Enantioselective synthesis of bicyclo[2.2.2]octenones using a copper-mediated oxidative dearomatization/[4 + 2] dimerization cascade

Article abstract of DOI:10.1021/ja711018z

An enantioselective approach to bicyclo[2.2.2]octenone structures utilizing a copper-mediated asymmetric oxidative dearomatization/[4 + 2] dimerization cascade is described. The total synthesis and absolute stereochemistry reassignment of (+)-aquaticol has been achieved using the methodology. Copyright

Full text of DOI:10.1021/ja711018z

Published on Web 02/12/2008
Enantioselective Synthesis of Bicyclo[2.2.2]octenones Using a
Copper-Mediated Oxidative Dearomatization/[4 + 2] Dimerization Cascade1
Suwei Dong, Jianglong Zhu, and John A. Porco, Jr.*
Department of Chemistry and Center for Chemical Methodology and Library DeVelopment (CMLD-BU),
Boston UniVersity, Boston, Massachusetts 02215
Received December 11, 2007; E-mail: porco@bu.edu
The bicyclo[2.2.2]octenone skeleton is found in a number of
natural products (Figure 1) including homodimers 12 and 2
(aquaticol)3 and the hetero adduct chamaecypanone C (3).4 Although
Diels-Alder cycloaddition of 2,4-cyclohexadienones and o-quinols
with activated alkenes has frequently been used for the synthesis
of bicyclo[2.2.2]octenones, 2,4-cyclohexadienones also have a high
propensity to undergo spontaneous [4 + 2] dimerization to homo-
Figure 1. Representative natural products containing the bicyclo [2.2.2]-
dimeric bicyclo[2.2.2]octenones.5 Although numerous synthetic
octenone core.
efforts utilizing oxidative dearomatization of substituted phenols
to construct the bicyclo[2.2.2]octenone core have been developed,6
the corresponding enantioselective process has not been reported.7
We have previously reported the highly enantioselective synthesis
of azaphilones involving copper-mediated oxidative dearomatization
of o-alkynylbenzaldehydes.8 Herein, we report a general protocol
for the enantioselective oxidative hydroxylation of phenols (Scheme
1) followed by homodimerization to bicyclo[2.2.2]octenones.
We first investigated oxidation of the 2,5-disubstituted phenol
carvacrol (4) using conditions previously reported for 2,4-dihy-
droxybenzaldehyde substrates en route to the azaphilones8 (Table
1, entry 1). In the event, reaction of 4 with a [(-)-sparteine]2Cu2O2-
(PF6)2 complex and N,N-diisopropylethylamine (DIEA) in CH2Cl2
at -78 °C (16 h) afforded a mixture of the [4 + 2] dimer
(3S,10S)-1 in 25% isolated yield (99% ee by chiral HPLC analysis)
and biaryl coupling product 5 (23%).9 The backbone structure and
absolute configuration of (3S,10S)-1 were determined by compari-
son to NMR and CD spectral data reported for natural product
(3R,10R)-1.2,10
Scheme 1. Enantioselective Oxidative Dearomatization/[4 + 2]
Cycloaddition Cascade
Table 1. Optimization of the Oxidative Dearomatization/
Dimerization of Carvacrol (4)
entry
solvent
base
conversiona (%)
(3S,10S)-1:5c
1
2
3
4
CH2Cl2
THF
THF
CH3CH2CN
acetone
THF
DIEA
LiHMDS
DIEA
DIEA
DIEA
70 (25)b
67 (58)
69 (58)
40
25
83 (80)
1:1.5
>40:1
>40:1
1.6:1
3:1
>40:1
Further optimization studies revealed that use of LiHMDS to
generate the phenolate in THF as solvent,11 followed by oxidative
dearomatization, cleanly afforded dimer 1 in 58% isolated yield
(>99% ee) with a trace amount of biaryl formation (Table 1, entry
2). Use of DIEA as base in THF (entry 3) also led to preferential
formation of dimer 1. This result, along with reactions in propi-
onitrile (entry 4) and acetone (entry 5), revealed a strong solvent
effect for the reaction. Solvent and ligand effects reported in the
literature12 have generally been attributed to the equilibrium of
binuclear copper-peroxo (P, µ-η2:η2-peroxodicopper(II)) and cop-
per-oxo (O, bis(µ-oxo)dicopper(III)) complex forms.13,14 In the case
at hand, the solvent effects may be rationalized by greater levels
of the corresponding radical abstracting15 [(-)-sparteine]2bis(µ-
oxo)dicopper(III) (O) complex in CH2Cl2 and the electrophilic µ-η2:
η2-peroxodicopper(II) (P) complex in THF. Although evaluation
of alternative counterions16 (e.g. BF4-, OTf-, Cl-) to favor
formation of the corresponding P complex did not show substantial
5
6d
LiOH‚H2O
