Synthesis of 2-cyclopentenones by gold(I)-catalyzed rautenstrauch rearrangement

Article abstract of DOI:10.1021/ja051689g

The rearrangement of 1-ethynyl-2-propenyl pivaloates to cyclopentenones catalyzed by cationic triphenylphosphinegold(I) complexes is described. The reaction tolerates both alkyl and aryl substitution at the acetylenic and olefinic positions. Importantly, the gold(I)-catalyzed rearrangement of enantioenriched propargyl pivaloates proceeds with excellent chirality transfer, thus providing a practical method for the enantioselective synthesis of cyclopentenones. Copyright

Full text of DOI:10.1021/ja051689g

Published on Web 04/02/2005
Synthesis of 2-Cyclopentenones by Gold(I)-Catalyzed Rautenstrauch
Rearrangement
Xiaodong Shi, David J. Gorin, and F. Dean Toste*
Center for New Directions in Organic Synthesis, Department of Chemistry, UniVersity of California,
Berkeley, California 94720
Received March 17, 2005; E-mail: fdtoste@uclink.berkeley.edu
Table 1. Au(I)-Catalyzed Cyclopentenone Synthesis
The importance of cyclopentenones as building blocks for organic
synthesis continues to inspire the development of general methods
for their stereoselective preparation.1-3 In 1984, Rautenstrauch
reported that palladium(II) complexes catalyzed the isomerization
of 1-ethynyl-2-propenyl acetates (1) to cyclopentenones (eq 1).4
This reaction and related rearrangements5 are proposed to proceed
through a metal carbene intermediate, such as 2, arising from a
1,2-acetate migration. While the Rautenstrauch rearrangement
provided an efficient route to cyclopentenones, it was limited to
the preparation of achiral cyclopentenones substituted at the 2 and
3 positions (eq 1). On the basis of recent examples of gold(I)-
catalyzed cyclizations of enynes,6 we hypothesized that these
catalysts might afford an increase in the scope of this reaction and
allow the preparation of chiral cyclopentenones.
In light of our previous success employing Ph3PAuOTf in
methylene chloride for carbon-carbon bond formation,6b,7 we chose
this catalyst system in preliminary studies of the rearrangement (eq
2). To develop catalysts that would permit the synthesis of chiral
cyclopentenones, we initiated our investigation with a substrate (4)
containing a trisubstituted olefin. We were pleased to find that
rearrangement of 4, catalyzed by 5 mol % Ph3PAuOTf in methylene
chloride, did afford desired cyclopentenone 5, however, in only
30% yield. Examination of the effect of solvent on the reaction
revealed that acetonitrile produced the desired adduct with a marked
improvement in yield. The yield was further improved by changing
the ester from acetate to pivaloate.8
a Isolated yield after column chromatography. b With 5 mol % PPh3AuOTf
employed.
tenones 15 and 19 as a result of olefin isomerization into conjugation
with the aryl group.
A 1:1 diastereomeric mixture of 20, derived from (S)-(-)-perill-
aldehyde, underwent Au-catalyzed isomerization to produce bicyclic
enone 21 as a 1:1 mixture of diastereomers (eq 3). We envisioned
two scenarios to account for this diastereoselectivity: the stereo-
chemistry of the starting ester is lost in generating a carbene-like
intermediate (such as 2) that undergoes subsequent cyclization with
no selectivity, or the stereochemistry of the starting pivaloate influ-
ences that of the product. To probe this question, diastereoenriched
20 was subjected to the reaction condition furnishing 21 as a 7:1
mixture of diastereomers, strongly suggesting that stereochemistry
of the starting ester influences that of the product cyclopentenone.
With optimized reaction conditions in hand, we set out to define
the scope of the cyclopentenone synthesis. The reaction is highly
tolerant of substitution at the acetylenic position of the 1-ethynyl-
2-propenyl pivaloates (Table 1). In addition to unsubstituted alkynes,
the gold(I)-catalyzed reaction proceeded smoothly with substrates
containing aryl- (entry 2), alkyl- (entry 3), and vinyl-substituted
alkynes (entry 4). Cyclization of the latter produced exo-methylene
cyclopentenone 13 after isomerization of the iso-propenyl group
into conjugation with the ketone. The reaction also showed excellent
scope with respect to substitution on the olefin. Specifically, 1,1-
disubstituted (entries 1-4), 1,2-disubstituted (entry 5), and cyclic
(entries 6 and 7) alkenes participated in the cyclization. Rearrange-
ment of styrenyl substrates 14 and 18 afforded 3-phenylcyclopen-
On the basis of this observation, a series of enantioenriched
propargyl pivaloates9 were prepared in order to examine the chirality
transfer in the cyclization. Rearrangement of enantioenriched 24
(93% ee) under the standard conditions (Ph3PAuOTf, CH3CN, rt)
cleanly afforded 25, however, with only 68% ee. Switching the
counterion from triflate to hexafluoroantimonate and lowering the
temperature to -20 °C allowed for isolation of 25 in 86% yield
9
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J. AM. CHEM. SOC. 2005, 127, 5802-5803
