Rh(I)-catalyzed [(3 + 2) + 1] cycloaddition of 1-yne/ene-vinylcyclopropanes and CO: Homologous pauson-khand reaction and total synthesis of (±)-α-agarofuran

Article abstract of DOI:10.1021/ol100625e

A novel Rh(I)-catalyzed [(3 + 2) + 1] cycloaddition, which can be regarded as a homologous Pauson-Khand reaction, was developed to synthesize bicyclic cyclohexenones and cyclohexanones, enabling a new approach for synthesis of six-membered carbocycles ubiquitously found in natural products and pharmaceutics. The significance of the Rh-catalyzed [(3 + 2) + 1] cycloaddition has been demonstrated by the total synthesis of a furanoid sesquiterpene natural product, α-agarofuran, in which the bicyclic skeleton was constructed by the [(3 + 2) + 1] reaction of 1-yne-VCP and CO.

Full text of DOI:10.1021/ol100625e

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2528-2531
Rh(I)-Catalyzed [(3 + 2) + 1]
Cycloaddition of 1-Yne/
Ene-vinylcyclopropanes and CO:
Homologous Pauson-Khand Reaction
and Total Synthesis of (()-r-Agarofuran
Lei Jiao, Mu Lin, Lian-Gang Zhuo, and Zhi-Xiang Yu*
Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of
Bioorganic Chemistry and Molecular Engineering, College of Chemistry, Peking
UniVersity, Beijing 100871, China
yuzx@pku.edu.cn
Received March 16, 2010
ABSTRACT
A novel Rh(I)-catalyzed [(3 + 2) + 1] cycloaddition, which can be regarded as a homologous Pauson-Khand reaction, was developed to
synthesize bicyclic cyclohexenones and cyclohexanones, enabling a new approach for synthesis of six-membered carbocycles ubiquitously
found in natural products and pharmaceutics. The significance of the Rh-catalyzed [(3 + 2) + 1] cycloaddition has been demonstrated by the
total synthesis of a furanoid sesquiterpene natural product, r-agarofuran, in which the bicyclic skeleton was constructed by the [(3 + 2) +
1] reaction of 1-yne-VCP and CO.
Six-membered rings are ubiquitous in organic molecules.
Therefore, developing reactions to synthesize six-membered
rings is one of the key endeavors in the science of synthesis.
Today, the Diels-Alder reaction is arguably the most powerful
method to construct six-membered rings.1 However, developing
new cycloaddition reactions2 for the synthesis of six-membered
rings is still in high demand due to the inquiries for function-
alized six-membered rings that are impossible or very difficult
to approach by existing methods. Herein we report a new Rh(I)-
catalyzed [(3 + 2) + 1] reaction3 of 1-yne/ene-vinylcyclopro-
panes (1-yne/ene-VCPs), a homologous Pauson-Khand reac-
tion, to reach bicyclic cyclohexenone and cyclohexanone
derivatives as a practical protocol in six-membered ring
synthesis. We further demonstrate its potential application by
using this reaction in the total synthesis of a furanoid sesquit-
erpene natural product, R-agarofuran.
(1) Recent reviews on the Diels-Alder reaction: (a) Corey, E. J. Angew.
Chem., Int. Ed. 2002, 41, 1650. (b) Nicolaou, K. C.; Snyder, S. A.;
Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41,
1668. (c) Takao, K.; Munakata, R.; Tadano, K. Chem. ReV. 2005, 105, 4779.
(d) Wessig, P.; Mu¨ller, G. Chem. ReV. 2008, 108, 2051. (e) Reymond, S.;
Cossy, J. Chem. ReV. 2008, 108, 5359. (f) Pellissier, H. Tetrahedron 2009,
65, 2839. (g) Juhl, M.; Tanner, D. Chem. Soc. ReV. 2009, 38, 2983.
(2) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49.
