Total synthesis of (+)-asteriscanolide: Further exploration of the rhodium(I)-catalyzed [(5+2)+1] reaction of ene-vinylcyclopropanes and CO

Article abstract of DOI:10.1002/asia.201100805

The total synthesis of (+)-asteriscanolide is reported. The synthetic route features two key reactions: 1) the rhodium(I)-catalyzed [(5+2)+1] cycloaddition of a chiral ene-vinylcyclopropane (ene-VCP) substrate to construct the [6.3.0] carbocyclic core with excellent asymmetric induction, and 2) an alkoxycarbonyl-radical cyclization that builds the bridging butyrolactone ring with high efficiency. Other features of this synthetic route include the catalytic asymmetric alkynylation of an aldehyde to synthesize the chiral ene-VCP substrate, a highly regioselective conversion of the [(5+2)+1] cycloadduct into its enol triflate, and the inversion of the inside-outside tricycle to the outside-outside structure by an ester-reduction/elimination to enol-ether/hydrogenation procedure. In addition, density functional theory (DFT) rationalization of the chiral induction of the [(5+2)+1] reaction and the diastereoselectivity of the radical annulation has been presented. Equally important is that we have also developed other routes to synthesize asteriscanolide using the rhodium(I)-catalyzed [(5+2)+1] cycloaddition as the key step. Even though these routes failed to achieve the total synthesis, these experiments gave further useful information about the scope of the [(5+2)+1] reaction and paved the way for its future application in synthesis.

Full text of DOI:10.1002/asia.201100805

DOI: 10.1002/asia.201100805
Total Synthesis of (+)-Asteriscanolide: Further Exploration of the
Rhodium(I)-Catalyzed [(5+2)+1] Reaction of Ene-Vinylcyclopropanes and
CO
Yong Liang, Xing Jiang, Xu-Fei Fu, Siyu Ye, Tao Wang, Jie Yuan, Yuanyuan Wang, and
Zhi-Xiang Yu*[a]
Abstract: The total synthesis of (+)-as-
teriscanolide is reported. The synthetic
route features two key reactions: 1) the
rhodium(I)-catalyzed [(5+2)+1] cyclo-
addition of a chiral ene-vinylcyclopro-
pane (ene-VCP) substrate to construct
the [6.3.0] carbocyclic core with excel-
lent asymmetric induction, and 2) an
alkoxycarbonyl-radical cyclization that
builds the bridging butyrolactone ring
with high efficiency. Other features of
this synthetic route include the catalyt-
ic asymmetric alkynylation of an alde-
hyde to synthesize the chiral ene-VCP
substrate, a highly regioselective con-
version of the [(5+2)+1] cycloadduct
into its enol triflate, and the inversion
of the inside–outside tricycle to the
outside–outside structure by an ester-
reduction/elimination to enol-ether/hy-
drogenation procedure. In addition,
density functional theory (DFT) ration-
alization of the chiral induction of the
[(5+2)+1] reaction and the diastereo-
selectivity of the radical annulation has
been presented. Equally important is
that we have also developed other
routes to synthesize asteriscanolide
using
the
rhodium(I)-catalyzed
[(5+2)+1] cycloaddition as the key
step. Even though these routes failed
to achieve the total synthesis, these ex-
periments gave further useful informa-
tion about the scope of the [(5+2)+1]
reaction and paved the way for its
future application in synthesis.
Keywords: annulation · cycloaddi-
tion · radical reactions · rhodium ·
total synthesis
Introduction
tion provides an efficient way to obtain fused [5–8] and [6–
8] ring-systems.[2] To demonstrate the utility of this new
[(5+2)+1] reaction, we have applied a tandem [(5+2)+1]
cycloaddition/aldol reaction strategy to the syntheses of
three linear triquinane natural products: (ꢀ)-hirsutene, (ꢀ)-
1-desoxyhypnophilin, and (ꢀ)-hirsutic acid C.[3] The
[(5+2)+1] reaction has also been shown to be effective in
the syntheses of (ꢀ)-pentalenene and (ꢀ)-asterisca-3(15),6-
diene.[4]
The value of new reactions becomes apparent when they are
utilized in the synthesis of complex molecules. In exploring
synthetic routes to the target molecule, we can further un-
derstand the scope and features of these new transforma-
tions. In 2007, we developed the rhodium-catalyzed two-
component [(5+2)+1] cycloaddition reaction of ene-vinylcy-
clopropanes (ene-VCPs) and CO (Scheme 1).[1] This reac-
Since the discovery of (+)-asteriscanolide (1) in 1985,[5a] it
has captured the attention of the organic chemical commun-
Scheme 1. Rhodium(I)-catalyzed [(5+2)+1] reaction of ene-vinylcyclo-
propanes and CO.
[a] Dr. Y. Liang, X. Jiang, X.-F. Fu, Dr. S. Ye, T. Wang, J. Yuan,
Dr. Y. Wang, Prof. Dr. Z.-X. Yu
ity because of its unique structure; its challenging sesquiter-
penoid framework contains an uncommon [6.3.0] carbocyclic
system bridged by a butyrolactone fragment and five cis ste-
reocenters. There have only been a few successful total syn-
theses of (+)-asteriscanolide reported to date,[6,7] although a
considerable amount of effort has been devoted to it.[8] In
all of these syntheses, one of the most formidable tasks was
to efficiently construct the eight-membered carbocycle.[9] In
1988, Wender et al. employed a nickel(0)-catalyzed intramo-
Beijing National Laboratory for Molecular Sciences (BNLMS)
Key Laboratory of Bioorganic Chemistry and
Molecular Engineering of Ministry of Education
College of Chemistry, Peking University
Beijing 100871 (China)
Fax : (+86)10-6275-1708
E-mail: yuzx@pku.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100805.
