Enantioselective total synthesis of (+)-asteriscanolide via Rh(i)-catalyzed [(5+2)+1] reaction

Article abstract of DOI:10.1039/c1cc11005e

The total synthesis of (+)-asteriscanolide starting from two commercially available materials has been accomplished in 19 steps with a 3.8% overall yield. The key reaction is a chiral ene-vinylcyclopropane substrate induced Rh(i)-catalyzed [(5+2)+1] cycloaddition that efficiently constructs the [6.3.0] carbocyclic core with complete asymmetric induction.

Full text of DOI:10.1039/c1cc11005e

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COMMUNICATION
Enantioselective total synthesis of (+)-asteriscanolide via Rh(I)-catalyzed
[(5+2)+1] reactionw
Yong Liang, Xing Jiang and Zhi-Xiang Yu*
Received 21st February 2011, Accepted 23rd March 2011
DOI: 10.1039/c1cc11005e
The total synthesis of (+)-asteriscanolide starting from two
commercially available materials has been accomplished in
19 steps with a 3.8% overall yield. The key reaction is a chiral
ene-vinylcyclopropane substrate induced Rh(I)-catalyzed
[(5+2)+1] cycloaddition that efficiently constructs the [6.3.0]
carbocyclic core with complete asymmetric induction.
also been proved efficient in the syntheses of (ꢀ)-pentalenene
and (ꢀ)-asterisca-3(15),6-diene.9
Since (+)-asteriscanolide (1) has a [5–5–8] ring system, we
were eager to use the [(5+2)+1] reaction to achieve this goal.
We also tried to employ a chiral precursor to build a chiral
[(5+2)+1] cycloadduct and to finish its asymmetric synthesis.
Retrosynthetically, the bridging butyrolactone ring of 1 could
be built up through a free-radical annulation of selenocarbonate
2.10 Substrate 2 could be derived from the fused [5–8] bicyclic
cyclooctenone 3, product of a Rh(I)-catalyzed [(5+2)+1]
cycloaddition of ene-VCP 4 and CO (Scheme 2). However,
in this synthetic route, there are several challenging problems
to be solved. First and foremost, there had been no example of
a chiral substrate induced [(5+2)+1] reaction before we
started the total synthesis.6 That is to say, the reactivity and
diastereoselectivity of the key [(5+2)+1] cycloaddition using
substrates with a pre-existing chirality center were not well
established at that moment. Second, in principle, four stereo-
isomers could be generated from this reaction. According to
the structure of 1, three stereocenters (C1, C2, and C9) are in
cis configurations. If the configuration of one carbon is not
correct, the inversion of the stereocenter should be considered.
Last but not the least, the alkoxycarbonyl radical cyclization
was rarely used to construct a bridged ring system,11 and the
stereoselectivity of this radical process is not clear. Herein, we
report the asymmetric total synthesis of (+)-asteriscanolide
(1) highlighting the use of a chiral substrate induced Rh(I)-
catalyzed [(5+2)+1] cycloaddition to efficiently construct the
[6.3.0] carbocyclic skeleton and the alkoxycarbonyl radical
annulation to build the bridging butyrolactone ring.
Isolated in 1985, (+)-asteriscanolide (1) has captured the
attention of the synthetic community due to its unique
structure.1 Its challenging sesquiterpenoid framework contains
an uncommon [6.3.0] carbocyclic system bridged by a butyro-
lactone fragment and five cis stereocenters (Scheme 1). There
have been only a few successful total syntheses reported to
date,2,3 although considerable amounts of efforts were devoted
to its total synthesis.4 In all these syntheses, one of the most
formidable tasks was to efficiently construct the eight-
membered carbocycle of 1.5 The Wender group employed a
Ni(0)-catalyzed intramolecular [4+4] cycloaddition as the
pivotal step to construct the tricyclic core and achieved the
first enantioselective total synthesis of (+)-asteriscanolide
in 13 steps.2a In 2000, the Snapper group incorporated a
ring-opening metathesis/Cope rearrangement strategy to reach
the tricyclic skeleton and finished the asymmetric synthesis of
1 in 9 steps.2c In the same year, using ring-closing metathesis
strategies to build the tricyclic cyclooctenes, Paquette and
co-workers completed the asymmetric synthesis of 1 in 13
steps,2b and the Krafft group synthesized (ꢀ)-1 in 19 steps,3
respectively.
