Organocatalytic Michael cycloisomerization of bis(enones): The intramolecular Rauhut-Currier reaction

Article abstract of DOI:10.1021/ja0121686

The utilization of enones as latent enolates enables regioselective enolate formation from chemically robust presursors. In this communication, we report a catalytic Michael cycloisomerization of bis(enones) under Morita-Baylis-Hillman conditions. Upon ex

Full text of DOI:10.1021/ja0121686

Published on Web 02/26/2002
Organocatalytic Michael Cycloisomerization of Bis(enones):
The Intramolecular Rauhut-Currier Reaction
Long-Cheng Wang, Ana Liza Luis, Kyriacos Agapiou, Hye-Young Jang, and Michael J. Krische*
UniVersity of Texas at Austin, Department of Chemistry and Biochemistry, Austin, Texas 78712
Received September 13, 2001
The utilization of enones as latent enolates enables regioselective
enolate formation from chemically robust precursors. Seminal
studies by Stork establish enones as enolate precursors in stoichio-
metric processes.1 Recently, metal-catalyzed methods for the
nucleophilic activation of enones have been described, e.g. catalytic
reductive aldol2 and Michael processes.2g As demonstrated by the
Morita-Baylis-Hillman reaction, nucleophilic organic compounds
also may serve as efficient catalysts for enone activation.3 Though
realized in the context of aldehyde addition, the mechanistic motif
embodied by the Morita-Baylis-Hillman reaction may encompass
other electrophilic partners, including electron-deficient alkenes.4-6
Indeed, the phosphine-catalyzed dimerization of electron-deficient
alkenes reported by Rauhut and Currier predates the Morita-
Baylis-Hillman reaction.5a While the intramolecular Morita-
Baylis-Hillman reaction is known,7 the intramolecular Rauhut-
Currier reaction has not been described.8,9 In this account, we report
an intramolecular variant of the Rauhut-Currier reaction, i.e. an
organocatalytic Michael cycloisomerization of bis(enones). Upon
exposure to 10 mol % of tributylphosphine, bis(enone) substrates
afford both five- and six-membered-ring products. Notably, unsym-
metrical bis(enones) possessing sufficient steric or electronic bias
yield single isomeric products.
provides the cyclopentenes 15b and 15c as a 1:1 mixture of isomers,
while the homologous substrate 16a affords the cyclohexenes 16b
and 16c in a 7:1 ratio, respectively. These data suggest the initial
formation of tributylphosphine adducts is indiscriminate. For five-
membered ring formation, the kinetic phosphine adducts are trapped
via cyclization. In the case of six-membered ring formation, an
attenuated cyclization rate enables a preequilibrium of tributylphos-
phine adducts to be established, whereby cyclization becomes the
product- and rate-determining step. Further electronic differentiation
of the enone partners completely suppresses the competitive
cyclization manifold. For mono-enone mono-enoate 17a, a single
cycloisomerization product 17b is obtained.10 The ability to select
cyclization manifolds on the basis of electronic effects is under-
scored by the cyclization product 14a. Here, remote para substit-
uents direct the formation of a single isomeric cycloisomerization
product, cyclohexene 14b. The isomeric material 14c was not
detected.10
Initial efforts focused on defining optimal conditions for the
1
catalytic cycloisomerization of bis(enone) 5a. H NMR analysis
of reactions conducted in CDCl3, d6-acetone, and d6-DMSO allowed
a variety of nucleophilic catalysts to be assayed. Through this
preliminary screen, tributylphosphine was identified as the catalyst
of choice. Additionally, this study revealed a dramatic increase in
reaction rate with increasing solvent polarity. Reactions performed
in DMSO were complete in less than 10 min, but gave rise to
substantial quantities of oligomerized products. Oligomerization is
suppressed in a less polar medium and, for aroyl-substituted
substrates, acetone was found to be the best solvent. However, for
highly electrophilic bis(enones), e.g. furyl-substituted bis(enone)
11a, a less polar medium is required. In such cases, ethyl acetate
was found to promote cleaner conversion. Under these optimized
conditions, both aroyl- and heteroaroyl-containing bis(enones)
undergo cycloisomerization in good to excellent yields. Aliphatic
bis(enones) and mixed bis(enones) incorporating enoate moieties
also are viable substrates. However, owing to their reduced
electrophilicity, more forcing conditions are required to induce
cycloisomerization. Here, refluxing tert-butyl alcohol proved to be
the most effective medium.
In the absence of a significant electronic bias, steric factors direct
selectivity. The cycloisomerization of bis(enone) 3a, which incor-
porates a resident geminal dimethyl moiety in the tether, provides
3b as the exclusive cycloisomerization product. Similarly, mixed
bis(enone) 4a provides a single isomeric cycloisomerization product
4b.
Stereoselectivity is an issue for systems incorporating stereo-
centers in the tether. The optically pure xylose-derived mono-enone
mono-enoate 22a provides pentasubstituted cyclohexene 22b as a
single isomer.10 A model accounting for the observed stereoselec-
tivity is indicated.
Electronic differentiation of the reacting partners was investigated
as a means of enabling the chemoselective cycloisomerization of
unsymmetrical substrates. Aromatic-aliphatic mixed bis(enone) 15a
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10.1021/ja0121686 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Phosphine-Catalyzed Cycloisomerization of Bis(enones)a
In summary, we have developed a simple and effective organic
catalyst system for the cycloisomerization of bis(enones). This
methodology overcomes many limitations of metallic diene cy-
cloisomerization catalysts: both five- and six-membered-ring
formations occur readily, conformationally predisposed substrates
are not required, products of alkene isomerization are not formed,
and finally, functional group compatibility is broadened. An
enantioselective variant of the phosphine-catalyzed cycloisomer-
ization of bis(enones) will be the subject of a forthcoming report.
Acknowledgment. The authors acknowledge the Robert A.
Welch Foundation (F-1466), the NSF-CAREER program, the
Herman Frasch Foundation, the NIH (RO1 GM65149-01), the
THECB Advanced Research Program and donors of The Petroleum
Research Fund administered by the ACS for partial support of this
research.
Supporting Information Available: Spectral data for all new
compounds (1H NMR, 13C NMR, IR, HRMS) (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
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a Procedure: Tributylphosphine was added to a 0.1 M solution of
substrate in the indicated solvent and the reaction was allowed to stir at the
indicated temperature until complete. b Yield based on recovered starting
material. c 20 mol % PBu3 used.
Though detailed mechanistic studies have not been undertaken,
a plausible mechanism for the phosphine-catalyzed cycloisomer-
ization of bis(enones) is proposed below.6 Conjugate addition of
tributylphosphine I to the indicated bis(enone) provides enolate II.
Subsequent intramolecular conjugate addition to the appendant
enone yields zwitterionic intermediate III. Finally, proton-transfer
enables â-elimination of tributylphosphine to complete the catalytic
cycle. Cycloisomerization performed in d6-acetone did not yield
products incorporating deuterium, indicating that proton transfer
occurs between substrate molecules either inter- or, more likely,
intramolecularly.
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(10) Isomeric ratios were determined by 1H NMR. For ratios of >95:5, the
minor isomer was not observed.
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