Asymmetric total synthesis of ent-heliespirones A & C

Article abstract of DOI:10.1039/c0cc00481b

A concise 8-step synthetic route toward ent-heliespirones A & C is described. This synthetic strategy features a highly diastereoselective palladium-catalyzed Michael addition to form 3,5-trans lactone and a final biomimetic intramolecular oxa-spirocyclization.

Full text of DOI:10.1039/c0cc00481b

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Asymmetric total synthesis of ent-heliespirones A & Cw
Chong Huanga and Bo Liu*ab
Received 19th March 2010, Accepted 27th May 2010
First published as an Advance Article on the web 24th June 2010
DOI: 10.1039/c0cc00481b
A concise 8-step synthetic route toward ent-heliespirones
A & C is described. This synthetic strategy features a highly
diastereoselective palladium-catalyzed Michael addition to
form 3,5-trans lactone and a final biomimetic intramolecular
oxa-spirocyclization.
heliannuol C showed up with a linear 21-step synthetic
route in 2003 and was featured with a lipase-catalyzed
desymmetrization of the diol.5d
Although the transformation following the biogenetic path-
way seems to be a straightforward way to reach heliespirones
A & C enantioselectively from heliannuol C via a semi-
synthetic way, we preferred a concise total synthesis toward them.
Herein we would like to describe our achievements on the
asymmetric total synthesis leading to ent-heliespirones A & C.
As illustrated in Fig. 2, ent-heliespirones A & C can be
retrosynthetically derived from compound I via a biomimetic
oxaspirocycliation. The precursor I might be achieved from
intermediate II by transforming the primary alcohol to a
terminal alkene. The two stereocenters of compound III are
devised to be installed respectively through Michael addition
to compound IV with reagent V in a substrate–controlling
manner and Sharpless AD of compound VI in a chiral
ligand–controlling manner, respectively.
Thus, the known compound 17 was choosen as the starting
material and was smoothly transformed to chiral diol 2 with
96% ee in 98% yield under Sharpless AD condition. Then diol
2 was converted to Z-disubstituted enester 3 with Lindlar
catalyst in the presence of hydrogen, which was used without
purification and further cyclized to form lactone 4 catalyzed by
para-toluenesulfonic acid (Scheme 1).8
In 1998, the first member of heliespirone family, heliespirone
A, was isolated from cultivar sunflowers var. SH-222s by
Macias’ group. The primary structure was proposed based on
extensive NMR spectra.1 Eight years later, the same group
reported two siblings in this family, heliespirones B & C
namely, from the same species.2 They revised the structure
of heliespirone A at the same time by comparing its character-
ization data with those of heliespirones B & C and heliannuols
B, D, E and F (Fig. 1).3
Heliespirones embrace a novel oxa-spirocyclic sesquiterpene
skeleton and show potential allelopathic activity in the
coleoptiles bioassay. The arresting bioactivity and unusual
natural structure make them attractive synthetic targets; their
total synthesis has not been reported yet. From a biogenetic
view, heliespirones A & C might be achieved from heliannuol
C via oxidation of the phenol ring and the following intra-
molecular oxa-Michael addition. Heliespirone B could be
transformed from heliannuol A through a similar pathway.2
Heliannuol C is one of the most active members of the
heliannuol family, showing germination inhibition of lettuce
and cress even in nM concentration.3a,4 To the best of our
knowledge, there have been only three total syntheses since the
isolation of heliannuol C, which include two total syntheses of
racemic heliannuol C and one enantioselective total synthesis.5
In order to install the C3 stereocenter with good selectivity,
a 1,4-addition of an aryl ring to lactone 4 was studied
carefully. First, various organocuprates 5a were prepared by
mixing aryl lithium, derived from bromide 5b, with different
copper salts including CuI, CuBrSMe2, CuCN etc.9 However,
all efforts at promoting such a Michael addition, with or
without a Lewis acid, proved sterile. Subsequently, the palladium-
catalyzed 1,4-addition of bromide 5b, with Pd(PPh3)4/TEA or
Pd(OAc)2/TEA/HCO2H,10 was attempted, but did not afford
the desired adduct either. Inspired by the recent report on
palladium-catalyzed C–H activation,11 we applied Pd(OAc)2
in TFA/DCM (4/1) to catalyze the coupling of lactone 4
Venkateswaran group developed
a
12-step synthetic
route to racemic heliannuol C, by employing a Claisen
orthoester rearrangement and a Dieckmann cyclization from
6-hydroxycoumarin.5a,b A more concise racemic synthesis was
elegantly attained through an aromatic Claisen rearrangement
and the following biomimetic phenol epoxide cyclization in 7
steps by Vyvyan’s group;5c however, the direct asymmetric
version of such a strategy towards enantiopure heliannuol C
has not been developed yet, since few methods on enantio-
selective aromatic Claisen rearrangement have been explored.6
The only example of the enantioselective total synthesis of
a Key Laboratory of Green Chemistry & Technology of Ministry of
Education, College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China. E-mail: chembliu@scu.edu.cn;
Fax: +86 28 8541 3712; Tel: +86 28 8541 3712
b Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, CAS, 345 Lingling Road,
Shanghai 200032, P. R. China
w Electronic supplementary information (ESI) available: Experimental
details and characterization data for the new compounds. See DOI:
10.1039/c0cc00481b
Fig. 1 Molecular structures of heliespirones and heliannuols A & C.
ꢀc
This journal is The Royal Society of Chemistry 2010
5280 | Chem. Commun., 2010, 46, 5280–5282

