Cycloisomerization of 1,6-enynes: Asymmetric multistep preparation of a hydrindane framework in water with polymeric catalysts

Article abstract of DOI:10.1021/ol047700j

(Chemical Equation Presented) Cycloisomerization of 1,6-enynes proceeded smoothly in water under heterogeneous conditions in the presence of a palladium complex supported on polystyrene-poly(ethylene glycol) copolymer resin to give the corresponding cyclo

Full text of DOI:10.1021/ol047700j

ORGANIC
LETTERS
2005
Vol. 7, No. 2
291-293
Cycloisomerization of 1,6-Enynes:
Asymmetric Multistep Preparation of a
Hydrindane Framework in Water with
Polymeric Catalysts
Yasushi Nakai and Yasuhiro Uozumi*
Institute for Molecular Science (IMS), CREST, and The Graduate UniVersity for
AdVanced Studies, Higashiyama 5-1, Myodaiji, Okazaki 444-8787, Japan
uo@ims.ac.jp
Received November 9, 2004
ABSTRACT
Cycloisomerization of 1,6-enynes proceeded smoothly in water under heterogeneous conditions in the presence of a palladium complex
supported on polystyrene-poly(ethylene glycol) copolymer resin to give the corresponding cyclopentanes with a high level of chemical greenness.
Multistep asymmetric synthesis of a hydrindane framework was achieved via palladium-catalyzed asymmetric
π-allylic alkylation, propargylation,
and cycloisomerization of 1,6-enynes, where all three steps were performed in water with recyclable polymeric catalysts.
The multistep process approach using polymeric reagents has
become an important goal in synthetic organic chemistry.1
Recently, we have developed various catalytic organic
transformations in water with recyclable amphiphilic polymer-
supported transition metal complexes combining the advan-
tages of both aqueous- and heterogeneous-switching of a
given reaction into a single system.2,3 If a multistep asym-
metric organic synthesis can be achieved in water under mild
conditions with recyclable polymeric catalysts, the synthesis
represents what may be considered an ideal chemical
process.4 Here we report the development of a fully
environmentally benign heterogeneous catalytic system under
aqueous conditions for palladium-promoted cycloisomeriza-
tion of 1,6-enynes to give cyclopentanes. The asymmetric
synthesis of a hydrindane framework was achieved via a
palladium-catalyzed asymmetric π-allylic alkylation,5,6 pro-
pargylation of an active methine compound with a polymeric
(3) For reviews on heterogeneous-switching, see: (a) Bailey, D. C.;
Langer, S. H. Chem. ReV. 1981, 81, 109. (b) Shuttleworth, S. J.; Allin, S.
M.; Sharma, P. K. Synthesis 1997, 1217. (c) Shuttleworth, S. J.; Allin, S.
M.; Wilson, R. D.; Nasturica, D. Synthesis 2000, 1035. (d) Do¨rwald, F. Z.
Organic Synthesis on Solid Phase; Wiley-VCH: Weinheim, 2000. (e)
Leadbeater, N. E.; Marco, M. Chem. ReV. 2002, 102, 3217. (f) McNamara,
C. A.; Dixon, M. J.; Bradley, M. Chem. ReV. 2002, 102, 3275. (g) De Vos,
D. E., Vankelecom, I. F. J., Jacobs, P. A., Eds. Chiral Catalyst Immobiliza-
tion and Recycling; Wiley-VCH: Weinheim, 2000. (h) Fan, Q.-H.; Li,
Y.-M.; Chan, A. S. C. Chem. ReV. 2002, 102, 3385.
(4) For studies on polymer-supported palladium catalysts reported by
the author’s group, see: (a) Uozumi, Y.; Danjo, H.; Hayashi, T. Tetrahedron
Lett. 1997, 38, 3557. (b) Danjo, H.; Tanaka, D.; Hayashi, T.; Uozumi, Y.
Tetrahedron 1999, 55, 14341. (c) Uozumi, Y.; Danjo, H.; Hayashi, T. J.
Org. Chem. 1999, 64, 3384. (d) Uozumi, Y.; Watanabe, T. J. Org. Chem.
1999, 64, 6921. (e) Uozumi, Y.; Nakai, Y. Org. Lett. 2002, 4, 2997. (f)
Uozumi, Y.; Kimura, T. Synlett 2002, 2045. (g) Hocke, H.; Uozumi, Y.
Synlett 2002, 2049. (h) Uozumi, Y.; Kobayashi, Y. Heterocycles 2003, 59,
71. (i) Uozumi, Y.; Nakao, R. Angew. Chem., Int. Ed. 2003, 42, 194.
(1) (a) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach,
A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S.
J. J. Chem. Soc., Perkin Trans. 1 2000, 3815. (b) Bapna, A.; Vickerstaffe,
E.; Warrington, B. H.; Ladlow, M.; Fan, T.-P. D.; Ley, S. V. Org. Biomol.
Chem. 2004, 2, 611. (c) Storer, R. I.; Takemoto, T.; Jackson, P. S.; Brown,
D. S.; Baxendale, I. R.; Ley, S. V. Chem. Eur. J. 2004, 10, 2529.
(2) For reviews on aqueous-switching, see: (a) Li, C.-J.; Chan, T.-H.
Organic Reactions in Aqueous Media; Wiley-VCH: New York, 1997. (b)
Grieco, P. A. Organic Synthesis in Water; Kluwer Academic Publishers:
Dordrecht, 1997. (c) Herrmann, W. A.; Kohlpaintner, C. W. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1524. (d) Lindstro¨m, U. M. Chem. ReV. 2002, 102,
2751.
10.1021/ol047700j CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/18/2004