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FULL PAPERS
lecular [(4+4)] cycloaddition as
the pivotal step in the construc-
tion of the tricyclic core and
achieved the first total synthesis
of
(+)-asteriscanolide
in
13 steps.[6a] In 2000, Limanto
and Snapper incorporated
ring-opening-metathesis/Cope-
a
rearrangement strategy to reach
the tricyclic skeleton and finish-
ed the asymmetric synthesis of
compound 1 in 9 steps.[6c] In the
same year, using ring-closing-
metathesis strategies to build
the tricyclic cyclooctene, Pa-
quette and co-workers complet-
Scheme 3. Retrosynthetic analysis of strategy I.
ed the enantioselective total synthesis of compound 1 in
13 steps,[6b] and the Krafft group synthesized compound (ꢀ)-
1 in 19 steps.[7] Recently, we reported our approach to the
enantioselective total synthesis of (+)-asteriscanolide based
on a chiral substrate-induced rhodium(I)-catalyzed [(5+2)+
1] reaction.[10] Herein, we report a full account of our cumu-
lative efforts that eventually led to the successful synthesis
of the target molecule, and which also serves as further ex-
ploration of the scope and features of the rhodium(I)-cata-
lyzed [(5+2)+1] reaction in synthesis.
compounds (Scheme 3). In addition to strategy I, we came
up with three other strategies (Scheme 2) for constructing
the tricyclic skeleton of compound 1 in a single step. These
attempts, whether successful or not, would tell us more in-
formation about the scope of the [(5+2)+1] reaction.
Test of Strategy I
As shown in Scheme 3, ester 2 can be easily synthesized
from allylic alcohol 9[6c] and (E)-3-cyclopropylacrylic acid
(8).[11] This substrate incorporates two features not previous-
ly studied in the rhodium(I)-catalyzed [(5+2)+1] reaction,
namely, an ester group as the tethering chain and the inclu-
sion of an olefin moiety in a pre-existing five-membered
ring. When substrate 2 was tested under the standard reac-
tion conditions[1a] (CO/N2 0.2:0.8, 1 atm, 5 mol%
[{Rh(CO)2Cl}2] catalyst, 1,4-dioxane as solvent, 908C;
Scheme 4), no desired [(5+2)+1] product 7 was observed
and most of the unreacted starting material was recovered
(Scheme 4). To investigate why substrate 2 did not undergo
the [(5+2)+1], another ester-tethered ene-VCP (10), which
did not contain a five-membered ring, was synthesized and
subjected to the reaction (Scheme 4). Again, no [(5+2)+1]
product 11 was obtained under the catalysis of
[{Rh(CO)2Cl}2], and only compound 10 was recovered. The
failure of the ester-tethered substrate in the [(5+2)+1] reac-
tion could be due to the fact that the ester adopts a transoid
form, thereby keeping the ene
Results and Discussion
Attempts towards the Single-Step Construction of the
Tricyclic Core of Asteriscanolide
Because (+)-asteriscanolide (1) is a [5-5-8] tricyclic natural
product, in our initial synthesis, we were eager to use the
[(5+2)+1] reaction to construct its tricyclic core in one step.
Analysis of the structure of compound 1 allowed us to pro-
pose that the most-efficient and appealing strategy for the
synthesis of compound 1 using the [(5+2)+1] cycloaddition
reaction would be to employ ester-tethered cyclopentene-
VCP 2 as the substrate (strategy I; Scheme 2). We envi-
sioned that strategy I would provide a new route to this
complex natural product in only 4 steps from two known
and VCP moieties far away
from one another (Scheme 4).
It has been reported that such a
conformational
disadvantage
could be overcome by the use
of a polar solvent.[12] For in-
stance, a cationic rhodium(I)
species, derived from [{Rh-
AHCTUNGRTEN(GNUN cod)Cl}2] (cod=1,5-cycloocta-
diene) and AgSbF6 efficiently
catalyzed the intramolecular
[(5+2)] reaction of ester-teth-
ered yne-VCP derivatives in
(CF3)2CHOH.[12] Therefore, we
Scheme 2. Strategies I–IV for the one-step construction of the tricyclic core of asteriscanolide.
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Total Synthesis of (+)-Asteriscanolide
methyl substituent at the terminal position of the ene
moiety (13) was prepared and tested (Scheme 5). We found
that the [(5+2)+1] reaction of 13 could occur, but the pres-
ence of a methyl group in the ene moiety greatly decreased
the reaction rate and yield (the transformation of 13 into 14
needed 90 h at 908C to afford the product in 40% yield) as
compared with the reaction of its parent ene-VCP 15[1a]
(36 h, 808C, 81% yield; Scheme 5). This result indicates that
the [(5+2)+1] reaction is sensitive to the substitution of the
ene moiety. Based on previous mechanistic studies,[14] we be-
lieve that the introduction of a methyl group into the ene
moiety of the ene-VCP increases the energy of the alkene-
insertion transition state, thus making the [(5+2)+1] reac-
tion more difficult than that of the unsubstituted ene-VCP.
Test of Strategies III and IV
At this point, we considered the tricyclic cyclooctadiene 17,
which was synthesized from the nickel(0)-catalyzed [(4+4)]
cycloaddition in the synthesis of asteriscanolide reported by
Wender et al.,[6a] as a potential target (Scheme 6). Retrosyn-
Scheme 4. Test of strategy I.
tried the [(5+2)+1] reaction of compound 10 and CO using
(CF3)2CHOH as solvent. However, the desired reaction did
not work under these conditions either. These results indi-
cate that the [(5+2)+1] reaction cannot tolerate ene-VCPs
with an ester group in the tethering chain.
Test of Strategy II
Our previous studies indicated that the [(5+2)+1] reaction
was tolerant of ether-tethered ene-VCP substrates.[1a,b]
Therefore, we turned our attention to strategy II
(Scheme 2). After a four-step synthesis,[13] substrate 3 was
prepared. However, after many attempts under various con-
ditions, the desired tricyclic product 12 could not be ob-
tained (Scheme 5). Substrate 3 was either recovered or de-
Scheme 6. Retrosynthetic analysis of strategies III and IV.
thetically, intermediate 17 could be derived from two differ-
ent [(5+2)+1] reaction precursors (4 and 5; Scheme 6). The
challenge of this design was whether electron-deficient
cyclic olefins could be compatible in the rhodium(I)-cata-
lyzed [(5+2)+1] reaction or not. We synthesized ene-VCPs
4 and 5 in 7 and 3 steps, respectively.[13] Then, we tried the
key rhodium(I)-catalyzed [(5+2)+1] cycloaddition reactions
under various conditions. To our disappointment, both sub-
strates 4 and 5 failed to give the target cycloadducts
(Scheme 7). A further test of the [(5+2)+1] reaction of acy-
clic olefin 21 with an electron-withdrawing group in the
VCP moiety was also unsuccessful (Scheme 7), thereby sug-
gesting that electron-deficient alkenes are not compatible in
the [(5+2)+1] cycloaddition.