10.1021/ol100625e  2010 American Chemical Society
Published on Web 05/13/2010

Our design of the [(3 + 2) + 1] reaction was inspired by the
great success of the Pauson-Khand reaction, which is a
powerful method to synthesize five-membered rings (cyclo-
pentenone) using alkynes, alkenes, and CO, intramolecularly
or intermolecularly (Scheme 1a).4 This reaction has been widely
Scheme 2
. (a) Previously Reported Prototype [(3 + 2) + 1]
Reaction and (b) New Activation Strategya
Scheme 1
. (a) Pauson-Khand Reaction and (b) Designed
Homologous Pauson-Khand Reaction
a 1,2-DCB ) 1,2-dichlorobenzene.
applied the previous [3 + 2] reaction conditions,7b together with
a low pressure of CO (Table 1, entry 1). Gratifyingly, we
used in total syntheses of natural products. We envisioned that
there is an opportunity to transform this Pauson-Khand [(2 +
2) + 1] cycloaddition to a homologous [(3 + 2) + 1]
counterpart by replacing the alkene with a cyclopropane unit
(Scheme 1b), which has been well documented as an equivalent
of a 2-π component in many organic and organometallic
reactions.5 In principle, we regard this design as a homologous
Pauson-Khand reaction. Narasaka and co-workers have previ-
ously reported the [(3 + 2) + 1] cycloaddition of yne-
cyclopropanes (yne-CP), but unfortunately, the preliminary
result was acquired under harsh conditions (reaction temperature
160 °C, 4 atm CO, >48 h) that inevitably led to side reactions
and severely limited its synthetic utility (Scheme 2a).6
Previously we have reported that vinylcyclopropane can
act as a three-carbon synthon to achieve intramolecular [3
+ 2] cycloadditions.7 The vinyl group was found to act as
an activating group that facilitates the ring opening of
cyclopropane under much milder conditions.7,8 We hope to
apply this activation strategy9 to the development of a
synthetically practical [(3 + 2) + 1] process using 1-yne-
VCP as the potential substrate (Scheme 2b).
Table 1. Reaction Conditions for the [(3 + 2) + 1]
Cycloadditiona
CO
temp time yield
entry
catalyst
(atm) solventb (°C)
(h)
(%)c
1
2
3
4
5
[Rh(dppp)]SbF6
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
0.2
0.2
0.2
1
DCE
80
80
80
80
70
8
4
1.5
6
4
25d
64
81
39
78
dioxane
toluene
toluene
toluene
0.2
a Conditions: 5 mol % of the catalyst, substrate concentration 0.05 M.
b DCE ) 1,2-dichloroethane. c Isolated yield after column chromatography.
d Together with a 59% yield of the [3 + 2] cycloadduct.7b
observed the formation of 25% of the bicyclic cyclohexenone
cycloadduct 2, albeit the major part of 1-yne-VCP 1 underwent
the [3 + 2] cycloaddition.7b We then tested the reaction
conditions for the [(5 + 2) + 1] cycloaddition10 ([Rh(CO)2Cl]2
as catalyst, employing 0.2 atm CO + 0.8 atm N211). To our
delight, the [(3 + 2) + 1] cycloadduct 2 was obtained in a
greatly improved yield (Table 1, entry 2). Toluene was found
to be an optimal solvent, giving rise to an 81% yield of 2. Higher
CO pressure (1 atm) and decreased temperature (70 °C) were
both found to diminish the efficiency of the reaction (Table 1,
entries 4 and 5). A control experiment employing yne-
cyclopropane 1a was also conducted under optimal conditions
(Table 1). We found that no corresponding [(3 + 2) + 1]
cycloadduct was generated under such mild conditions. This
indicated that the vinyl unit is crucial for the observed reactivity
of cyclopropane. Thus, by introducing a vinyl group to the
cyclopropane unit, we successfully achieved the [(3 + 2) + 1]
process under much more operable and milder conditions, which
greatly improved its synthetic utility as compared with the
previous method.
Our test of the above design started with the vinylcyclopro-
pane substrate 1 with a terminal alkyne substitution. We first
(3) We suggest here a new nomenclature for the two-component
cycloaddition of an ene/yne-VCP substrate and CO. It is referred to as [(3
+ 2) + 1] cycloaddition, where the “3 + 2” part comes from one molecule,
the “1” part comes from another molecule.
