Epoxidation of Cyclic Enones

In 1976, using the parent quinine as a catalyst and 30% aqueous hydroperoxide as an oxidant, the asymmetric epoxidation of cyclic enones, such as naphthoquinones, was explored by Wynberg and coworkers [13]. However, the resulting enantioselec-tivity was minimal. Their further attempt under biphasic conditions with N-benzyl-quininium chloride 1 as the catalyst and t-BuOOH as the oxidant also resulted in very low enantioselectivities (up to 20% ee for the epoxidation of various cyclohexe-nones) [14]. However, the use of the dimeric form of Wynberg s catalysts 6 and 7 resulted in somewhat better (up to 63% ee with cyclohexenone) asymmetric 

Very recently, using structurally varied PTCs based on quinine, quinidine, dihydroquinine, and dihydroquinidine, Berkessel and coworkers conducted the asymmetric epoxidation of 2-methylnaphthoquinone (precursor of vitamin K3) with an aqueous solution of NaOCl at —10 °C in chlorobenzene [18], Among these new catalysts, the phase-transfer catalyst 13 bearing an extra chiral moiety at the quinudidine nitrogen atom provided an enantioseledivity of 79% ee with good yield (86%). However, it was found that the best results were achieved with the readily 

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The first highly enantioselective epoxidation of cyclic enones was developed by List et al. by using hydrogen peroxide as the oxidant and a chiral primary amine salt as the organocatalyst. A series of primary amine salts were investigated for this reaction and the best results were obtained with a quinine-derived primary amine salt, which provided excellent enantioselectivities of up to 99% ee for a variety of cyclic enones, as shown in Scheme 7.7. 

Iminium catalysis has been quite successful for asymmetric epoxidation of a,P-unsaturated carbonyl compounds, particularly, enals. Enones have remained difficult substrates. Recently, List and coworkers reported an enantioselective epoxidation of cyclic enones with either cinchona-based primary amine 38 or a counter-anion catalytic systan 149 combining a chiral vicinal diamine and a chiral phosphoric acid [69], High enantioseleclivities could be achieved in a number of cyclic enones (Scheme 5.40). 

With environmental consideration in mind, the group has developed a version in concentrated media, i.e. without dichloromethane and only three equivalents of isopropanol. ° For instance, the ketone 64 was converted into the alcohol 65 in 93% yield and 95% enantiomeric excess using only 10 mol% of titanium-BINOL catalyst (Conditions B, Scheme 7.36). A slight decrease of efficiency was observed using 5 mol% of catalyst (Conditions C). The efficiency of the method was illustrated by a tandem asymmetric ally-lation/diastereoselective epoxidation reaction of cyclic enones that is based on the use of the allylation catalyst for a subsequent epoxidation with TBHP, as illustrated in Scheme 7.37. ° ... 

In 2010, Tanaka s group investigated whether a chiral cyclic a-amino acid included in an oligopeptide chain could catalyze the epoxidation of different enones with high enantiomeric excess. They demonstrated that the a-helical secondary structure of the peptide catalyst is directly related to the chosen a,a-disubstituted amino acid [134]. Thus, they found that 5 mol% of a-helical nonamer 92 with urea-H2O2 as oxidant can catalyze the reaction with ee > 95% (Scheme 12.18). 

More recently. List and co-workers [169], have reported the asymmetric epox-idation of cyclic enones, using a chiral primary diamine (111) and a phosphoric acid derived from BINOL (112) (Scheme 12.29). With H2O2 as oxidant, the epoxides were obtained in good yields (63-82%) and moderate to good enantioselectivities (78-98%). They also tested amine 113, which provided better ee s (92 to 99%) and slightly lower yields (49-85% (Scheme 12.29). 

A mini-review focused on the recent achievements in gold-catalysed oxygen tfansfer reactions of tethered alkynones, diynes, or alkynyl epoxides to cyclic enones has described the corresponding mechanisms. ... 