Recently, a Rh(I)-catalyzed two-component [(5+2)+1]
cycloaddition of ene-vinylcyclopropanes (ene-VCPs) and CO
was developed by our group (Scheme 1).6 This reaction
provides an efficient way to obtain fused [5–8] and [6–8] ring
systems.7 We have applied a tandem [(5+2)+1] cyclo-
addition/aldol reaction strategy to the syntheses of three linear
triquinane natural products, (ꢀ)-hirsutene, (ꢀ)-1-desoxyhypno-
philin, and (ꢀ)-hirsutic acid C.8 The [(5+2)+1] reaction has
Our total synthesis began with the catalytic asymmetric
alkynylation of aldehyde 6 (Scheme 3).12 We found that the
nucleophilic addition of cyclopropylacetylene (5) to aldehyde 6
gave propargylic alcohol 7 in 94% ee and 90% yield in the
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. E-mail: yuzx@pku.edu.cn;
Fax: +86-10-6275-1708; Tel: +86-10-6276-7735
w Electronic supplementary information (ESI) available: Experimental
procedures, compound characterization, and NMR spectra. See DOI:
10.1039/c1cc11005e
Scheme
1
Asteriscanolide and Rh(I)-catalyzed [(5+2)+1]
cycloaddition.
c
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Chem. Commun., 2011, 47, 6659–6661 6659

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(Scheme 4). It was found that ketone 11 could be converted
into enol triflate 12 using trifluoromethanesulfonic anhydride
and 2,6-di-tert-butyl-4-methylpyridine with good regioselectivity
(regioisomeric ratio = 88 : 12).15 Enol triflate 12 was then
subjected to an iron-catalyzed cross-coupling reaction to give
cyclooctadiene 13.16 Subsequent epoxidation with mCPBA
regioselectively occurred on the more electron-rich trisubstituted
olefin and afforded epoxide 14 with excellent diastereoselectivity
(dr 4 95 : 5). Treatment of 14 with diethylaluminum 2,2,6,6-
tetramethylpiperidide led to regioselective formation of 15.17
Protection of 15 with PMBCl, followed by deprotection of the
TBS group, gave alcohol 17 with opposite configuration at C1
with respect to that in 1. To invert this configuration, 17 was
oxidized to ketone 18 by Dess–Martin periodinane. Then
using a bulky reducing reagent DIBAl-H at ꢁ78 1C, the
desired alcohol 19 with correct configuration at C1 was
generated exclusively.
Scheme 2 Retrosynthetic analysis.
At this point, we intended to utilize the key alkoxycarbonyl
radical annulation to construct the bridging butyrolactone ring
of 1 (Scheme 5). After selenocarbonate 20 was synthesized, we
conducted the radical cyclization of 20 in the presence of
AIBN and n-Bu3SnH.10 Gratifyingly, the tricyclic compound
21 was obtained as a single stereoisomer in 95% yield.18
However, the configuration of C3 was opposite to that in 1.
To complete the synthesis, epimerizing the C3 stereocenter of
21 was necessary. Attempts to convert the inside–outside
to the outside–outside tricycle through the deprotonation/
protonation strategy were unsuccessful.19 A similar problem
was also encountered by Krafft and co-workers in their total
synthesis of asteriscanolide.3 As an alternative strategy,
lactone 21 was reduced by DIBAl-H to give a mixture of
hemiacetals, which were smoothly converted into enol ether 23
with methanesulfonyl chloride and triethylamine (Scheme 5).20
Subsequent hydrogenation of 23 successfully installed the
hydrogen at C3 with correct configuration. Meanwhile, the
PMB group was removed and the exo CQC double bond was
Scheme 3 Reagents and conditions: (a) 18 mol% Zn(OTf)2, 22 mol%
chiral ligand 8, 65 mol% Et3N, toluene, 55 1C, 90%, 94% ee;
(b) Red-Al, THF, 40 1C, 92%; (c) TBSCl, imidazole, DMAP, DMF,
40 1C, 96%; (d) 0.2 atm CO + 0.8 atm N2, 5 mol% [Rh(CO)2Cl]2,
toluene, 90 1C, 70%.
