Exocyclic double bond epoxidation

His approach was to remove both epoxides to leave alkene and ketone and to mask the exocyclic double bond and the original ketone-giving intermediate (64) - so... 

The key intermediate in Tobe et al. s synthesis of (+)-marasmic acid (27), 1-oxa-spirohexane (26), was accessed via a photocycloaddition between enone 24 and 1 (Scheme 19.6) [8], The photocydoadduct 25 was obtained in 73% yield with the desired isomer consisting of 91% of the material. The structure of the minor product obtained from this cycloaddition was not confirmed. Reduction of the carbonyl group of 25 and epoxidation of the exocyclic double bond gave 26. An acid-catalyzed rearrangement of 26 afforded the core structure of marasmic acid and was subsequently taken on to complete the synthesis of this natural product. 

Oxidation of a methylenecycloproparene gives products of exocyclic double bond cleavage140. Epoxidation has been performed with /w-chloroperoxybenzoic acid and 2-hydroxyethanones result (equation 37). The choice of reagent ensured that oxaspiropen-... 

Once the two TBS protecting groups have been removed with hydrofluoric acid as a source ot fluoride, the epoxide at C l 2 is constructed as the last step ot the overall synthesis. For this purpose di methyldioxirane (63> is utilized. It is conceivable that epoxidation could also have occurred at the exocyclic double bond at C 16, or that attack by the dimethyldioxirane could have taken place from the top face of the macrocycle. Schinzrr obtained the desired natural product (-)-epothilone A (la) in 48S yield 1. I IF, CH,CN/Et20. RT. 65f. ... 

R)-lrans-Verbenol (77) is epoxidized five times as fast as (S)-/rarcs-verbenol when (+)-DlPT is used in the catalyst [77]. For allylic alcohols with an exocyclic double bond, kinetic resolution gives 2-methylenecyclohexanol (78) with 80% ee in 46% yield when (-)-DIPT is used [119]. 

The majority of this work is confined to the synthesis of the epoxy derivatives of natural terpenes bearing an exocyclic double bond (see table overleaf). The stereochemical course of the reaction is governed by the factors discussed in Section 4.5.1.3.1. Umbellulone 1 was smoothly converted under typical Weitz-Scheffer conditions to a single epoxyumbellulone 233. (+)-Pulegone 3 gave a mixture of cis- and /ram-epoxides in a ratio 64.5 35.5, while piperitenone oxide 6 yielded piperitenone dioxide 7 as the sole product34,35. Epoxidation of pinocarvone 8... 

As shown in Section 4.5.1.3.2.2.1., epoxidation of the exocyclic conjugated double bond in terpenes usually leads to a mixture of diastereomeric epoxides. The situation changes when one moves to terpenes with endocyclic conjugated double bonds. Epoxidation of this class of compounds has been thoroughly studied35 40-42, and it has been shown that such epoxidation, under Weitz-Scheffer conditions, is stereospecific, resulting in the formation of a single epoxide 1-89 and 942. 

These compounds are conveniently obtained by epoxidation of the exocyclic double bond in the sugar skeleton. Such oxidation with m-chloroperbenzoic acid (MCPBA) usually proceeds with moderate selectivity. Treatment of homologated galactose 73 with MCPBA afforded both epoxides 74 and 75 in a 3 1 ratio these compounds are synthons for the preparation of antibiotic olguinine (O Scheme 22) [1]. 

Upon epoxidation with peracids, alkylidenecycloproparenes react at the exocyclic double bond and are converted to hydroxy ketones 15. Epoxidation of l-(diphenylmethylene)cyclo-propa[6]naphthalene with dimethyldioxirane at — 18 "C afforded the epoxide, 3, 3 -diphenyl-spiro l//-cyclopropa[2ft]naphthalene-l,2 -oxirane (16), which was characterized by H and CNMR. This is the first oxaspiropentene ever characterized. Under non-acidic conditions rearrangement of the epoxide 16 to 2,2-diphenylcyclobuta[6]naphthalen-l(2//)-one (17) occurred in 86% overall yield. 

As was described above (see page 16), K. Wada et al. [59] have isolated the epimeric alcohols (87) and (88) from the culture filtrate of fungus Aspergillus oryzae and have established their structures and relative configurations, but their absolute configurations remained unknown. Later on, Brazilian chemists [68] accomplished the synthesis of alcohols having the structures (80) and (89) from the manool (4). The latter was epoxidised selectively at exocyclic double bond, and the mixture of epoxides (90) and... 

A single-step benzoylation-oximation has been described on 4-hydroxy-coumarin by the use of PhCCl=NOH and EtjN in boiling methanol. When 7-methoxy-8-prenylcoumarin (osthol) or its epoxide was treated with various Lewis acids, several products were obtained. These resulted from migration or disappearance of the exocyclic double bond, abnormal Friedel-Crafts phenyl-ation, hydration, cyclization, or demethylation. A novel ring-opening of coumarins was effected by treatment with alkyl halides and NaH in THF. The c/5-o-alkoxycinnamic acid was obtained mainly or exclusively. 

Caryophyllane-2,6-a- and -P-oxides have been prepared from (— )-isocaryophyll-ene. Intramolecular epoxide opening has been studied for seven diols prepared by oxidation of the exocyclic double-bond of caryophyllene and isocaryophyllene epoxides. ... 

Wiesner carried out pioneering studies on the photocycloaddtion of vinylogous imides in the 1960s, and he first applied the intramolecular photochemical [2 + 2] enone-olefin cycloaddition reaction in natural product synthesis. In his landmark synthesis of 12-e/>i-lycopodine, compound 186 is irradiated to give a 70% yield of photoadduct 187. Protection of the ketone, epoxidation of the exocyclic double bond, and reduction of the epoxide give ketal alcohol 188. Deprotection of the ketal and spontaneous refro-aldol fragmentation lead to the diketone 190. Of note is that the bond cleaved in this retro-a do pathway (i.e., 189 to 190) is different from that of typical de Mayo reactions. Diketone 190 transforms to the tetracyclic alcohol 191 via aldol reaction, and this alcohol is converted to 12-e/7/-lycopodine in four steps. 

This endeavor called for a stereoselective a-epoxidation of the exocyclic double bond in lactone 11. A first test with m-chloroperoxybenzoic acid provided a 5 1 mixture of two epoxides, with unfortunately only the minor one representing the configuration of the natural product 14. 

In the third sequence, the diastereomer with a /i-epoxide at the C2-C3 site was targeted (compound 1, Scheme 6). As we have seen, intermediate 11 is not a viable starting substrate to achieve this objective because it rests comfortably in a conformation that enforces a peripheral attack by an oxidant to give the undesired C2-C3 epoxide (Scheme 4). If, on the other hand, the exocyclic methylene at C-5 was to be introduced before the oxidation reaction, then given the known preference for an s-trans diene conformation, conformer 18a (Scheme 6) would be more populated at equilibrium. The A2 3 olefin diastereoface that is interior and hindered in the context of 18b is exterior and accessible in 18a. Subjection of intermediate 11 to the established three-step olefination sequence gives intermediate 18 in 54% overall yield. On the basis of the rationale put forth above, 18 should exist mainly in conformation 18a. Selective epoxidation of the C2-C3 enone double bond with potassium tm-butylperoxide furnishes a 4 1 mixture of diastereomeric epoxides favoring the desired isomer 19 19 arises from a peripheral attack on the enone double bond by er/-butylper-oxide, and it is easily purified by crystallization. A second peripheral attack on the ketone function of 19 by dimethylsulfonium methylide gives intermediate 20 exclusively, in a yield of 69%. 

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