(4) Selected reviews on the Pauson-Khand reaction: (a) Chung, Y. K.
Coord. Chem. ReV. 1999, 188, 297. (b) Brummond, K. M.; Kent, J. L.
Tetrahedron 2000, 56, 3263. (c) Gibson, S. E.; Stevenazzi, A. Angew. Chem.,
Int. Ed. 2003, 42, 1800. (d) Shibata, T. AdV. Synth. Catal. 2006, 348, 2328.
(5) Selected recent reports on cyclopropane participating cycloaddition
reactions: (a) Kang, Y.-B.; Sun, X.-L.; Tang, Y. Angew. Chem., Int. Ed.
2007, 46, 3918. (b) Ivanova, O. A.; Budynina, E. M.; Grishin, Y. K.;
Trushkov, I. V.; Verteletskii, P. V. Angew. Chem., Int. Ed. 2008, 47, 1107.
(c) Jackson, S. K.; Karadeolian, A.; Driega, A. B.; Kerr, M. A. J. Am. Chem.
Soc. 2008, 130, 4196. (d) Pohlhaus, P. D.; Sanders, S. D.; Parsons, A. T.;
Johnson, J. S. J. Am. Chem. Soc. 2008, 130, 8642. (e) Perreault, C.;
Goudreau, S. R.; Zimmer, L. E.; Charette, A. B. Org. Lett. 2008, 10, 689.
(f) Parsons, A. T.; Johnson, J. S. J. Am. Chem. Soc. 2009, 131, 3122.
(6) Koga, Y.; Narasaka, K. Chem. Lett. 1999, 7, 705.
(7) (a) Jiao, L.; Ye, S.; Yu, Z.-X. J. Am. Chem. Soc. 2008, 130, 7178.
(b) Jiao, L.; Lin, M.; Yu, Z.-X. Chem. Commun. 2010, 46, 1059. (c) Li,
Q.; Jiang, G.-J.; Jiao, L.; Yu, Z.-X. Org. Lett. 2010, 12, 1332.
Org. Lett., Vol. 12, No. 11, 2010
2529

Various 1-yne-VCP substrates were submitted to the opti-
mized reaction conditions to explore the scope and limitation
of this homologous Pauson-Khand reaction (Table 2). It was
excellent, well demonstrating the efficiency and synthetic
potential of this [(3 + 2) + 1] process. The products of this
homo-Pauson-Khand reaction possess a functionalized six-
membered ring bearing an R,ꢀ-unsaturated ketone functional
group and a vinyl-substituted quarternary carbon, which will
provide access to further functionalization and operation.
We also wondered whether this vinyl activation strategy is
potent enough to promote the cycloaddition between an olefin,
cyclopropane, and CO, which was never achieved before. For
this purpose, the reactions of 1-ene-VCP substrates 15 and 17
were conducted (entries 8 and 9). To our delight, these reactions
proceeded smoothly to give cis-fused bicyclic cyclohexanone
products in moderate yields.12 This further showcases the
success of the vinyl activation protocol for promoting the
cyclopropane-participating cycloaddition reactions.
Table 2. Rh(I)-Catalyzed [(3 + 2) + 1] Cycloaddition
Reactionsa
The results represent the first synthetically practical homo-
Pauson-Khand reaction under mild and easy-to-operate condi-
tions to synthesize multifunctional bicyclic cyclohexenones and
cyclohexanones. We hope to demonstrate its synthetic potential
further by using this reaction as a key step in natural product
synthesis. Our attention was drawn to the unique tricyclic
structure of the furanoid sesquiterpene natural products.13 It was
envisioned that, the tricyclic core of agarofuran could be
constructed from a 6,6-bicyclic structure, which is easily
accessible by our homo-Pauson-Khand approach (Figure 1).
Figure 1. Agarofuran sesquiterpene natural products and retrosyn-
thetic analysis utilizing the [(3 + 2) + 1] reaction.