All of these unsuccessful tests of strategies I–IV for the
one-step construction of the tricyclic core of asteriscanolide
(described above) show that electron-withdrawing groups,
such as esters, cannot be introduced as the chain tether or
the substituent of the alkene, and that the ene-VCP sub-
strates with alkenes in pre-existing five-membered rings are
not suitable for the rhodium(I)-catalyzed [(5+2)+1] reac-
tion.
Scheme 5. Test of strategy II.
composed in all cases. This result suggests that cyclopen-
tene-VCP substrates are not suitable for the [(5+2)+1] cy-
cloaddition reaction. The failure of cyclopentene as the
alkene substrate prompted us to investigate whether the ene
moiety in the [(5+2)+1] reaction could only be a terminal
alkene. To address this issue, an ene-VCP substrate with a
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the least, only a few examples have been reported for the
use of an alkoxycarbonyl-radical-cyclization reaction to con-
struct a bridged ring system,[16] and the stereoselectivity of
this radical process was not clear.
Study of the Chiral Induction of the [(5+2)+1] Reaction
Our execution of this plan began with the alkynylation of al-
dehyde 28 (Scheme 9). The resulting propargylic alcohol 29
was converted into allylic alcohol 26 by treatment with Red-
Scheme 7. Test of strategies III and IV.
Synthesis of (ꢀ)-Asteriscanolide Using a Stepwise
[(5+2)+1] Cycloaddition/Radical-Annulation Strategy
To reach the target molecule, we designed a stepwise strat-
egy (strategy V) to build the tricyclic skeleton of asterisca-
nolide. As shown in Scheme 8, the bridging butyrolactone
Scheme 9. Reagents and conditions: a) nBuLi, THF, ꢁ788C to RT;
b) Red-Al, THF, 408C, 93% over two steps; c) TBSCl, imidazole,
DMAP, DMF, 408C, 96%. THF=tetrahydrofuran, Red-Al=sodium
bis(2-methoxyethoxy)aluminumhydride,
TBS=tert-butyldimethylsilyl,
DMAP=4-dimethylaminopyridine, DMF=N,N-dimethylformamide.
Al. Substrate 26 was then subjected to the key [(5+2)+1]
cycloaddition reaction under the standard conditions. The
desired fused [5–8] bicyclic cyclooctenone 25 was isolated in
30% yield with a diastereomeric ratio of 75:25 (Scheme 9).
When this reaction was conducted in toluene, the reaction
yield increased to 47%, but the diastereoselectivity de-
creased to 55:45. We envisioned that a bulkier substituent at
the allylic position of the VCP moiety could greatly improve
the diastereoselectivity.[17] Therefore, we transformed allylic
alcohol 26 into TBS-protected 30 and then examined the
key [(5+2)+1] reaction (Scheme 9). Under the standard
conditions, bicyclic cyclooctenone 31 was obtained with ex-
cellent diastereoselectivity (d.r.>95:5), but the reaction
yield was only 30%. To our delight, when toluene (rather
than 1,4-dioxane) was used as the solvent, the yield was im-
proved to 70%, together with the same diastereoselectivity
(d.r.>95:5). In this substrate-induced [(5+2)+1] cycloaddi-
tion reaction, two new stereocenters (C2 and C9) were gen-
erated with a cis configuration, which corresponded to their
analogous configurations in compound 1. However, the hy-
drogen atom at the C1 position is in a trans configuration
with respect to the bridgehead hydrogen atoms at the C2
and C9 positions. This configuration is opposite to that in
compound 1. Considering the possibility that the stereocen-
ter at the C1 position, which contains a hydroxy substituent,
Scheme 8. Retrosynthetic analysis of first-generation strategy V.
ring could be constructed through the free-radical-annula-
tion of selenocarbonate 24,[15] and the [6.3.0] carbocyclic
system could be achieved by the rhodium(I)-catalyzed
[(5+2)+1] reaction of ene-VCP 26 with a hydroxy group at
the allylic position of the VCP moiety. However, in this syn-
thetic route, there were several challenging problems to be
solved. First and foremost, there were no established strat-
egies for performing the key [(5+2)+1] cycloaddition step
using substrates with a pre-existing chiral center with good
reactivities and diastereoselectivities. Second, four stereoiso-
mers could be generated from this substrate-induced
[(5+2)+1] reaction. According to the structure of 1, three
stereocenters (C1, C2, and C9) have a cis configuration. If
the configuration of one carbon atom is not correct, inver-
sion of the stereocenter should be considered. Last but not
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Total Synthesis of (+)-Asteriscanolide
can be inverted by a traditional oxidation/reduction strategy,
we believed that, if the chiral propargylic alcohol 29 could
be synthesized, the success of this highly diastereoselective
[(5+2)+1] reaction would lay the foundation for the final
enantioselective total synthesis of compound 1.
repulsion, as shown by the O-C1-C2-C3 dihedral angle of
728 and the O-C1-C11-C12 dihedral angle of 468 (Figure 1).
Radical Annulations to Build the Bridging Butyrolactone
Ring
We applied DFT calculations to investigate the origin of
the high diastereoselectivity observed for the [(5+2)+1] re-
action of compound 30.[14,18] DFT calculations had previous-
ly shown that the stereoselective step of the [(5+2)+1] reac-
After efficiently constructing the [6.3.0] carbocyclic core
with excellent asymmetric induction, we turned our atten-
tion to the introduction of the bridging butyrolactone ring.
Wittig olefination of ketone 31, followed by deprotection of
the TBS group, gave alcohol 33 with the opposite configura-
tion at the C1 position with respect to that in compound 1
(Scheme 10). To invert this configuration, compound 33 was
converted into ketone 34 by Dess–Martin oxidation. Then
using the bulky reducing reagent DIBAl-H at ꢁ788C, the
desired alcohol 35 with correct configuration at the C1 posi-
tion was generated (Scheme 10). After alcohol 35 was con-
verted into selenocarbonate 36, we conducted the radical
cyclization of compound 36 in the presence of AIBN and
nBu3SnH.[15] Gratifyingly, the tricyclic compound 37 was ob-
tained as a single stereoisomer in good yield (Scheme 10).
However, the configuration of the stereocenter at the C3
position was opposite to that of 1.