a Conversion based on recovered starting materials. b Isolated yield of
dimer (3S,10S)-1 in parenthesis. c Ratio was determined by 1H NMR analysis
of (3S,10S)-1 and 5. d One equivalent of base was used to prepare the lithium
phenolate.
with a noticeable lower conversion observed for substrate 6.
Substrate 10 (entry 3) bearing an electron-donating methoxy group
at C5 was also successfully converted into dimer 11 after ther-
molysis of the crude monomer.10 Attempted oxidation of 2,5-
disubstituted phenols with electron-withdrawing groups at C5 gave
poor conversion.10 Phenol 12 bearing a bulky substituent at C2
(entry 4) did not afford a [4 + 2] dimer but instead produced
catechol 13.11 Attempted oxidation of the lithium phenolate derived
from 2,6-dimethylphenol 14 led to the isolation of biaryl 15 and
quinone 16 (entry 5) instead of the expected [4 + 2] dimer.17
Oxidation of 2,3-disubstituted phenol 17 (entry 6) also led to the
isolation of the corresponding catechol product 18, further under-
scoring the steric control aspects of the oxidation.
improvement over PF6 ,
- 10 we found that preformation of the pheno-
late with LiOH increased conversion and afforded dimer 1 in good
yield and high enantioselectivity (>99% ee) (Table 1, entry 6).
To evaluate the scope and limitations of this methodology, a
number of phenol substrates were transformed into lithium phe-
nolates and subsequently subjected to copper-mediated oxidative
dearomatization (Table 2). Use of 2,5-dimethyl and 2-methyl-5-
tert-butyl substituted phenols 6 (entry 1) and 7 (entry 2) led to the
production of [4 + 2] dimers 8 and 9 in high enantioselectivity,
Interestingly, oxidation of the substrate 2,4-dimethyl phenol 19
led to the isolation of two dimeric structures 20 and ent-8 (Table
2, entry 7) after column chromatography. Product analysis revealed
that the initially formed o-quinol 21 (Scheme 2) underwent [4 +
2] dimerization to 20 or stereoselective R-ketol rearrangement18 to
9
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J. AM. CHEM. SOC. 2008, 130, 2738-2739
10.1021/ja711018z CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Enantioselective Synthesis of (+)-Aquaticol
Table 2. Copper-Mediated Asymmetric Oxidative
Dearomatization/[4 + 2] Dimerizationa
suggests that use of (-)-sparteine completely overrides the slight
chirality induction from the 7-R center of (+)-cuparenol (25).
In conclusion, we have developed a highly enantioselective
approach to bicyclo[2.2.2]octenones involving asymmetric oxidation
of substituted phenols to o-quinols followed by homochiral dimer-
ization. Our studies have revealed a facile ketol rearrangement/
dimerization of o-quinols derived from 2,4-disubstituted phenols
and have culminated in the enantioselective synthesis of (+)-
aquaticol. Further studies, including asymmetric oxidative dearo-
matization of other substrates and mechanistic experiments, are
currently in progress and will be reported in due course.
Acknowledgment. Financial support from the NIH (GM-
073855 and P50 GM067041), Wyeth Pharmaceuticals, and Merck
Research Laboratories is gratefully acknowledged. We thank Prof.
Ste´phane Quideau (IECB, ISM UMR-CNRS 5225, University of
Bordeaux) for providing a sample of (+)-aquaticol and Dr. Shun
Su (Boston University) for helpful discussions.
a Reaction conditions: 1.0 equiv of lithium phenolate, 1.1 equiv of [(-)-
sparteine]2Cu2O2(PF6)2 complex, 3 Å MS, O2, THF, -78 °C, 16 h. b Isolated
yield after chromatography. c Yield based on recovered starting materials
in parenthesis. d Product obtained from thermolysis of the crude oxidation
product (neat) at 50 °C (40 min). e Product obtained from thermolysis of
the crude oxidation product (80 °C, 16 h).
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Scheme 2. Rearrangement of 4-Alkyl-2,4-cyclohexadienones
References
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dimerization methodology provides a rapid entry to the homochiral
dimer (+)-aquaticol (2, Scheme 3). Enantiomerically pure (+)-
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cuparene (26) following a known procedure.6c Asymmetric oxidative
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