PTC base, and palladium-catalyzed cycloisomerization of
1,6-enynes, where all three steps were performed in water
with recyclable polymeric catalysts.
Table 1. Cycloisomerization of 1,6-Enynes in Water with a
PS-PEG Resin-Supported Palladium Catalysta
Transition metal-catalyzed carbocyclization of enynes
offers a powerful means to construct a variety of synthetically
useful carbo- and heterocycles with high levels of atom
economy.7,8 Cycloisomerization of 1,6-enynes 2 was found
to proceed in water9 in the presence of the amphiphilic
polystyrene-poly(ethylene glycol) (PS-PEG) resin-supported
palladium complex 1 (Figure 1) and HCOOH. Representative
Figure 1. PS-PEG-supported Pd(dba)(triarylphosphine)2.
results are summarized in Table 1. The acyclic enynes 2a
and 2b gave the cyclopentanes 3a and 3b in 91 and 92%
yields, respectively (entries 1 and 2). The cyclic enynes 2c-f
also underwent cyclization under similar conditions to afford
the corresponding bicyclic products 3c-f in high yields
(entries 3-6).
A typical procedure for the reaction of the cyclohexenyl
substrate 2d is as follows. A mixture of the enyne 2d, 1 mol
% palladium of polymeric 1, and 100 mol % HCOOH was
shaken in water at 25 °C for 48 h. In the aqueous medium,
the hydrophobic substrate 2 diffused into the hydrophobic
PS matrix to undergo palladium-catalyzed cycloisomeriza-
tion. The resin beads holding the resulting hydrophobic
product 3 were then separated from the aqueous medium by
filtration. They were extracted with supercritical carbon
dioxide (scCO2) to give the polymeric catalyst and the desired
product 3d in 90% yield with high purity (>98% purity on
1H NMR) without chromatographic purification. Both the
recovered catalyst beads and the aqueous filtrate were reused
several times without any additional charge of palladium and
exhibited no loss of catalytic activity for this green protocol
(Scheme 1).
a All reactions were carried out in water at 25 °C for 48 h. 2 (mol)/1
(mol)/HCOOH (mol)/H2O (L) ) 1.0/0.01/1.0/3.3. b Isolated yield. c Small
1
amount of olefin regioisomer was detected by H NMR.
potential of the amphiphilic resin-based heterogeneous aque-
ous catalytic system in the synthesis of a bicyclic carbon
Scheme 1
With this efficient cycloisomerization protocol in hand,
we turned our attention to demonstrating the synthetic
(5) For a recent review on asymmetric π-allylic substitution, see: (a)
Acemoglu, L.; Williams, J. M. J. Handbook of Organopalladium Chemistry;
Negishi, E., Ed.; Wiley: New York, 2002. (b) Trost, B. M.; Crawley, M.
L. Chem. ReV. 2003, 103, 2921.
(6) (a) Uozumi, Y.; Danjo, H.; Hayashi, T. Tetrahedron Lett. 1998, 39,
8303. (b) Uozumi, Y.; Shibatomi, K. J. Am. Chem. Soc. 2001, 123, 2919.
(c) Shibatomi, K.; Uozumi, Y. Tetrahedron: Asymmetry 2002, 13, 1769.
(d) Uozumi, Y,; Tanaka, H.; Shibatomi, K. Org. Lett. 2004, 6, 281
(7) For a recent review, see: Aubert, C.; Buisine, O.; Malacria, M. Chem.
ReV. 2002, 102, 813.
(8) Trost, B. M.; Tanoury, G. J.; Lautens, M.; Chan, C.; MacPherson,
D. M. J. Am. Chem. Soc. 1994, 116, 4255. Trost, B. M.; Romero, D. L.;
Rise, F. J. Am. Chem. Soc. 1994, 116, 4268.
(9) It has been reported that Pd-catayzed cycloisomerization was ac-
celerated by water; see: Fairlamb, I. J. S.; Pike, A. C.; Ribrioux, S. P. C.
P Tetrahedron Lett. 2002, 43, 5327.
292
Org. Lett., Vol. 7, No. 2, 2005