Next, we performed DFT calculations to better under-
stand the diastereoselectivity of this radical process.[19] When
compound 36 underwent the radical annulation reaction, the
trans-radical-addition transition state TS-trans-37 was
1.6 kcalmolꢁ1 lower in terms of Gibbs free energy than the
cis-radical-addition transition state TS-cis-38 (in benzene;
Figure 2a), thereby suggesting that the radical addition
greatly favors the trans product 37. This observation agrees
with the experimental data (Scheme 10). Through examining
these two transition states, we found that, in the disfavored
cis-addition state TS-cis-38, the alkoxycarbonyl radical and
ꢁ
tion is the alkene insertion into the Rh C bond of the rho-
dacycle, which is generated from the alkene coordination of
VCP to rhodium and a subsequent cyclopropane-cleavage
step.[1a] In principle, four stereoisomers could be generated
from the irreversible alkene-insertion step in the reaction of
compound 30 (the corresponding transition states located by
DFT calculations are shown in Figure 1). It was found that
the most-favored alkene-insertion transition state is TS-
trans1,2-cis2,9, which leads to the observed product, com-
pound 31. The other three transition states are all 3–5 kcal
molꢁ1 higher than TS-trans1,2-cis2,9 in terms of Gibbs free
energy. Therefore, the three corresponding stereoisomers
would not be generated in this [(5+2)+1] reaction. Through
analyzing the structures of these four transition states, we
found that, in the disfavored transition states, TS-trans1,2-
trans2,9 and TS-cis1,2-trans2,9, the O-C1-C11-C12 dihedral
angles were both about 258, thereby indicating that there
was obvious steric repulsion between the OTBS and C12
groups. In another disfavored transition state, TS-cis1,2-cis2,9,
the bulky OTBS group occupied a position on the more-en-
cumbered endo face, which also led to severe steric repul-
sion between the OTBS group and the C3 and C12 groups.
In contrast, in TS-trans1,2-cis2,9, there was no serious steric
Figure 1. DFT-computed structures and Gibbs free energies of alkene-insertion transition states in the rhodium(I)-catalyzed [(5+2)+1] cycloaddition re-
action (distances are given in ꢁ, Gtoluene =Gibbs free energy in toluene, Ggas =Gibbs free energy in the gas phase).
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states, TS-trans-43 and TS-cis-
44, respectively (for precursor
42, see Scheme 11; Figure 2b).
The computational results sug-
gested that the energy differ-
ence between these two com-
peting transition states was neg-
ligible, and predicted that both
the trans and cis products (43
and 44, respectively) would be
generated without selectivity.
Through analyzing the transi-
Scheme 10. Reagents and conditions: a) methyltriphenylphosphonium bromide, tBuOK, C6H6, 408C; b) TBAF, tion-state structures, we found
THF, 408C, 77% over two steps; c) DMP, NaHCO3, CH2Cl2, RT; d) DIBAl-H, CH2Cl2, ꢁ788C, 88% over two
steps; e) (1) Py, DMAP, THF, triphosgene, C6H6, RT, (2) PhSeH, 408C; f) nBu3SnH, AIBN, C6H6, reflux, 78%
over two steps. TBAF=tetrabutylammonium fluoride, DMP=Dess–Martin periodinane, DIBAl-H=diisobu-
tylaluminum hydride, Py=pyridine, AIBN=azobisisobutyronitrile.
that the strain of forming the
five-membered ring in TS-cis-
44 was still much larger than
that in TS-trans-43, thus favor-
ing the trans addition (Fig-
the endo alkene of the eight-membered carbocycle are in an
almost-eclipsed conformation, as shown by the O-C1-C2-C3
dihedral angle of only 198 (Figure 2a). However, the corre-
sponding dihedral angle became much bigger in TS-trans-37
(388, Figure 2a), thus making the trans addition (TS-trans-
37) more favorable. Based on this mechanistic information,
we envisioned that if the exo methylidene group of the
eight-membered carbocycle was changed into a much-bulki-
er ethylenedioxy group, the cis-radical addition might
become favored owing to the change of conformation of the
eight-membered carbocycle. Therefore, we calculated the
free energies of the trans- and cis-radical-addition transition
ure 2b). However, there was an additional steric repulsion
between the alkene and ketal moieties in TS-trans-43 com-
pared with TS-cis-44, which favors the cis-addition instead
(Figure 2b). Consequently, these two conflicting factors
render the two transition states very close in energy.
To confirm the above DFT prediction, radical-annulation
precursor 42 was prepared and tested (Scheme 11). As ex-
pected, a mixture of two inseparable diastereomers (43 and
44) was obtained from the radical-cyclization reaction. Un-
fortunately, the compound with the desired configuration at
the C3 position, tricyclic compound 44, was only a minor
product (Scheme 11).
Figure 2. DFT-computed structures and Gibbs free energies of radical addition transition states in the radical annulations (distances are given in ꢁ,
benzene =Gibbs free energy in benzene, Ggas =Gibbs free energy in the gas phase).
G
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Total Synthesis of (+)-Asteriscanolide
endo C7=C8 double bond into the hydroxy group at the C8
position by hydroboration/oxidation. However, in the pres-
ence of para-methylbenzenesulfonic acid, the exo C=C
double bond of compound 37 shifted to the endo C6=C7
double bond, and no desired compound 48 was observed
(Scheme 13). Then we tried the allylic oxidation of com-
pounds 37 or 47 in order to introduce the hydroxy group at
the C8 position. Unfortunately, treatment of compounds 37
or 47 with SeO2/TBHP only produced the allylic-oxidation
product with undesired regioselectivity (Scheme 13). There-
fore, we had to explore other approaches to build the bridg-
ing butyrolactone ring with the correct configuration.
Scheme 11. Reagents and conditions: a) HOCH2CH2OH, TsOH·H2O,
C6H6, reflux under a Dean–Stark trap; b) DMP, NaHCO3, CH2Cl2, RT;
c) DIBAl-H, CH2Cl2, ꢁ788C, 58% over three steps; d) (1) Py, DMAP,
THF, triphosgene, C6H6, RT, (2) PhSeH, RT; e) nBu3SnH, AIBN, C6H6,
reflux, 68% over two steps. Ts=para-toluenesulfonyl.
At this stage, we intended to epimerize the stereocenter
at the C3 position. Deprotonation of the “inside” hydrogen
at the C3 position (shown in a circle,[20] Scheme 12) of the
Scheme 13. Reagents and conditions: a) TsOH·H2O, CHCl3, 608C, 87%;
b) SeO2, tBuOOH, CH2Cl2, 258C, 90%; c) SeO2, tBuOOH, CH2Cl2,
258C, 78%.
