Vinyl ethers oxidative cyclization

Radical cyclization of polyfunctional 5-hexenyl halides mediated by Et2Zn and catalyzed by nickel or palladium salts has been demonstrated to produce stereoselectively polyfunctional 5-membered carbo- and heterocycles [56, 57]. Based on this strategy a formal synthesis of methylenolactocin (11) was achieved (Scheme 20). The acetal 130, readily being built up by asymmetric alkylation of aldehyde 127 followed by reaction with butyl vinyl ether and NBS, served as the key intermediate for the construction of the lactone ring. Nickel(II)-catalyzed carbometallation was initiated with diethylzinc to yield exclusively the frans-disubstituted lactol 132, which could be oxidized directly by air to 134. Final oxidation under more forcing conditions then yielded the lactone (-)-75 as a known intermediate in the synthesis of (-)-methylenolactocin (11) [47aj. 

Beckwith has observed moderate diastereoselectivity in this reaction involving cyclic systems. The cyclizations of allyl and homoallyloxycarbonyloxy radicals are potentially useful as radical based alternatives for an overall oxidation or hydrolysis of a double bond, and also various further transformations of the cyclic carbonates can lead to synthetically useful products.62b In contrast, simple alkoxycarbonyloxy radicals 91a add intermolecularly to ethyl vinyl ether to give, ultimately, carbonates of glycoaldehyde derivatives 91b, Scheme 37.62a... 

When the anisolium complex generated by the addition of MVK to the 2-methoxytetra-hydronaphthalene complex 59 is utilized in the above cyclization sequence, the tricyclic oxonium complex 61 is generated (Scheme 6). Deprotonation of 59 with pyridine forms the extended vinyl ether complex 60, which cydizes and eliminates water to form 61 when exposed to TBSOTf. Hydrolysis of 61, followed by oxidation of the metal fragment, yields the dienone 62 in 15 % yield (based on 59). 

R)-(-)-2,2-Diphenylcyclopentanol (1) is a highly effective chiral auxiliary in asymmetric synthesis. Hydrogenation of chiral 0-acetamidocrotonates derived from this alcohol has afforded the corresponding 0-amido esters with high diastereoselectivity (96% de).6 In addition, (R)-1 has been used as a chiral auxiliary in Mn(lll)-based oxidative free-radical cyclizations to provide diastereomerically enriched cycloalkanones (60% de).7 Our interest in (R)-(-)-2,2-diphenylcyclopentanol is its utility as a chiral auxiliary in Lewis acid-promoted, asymmetric nitroalkene [4+2] cycloadditions. The 2-(acetoxy)vinyl ether derived from alcohol (R)-1 is useful for the asymmetric synthesis of 3-hydroxy-4-substituted pyrrolidines from nitroalkenes (96% ee).8 In a similar fashion, a number of enantiomerically enriched (71-97% ee) N-protected, 3-substituted pyrrolidines have been prepared in two steps from 2-substituted 1-nitroalkenes and (R)-2,2-diphenyl-1-ethenoxycyclopentane (2) (see Table).9... 

Cyclization of vinyl ether epoxides, Epoxy dihydropyranes undergo cyclization in the presence of Lewis acids. Thus treatment of 1 with basic alumina affords 2 in almost quantitative yield. The product can be converted into the keto aldehyde 5 by treatment with a mineral acid followed by oxidation. Another useful reaction of 2 is conversion to the keto lactone 3 by singlet oxygen. 

The ubiquitous and reversible formation of radical cations in photoelectrochemical transformations allows pericyclic reactions to take place upon photocatalytic activation since the barriers for pericyclic reactions are often lower in the singly oxidized product than in the neutral precursor. For example, ring openings on irradiated CdS suspensions are known in strained saturated hydrocarbons [176], and formal [2 -I- 2] cycloadditions have been described for phenyl vinyl ether [ 177] and A-vinyl carbazole [178]. The cyclization of nonconjugated dienes, such as norbomadiene, have also been reported [179]. A recent example involves a 1,3-sigmatropic shift [180]. 

