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 While Diels-Alder cycloaddition of 2,4-cyclohexadienones and ortho-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 homodimeric bicyclo[2.2.2]octenones.5 Although numerous synthetic 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.
Figure 1.
Representative Bicyclo[2.2.2]octenone-Containing Natural Products
Scheme 1.
Enantioselective Oxidative Dearomatization/[4+2] Cycloaddition Cascade
We first investigated oxidation of the 2,5-disubstituted phenol carvacrol (4) using conditions previously reported for 2,4-dihydroxybenzaldehyde substrates enroute 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 comparison to NMR and CD spectral data reported for natural product (3R,10R)-1.2, 10
Table 1.
Optimization of the Oxidative Dearomatization/Dimerization of Carvacrol (4)
 | ||||
|---|---|---|---|---|
| entry | solvent | base | conversiona (%) | (3S,10S)-1 : 5c |
| 1 | CH2Cl2 | DIEA | 70 (25)b | 1 : 1.5 |
| 2 | THF | LiHMDS | 67 (58) | > 40 : 1 |
| 3 | THF | DIEA | 69 (58) | > 40 : 1 |
| 4 | CH3CH2CN | DIEA | 40 | 1.6 : 1 |
| 5 | acetone | DIEA | 25 | 3 : 1 |
| 6d | THF | LiOH·H2O | 83 (80) | > 40 : 1 |
Conversion based on recovered starting materials.
Isolated yield of dimer (3S,10S)-1 in parenthesis.
Ratio was determined by 1H NMR analysis of (3S,10S)-1 and 5.
1.0 equiv base was used for preparing the lithium phenolate.
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 propionitrile (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 copper-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 improvement over PF6−,10 we found that pre-formation of the phenolate 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 phenolates 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, with a noticeable lower conversion observed for substrate 6. Substrate 10 (entry 3) bearing an electrondonating methoxy group at C5 was also successfully converted into dimer 11 after thermolysis 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 underscoring the steric control aspects of the oxidation.
Table 2.
Copper-Mediated Asymmetric Oxidative Dearomatization /[4+2] Dimerizationa
| entry | phenol | product | yieldb (%) | ee (%) |
|---|---|---|---|---|
| 1 |  |
 |
40(67)c | 98 |
| 2 |  |
 |
82(92) | 99 |
| 3 |  |
 |
52(80) | 99 |
| 4 |  |
 |
50(64) | - |
| 5 |  |
 |
40(53)15 12(16)16 |
- |
| 6 |  |
 |
23(82) | - |
| 7 |  |
 |
25(37) 7(10) |
99 20 99 ent-8 |
| 8 |  |
 |
51(77) | 99 |
Reaction conditions: 1.0 equiv of lithium phenolate, 1.1 equiv of [(−)- sparteine]2Cu2O2(PF6)2 complex, 3Å MS, O2, THF, −78 °C, 16 h.
Isolated yield after chromatography.
Yield based on recovered starting materials in parenthesis.
Product obtained from thermolysis of the crude oxidation product (neat) at 50 °C (40 min).
Product obtained from thermolysis of the crude oxidation product (80 °C, 16 h).
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 ortho-quinol 21 (Scheme 2) underwent [4+2] dimerization to 20 or stereoselective a-ketol rearrangement 18 to 22 which further dimerized to ent-8. Comparison of the optical rotations of 8 and ent-8 indicates that these two compounds have opposite absolute configurations.10 In order to further probe this process, phenol 23 was investigated as an oxidation substrate (entry 8). To our surprise, ortho-quinol 24 did not dimerize at room temperature and the monomer could be observed by crude NMR analysis.10 However, attempts to purify this intermediate on silica gel led to decomposition and recovery of only a small amount of dimer ent-9. Thermolysis of monomer 24 in benzene cleanly afforded dimer ent-9. Based on this information, it is apparent that the α-ketol rearrangement affords an isomeric ortho-quinol possessing an unsubstituted cis-alkene moiety which is more reactive in [4+2] dimerization.
Scheme 2.
Rearrangement of 4-alkyl-2,4-cyclohexadienones
The copper-mediated asymmetric oxidative dearomatization/dimerization methodology provides a rapid entry to the homochiral dimer (+)-aquaticol (2, Scheme 3). Enantiomerically pure (+)-cuparenol (25) was prepared from commercially available (+)-cuparene (26) following a known procedure.6c Asymmetric oxidative dearomatization of the derived lithium phenolate 27 furnished (+)-aquaticol (2) ([α]D22 = + 46.1°, c = 0.65, CHCl3) as a single diastereomer. X-ray crystal structure analysis of 2 further confirmed its relative stereochemistry and reassignment of the absolute configuration.6c, 10 A control experiment using N,N-di-tert-butylethylenediamine as achiral ligand in the oxidation generated a mixture of 2 and its epimer at C3 and C10 in 43:57 ratio,10 which suggests that use of (−)- sparteine completely overrides the slight chirality induction from the 7-R center of (+)-cuparenol (25).
Scheme 3.
Enantioselective Synthesis of (+)-aquaticol
In conclusion, we have developed a highly enantioselective approach to bicyclo[2.2.2]octenones involving asymmetric oxidation of substituted phenols to ortho-quinols followed by homochiral dimerization. Our studies have revealed a facile ketol shift/dimerization of ortho-quinols derived from 2,4-disubstituted phenols and have culminated in the enantioselective synthesis of (+)-aquaticol. Further studies, including asymmetric oxidative dearomatization of other substrates and mechanistic experiments, are currently in progress and will be reported in due course.
Supplementary Material
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.
Acknowledgment
Financial support from the NIH (GM-073855 and P50 GM067041), Wyeth Pharmaceuticals, and Merck Research Laboratories is gratefully acknowledged. We thank Prof. Stéhane Quideau (IECB, ISM UMR-CNRS 5225, University of Bordeaux) for providing a sample of (+)-aquaticol and Dr. Shun Su (Boston University) for helpful discussions.
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Supplementary Materials
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.