Intermediate epoxide

For the formation of substituted THF rings (Route a, Scheme 8.1), Kishi developed a procedure based on the hydroxy-directed epoxidation of a y-alkenol [10]. Epoxidation of bishomoallylic alcohol 3 by TBHP/VO(acac)2 by this approach, followed by treatment of the intermediate epoxide 4 with acetic acid, gave the TH F derivative 5 of isolasalocid A (a 5-exo cydization Scheme 8.2) [11]. Further epoxidation of 5 (a y-alkenol) under the same conditions, followed by acetylation, afforded epoxide 6. For the synthesis of the natural product, the configuration of epoxide 6 had to be inverted before the second cydization reaction. Epoxide 6 was consequently hydrolyzed under acid conditions to the corresponding diol and was then selectively... 

Racemic 5-methyl-5 -(sodiomethyl)-A-(4-methylphenylsulfonyl)sulfoximine reacts with ketones to give an initial methylene transfer which produces an intermediate epoxide that is ring expanded to the oxctanc56. Application to 4-rerf-butylcyclohexanonc affords a single oxetane in 69% yield. While only achiral alkylidcne transfer reagents were utilized, in principle this reaction is amenable to the asymmetric synthesis of oxetanes. 

Practical considerations limit, the scalability of this reaction due to the highly reactive and water sensitive intermediates formed. Furthermore, the time required for removal of large amounts of solvent in vacuo allows for the opening of the intermediate epoxide leading to diol formation. 

The epoxidation can be done either with peroxy acids or DMDO. In the former case, the rearrangement is catalyzed by the carboxylic acid that is formed, whereas with DMDO, the intermediate epoxides can sometimes be isolated. 

The first synthesis of Taxol was completed by Robert Holton and co-workers and is outlined in Scheme 13.53. One of the key steps occurs early in the synthesis in sequence A and effects fragmentation of 4 to 5. The intermediate epoxide 4 was prepared from a sesquiterpene alcohol called patchino. 35 The epoxide was then converted to 5 by a BF3-mediated rearrangement. 

Reactivity of protonated epoxide. There is believed to be a zone of intermediate epoxide reactivity that is optimum for initiating the carcinogenic process [57-59], The molecule must be able to undergo the necessary reactions, yet not be so active it will interact prematurely with other cellular species. 

An interesting recent report by Shibasaki deals with a Zr-catalyzed process whereby various cyclic and acyclic alkenes are directly converted to their corresponding p-cyanohy-drins, presumably via an intermediate epoxide [114]. One catalytic enantioselective version has been reported, as shown in Eq. 6.23. This promising initial result augurs well for future developments of this synthetically useful transformation. 

The oxidative cyclization of vinylallenes need not be directed by a pendant hydroxyl group in order to succeed. The higher reactivity of the allene compared with the exocyclic methylene group in 73 (Eq. 13.23) with monoperphthalic acid leads primarily to the allene oxide which rearranges to cydopentenone 74 [27]. Inevitably some epoxidation of the alkene also takes place during the reaction. When m-CPBA is used as the oxidant, another side reaction is associated with m-chlorobenzoic add-mediated decomposition of the intermediate epoxide. It is possible to overcome this problem by performing the epoxidation in dichloromethane in a two-phase system with aqueous bicarbonate so as to buffer the add [28]. 

When allenyl aldehydes are allowed to react with DMDO, the aldehyde moiety is not oxidized to the acid except for monosubstituted allenes [21]. In all other cases, the carbonyl oxygen participates as a nucleophile in the opening of the intermediate epoxide. From 2,2,5-trimethy]-3,4-hexadienal 67, for example, five different products can be synthesized selectively under different reaction conditions (Scheme 17.22). When p-toluenesulfonic acid (TsOH) is present or DMDO is formed in situ, then the initially formed allene (mono)oxide reacts with the aldehyde moiety to give 68 or 69. In the presence of excess DMDO and the absence of acid, three other products (70-72) can be formed via the spirodioxide intermediate. These reactions, however, seem to be less general compared with similar reactions of allenyl acids and allenyl alcohols. y-Allenylaldehydes 73 can be cyclized to five-membered hemiacetals 74 via the spirodioxide intermediate. 

Scheme 2.2.7.16 Synthesis of nitrile (R)-30 through intermediate epoxide (S)-29a.

Epoxidation of dihydromyrcenol gives an intermediate epoxide that can be hydrogenated to hydroxycitronellol. Treatment of the diol with acid can also give the a-,P-citronellol and the a-citronellol can be isomerized to the P-citronellol (27) (110). The diol, hydroxycitronellol, is also useful for producing hydroxycitronellal, a lily-of-the-valley fragrance material. 

Oxidation of Other Arenes. Aromatic compounds with longer alkyl side chains can be converted to ketones or carboxylic acids. All the previously discussed reagents except Cr02Cl2 usually afford the selective formation of ketones from alkyl-substituted arenes. Oxidation with Cr02Cl2 usually gives a mixture of products. These include compounds oxidized in the P position presumably formed via an alkene intermediate or as a result of the rearrangement of an intermediate epoxide.110,705... 

Dimethylsulfonium methylide reacts smoothly with o- and p-hydroxybenzylidene ketones (208), giving 2-(o-hydroxyphenyl)- and 2-(p-hydroxyphenyl)-2,5-dihydrofurans (209). It is thought likely that the intermediate epoxide is converted to a quinone methide in which the alkoxide group is in a favourable position to add, thereby allowing ring closure to the dihydrofuran ring (Scheme 54) (79CC438). 

Eq. 012). Similarly, attempted epoxidation of 2-propony 1 -p-creeol proved lUkauecewful because the intermediate epoxide suffered ready rearrangement in the epoxidation medium, giving 2,5-dimetliyJbenxo-... 

A 1,2-diol arising from a trans-hydroxylation process is formed from an alkene by way of an intermediate epoxide which is subjected to a ring-opening reaction and hydrolysis. The epoxides may be isolated when the alkene is reacted with perbenzoic add or m-chloroperbenzoic acid (Section 4.2.56, p. 457) in a solvent such as chloroform or dichloromethane the preparation of epoxides by this method and by other important procedures are discussed and illustrated... 

The intrinsic instability of235 makes its existence difficult to prove intramolecular closure to 4-hydroxy-1-deoxyartemisinin 236 or simple aqueous hydrolysis leads to its destruction. If 235 (and related structures) were the bottleneck through which the artemisinin class exerted its antimalarial effect, then replacement of 0-13 by CH2 might give an isolable intermediate epoxide of greater stability, but also with lesser activity. 

An additional step in the radical mechanism has been suggested namely, that collapse of C-4 radical intermediate 234 to a neutral but highly reactive alkoxy-epoxide 235 occurs (Scheme 5).104 Protein alkylation then presumably occurs via 235 and not radical intermediates such as 234. Unfortunately, epoxide 235 is probably too unstable to be handled or identified. In the case of 258 however, we were granted the opportunity to test the hypothesis that an intermediate epoxide was responsible for the mode of action. Of the series of three tetracycles, 258 retained nearly two-thirds of the activity of artemisinin. The Fe(II)-induced rearrangement product 281, a quite stable epoxide was submitted for antimalarial assay and found to be completely devoid of activity. As 258 is a potent antimalarial but the epoxide 281 is not, it seems reasonable to suggest that the antimalarial activity of 258 is unrelated to epoxy intermediates. 

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