View Article Online
Scheme 3 Construction of quinone 9.
then oxidized to the corresponding key cyclisation precursor,
quinone 9(Scheme 3).
Thus, the biomimetic oxa-spirocyclization leading to
heliespirones A & C needed to be investigated by following
the synthetic plan. In general, the intramolecular oxa-Michael
addition to quinone, resulting in a oxaspiro-[4,5]-dec-7-
ene-6,9-dione, had been studied very rarely (Scheme 4). Cohen
et al. reported that quinone 10, with a so-called trialkyl lock,
could be facilely transformed to oxaspiral cycle 11; however,
those isomeric unlocked quinones 14a–14d did not show any
reactivity under acid or alkali conditions.16 Giles et al.
described a formal intramolecular oxa-Michael addition using
the substrate with a whole sp2-hybridized carbon linker, which
is structurally and inherently different from that in compound
9.17 Other groups found that the oxaspirocycle formed only
as a side product in some cases.18 So the intramolecular
oxa-Michael addition of quinone 9 is actually not so reasonable
as it appears at first glance.
Fig. 2 Synthetic strategy towards heliespirones A & C.
Scheme 1 Enantioselective construction of lactone 4.
In fact, a number of Brønsted acids, Lewis acids and Lewis
bases were carefully evaluated, including CeCl3, PPTS, TsOH,
and 1,4-dimethoxy-2-methylbenzene (5c). To our delight,
compound 6 with the proper stereochemistry was formed,
but with less than 20% conversion. Failure to improve the
conversion any further forced us to search for other effective
methods. Eventually, addition of aryl boronic acid 5d12 to the
a,b-unsaturated lactone 4 was successfully realized in 88%
yield with more than 95% de by employing Ohta’s method,13
although no reaction occurred with Pd(OAc)2/ bipyridine as
the catalyst in HOAc–THF–H2O solvent system (Scheme 2).14
The resultant adduct 6 was reduced with lithium boro-
hydride to afford triol 7, which was treated with o-nitrophenyl-
selenocyanate and tributylphosphine,15 followed by treatment
with peroxide to produce compound 8. Compound 8 was
Scheme 2 Diastereoselective construction of 1,4-adduct 6.
Scheme 4 Previous work of intramolecular oxa-Michael addition.
Chem. Commun., 2010, 46, 5280–5282 | 5281
ꢀc
This journal is The Royal Society of Chemistry 2010