presence of Zn(OTf)2, triethylamine, and chiral ligand 8
developed by Jiang and co-workers.13 Reduction with Red-Al
converted 7 into allylic alcohol 9. Substrate 9 was then
subjected to the key [(5+2)+1] cycloaddition reaction under
the standard conditions (0.2 atm CO + 0.8 atm N2, 5 mol%
[Rh(CO)2Cl]2 as catalyst, dioxane as solvent, 90 1C).6a The
desired fused [5–8] bicyclic cyclooctenone was isolated in 30%
yield with a diastereomeric ratio of 75 : 25. We envisioned that
a bulkier substituent at the allylic position of the VCP moiety
could greatly improve the diastereoselectivity.14 Therefore, we
transformed allylic alcohol 9 to a TBS-protected substrate 10
and then examined the key [(5+2)+1] cycloaddition reaction
(Scheme 3). Under the standard conditions, bicyclic cyclo-
octenone 11 was obtained with excellent diastereoselectivity
(dr 4 95 : 5), but the reaction yield was only 30%. To our
delight, when toluene (rather than dioxane) was used as
solvent, the yield can be improved to 70% together with the
same diastereoselectivity (dr 4 95 : 5). In this reaction, two
new stereocenters (C2 and C9) are generated with a cis
configuration, which is in accordance with the configuration
in 1. However, the hydrogen atom at C1 is in a trans
configuration with respect to the bridgehead hydrogen atoms
at C2 and C9. This is opposite to that in 1. Considering the
possibility that the C1 stereocenter with a hydroxyl substituent
can be inverted through the traditional oxidation/reduction
strategy, we believed that the success of this highly diastereo-
selective asymmetric [(5+2)+1] reaction laid the foundation
for the enantioselective total synthesis of 1.
Scheme 4 Reagents and conditions: (a) Tf2O, 2,6-di-tert-butyl-4-
methylpyridine, CH2Cl2, 25 1C, regioisomeric ratio
= 88 : 12;
(b) Fe(acac)3, 1-methyl-2-pyrrolidinone, MeMgBr, THF, ꢁ10 1C,
58% over two steps; (c) mCPBA, ethyl acetate, 0 1C; (d) 2,2,6,6-
tetramethylpiperidine, n-BuLi, Me2AlCl, benzene, 0 1C, 86% over two
steps; (e) NaH, PMBCl, DMF, 50 1C, 82%; (f) TBAF, THF, 40 1C,
90%; (g) DMP, NaHCO3, CH2Cl2, 25 1C; (h) DIBAl-H, CH2Cl2,
ꢁ78 1C, 84% over two steps.
After constructing the [6.3.0] carbocyclic core with high
efficiency, we turned our attention toward the introduction
of the oxygen at C8 and inversion of the C1 stereocenter
c
6660 Chem. Commun., 2011, 47, 6659–6661
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Notes and references
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5 For a recent review on the synthesis of eight-membered carbocycles
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and Z.-X. Yu, Chem.–Asian J., 2010, 5, 1555. For the first report of
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see: (c) P. A. Wender, G. G. Gamber, R. D. Hubbard and