Next, we wanted to prepare selenocarbonate 52 from
readily available [(5+2)+1] adduct 31; we expected that this
adduct would then undergo radical cyclization, to obtain an-
other tricyclic intermediate (51) that contained a C7=C8
double bond (Scheme 14). However, the conversion of the
C7-ketone group of compound 31 into the C7=C8 double
bond with high regioselectivity was challenging. Deprotona-
tion of the hydrogen atom at the C8 position was difficult to
achieve using a strong base under kinetically controlled con-
ditions because the C8 position is sterically more-hindered
than the C6 position. For example, the treatment of ketone
31 with LDA at ꢁ788C, followed by triflation with 2-[N,N-
bis(trifluoromethanesulfonyl)amino]pyridine, only gave the
desired enol triflate 53 with the C7=C8 double bond as a
minor product (53/54=33:67, as determined by integration
of the 1H NMR spectrum of the crude reaction mixture;
Scheme 12. Attempts at epimerizing the stereocenter at the C3 position.
tricyclic compound 37 was difficult to achieve under kineti-
cally controlled conditions owing to the steric congestion on
the concave face. Such a problem was also encountered by
Krafft et al. in their total synthesis of asteriscanolide.[7]
After many attempts, they discovered that the “inside” hy-
drogen at the C3 position of compound 45 (Scheme 12)
could be partially transformed into the “outside” hydrogen
using TBAT[21] as a base in refluxing acetonitrile for
29 hours.[7] However, in our case, this method was unsuccess-
ful for converting compound 37 into compound 38.
We reasoned that if the hydroxy group at the C8 position
could be introduced into compound 37 to give a compound
similar to compound 45, maybe
in this case, the stereocenter at
the C3 position could be invert-
ed by using the method report-
ed by Krafft et al.[7] Therefore,
we decided to obtain the tricy-
clic compound 48 with the endo
C7=C8 double bond through an
acid-catalyzed alkene isomeri-
zation and then convert the Scheme 14. Retrosynthetic analysis in second-generation strategy V.
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site to that of compound
1
(Scheme 18). The reason for
this stereochemistry should be
similar to that in the radical-an-
nulation reaction of compound
36. All efforts to directly invert
the configuration at the C3 po-
sition in compound 69 using the
deprotonation/protonation
strategy were unsuccessful.
Next, we removed the PMB
group of compound 69 by
DDQ oxidation, and tried to
epimerize the stereocenter at
the C3 position of the resulting
Scheme 15. Regioselectivity in the conversion of the [(5+2)+1] cycloadduct into its enol triflate.
Scheme 15). However, to our delight, ketone 31 was con-
verted into enol triflate 53 using trifluoromethanesulfonic
anhydride and 2,6-di-tert-butyl-4-methylpyridine with good
regioselectivity (53/54=88:12; Scheme 15).[22]
alcohol (70; confirmed by X-ray diffraction)[26] using the
method reported by Krafft et al.[7] However, none of the ex-
pected product 71 was observed under the reported condi-
Enol triflate 53 was then subjected to an iron-catalyzed
cross-coupling reaction to give cyclooctadiene 55
(Scheme 16).[23] Subsequent deprotection with TBAF gave
alcohol 56 with the opposite configuration at the C1 posi-
tion. After Dess–Martin oxidation and reduction with
DIBAl-H, the desired alcohol 58, which contained the cor-
rect configuration at the C1 position, was generated; this al-
cohol was then smoothly transformed into selenocarbonate
52. However, when selenocarbonate 52 was treated under
the radical cyclization conditions,[15] no desired tricyclic com-
pound 51 was obtained, but rather a mixture of unexpected
tetracyclic compounds (59) was isolated (Scheme 16). In this
radical process, the tricyclic radical intermediate B further
underwent an intramolecular 5-exo-trig secondary-alkyl-rad-
ical/alkene cyclization to form a more-stable tetracyclic ter-
tiary radical (C), which was then quenched with nBu3SnH to
give compound 59 (Scheme 16).[24]
After these attempts, we wanted to synthesize another
precursor (61) that contained an oxygen atom at the C8 po-
sition to test the radical-annulation reaction (Scheme 17).
Epoxidation of readily available cylooctadiene 55 with
mCPBA occurred regioselectively on the more-electron-rich
trisubstituted olefin and afforded epoxide 62 with excellent
diastereoselectivity (d.r.>95:5). Treatment of 62 with dieth-
ylaluminum 2,2,6,6-tetramethylpiperidide led to the regiose-
lective formation of compound 63 (Scheme 18).[25] Protec-
tion of 63 with PMBCl, followed by deprotection of the
TBS group and the inversion of the stereocenter at the C1
position, gave alcohol 67, which was transformed into the
radical annulation precursor 68.
Scheme 16. Reagents and conditions: a) [FeACHTNUTRGNEUNG(acac)3], 1-methyl-2-pyrrolidi-
none, MeMgBr, THF, ꢁ108C, 58% over two steps from compound 31;
b) TBAF, THF, 408C, 98%; c) DMP, NaHCO3, CH2Cl2, RT; d) DIBAl-H,
CH2Cl2, ꢁ788C, 48% over two steps; e) (1) Py, DMAP, THF, triphos-
gene, C6H6, 288C, (2) PhSeH, 288C; f) nBu3SnH, AIBN, benzene, reflux,
70% over two steps. acac=acetylacetonyl.
We then conducted the radical
cyclization of 68 in the presence
of AIBN and nBu3SnH.[15]
Gratifyingly, the expected tricy-
clic compound 69 was obtained
in excellent yield, although the
configuration of the stereocen-
ter at the C3 position was oppo- Scheme 17. Retrosynthetic analysis of third-generation strategy V.
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Chem. Asian J. 2012, 7, 593 – 604

Total Synthesis of (+)-Asteriscanolide
the enol ether successfully in-
stalled the hydrogen atom at
the C3 position with correct
configuration. Meanwhile, the
PMB group was removed, and
the exo C=C double bond was
also hydrogenated with 66:34
diastereoselectivity. The result-
ing alcohols 74 were formed as
a mixture of two inseparable
diastereomers.
Fortunately,
Dess–Martin oxidation of com-
pound 74 gave two separable
tricyclic ketones (75 and 76).