We selected R-agarofuran as our target molecule, and the
detailed synthetic route is depicted in Scheme 3. Starting from
the known cyclopropylidene ester 19,14 we prepared vinylcy-
clopropane iodide 21 using traditional transformations. Then
compound 21 was coupled with propargyl diester 22 to give
the gem-diester-tethered 1-yne-VCP 23. Krapcho decarboxy-
lation15 afforded monoester-substituted 1-yne-VCP 24, which
serves as the definitive cycloaddition precursor for our homo-
Pauson-Khand reaction. Gratifyingly, the key [(3 + 2) + 1]
reaction proceeded very well under the previously optimized
conditions, affording bicyclic cyclohexenone 25 in 86% isolated
yield with a good diastereoselectivity (trans:cis 15:1, the
structure of 25 was confirmed by X-ray crystal analysis of its
2,4-dinitrophenylhydrazone derivative, see the Supporting In-
formation).16 The observed trans selectivity could be rational-
ized by a postulated alkyne insertion transition state TS (Scheme
3). This alkyne insertion transition state is expected to adopt a
chair conformation and has its ester and vinyl groups, both of
a Reaction conditions: 5 mol % [Rh(CO)2Cl]2 as catalyst, 0.2 atm CO,
toluene as solvent, substrate concentration 0.05 M, unless otherwise
indicated. Ts ) tosyl, Ph ) phenyl, E ) COOMe. b The cycloadducts were
obtained as racemic compounds. c Isolated yields after column chromatography.
d 1 atm CO was used. e 1,4-Dioxane as solvent. f Together with 19% yield
of the [3 + 2] cycloadduct.7b
found that both terminal and internal alkynes were compatible
to afford bicyclic cyclohexenone cycloadducts, and the alkyne
substitution could be either an alkyl (entries 2, 4, 6, and 7) or
phenyl (entry 3) group. The tether length could allow the
formation of 5,6- (entries 1-4) and 6,6-bicyclic systems (entries
5-7), and a variety of tethers (nitrogen-, oxygen-, and gem-
diester) could be employed to construct hetero- and carbobi-
cyclic skeletons. The reaction yields were generally good to
2530
Org. Lett., Vol. 12, No. 11, 2010

Scheme 3.
Total Synthesis of (()-R-Agarofurana
a DIBAL-H ) diisobutylaluminum hydride, DMF ) dimethylformamide, DMP ) Dess-Martin periodinane.
which are in the equatorial positions, in a trans configuration.
This single reaction established the basic skeleton of agarofuran
efficiently, with the correct placement of a quaternary stereo-
center and an enone moiety for further elaboration. The key
intermediate 25 was converted to allylic alcohol 26 by Luche
reduction, and then the 2-hydroxyisopropyl unit was installed
by reaction with methylmagnesium bromide.17 Acid-catalyzed
intramolecular SN2′ reaction of diol 27 constructed the tetrahy-
drofuran framework of agaroguran,18 affording compound 28.
Finally, the vinyl unit was converted to the angular methyl group
by a hydroboration-oxidation-decarbonylation sequence, com-
pleting the synthesis of (()-R-agarofuran 30.19 The homo-
Pauson-Khand [(3 + 2) + 1] reaction is the crucial step in
the synthesis, which allowed the concomitant generation of the
enone functional group and a quaternary carbon stereocenter
diastereoselectively. The enone functional group was well
utilized in the subsequent structure-building steps, nicely
showcasing the synthetic utility of the [(3 + 2) + 1] process.
In conclusion, we have developed a new type of Rh(I)-catalyzed
[(3 + 2) + 1] cycloaddition of 1-yne/ene-vinylcyclopropanes and
CO using the vinyl activation strategy. The reaction features the
use of both alkynes and alkenes as two-carbon synthons,
efficient production of multifunctional bicyclic cyclohexenone
and cyclohexanone derivatives, and mild reaction conditions.
These discoveries represent the first synthetically practical
homo-Pauson-Khand-type [(3 + 2) + 1] cycloaddition utilizing
VCP as a three-carbon component. The formation of a vinyl-
substituted quaternary stereocenter and the carbonyl functional
group in this process enables further access to more complex
structures, as demonstrated by the synthesis of R-agarofuran.