More original is the Claisen rearrangement of the vinyl ether of alcohol 927 (made by Grignard addition of isobutenylmagnesium chloride to 2-butenal), which yielded 58% of the aldehyde 928, needing only reduction to the alcohol before acid cyclization to iso-rose oxide (929) and rose oxide (909). ° ... 

A different bond-forming reaction is operative in the synthesis of the 3-formyl-2-methyl-l,3-oxazines (364) from 3-aminopropyl vinyl ethers (363), which cyclize when reacted with chloral hydrate (Scheme 99) <86ZORi556>. A novel synthesis of 5-oxa-l-azabicyclo[4.4.0]decane (366) relies upon the photosensitized single-electron oxidation of A-(3-hydroxypropyl)piperidine (365) in the presence of 1,4-dicyanonaphthalene (Equation (43)) <88TL4153>. 

Enantiomerically pure samples of / -vinyI- -butyrolactone (98) were prepared starting from the diastereomerically pure bromoacetal 96 (obtained by separation of the 1 1 mixture of products from the corresponding vinyl ether, 1,2-butadiene-4-ol, and NBS) via purification of the major cyclization product 97. The bromoacetal obtained from 1-ethoxypropene was used in an approach to the dihydroagarofuran framework [66]. Bridged pyranosides were synthesized from cyclic iodoacetals [67]. Bicyclic acetals may be prepared with relative ease epialboatrin (100) was synthesized via a successful hypophosphite-mediated radical cyclization of the cyclic bromohydrin 99 [68] (Scheme 35). In one of the early examples reported by Ueno, bromoacetals obtained from butoxyallene, allylic alcohols, and NBS underwent efficient radical cyclization reactions providing easy access to a-methylene-y-butyrolactones after Jones oxidation [69]. 

Fig. (13) The ketoacetonide on allylation afforded the product (149) which on oxidation give the product (150) which on cyclization affords the ketone (151). The alcohol (152) obtained from (151) is converted to its vinyl ether (153), which undergoes to Claisen rearrangement yielding the unsaturated aldehyde (154). It is converted to alcohol (155) whose tosylate (156) on treatment with CoUmanis reagent furnished the ketoacetonide (145) whose transformation to aphidicolin (148) has already been described.

Alkylation of the enolate of (138) with methallyliodide gave the product (149) whose stereochemistry was assigned on the basis of equilibration experiment. It was converted to the dione (150) by oxidation with osmium tetrooxide and sodiumperiodate. The aldol cyclization of (150) effected with sodium hydride and trace of t-amyl alcohol in refluxing benzene afforded the enone (151) in 88% yield. Normal protic conditions (sodium hydroxide, ethanol) were not effective in this transformation. All attempts for its conversion to aphidicolin (148) by intermolecular additions proved fruitless and therefore were turned to intramolecular methods. Molecular models show clearly that the top face of the carbonyl group is less hindered to nucleophilic attack than is the bottom face. Thus the reduction of (151) with lithium aluminium hydride afforded the alcohol (152) whose vinyl ether (153) was subjected to pyrolysis for 2 hr at 360 C in toluene solution containing a small amount of sodium t-pentoxide to obtain the aldehyde (154) in 69% yield. Reduction and then tosylation afforded the alcohol (155) and tosylate (156) respectively. Treatment of this tosylate with Collman s reagent [67] (a reaction that failed in the model system) afforded the already reported ketoacetonide (145) whose conversion to aphidicolin (148) has been described in "Fig (12)". 

The projected free radical cyclization proceeded as planned to give 172. Ozonolysis of the vinyl group, oxidation of the resulting aldehyde to an acid, and alkylation with diazomethane provided projected intermediate 162. Reduction of the lactone provided 173. Treatment of 173 with 6-methoxytryptamine and pivalic acid then provided a nearly equal mixture of lactams 174 (isoreserpine stereochemistry at Cg) and 175 (reserpine stereochemistry at C3). The correct C3 stereoisomer was moved forward to 176 (protection of the tertiary alcohol followed by reduction of the lactam). The silyl ethers were removed, the secondary ether was re-protected, and reaction with samarium iodide accomplished reduction of the a-hydroxy ester to provide 177. Removal of the TBS group and esterification of the alcohol completed the synthesis of reserpine. 

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