Treatment of compound 75
with trimethylsilyl triflate and
2,6-lutidine, followed by acidic
hydrolysis, resulted in the par-
tial formation of the desired tri-
cyclic ketone 76. Finally, com-
pound 76 was regioselectively
oxidized into compound (ꢀ)-1
by ruthenium tetroxide using
the approach reported by Pa-
quette et al. (Scheme 19).[6b]
Scheme 18. Reagents and conditions: a) mCPBA, EtOAc, 08C; b) 2,2,6,6-tetramethylpiperidine, nBuLi,
Me2AlCl, C6H6, 08C, 86% over two steps; c) NaH, PMBCl, DMF, 508C, 82%; d) TBAF, THF, 408C, 90%;
e) DMP, NaHCO3, CH2Cl2, RT; f) DIBAl-H, CH2Cl2, ꢁ788C, 84% over two steps; g) (1) Py, DMAP, THF, tri-
phosgene, C6H6, 308C, (2) PhSeH, 308C; h) nBu3SnH, AIBN, C6H6, reflux, 95% over two steps; i) DDQ,
CH2Cl2/H2O (4:1), RT, 89%. mCPBA=meta-chloroperbenzoic acid, PMB=para-methoxybenzyl, DDQ=2,3-
dichloro-5,6-dicyano-1,4-benzoquinone.
tions (Scheme 18). Therefore, the next challenging problem
was to efficiently convert the inside–outside tricycle of com-
Asymmetric Synthesis of (+)-Asteriscanolide
pound 69 into the outside–outside tricycle.[27]
Having finished the total synthesis of racemic asteriscano-
lide, the asymmetric synthesis of (+)-asteriscanolide (1) can
be accomplished by using chiral [(5+2)+1] cycloadduct 31,
which can be prepared from (S)-propargylic alcohol 29 in 3
steps with excellent asymmetric induction. Gratifyingly, the
catalytic asymmetric alkynylation of the aldehyde has been
well-developed.[30] We found that nucleophilic addition of
cyclopropylacetylene (27) to aldehyde 28 gave propargylic
alcohol (S)-29 in 94% ee and 90% yield in the presence of
Completion of the Total Synthesis of (ꢀ)-Asteriscanolide
We then tried to use ester-reduction/elimination to enol-
ether/hydrogenation as an alternative strategy to the direct
inversion of the C3 configuration in compound 69. We
began by reducing lactone 69 with DIBAl-H to afford a mix-
ture of hemiacetals (72), which was then smoothly converted
into enol ether 73 with methanesulfonyl chloride and trie-
thylamine (Scheme 19).[28,29] Subsequent hydrogenation of
ZnACTHNUGTRENNG(U OTf)2, triethylamine, and chiral ligand 77 (developed by
Jiang and co-workers;[31] Scheme 20). With this chiral build-
ing block in hand, we repeated the above successful synthet-
ic route (Scheme 21). Finally, natural (+)-asteriscanolide (1)
was synthesized from two commercially available materials
in 19 steps and 3.8% overall yield.[10]
Conclusions
In summary, we have successfully achieved the asymmetric
total synthesis of (+)-asteriscanolide based on a chiral-sub-
strate-induced rhodium(I)-catalyzed [(5+2)+1] cycloaddi-
tion reaction to build the [6.3.0] carbocyclic core with high
efficiency. This accomplishment further demonstrates that
the [(5+2)+1] reaction is a powerful method for the con-
struction of complex molecules with eight-membered carbo-
cycles. During this total synthesis, the asymmetric induction
of the [(5+2)+1] reaction with a pre-existing chiral center
was investigated both experimentally and theoretically.
Scheme 19. Reagents and conditions: a) DIBAl-H, CH2Cl2, ꢁ788C;
b) CH3SO2Cl, Et3N, CH2Cl2, 258C, 85% over two steps; c) H2, Pd/C,
EtOH, 608C; d) DMP, NaHCO3, CH2Cl2, 258C, 46% (75) and 24% (76)
over two steps; e) (1) TMSOTf, 2,6-lutidine, CH2Cl2, 258C, (2) 1m HCl,
Et2O, 25 8C, 48% brsm; f) RuCl3, NaIO4, CH3CN/CCl4/H2O (1:1:1), 258C,
59%. TMS=trimethylsilyl, Tf=trifluoromethanesulfonyl, brsm=based
on recovered starting material.
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601

Z.-X. Yu et al.
FULL PAPERS
cyclization was explained by
DFT calculations. This result
will be helpful for understand-
ing the stereochemistry of simi-
lar type of radical-mediated
ring-closing processes.
Scheme 20. Preparation of the chiral propargylic alcohol using the chiral ligand reported by Jiang and co-work-
ers.[31]
Experimental Section
Indeed, despite several unsuccessful attempts, we have fur-
ther clarified the scope and limitations of the [(5+2)+1] re-
action. Other merits of this synthesis include the introduc-
tion of the bridging butyrolactone ring using a radical pro-
cess, the utilization of a catalytic asymmetric alkynylation of
an aldehyde to synthesize the chiral ene-VCP substrate, a
highly regioselective conversion of the [(5+2)+1] cycload-
duct into its enol triflate, and the inversion of the inside–
outside tricycle to the outside–outside structure by an ester-
reduction/elimination to enol-ether/hydrogenation proce-
dure. In addition, the unusual stereochemical alignment in-
volving inside–outside bridgehead centers from the radical
General
Full experimental procedures and characterization data can be found in
the Supporting Information.
(1R,3aR,9aR,Z)-1-(tert-Butyldimethylsilyloxy)-2,2-dimethyl-2,3,3a,4,6,7-
hexahydro-1H-cyclopenta[8]annulen-5
ACHTUNGTREN(NUNG 9aH)-one (31)
A
solution of 30 (1.50 g, 5.1 mmol) and [{Rh(CO)2Cl}2] (100 mg,
0.26 mmol) in anhydrous C6H5Me (310 mL) was degassed by bubbling
CO/N2 (balloon, pressurized mix of CO and N2 gas, 1:4 VVꢁ1) for 5 min.
Then, the reaction mixture was immersed in an oil bath heated at 908C
and stirred under the above atmosphere for 50 h. Next, the reaction mix-
ture was cooled to room temperature and concentrated under reduced
Scheme 21. Asymmetric synthesis of (+)-asteriscanolide.