A new type of arenesulphonylhydrazone fragmentation to alkynones has been reported. With N-bromosuccinimide in alcohols, the tosylhydrazone (86) yielded the cyclic alkynone (87), which was subsequently reduced to ( )-muscone [equation (56)]. The method may offer advantages over the Eschenmoser fragmentation of epoxy-tosylhydrazones in cases where epoxidation of crowded enones is difficult. 

The N-aminoaziridine version7 of the a,/3-epoxyketone->alkynone fragmentation is a possible alternative in situations where the simple tosylhydrazone version6-9 fails. The tosylhydrazone method often gives good yields at low reaction temperatures, but it tends to be unsuccessful with the epoxides of enones that are not cyclic or are not fully substituted at the /5-carbon atom. For example, it has been reported9 that 2,3-epoxycyclohexanone docs not produce 5-hexynal by the tosylhydrazone route. The A-aminoaziridine method can also be recommended for the preparation of acetylenic aldehydes as well as ketones. 

Interestingly, we were intrigued by the ESI mass spectrum of the compound, as the observed base peak consisted of [M-S02+Na]+. This led us to explore a thermal retro-Diels-Alder reaction that could afford the desired enone 69. It is noteworthy that the chemistry of cyclic enol-sulfites would appear to be an under-explored area with a few references reporting their isolation being found [57]. At last, we were also able to prepare epoxy ketone 70 from 69 in three steps, albeit epoxidation did not take place unless the TES group was removed. Spartan models reaffirmed our initial conformational assessment of enone 69 and epoxy ketone 70, which contain sp3-hybridized C8a and s/r-hybridized C8b (p s e u d o-. v/r - h y b r i d i zed C8b for 70) at the AB-ring junction (Fig. 8.12) and displayed the desired twisted-boat conformation in A-ring. 

Reaction at the C atom of nitronate salts is known with a variety of electrophiles, such as aldehydes (Henry reaction) and epoxides (191-193). Thus the incorporation of the nitro moiety and the cyclization event can be combined into a tandem sequence. Addition of the potassium salt of dinitromethane to an a-haloaldehyde affords a nitro aldol product that can then undergo intramolecular O-alkylation to provide the cyclic nitronate (208, Eq. 2.17) (59). This process also has been expanded to a-nitroacetates and unfunctionalized nitroalkanes. Other electrophiles include functionalized a-haloaldehydes (194,195), a-epoxyaldehydes (196), a-haloenones (60), and a-halosulfonium salts (197), (Chart 2.2). In the case of unsubstituted enones, it is reported that the intermediate nitronate salt can undergo formation of a hemiacetal, which can be acetylated in moderate yield (198). 

The at complex from DIB AH and butyllithium is a selective reducing agent.16 It is used tor the 1,2-reduction of acyclic and cyclic enones. Esters and lactones are reduced at room temperature to alcohols, and at -78 C to alcohols and aldehydes. Acid chlorides are rapidly reduced with excess reagent at -78 C to alcohols, but a mixture of alcohols, aldehydes, and acid chlorides results from use of an equimolar amount of reagent at -78 C. Acid anhydrides are reduced at -78 C to alcohols and carboxylic acids. Carboxylic acids and both primary and secondary amides are inert at room temperature, whereas tertiary amides (as in the present case) are reduced between 0 C and room temperature to aldehydes. The at complex rapidly reduces primary alkyl, benzylic, and allylic bromides, while tertiary alkyl and aryl halides are inert. Epoxides are reduced exclusively to the more highly substituted alcohols. Disulfides lead to thiols, but both sulfoxides and sulfones are inert. Moreover, this at complex from DIBAH and butyllithium is able to reduce ketones selectively in the presence of esters. 

The unusual nucleophilic epoxidation of /i-hydroxyenones under Sharpless conditions (see Section 4.5.1.3.2.1.) is also applicable to compounds 1 with endocyclic double bonds. The. sj H-epoxides are produced with complete selectivity. The stereochemical outcome of the reaction under Weitz-Scheffer conditions significantly differs from that observed for acyclic compounds. While the acyclic enones afforded preferentially the moderate ratio, cyclic ones gave predominantly s>7i-epoxides32. 

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