framework. When cycloisomerization of the 1,6-enyne 4 was
carried out in the presence of methyl acrylate at 80 °C, a
tandem cyclization took place to afford the hydrindane 6 in
90% yield via a one-pot cycloisomerization and subsequent
Diels-Alder reaction (Scheme 2).10
Scheme 3
Scheme 2
Asymmetric synthesis of the hydrindane (3aR,7aS)-3d was
also achieved in water with recyclable catalysts (Scheme 3).
The racemic cyclohexenyl ester rac-7 reacted with diethyl
malonate in aqueous Li2CO3 in the presence of PS-PEG
resin-supported chiral imidazoindole phosphine-Pd complex
9 (10 mol %) to give 90% ee of 8 in 92% yield. The
polymeric chiral palladium complex was reused three times
without any loss of stereoselectivity. Propargylation of the
cyclohexenylmalonate 8 with propargyl bromide was per-
formed with PS-PEG ammonium hydroxide 10, which has
been developed as an immobilized PTC base with a view
toward use in water to give a quantitative yield of the 1,6-
enyne (S)-2d.11 The polymeric ammonium reagent was
recovered as its bromide salt, which was reactivated by
washing with aqueous KOH and reused. The enyne (S)-2d
underwent cycloisomerization with the amphiphilic poly-
meric palladium 1 to afford 90% ee of the hydrindane (3aR,-
7aS)-3d in 94% yield.
In conclusion, we have developed a green and safe
protocol for the preparation of a chiral indane framework to
demonstrate the considerable potential of heterogeneous
catalytic organic transformations in water.
Acknowledgment. This work was supported by the
CREST program, sponsored by the JST.
Supporting Information Available: Characterization and
experimental procedures for compounds 1-3. This material
is available free of charge via the Internet at http://pubs.acs.org.
(10) (a) Meyer, F. E.; Ang, K. H.; Steinig, A. G.; de Meijere, A. Synlett
1994, 191. (b) Ang, K. H.; Bra¨se, S.; Steinig, A. G.; Meyer, F. E.; Llebaria,
A.; Voigt, K.; de Meijere, A. Tetrahedron 1996, 52, 11503.
(11) Shibatomi, K.; Nakahashi, T.; Uozumi, Y. Synlett 2000, 1643.
OL047700J
Org. Lett., Vol. 7, No. 2, 2005
293