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Chem. Asian J. 2012, 7, 593 – 604

Total Synthesis of (+)-Asteriscanolide
pressure. The crude mixture was purified by flash column chromatogra-
phy on silica gel (petroleum ether/EtOAc 100:1 to 50:1) to afford com-
pound 31 (1.15 g, 70%) as a pale-yellow oil: Rf =0.19 (petroleum ether/
EtOAc=20:1); ½aꢂ2D0 =ꢁ45.3 (c=1.18, CHCl3); 1H NMR (400 MHz,
CDCl3): d=ꢁ0.02 (s, 3H), 0.02 (s, 3H), 0.86 (s, 9H), 0.93 (s, 3H), 1.01 (s,
3H), 1.10 (t, J=12.4 Hz, 1H), 1.54–1.63 (m, 1H), 2.01–2.30 (m, 3H),
2.34–2.56 (m, 4H), 2.61–2.70 (m, 1H), 3.63 (d, J=4.4 Hz, 1H), 5.44–5.51
(m, 1H), 5.87–5.96 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): d=ꢁ4.9,
ꢁ4.2, 18.0, 22.0, 23.8, 25.8, 28.4, 36.9, 41.7, 44.6, 44.7, 46.7, 47.8, 89.2,
130.0, 133.9, 213.9 ppm; IR: n˜ =1255, 1367, 1464, 1706, 2957 cmꢁ1; HRMS
(ESI) calcd for C19H34NaO2Si: 345.2220; found: 345.2221.
7.8 Hz, 1H), 3.78 (d, J=6.9 Hz, 1H), 3.81 (s, 3H), 4.20 (d, J=11.3 Hz,
1H), 4.30 (d, J=7.7 Hz, 1H), 4.50 (d, J=11.3 Hz, 1H), 5.10 (s, 1H), 5.13
(s, 1H), 6.88 (d, J=8.4 Hz, 2H), 7.23 ppm (d, J=8.4 Hz, 2H); 13C NMR
(101 MHz, CDCl3): d=24.4, 25.2, 28.8, 29.9, 34.5, 38.1, 40.4, 43.1, 46.0,
46.3, 55.2, 70.4, 81.7, 89.8, 113.8, 113.9, 129.3, 130.3, 148.8, 159.2,
180.0 ppm; IR: n˜ =1251, 1520, 1620, 1769, 2939 cmꢁ1; HRMS (ESI) calcd
for C23H30NaO4: 393.2036; found: 393.2035.
Tricyclic Enol Ether (73)
To a solution of 69 (104 mg, 0.28 mmol) in anhydrous CH2Cl2 (2.5 mL) at
ꢁ788C was added DIBAl-H (1.0m in n-hexane, 0.9 mL, 0.9 mmol). After
stirred at ꢁ788C for 3 h, the reaction mixture was diluted with Et2O
(30 mL) and quenched with saturated potassium sodium tartrate solution
(30 mL). The aqueous layer was separated and extracted with Et2O. The
combined organic extracts were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure to give the crude prod-
uct 72, which was used in the next step without further purification. To a
solution of the crude 72 and triethylamine (291 mg, 2.88 mmol) in anhy-
drous CH2Cl2 (8 mL) was added methanesulfonyl chloride (85 mg,
0.74 mmol). The resulting mixture was stirred at 258C for 2 h before it
was diluted with Et2O and washed with saturated NaHCO3 solution and
brine. The organic phase was dried over MgSO4, filtered, and concentrat-
ed under reduced pressure to give a residue, which was purified by flash
column chromatography on silica gel (petroleum ether/EtOAc 50:1 to
20:1) to give compound 73 (85 mg, 85% over two steps) as a colorless
oil: Rf =0.10 (petroleum ether/EtOAc=50:1); ½aꢂ2D0 =+38.6 (c=0.76,
CHCl3); 1H NMR (400 MHz, CDCl3): d=0.96 (s, 3H), 1.07 (s, 3H), 1.40
(t, J=12.4 Hz, 1H), 1.57–1.74 (m, 2H), 1.85 (dd, J=12.4, 5.6 Hz, 1H),
1.95–2.04 (m, 1H), 2.21–2.31 (m, 2H), 2.34–2.52 (m, 2H), 3.17 (t, J=
8.3 Hz, 1H), 3.66 (d, J=10.2 Hz, 1H), 3.80 (s, 3H), 4.19 (d, J=11.2 Hz,
1H), 4.37 (d, J=8.2 Hz, 1H), 4.46 (d, J=11.2 Hz, 1H), 5.13 (s, 1H), 5.28
(s, 1H), 6.06 (s, 1H), 6.86 (d, J=8.4 Hz, 2H), 7.23 ppm (d, J=8.4 Hz,
2H); 13C NMR (101 MHz, CDCl3): d=23.8, 25.4, 26.8, 27.2, 38.9, 42.3,
42.6, 50.1, 50.3, 55.2, 69.8, 79.3, 96.0, 113.2, 113.7, 114.4, 129.2, 131.0,
142.9, 151.0, 159.0 ppm; IR: n˜ =1251, 1516, 1616, 1654, 2928 cmꢁ1; HRMS
(ESI) calcd for C23H31O3: 355.2268; found: 355.2264.
