediate in our total synthesis of ent-helies-
pirones A and C, prepared in six steps from commercially available
compounds.8 The primary and secondary alcohols in compound 4
were selectively protected with acetyl anhydride in the presence
of the tertiary alcohol to afford compound 5, which was converted
to phenol 6 after the routine treatment with an oxidation–reduc-
tion sequence. Based on our original design, in the presence of acid,
HO
HO
O
O
OH
OH
OH
OH
heliannuol E
epi-heliannuol E
O
O
O
O
O
O
heliespirone A
heliespirone C
⇑
Corresponding author. Tel./fax: +86 28 8541 3712.
E-mail address: chembliu@scu.edu.cn (B. Liu).
Figure 1. Structures of selected sesquiterpenes from Helianthus annuus.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.131

Y. Liu et al. / Tetrahedron Letters 52 (2011) 5802–5804
5803
OH
OAc
OMe
OMe
Br
8
a
not observed
Ref. 3
OH
+
OH
AcO
OH
O
O
HO
OMe
k1
7 steps
OMe S O
O
6
H+
OAc
O
OEt
2
1
b
OAc
O
HO
HO
OH
OH
OAc
OH
O
c
HO
OH
II
k2
I
O
S O
O
OH
O
SN2
heliannuol E
O
3
OAc
Scheme 1. Reagents and conditions: (a) SO2Cl2, triethylamine, DCM, 0 °C, 44%; (b)
CAN, aqueous MeCN, ꢀ10 °C, then Na2S2O4, THF/H2O, rt, 85%; (c) K2CO3, DMF/
MeCN, then 20% H2SO4 solution, ether/CHCl3, 82%.
OAc
HO
HO
OAc
OAc
O
OH
III
7', not observed
SN1 k3'
14
Br
OMe
OAc
OMe
1
OH
7
Ref. 3
1,3 diaxial repulsion
a
3
8
H
+
10
O
OH
OH
AcO
OMe
OAc
H
HO
OMe
6 steps
5
H
OH
R
2
OEt
AcO
R
OH
4
5
H
H
H
H
b
H
OH
OAc
OAc
k3>>k1,k2, k3'
SN1 k3
HO
10
OAc
OH
OAc
OH
R
=
AcO
OH
OAc
OAc
O
8
HO
HO
=
6
c
O
7
OAc
HO
HO
Scheme 3. Plausible mechanism for the formation of compound 7.
10
OAc
O
O
7
heliannnuol C
isolable product and the formation of its epimer, that is, compound
70 was not observed.
Scheme 2. Reagents and conditions: (a) Ac2O, DMAP, TEA, DCM, 0 °C, 95%; (b) CAN,
aqueous MeCN, ꢀ10 °C, then Na2S2O4, THF/H2O, rt, 90%; (c) p-TsOH, toluene, rt, 86%.
To prevent the decomposition of compound 7 in the course of
direct conversion of its primary hydroxyl to terminal double bond
with organoselenium and peroxide, the free phenol group was
protected as the tert-butyldiphenylsilyl ether, affording compound
9, the acetates of which were cleaved to give diol 10 with
diisobutylaluminum hydride.10 Subsequently, the primary alcohol
was transformed to terminal alkene 11 with organoselenium meth-
odology.3,11 Removing the silyl protective group of compound 11
smoothly converted it to epi-heliannuol E (Scheme 4),12 whose char-
acterization data were well consistent with those reported before
(see Supplementary data).
In summary, we have accomplished asymmetric total synthesis
of heliannuol E and epi-heliannuol E concisely, in 10 and 13 steps,
respectively, from the commercially available starting materials.
Our syntheses feature an intramolecular attacking on the sulfate
to form the dihydropyran ring of heliannuol E and an acyl trans-
fer-secondary carbocation capture sequence to construct the
dihydropyran ring of epi-heliannuol E. Total synthesis of other
members in this family is underway in our laboratory.
the tertiary alcohol had been anticipated to give a tertiary carbo-
cation, which might be subsequently captured by phenol to pro-
duce compound 8,9 an intermediate toward heliannuol C.
However, compound 7 was actually obtained instead under acidic
conditions with the C10 chirality retained (Scheme 2), the stereo-
chemistry of which was deduced from that of the final known com-
pound, epi-heliannuol E.