View Article Online
4 F. A. Macias, J. M. G. Molinillo, D. Chinchilla and J. C.
G. Galindo, In Allelopathy Chemistry and Mode of Action
of Allelochemicals, ed. F. A. Macias, J. M. G. Molinillo and
J. C. G. Galindo, CRC: Boca Raton, 2004, ch. 5.
5 (a) B. Biswas, P. K. Sen and R. V. Venkateswaran, Tetrahedron
Lett., 2006, 47, 4019; (b) B. Biswas, P. K. Sen and
R. V. Venkateswaran, Tetrahedron, 2007, 63, 12026;
(c) J. R. Vyvyan, J. M. Oaksmith, B. W. Parks and
E. M. Peterson, Tetrahedron Lett., 2005, 46, 2457;
(d) K. Tomoyo, S. Mitsuru and K. Shishido, Tetrahedron Lett.,
2003, 44, 8505.
6 (a) B. M. Trost and F. D. Toste, J. Am. Chem. Soc., 1998, 120,
815–816; (b) H. Ito, A. Sato and T. Taguchi, Tetrahedron Lett.,
1997, 38, 4815.
7 Compound 1 can be easily prepared by coupling ethyl propiolate
with prenyl bromideL. W. Bieber and M. F. da Silva, Tetrahedron
Lett., 2007, 48, 7088–7090.
Scheme 5 Completion of the total synthesis of ent-heliespirones
A & C.
LiClO4, DBU, etc. Finally, enantiopure ent-heliespirones A & C
were fortunately obtained from 9 with lithium chloride as a
mild Lewis acid in a satisfactory yield (Scheme 5).19 It is very
interesting that compound 17,20 the diastereoisomer of 9, does
not afford any oxacyclization product under all conditions.
Either no reaction occurs, or the alkene rearrangement takes
place giving compound 18. It is noteworthy that 9 can turn
into ent-heliespirones A & C automatically, albeit quite slowly,
during standing at room temperature, which indicates that
such a transformation should be a real process in nature.
These findings show that the trialkyl lock is unnecessary for
the intramolecular oxa-Michael addition of quinone to form
oxaspiro-[4,5]-dec-7-ene-6,9-dione if the stereochemical
requirement is matched. This could be a guide for total
syntheses of other natural products with similar skeleton, such
as conidione21 and strongylophorines-6 & -7.22
8 A. Ahmed, E. K. Hoegenauer, V. S. Enev, M. Hanbaur,
H. Kaehlig, E. Ohler and J. Mulzer, J. Org. Chem., 2003, 68,
3026–3042.
9 (a) D. Kim, J. Lee, P. I. Shim, J. I. Lim, T. Doi and S. Kim, J. Org.
Chem., 2002, 67, 772–781; (b) J.-P. Lumb and D. Trauner, Org.
Lett., 2005, 7, 5865–5868.
10 (a) G. E. Stokker, Tetrahedron Lett., 1987, 28, 3179–3182;
(b) S. Cacchi, Synthesis, 1984, 575–577.
11 (a) C. Jia, D. Piao, J. Oyamada, W. Lu, T. Kitamura and
Y. Fujiwara, Science, 2000, 287, 1992–1995; (b) C. Jia, D. Piao,
T. Kitamura and Y. Fujiwara, J. Org. Chem., 2000, 65, 7516–7522.
12 M. Yoshida, Y. Shoji and K. Shishido, Org. Lett., 2009, 11,
1441–1443.
13 T. Yamamoto, M. Iizuka, H. Takenaka, T. Ohta and Y. Ito,
J. Organomet. Chem., 2009, 694, 1325–1332.
14 X. Lu and S. Lin, J. Org. Chem., 2005, 70, 9651–9653.
15 (a) C. Ma, S. Schiltz, X. F. Le Gott and J. Prunet, Chem. Eur. J.,
2008, 14, 7314–7323; (b) D. L. Comins and A. Dehghani, J. Org.
Chem., 1995, 60, 794–795; (c) P. A. Grieco, S. Gilman and
M. Nishizawa, J. Org. Chem., 1976, 41, 1485–1486.
16 (a) R. T. Borchardt and L. A. Cohen, J. Am. Chem. Soc., 1973, 95,
8308–8313; (b) R. T. Borchardt and L. A. Cohen, J. Am. Chem.
Soc., 1972, 94, 9175–9182.
In summary, we have completed the first total synthesis of
ent-heliespirones A & C in eight steps from compound 1.
It features a highly enantioselective palladium-catalyzed
addition of aryl boronic acid to an unsaturated lactone, and
a biomimic intramolecular oxaspirocyclization of quinonyl
alcohol. Applying this synthetic strategy in enantioselective
syntheses of heliannuols C and E is under way in our
laboratory.
17 C. B. de Koning and R. G. F. Giles, J. Chem. Soc., Perkin Trans. 1,
1988, 3209.
18 (a) M. Kongkathip, B. Kongkathip, P. Siripong, C. Sangma,
S. Luangkamin, M. Niyomdecha, S. Pattanapa, S. Piyaviriyagul
and P. Kongsaeree, Bioorg. Med. Chem., 2003, 11, 3179–3191;
(b) D. Creed, H. Werbin and E. T. Strom, J. Am. Chem. Soc., 1971,
93, 502–511.
19 The synthetic heliespirones A & C proved enantiomers of natural
products. The characterization data of synthetic samples fit well
with those of natural samples, and the NOE diffference spectrums
were in accord with ent-heliespirones A & C. Please see electronic
supplementary informationw for details.
We appreciate the financial support from NSFC (20702032,
20872098), MOE (IRT0846), and MOST (2010CB833200). We
also thank Analytical & Testing Center of Sichuan University
for NMR recording.
20 This compound was obtained in a different synthetic route starting
from chiral auxiliary
Notes and references
1 F. A. Macias, R. M. Varela, A. Torres and J. M. G. Molinillo,
Tetrahedron Lett., 1998, 39, 427–430.
2 F. A. Macias, J. L. G. Galindo, R. M. Varela, A. Torres, J. M.
G. Molinillo and F. R. Fronczek, Org. Lett., 2006, 8, 4513–4516.
3 For isolation of heliannuols B-D: (a) F. A. Macias, J. M.
G. Molinillo, R. M. Varela and A. Torres, J. Org. Chem., 1994,
59, 8261–8266; (b) For isolation of heliannuol E: F. A. Macias,
R. M. Varela, A. Torres and J. M. G. Molinillo, Tetrahedron Lett.,
1999, 40, 4725–4728; (c) For isolation of heliannuol
F:F. A. Macias, R. M. Varela, A. Torres and J. M. G. Molinillo,
J. Nat. Prod., 1999, 62, 1636–1639.
21 L. Garrido, E. Zubia, M. J. Ortega and J. Salva, J. Nat. Prod.,
2002, 65, 1328.
22 J. Salva and D. J. Faulkner, J. Org. Chem., 1990, 55, 1941.
ꢀc
This journal is The Royal Society of Chemistry 2010
5282 | Chem. Commun., 2010, 46, 5280–5282