L. Zhang, J. Am. Chem. Soc., 2002, 124, 2876.
Scheme 5 Reagents and conditions: (a) (1) Py, DMAP, THF,
triphosgene, benzene, 30 1C; (2) PhSeH, 30 1C; (b) n-Bu3SnH, AIBN,
benzene, reflux, 95% over two steps; (c) DIBAl-H, CH2Cl2, ꢁ78 1C;
(d) CH3SO2Cl, Et3N, CH2Cl2, 25 1C, 85% over two steps; (e) H2,
Pd/C, EtOH, 60 1C, dr = 66 : 34; (f) DMP, NaHCO3, CH2Cl2, 25 1C,
46% (25) and 24% (26) over two steps; (g) (1) TMSOTf, 2,6-lutidine,
CH2Cl2, 25 1C; (2) 1 M HCl, Et2O, 25 1C, 48% brsm; (h) RuCl3,
NaIO4, CH3CN/CCl4/H2O (1 : 1 : 1), 25 1C, 59%.
hydrogenated with 66 : 34 diastereoselectivity. Subsequent
Dess–Martin oxidation of 24 gave two separable tricyclic
ketones 25 and 26. Treatment of 25 with trimethylsilyl triflate
and 2,6-lutidine, followed by acidic hydrolysis, resulted in
partial formation of the desired tricyclic ketone 26. Finally,
compound 26 was regioselectively oxidized to natural
product (+)-1 by ruthenium tetroxide using Paquette’s
approach.2b,21 Therefore, (+)-asteriscanolide was synthesized
from two commercially available materials in 19 steps and
3.8% overall yield.
7 For selected recent examples of Rh(I)-catalyzed cycloadditions to
construct fused ring systems, see: (a) L. Jiao, M. Lin and Z.-X. Yu,
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Tetrahedron Lett., 2009, 50, 155; (c) C. Yuan, L. Jiao and
Z.-X. Yu, Tetrahedron Lett., 2010, 51, 5674.
9 X. Fan, L.-G. Zhuo, Y. Q. Tu and Z.-X. Yu, Tetrahedron, 2009,
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10 M. D. Bachi and E. Bosch, J. Org. Chem., 1992, 57, 4696.
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129, 14556; (b) B. M. Trost, J. Waser and A. Meyer, J. Am. Chem.
Soc., 2008, 130, 16424.
In summary, we have successfully achieved the asymmetric
total synthesis of (+)-asteriscanolide based on a chiral
substrate induced Rh(I)-catalyzed [(5+2)+1] cycloaddition
to build the [6.3.0] carbocyclic core with high efficiency.
This further demonstrates that the [(5+2)+1] reaction is a
powerful method for the construction of complex molecules
with eight-membered carbocycles. Other merits from this
synthesis include the utilization of catalytic asymmetric
alkynylation of aldehyde to synthesize the chiral ene-VCP
substrate, highly regioselective conversion of the [(5+2)+1]
cycloadduct to its enol triflate, the introduction of the bridging
butyrolactone ring by a radical process, and the inversion of
the inside–outside tricycle to the outside–outside structure by
an ester-reduction/elimination to enol ether/hydrogenation
procedure.
12 (a) D. E. Frantz, R. Fassler and E. M. Carreira, J. Am. Chem. Soc.,
¨
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17 L. A. Paquette, I. Efremov and Z. Liu, J. Org. Chem., 2005, 70,
505.
18 A DFT-computed 3D picture of lactone 21 is given in the ESIw.
19 For
examples
of
inside-outside
stereochemistry,
see:
(a) J. D. Winkler, B.-C. Hong, J. P. Hey and P. G. Williard,
J. Am. Chem. Soc., 1991, 113, 8839; (b) J. D. Winkler,
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We thank Natural Science Foundation of China (20825205)
and 973 Program (2010CB833203 and 2011CB808603) for
financial support. We also thank Profs. Paul A. Wender of
Stanford University, Chuo Chen of University of Texas
Southwestern Medical Center at Dallas, and Hao Xu of
Georgia State University for helpful discussions.
20 F. E. Ziegler, W. T. Cain, A. Kneisley, E. P. Stirchak and
R. T. Wester, J. Am. Chem. Soc., 1988, 110, 5442.
21 Compound 25 can be oxidized to 7-epi-asteriscanolide 10 using the
same approach. See the ESI for detailsw.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 6659–6661 6661