(8) For representative reports, see: (a) Wender, P. A.; Takahashi, H.;
Witulski, B. J. Am. Chem. Soc. 1995, 117, 4720. (b) Trost, B. M.; Toste,
F. D.; Shen, H. J. Am. Chem. Soc. 2000, 122, 2379. (c) Wender, P. A.;
Gamber, G. G.; Hubbard, R. D.; Zhang, L. J. Am. Chem. Soc. 2002, 124,
2876. (d) Yu, Z.-X.; Wender, P. A.; Houk, K. N. J. Am. Chem. Soc. 2004,
126, 9154. (e) Wender, P. A.; Gamber, G. G.; Hubbard, R. D.; Pham, S. M.;
Zhang, L. J. Am. Chem. Soc. 2005, 127, 2836.
(9) The vinyl group activation strategy was also demonstrated by
Wender’s group in [2 + 2+ 1] cycloaddition reactions; see: (a) Wender,
P. A.; Croatt, M. P.; Deschamps, N. M. J. Am. Chem. Soc. 2004, 126, 5948.
(b) Wender, P. A.; Deschamps, N. M.; Williams, T. J. Angew. Chem., Int.
Ed. 2004, 43, 3076. (c) Wender, P. A.; Croatt, M. P.; Deschamps, N. M.
Angew. Chem., Int. Ed. 2006, 45, 2459. (d) Pitcock Jr, W. H.; Lord, R. L.;
Baik, M.-H. J. Am. Chem. Soc. 2008, 130, 5821. For a review, see: (e)
Croatt, M. P.; Wender, P. A. Eur. J. Org. Chem. 2010, 19.
(10) Wang, Y.; Wang, J.; Su, J.; Huang, F.; Jiao, L.; Liang, Y.; Yang,
D.; Zhang, S.; Wender, P. A.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 10060.
(11) [Rh(CO)2Cl]2-catalyzed Pauson-Khand reaction was also found
to be optimal under low CO pressure, see: Kobayashi, T.; Koga, Y.;
Narasaka, K. J. Organomet. Chem. 2001, 624, 73.
(12) We also attempted the [(3 + 2) + 1] reaction of a 1-ene-VCP
substrate with elongated tether. Unfortunetely, the reaction afforded a
complex mixture, and no corresponding 6,6-bicyclic cyclohexanone product
was isolated.
Acknowledgment. We thank the Natural Science Foundation
of China (20825205-National Science Fund for Distinguished
Young Scholars, and 20672005), the Ministry of Education of
China (108001), and the National Basic Research Program of
China-973 Program (2010CB833203) for financial support.
(13) Maheshwari, M. L.; Jain, T. C.; Bates, R. B.; Bhattacharyya, S. C.
Tetrahedron 1963, 19, 1079.
Supporting Information Available: Experimental details.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Henderson, J. R.; Parvez, M.; Keay, B. A. Org. Lett. 2007, 9, 5167.
(15) Krapcho, A. P.; Glynn, G. A.; Grenon, B. J. Tetrahedron Lett. 1967,
8, 215.
(16) The [(3 + 2) + 1] cycloaddition of gem-diester-tethered substrate
23 was also conducted under identical conditions. However, the reaction
was very sluggish, and the yield was unsatisfactory.
OL100625E
(18) Huffman, J. W.; Desai, R. C. J. Org. Chem. 1982, 47, 3254.
(19) Reports on R-agarofuran synthesis: (a) Barrett, H. C.; Buchi, G.
J. Am. Chem. Soc. 1967, 89, 5665. (b) Marshall, J. A.; Pike, M. T. J. Org.
Chem. 1968, 33, 435. (c) Asselin, A.; Mongrain, M.; Deslongchamps, P.
Can. J. Chem. 1968, 46, 2817. For a review, see: (d) Spivey, A. C.; Weston,
M.; Woodhead, S. Chem. Soc. ReV. 2002, 31, 43.
(17) Levine, S. R.; Krout, M. R.; Stoltz, B. M. Org. Lett. 2009, 11, 289.
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