tert-Butyldimethyl((1R,3aR,4Z,8Z,9aS)-2,2,5-trimethyl-2,3,3a,6,7,9a-
hexahydro-1H-cyclopenta[8]annulen-1-yloxy)silane (55)
To a solution of 2,6-di-tert-butyl-4-methylpyridine (1.16 g, 5.67 mmol) in
anhydrous CH2Cl2 (30 mL) was added sequentially trifluoromethanesul-
fonic anhydride (1.32 g, 4.68 mmol) and
a solution of 31 (890 mg,
2.76 mmol) in anhydrous CH2Cl2 (30 mL). The reaction mixture was
stirred at 258C for 12 h. Afterwards, the solvent was removed by evapo-
ration under reduced pressure, the residue was dissolved in 150 mL Et2O,
washed with 1m HCl solution and brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The resulting brown oil was fil-
tered through a pad of silica gel and the filtrate was concentrated under
reduced pressure to give the crude product 53, which was used in the
next step without further purification. A solution of crude 53 in THF
(35 mL) was added to a mixture of [FeACHTNUGTRENUNG(acac)3] (199 mg, 0.56 mmol) and
1-methyl-2-pyrrolidinone (3 mL), and the resulting mixture was cooled to
ꢁ108C. MeMgBr (3.0m in Et2O, 3.5 mL, 10.5 mmol) was added dropwise
and the reaction mixture was allowed to warm to room temperature and
stirred overnight. Then, to the reaction mixture was added saturated
NH4Cl solution and Et2O, and the aqueous layer was extracted with
Et2O. The combined organic phase was washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica gel (petroleum
ether) to give compound 55 (515 mg, 58% over two steps) as a colorless
oil: Rf =0.39 (petroleum ether); ½aꢂ2D0 =+13.8 (c=1.00, CHCl3); 1H NMR
(400 MHz, CDCl3): d=0.04 (s, 3H), 0.05 (s, 3H), 0.89 (s, 9H), 0.92 (s,
3H), 0.98 (s, 3H), 1.24 (t, J=12.4 Hz, 1H), 1.66 (s, 3H), 1.73 (dd, J=
12.4, 7.6 Hz, 1H), 1.79 (dt, J=14.1, 6.8 Hz, 1H), 2.02–2.12 (m, 1H), 2.39–
2.48 (m, 1H), 2.58–2.66 (m, 1H), 2.84–2.92 (m, 1H), 3.14–3.24 (m, 1H),
3.46 (d, J=7.7 Hz, 1H), 5.09 (d, J=4.6 Hz, 1H), 5.41 (ddd, J=11.0, 5.5,
2.4 Hz, 1H), 5.50–5.57 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): d=
ꢁ4.5, ꢁ3.8, 18.2, 21.2, 23.8, 26.0, 26.6, 27.8, 32.0, 38.3, 40.7, 46.0, 50.5,
(+)-Asteriscanolide (1)
To a mixture of compound 76 (10.5 mg, 0.044 mmol) and sodium period-
ate (47.0 mg, 0.22 mmol) in CH3CN/CCl4/H2O (3 mL, 1:1:1, VVꢁ1 Vꢁ1
)
was added ruthenium trichloride (4.7 mg, 0.023 mmol). After stirring at
258C for 9 h, the reaction mixture was diluted with CH2Cl2, washed with
water, dried over MgSO4, and filtered. After the solvent was evaporated
under reduced pressure, the residue was subjected to flash column chro-
matography on silica gel (petroleum ether/EtOAc=3:1) to give com-
pound 1 (6.6 mg, 59%) as a white solid: Rf =0.16 (petroleum ether/
EtOAc=3:1); m.p.=155–1568C (lit. m.p.=1788C,[5a] 156–1588C,[6b] 163–
1658C,[6c] 142–1438C[7b]); ½aꢂD20 =+11.8 (c=0.28, CHCl3; lit. value=
+12.1,[5a] +8.5,[6b] +16.6[6c]); 1H NMR (400 MHz, CDCl3): d=1.00 (s,
3H), 1.13 (d, J=6.3 Hz, 3H), 1.20 (s, 3H), 1.31–1.44 (m, 2H), 1.51–1.62
(m, 1H), 1.76–1.85 (m, 1H), 1.88–2.01 (m, 2H), 2.19 (t, J=13.4 Hz, 1H),
2.36–2.57 (m, 2H), 2.72 (ddd, J=12.3, 9.6, 6.3 Hz, 1H), 3.21 (dt, J=11.9,
6.8 Hz, 1H), 3.73 (dt, J=10.5, 5.3 Hz, 1H), 4.27 ppm (d, J=5.2 Hz, 1H);
13C NMR (101 MHz, CDCl3): d=13.2, 22.4, 23.0 (2 C), 24.5, 28.0, 38.4,
40.7, 43.2, 45.66, 45.72, 50.2, 90.9, 177.8, 213.6 ppm; IR: n˜ =1274, 1475,
1698, 1769, 2928 cmꢁ1; HRMS (ESI) calcd for C15H22NaO3: 273.1461;
found: 273.1463.
88.7, 128.6, 128.7, 133.7, 136.4 ppm; IR: n˜ =1255, 1363, 1468, 2935 cmꢁ1
;
HRMS (ESI) calcd for C20H36NaOSi: 343.2428; found: 343.2431.
Tricyclic Lactone (69)
To a mixture of 67 (101 mg, 0.29 mmol), DMAP (27 mg, 0.22 mmol), and
pyridine (0.88 g, 11.1 mmol) in anhydrous THF (8 mL) was added a solu-
tion of triphosgene (145 mg, 0.49 mmol) in anhydrous C6H6 (8 mL). After
stirring at 308C for 3 h, freshly distilled PhSeH (387 mg, 2.46 mmol) was
added and the reaction mixture was stirred at 308C for 16 h before H2O
(100 mL) and Et2O (100 mL) were added. The aqueous layer was sepa-
rated and extracted with Et2O. The combined organic phase was washed
sequentially with 1m HCl, H2O, and saturated NaHCO3 solution, dried
over MgSO4, filtered, and concentrated under reduced pressure. The re-
sulting yellow oil was filtered through a pad of silica gel, and the filtrate
was concentrated under reduced pressure to give the crude 68, which was
used in the next step without further purification. To a solution of the
crude 68 and AIBN (21 mg, 0.13 mmol) in anhydrous C6H6 (60 mL) was
added nBu3SnH (360 mg, 1.20 mmol). The resulting mixture was heated
to reflux in an oil bath (908C) for 3.5 h. The solvent was removed by
evaporation under reduced pressure, and the residue was purified by
flash column chromatography on silica gel (petroleum ether/EtOAc 50:1
to 10:1) to afford compound 69 (104 mg, 95% over two steps) as a color-
less oil: Rf =0.35 (petroleum ether/EtOAc=5:1); ½aꢂ2D0 =+36.0 (c=0.87,
Acknowledgements
We thank the Natural Science Foundation of China (20825205–National
Science Fund for Distinguished Young Scholars and 20672005) and the
National Basic Research Program of China (2010CB833203 and
2011CB808603–973 Program) for financial support.
1
CHCl3); H NMR (400 MHz, CDCl3): d=1.01 (s, 3H), 1.05 (s, 3H), 1.34–
1.45 (m, 2H), 1.69–1.82 (m, 2H), 1.89–2.02 (m, 1H), 2.08–2.25 (m, 2H),
2.39 (dq, J=12.8, 6.4 Hz, 1H), 2.50–2.63 (m, 2H), 2.77 (dd, J=15.4,
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Received: September 27, 2011
Published online: December 23, 2011
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