The plausible mechanism for the transformation from
compound 6 to 7 is depicted in Scheme 3. Firstly, the tertiary car-
bocation I could be generated when compound 6 was treated with
para-toluenesulfonic acid; then a secondary carbocation III could
be produced in quick equilibrium with intermediate I via interme-
diate II through acetyl transfer. Interestingly, the intramolecular
SN1 capture of secondary carbocation by phenol (k3) might be
the most facile process, compared to the transition states of other
process (k1, k2, k0 ), since compound 7 was achieved as the only
3

5804
Y. Liu et al. / Tetrahedron Letters 52 (2011) 5802–5804
References and notes
OAc
OAc
TBDPSO
HO
1. (a) Macias, F. A.; Varela, R. M.; Torres, A.; Molinillo, J. M. G.; Fronczek, F. R.
b
a
Tetrahedron Lett. 1993, 34, 1999–2002; (b) Macias, F. A.; Molinillo, J. M. G.;
Varela, R. M.; Torres, A.; Fronczek, F. R. J. Org. Chem. 1994, 59, 8261–8266; (c)
Macias, F. A.; Varela, R. M.; Torres, A.; Molinillo, J. M. G. Tetrahedron Lett. 1999,
40, 4725–4728; (d) Macias, F. A.; Varela, R. M.; Torres, A.; Molinillo, J. M. G. J.
Nat. Prod. 1999, 62, 1636–1639; (e) Macias, F. A.; Torres, A.; Galindo, J. L. G.;
Verela, R. M.; Alvarez, J. A.; Molinillo, J. M. G. Phytochemistry 2002, 61, 687–692.
2. (a) Macias, F. A.; Varela, R. M.; Torres, A.; Molinillo, J. M. G. Tetrahedron Lett.
1998, 39, 427–430; (b) Marcias, F. A.; Galindo, J. L. G.; Varela, R. M.; Torres, A.;
Molinillo, J. M. G.; Fronczek, F. R. Org Lett. 2006, 8, 4513–4516.
3. Huang, C.; Liu, B. Chem. Commun. 2010, 5280–5282.
4. (a) Doi, F.; Ogamino, T.; Sugai, T.; Nishiyama, S. Synlett 2003, 411–413; (b)
Vyvyan, J. R.; Oaksmith, J. M.; Parks, B. W.; Peterson, E. M. Tetrahedron Lett.
2005, 46, 2457–2460.
5. (a) Sato, K.; Yosimura, T.; Shindo, M.; Shishido, K. J. Org. Chem. 2001, 66, 309–314;
(b) Doi, F.; Ogamino, T.; Sugai, T.; Nishiyama, S. Tetrahedron Lett. 2003, 44, 4877–
4880; (c) Kamei, T.; Shindo, M.; Shishido, K. Synlett 2003, 2395–2397; (d) Kamei,
T.; Takahashi, T.; Yosida, M.; Shishido, K. Heterocycles 2009, 78, 1439–1444.
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2009, 65, 6341–6347.
OAc
OAc
O
O
7
9
OH
TBDPSO
TBDPSO
c
OH
OH
O
11
O
10
HO
d
OH
O
7. Kato, N.; Tomita, D.; Maki, K.; Kanai, M.; Shibasaki, M. J. Org. Chem. 2004, 69,
6128–6130.
8. Efforts on the direct transformations from compound 1 to epi-heliannuol E failed.
epi-heliannuol E
Scheme 4. Reagents and conditions: (a) TBDPSCl, DMAP, imidazole, DCM, rt, 90%; (b)
DIBAL-H, DCM, 0 °C, 72%; (c) nBu3P, o-NO2PhSeCN, THF, 0 °C, then 30% H2O2; (d)
TBAF, THF, 0 °C, 63% for two steps.
OH
19% yield
conditions
OH
for 3 steps
complex
mixture
compound 1
not optimized
AcO
OH
Acknowledgments
We appreciate the financial support from NSFC (20872098,
21021001), the Ministry of Education of China (NCET, IRT0846),
and National Basic Research Program of China (973 Program,
2010CB833200). We also thank Analytical & Testing Center of Sich-
uan University for NMR recording.
9. Youssefyeh, R. D.; Campbell, H. F.; Klein, S.; Airey, J. E.; Darkes, P.; Powers, M.;
Schnapper, M.; Neuenschwander, K.; Fitzpatrick, L. R.; Pendley, C. E.; Martin, G.
E. J. Med. Chem. 1992, 35, 895–903.
10. Nishikawa, T.; Urabe, D.; Isobe, M. Angew. Chem., Int. Ed. 2004, 43, 4782–4785.
11. (a) Ma, C.; Schiltz, S.; Le Goff, X. F.; Prunet, J. Chem. Eur. J. 2008, 14, 7314–7323;
(b) Comins, D. L.; Dehghani, A. J. Org. Chem. 1995, 60, 794–795; (c) Grieco, P. A.;
Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485–1486.
12. (a) For racemic synthesis of epi-heliannuol E, see Ref. 4; (b) For an asymmetric
synthesis, see Ref. 5b; For racemic synthesis of O-methyl epi-heliannuol E, see:
(c) Sabui, S. K.; Venkateswaran, R. V. Tetrahedron 2003, 59, 8375–8381.
Supplementary data
Supplementary data associated (characterization data for new
compounds) with this Letter can be found, in the online version,
at doi:10.1016/j.tetlet.2011.08.131.