10.1021/ja051689g CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Cyclopentenone Synthesis
C-C bond formation prior to scission of the stereogenic C-O bond
is operative. Efforts aimed at utilizing Au(I) complexes as catalysts
for other rearrangements are ongoing in our laboratories.
Acknowledgment. We gratefully acknowledge the University
of California, Berkeley, Boehringer Ingelheim, and Merck Research
Laboratories for financial support. The Center for New Directions
in Organic Synthesis is supported by Bristol-Myers Squibb as a
Sponsoring Member, and Novartis Pharma as a Supporting Member.
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
of charge on the Internet at http://pubs.acs.org.
References
(1) Asymmetric Pauson-Khand-type reactions catalyzed by Co: (a) Hiroi,
K.; Watanabe, T.; Kawagishi, R.; Abe, I. Tetrahedron: Asymmetry 2000,
11, 797-808. (b) Sturla, S. J.; Buchwald, S. L. J. Org. Chem. 2002, 67,
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(2) For catalytic asymmetric Nazarov cyclizations, see: (a) Liang, G.; Trauner,
D. J. Am. Chem. Soc. 2004, 126, 9544. (b) Aggarwal, V. K.; Belfield, A.
J. Org. Lett. 2003, 5, 5075. For asymmetric Nazarov cyclizations of chiral
allenes, see: (c) Tius, M. A. Acc. Chem. Res. 2003, 36, 284.
(3) For alternative asymmetric syntheses of cyclopentenones, see: (a) Tanaka,
K.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 10296. (b) Barluenga, J.;
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a Isolated yield after column chromatography; % ee determined using
chiral HPLC or GC (see Supporting Information for details).
Scheme 1. Proposed Mechanism for the Au(I)-Catalyzed
Cyclopentenone Synthesis
(4) Rautenstrauch, V. J. Org. Chem. 1984, 49, 950.
(5) (a) Mainetti, E.; Mourie´s, V.; Fensterbank, L.; Malacria, M.; Marco-
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D. J.; Echavarren, A. M. Chem.sEur. J. 2003, 9, 2627. (d) Mamane, V.;
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Luzung, M. R.; Markham, J. P.; Toste, F. D. J. Am. Chem. Soc. 2004,
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(e) For an excellent review of homogeneous gold-catalyzed reactions,
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(8) Under these conditions (5% catalysts, 0.1 M acetonitrile, rt, 14 h), other
metal complexes produced the following results: AgOTf (100% recovered
4, 0% 5); AuCl3 (0% 4, 50% 5); PdCl2(MeCN)2 (62% 4, 0% 5); PtCl2
(100% 4, 0% 5), CuBr (100% 4, 0% 5).
and with 91% ee (Table 2, entry 3). Under these conditions, Au(I)-
catalyzed rearrangement of enantioenriched propargyl pivaloates
delivered cyclopentenones with excellent chirality transfer (Table
2).10
A mechanistic hypothesis that accounts for the stereochemical
course of the Au(I)-catalyzed rearrangement is shown in Scheme
1. Intramolecular 1,2-addition of the ester onto the alkyne, induced
by coordination of the alkyne to a cationic gold(I) complex, affords
vinyl gold species 30. The stereoselectivity of the gold(I)-catalyzed
cyclization can be accounted for by an intramolecular cyclization
that proceeds through a transition state (31) in which the leaving
group occupies a position orthogonal to the plane of the olefin.11
This cyclization produces cationic intermediate 32, which upon
elimination of cationic gold(I), affords diene 33.12 Finally, cyclo-
pentadiene 33 is hydrolyzed to cyclopentenone 5.
(9) Enantioenriched propargyl alcohols were prepared by reduction of the
corresponding ketone with R-Alpine-Borane and the absolute stereo-
chemistry assigned according to Midland, M. M.; McDowell, D. C.; Hatch,
R. L.; Tramontano, A. J. Am. Chem. Soc. 1980, 102, 867.
(10) The absolute stereochemistry of cyclopentenone 23 ([R]D ) -174 (c 1.25,
CHCl3)) was assigned by comparison of optical rotation to that reported
in the literature ([R]D ) -141 (c 0.14, CHCl3)). Hua, D. H. J. Am. Chem.
Soc. 1986, 108, 3835. The stereochemistry of the remaining cyclopen-
tenones was assigned by analogy.
(11) This transition state also accounts for the observation that rearrangement
of a 1:2 mixture of Z:E olefin isomers (34) returned the Z-isomer unreacted.
Cyclization of the Z-isomer would require that the olefin substituent come
into close proximity to the vinyl gold.
In conclusion, we have developed a Au(I) catalyst for the re-
arrangement of 1-ethynyl-2-propenyl pivaloates to cyclopentenones.
The gold(I)-catalyzed reactions are tolerant of substitution at the
acetylenic and olefinic positions (except for Z-olefins), thus provid-
ing access to a wide range of cyclopentenones under exceptionally
mild conditions. Additionally, enantioenriched cyclopentenones can
be prepared by the gold(I)-catalyzed cyclization of enantioenriched
propargyl alcohols. The high degree of chirality transfer in these
rearrangements suggests that, in this case, a mechanism involving
(12) In accord with this proposed intermediate, diene 37 was isolated from
cycloisomerization of 36.
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