Epoxides 3-Epoxy ketones

The opening of epoxides with neighboring keto groups, accompanied by vinylogous jS-elimination, has already been mentioned (section V). This is an extension of the jS-elimination reactions which occur when a,p- or jS,y-epoxy ketones are opened with acid or base. a,jS-Epoxy ketones give a-substituted a,jS-unsaturated ketones [(162), for example], and j5,y-epoxy ketones give y-substituted a,jS-unsaturated ketones [(163), for example] ... 

Double bonds in a,/3-unsaturated keto steroids can be selectively oxidized with alkaline hydrogen peroxide to yield epoxy ketones. In contrast to the electrophilic addition mechanism of peracids, the mechanism of alkaline epoxidation involves nucleophilic attack of hydroperoxide ion on the con-... 

A decisive solvent effect is also observed with other a,/ -epoxy ketones. Specifically, 3jS-hydroxy-16a,17a-epoxypregn-5-en-20-one and its acetate do not react with thiocyanic acid in ether or chloroform. However, the corresponding thiocyanatohydrins are formed by heating an acetic acid solution of the epoxide and potassium thiocyanate. As expected, the ring opening reaction is subject to steric hindrance. For example, 3j6-acetoxy-14f ,15f5-epoxy-5) -card-20(22)-enoIide is inert to thiocyanic acid in chloroform, whereas the 14a,15a-epoxide reacts readily under these conditions.Reactions of 14a,15a-epoxides in the cardenolide series yields isothiocyanatohydrins, e.g., (135), in addition to the normal thiocyanatohydrin, e.g., (134). 

Now that the allylic oxidation problem has been solved adequately, the next task includes the introduction of the epoxide at C-l and C-2. When a solution of 31 and pyridinium para-tolu-enesulfonate in chlorobenzene is heated to 135°C, the anomeric methoxy group at C-l 1 is eliminated to give intermediate 9 in 80% yield. After some careful experimentation, it was found that epoxy ketone 7 forms smoothly when enone 9 is treated with triphenyl-methyl hydroperoxide and benzyltrimethylammonium isopropoxide (see Scheme 4). In this reaction, the bulky oxidant adds across the more accessible convex face of the carbon framework defined by rings A, E, and F, and leads to the formation of 7 as the only stereoisomer in a yield of 72%. 

It should be noted that epoxidation of a dienone with mCPBA or other electrophilic epoxidation reagents proceeds with complementary regioselectivity, yielding y,8-epoxy enones instead of the ot,P-epoxy ketones discussed above. This feature has been utilized in several natural product syntheses Scheme 9.8 demonstrates... 

Epoxides can also be rearranged to aldehydes or ketones on treatment with certain metallic catalysts.A good way to prepare p-diketones consists of heating a,P-epoxy ketones at 80-140°C in toluene with small amounts of (Ph3P)4Pd and 1,2-bis(diphenylphosphino)ethane. ... 

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. 

An exploration of structural modifications on the activity of prolinol catalysts has been published <06T12264>. More electron-rich aromatic rings on the prolinol scaffold improve the activity in the epoxidation of a, 3-enones. The reaction of 10 with an enone and f-BuOOH provides the epoxy-ketones with moderate levels of enantioselectivity. 

Pyrazoles were synthesized in the authors laboratory by Le Blanc et al. from the epoxy-ketone as already stated in Sect. 3.1.1a, Scheme 35 [80]. The synthetic strategy employed by Le Blanc et al. [80] was based upon that the strategy published by Bhat et al. [81] who also described the synthesis of pyrazoles but did not report cytotoxic evaluation on the synthesized compounds. Scheme 48 shows the synthesis of the most active compound (178). Dissolution of the epoxide (179) with a xylenes followed by treatment with p-toluenesulfonic acid and hydrazine hydrate produced the pure nitro-pyrazole 180 in good yield (60%). Catalytic hydrogenation with palladium on activated carbon allowed the amino-pyrazole (178) to be obtained in a pure form. This synthesis allowed relatively large numbers of compounds to be produced as the crude product was sufficiently pure. Yield, reaction time, and purification compared to reported approaches were improved [50, 61, and 81]. Cytotoxicity of these pyrazole analogs was disappointing. The planarity of these compounds may account for this, as CA-4, 7 is a twisted molecule. 

As a, (3-unsaturated ketones are electron-poor alkenes, they do not generally give epoxides when treated with peracids. They can be epoxidized with hydrogen peroxide which involves nucleophilic attack by HOO- to give the epoxy ketone (Figure 4.1). 

In the epoxidation process (Figure 4.4), the oxygen of the enone s carbonyl function first coordinates with the zinc atom. The ethylperoxy anion then attacks the (3-position, which constitutes a Michael-type addition. The subsequent cyclization gives the epoxy ketone and the zinc alkoxide. 

Table 4.2 a,p-Epoxy ketones prepared by epoxidation of ( )-2-alkyliden-l-oxo-l,2,3,4-tetrahydronaphthalenes using diethylzinc and (lR,2R)-V-methylpseudoephedrine[8l... 

Table 4.3 a, P-Epoxy ketones prepared by epoxidation of a-enones using diethylzinc and (1R, 2R)-/V-methylpseudoephedrine (according to the relevant publication)181. 

Epoxidation is another important area which has been actively investigated on asymmetric phase transfer catalysis. Especially, the epoxidation of various (i.)-a,p-unsaturated ketones 68 has been investigated in detail utilizing the ammonium salts derived from cinchonine and cinchonidine, and highly enantioselective and diastereoselective epoxidation has now been attained. When 30 % aqueons H202 was utilized in the epoxidation of various a, 3-unsaturated ketones 68, use of the 4-iodobenzyl cin-choninium bromide 7 (R=I, X=Br) together with LiOH in Bu20 afforded the a,p-epoxy ketones 88 up to 92% ee,1641 as shown in Table 5. The O-substituted... 

A recent synthesis of the phenylisoserine side-chain of taxol is shown in Scheme 18. The enone 21 was obtained in high yield by condensation of benzal-dehyde with pinacolone. Employing the non-aqueous two-phase epoxidation protocol, epoxide 22 was obtained in 76% yield and 94% e.e. Recrystallisation of the epoxide furnished the desired enantiomer in 97 % e. e. Subsequent manipulations of the epoxy-ketone gave the taxol side-chain 23 with the required stereochemistry (Scheme 18). 

Racemic Diels-Alder adducts 47/48 and 31/49 reacted with MCPBA in chlorofomi and afforded epoxides 179 (82 %) and 180 (86 %), respectively. Saponification of 179 with K2CO3 in aqueous methanol in the presence of fonnalin gave epoxy-ketone 181 (79 %). Treatment of 7-oxanorbom-5-en-2-one (7) with... 

Asymmetric epoxidation of a,jS-unsaturated ketones represents an efficient method for the preparation of optically active a,jS-epoxy ketonesJ Recently, a new and very efficient catalytic system for enantioselective epoxidation of ( )-a,jS-enones to the corresponding trans-epoxy ketones has been developed based on a BlNOL-zinc complexJ Very high yields and excellent diastereo- and enantioselectivities are achieved at room temperature using cumene hydroperoxide (CMHP) as the terminal oxidant and performing the reaction in diethyl ether. A combination of enantio-merically pure BINOL and diethylzinc readily affords the active catalyst in situ (Figure 6.13). ... 

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