Enantioselective Synthesis of Bicyclo[2.2.2]octenones Using a Copper-Mediated Oxidative Dearomatization/[4 + 2] Dimerization Cascade

Abstract

The bicyclo[2.2.2]octenone skeleton is found in a number of natural products (Figure 1) including homodimers 1 2 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] We first investigated oxidation of the 2,5-disubstituted phenol carvacrol (4) using conditions previously reported for 2,4-dihydroxybenzaldehyde substrates enroute to the azaphilones 8 (Table 1, entry 1). In the event, reaction of 4 with a [(−)-sparteine] 2 Cu 2 O 2 (PF 6 ) 2 complex and N,N-diisopropylethylamine (DIEA) in CH 2 Cl 2 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, 10Further 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 literature 12 have generally been attributed to the equilibrium of binuclear copper-peroxo (P, μ-η 2 :η 2 -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 abstracting 15 [(−)-sparteine] 2 bis(μ-oxo)dicopper(III) (O) complex in CH 2 Cl 2 and the electrophilic μ-η 2 :η 2 -peroxodicopper(II) (P) complex in THF. Although evaluation of alternative counterions 16 (e.g. BF 4 − , OTf − , Cl − ) to favor formation of the corresponding P complex did not show substantial improvement over PF 6 −,10 we found that pre-formation of the phenolate with LiOH E-mail: porco@bu.edu. 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...

Microwave-Based Reaction Screening: Tandem Retro-Diels–Alder/Diels–Alder Cycloadditions ofo-Quinol Dimers

“…In all cases, Diels-Alder cycloaddition between o -quinol 4 and dienophiles 9 proceeded in a highly diastereoselective fashion with [4+2] adducts 10a–g isolated in moderate to excellent yields. Structure elucidation of products using 2D NMR experiments or X-ray crystallography confirmed that endo -[4+2] cycloadducts were the predominate products isolated from the reactions, 12 which is in accordance with both experimental results and theoretical calculations in literature that secondary orbital overlap is believed to govern endo -selectivity. 17 Facial selectivity could be explained by either sterics or hyperconjugation effects according to our computational studies ( vide infra ).…”

“…14 Based on UPLC-MS data, reactions showing major peaks in the HPLC trace were scaled up (0.06 mmol, 20 mg substrate) using a SiC chip as passive heating element in a single mode microwave reactor. 12 The results of the reaction screening indicated that dimer 2 was completely consumed in all cases. Of the 57 reactions, 12 afforded products corresponding to [4+2] adducts between the o -quinol and alkene reaction partners, and other reactions afforded product 8 (Scheme 2), likely generated from a dienone-phenol rearrangement of intermediate 4 .…”

“…12 Representative structures were shown in Figure 1. A number of alkene partners were selected based on retro-[4+2]/[4+2] cycloadditions of o -quinol dimers and MOB dimers reported in the literature.…”

Heterogeneous Catalytic Hydrogenation Reactions in Continuous‐Flow Reactors

“…The system could be operated continuously for 20 h without loss of catalyst activity (Scheme 3 c). [74] A related continuous-flow procedure was adopted for the enantioselective synthesis of bicycle- [75] and the microtubule inhibitor (+)-chamaecypanone C. [76] A continuous process was established for the production of 2,2,6,6-tetramethylpiperidin-4-ol over Cu-Cr/g-Al 2 O 3 in a fixedbed reactor (Scheme 4 a). While the selectivity decreased from 98 % at 98 8C to 77 % at 152 8C, it increased from 75 % to 92 % with the increase of hydrogen pressure from 10 bar to 40 bar.…”

Phase‐Transfer‐Catalyzed Oxazirid­ine‐Mediated Hydroxylative Phenol and Naphthol Dearomatization

“…[2] Among these, hydroxylative phenol and naphthol dearomative strategies play a pivotal role in metabolite degradation [3] through the formation of the 6-hydroxy-2,4-cyclohexadienone moiety 1, [4] which thus represents a key structural intermediate in the biomimetic total synthesis of natural products, including bacchopetiolone [5] (2), bisorbicillinol [6] (3), sclerotiorin [7] (4), and arianciamycinone [8] (5) (Figure 1). The transformation of phenols and naphthols into the corresponding ortho-quinol products was investigated by using a variety of reagents including peracids, [9] (PhSeO) 2 O, [10] hypervalent iodine compounds, [11] as well as (oxo)-or (peroxo)metal species either in a stoichiometric [12] or catalytic [13] amount. Unfortunately, these methodologies often exhibit low chemo-and regioselectivities due to side-reactions including competitive para oxidation, [11f,13b] overoxidation of alkene functions, [11d] α-ketol rearrangement [12,13a] or phenol homocoupling [11f,12] (Scheme 1).…”