Exocyclic methylene alcohols

Cyclization, solvolytic, 54, 84 Cycloalkene oxides, 1-methyl, conversion to exocyclic methylene alcohols, 53, 20 Cyclobutadiene, generation in situ, 50, 23... 

Ethyl vinyl ether, 54, 71 Exocyclic methylene alcohols, from 1-methylcycloalkene oxides, 53, 20 Extractor, 54, 90... 

The submitters used about three molar equivalents of lithium diethylamide in about twice as much solvent. The checkers found that an amount of base slightly in excess of one molar equivalent was sufficient to convert the epoxide to exocyclic methylene alcohol of superior purity. 

Pinocarveol has been prepared by the autoxidation of a-pinene,5 by the oxidation of /S-pinene with lead tetraacetate,6 and by isomerization of a-pinene oxide with diisobutylalumi-num,7 lithium aluminum hydride,8 activated alumina,9 potassium ferf-butoxide in dimethylsulfoxide,10 and lithium diethylamide.11 The present method is preferred for the preparation of pinocarveol, since the others give mixtures of products. It also illustrates a general method for converting 1-methylcy-cloalkene oxides into the corresponding exocyclic methylene alcohols.11 The reaction is easy to perform, and the yields are generally high. 

Cydoalkene oxides, 1-methyl, conversion to exocyclic methylene alcohols, 53, 20... 

Another route to a methyl-branched derivative makes use of reductive cleavage of spiro epoxides ( ). The realization of this process was tested in the monosaccharide series. Hittig olefination of was used to form the exocyclic methylene compound 48. This sugar contains an inherent allyl alcohol fragmenC the chiral C-4 alcohol function of which should be idealy suited to determine the chirality of the epoxide to be formed by the Sharpless method. With tert-butvl hydroperoxide, titanium tetraisopropoxide and (-)-tartrate (for a "like mode" process) no reaction occured. After a number of attempts, the Sharpless method was abandoned and extended back to the well-established m-chloroperoxybenzoic acid epoxida-tion. The (3 )-epoxide was obtained stereospecifically in excellent yield (83%rT and this could be readily reduced to give the D-ribo compound 50. The exclusive formation of 49 is unexpected and may be associated with a strong ster chemical induction by the chiral centers at C-1, C-4, and C-5. 

Studies directed toward the synthesis of bicyclomycin have resulted in the discovery of efficient routes to the construction of the 2-oxa-8,10-diazabicyclo[4.2.2]decane system (160). Thus, the monolactim ether (155) with a hydroxypropyl side chain at position 3, on oxidation with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), gave the product (156) in good yield, presumably via an iminium species (Scheme 51). No trace of the spiro compound (157) could be detected in this reaction. The formation of (156) is probably kinetically controlled. Prior protection of the alcohol as a silyl ether, followed by DDQ oxidation, gave the pyrazinone (158) subsequent deprotection and acid treatment gave the thermodynamically preferred spiro compound (159). The method has been extended to the synthesis of (160), having an exocyclic methylene this compound is a key intermediate in the total synthesis of bicyclomycin [88JCS(P1)2585]. 

C is-fused tetrahydrofurans are produced when 2-cycloalkenyl-substituted ethanol derivatives are cy-clized via 5-exo ring closure (equation 14 and Table 5). The related 1-cycloalkenyl alcohol systems also yield cri-fused tetrahydrofurans upon reaction with phenylselenyl reagents, similar to their carboxylic acid analogs (see equation 12).60 A sulfoetherification to a fused ring tetrahydrofuran from a system with an exocyclic methylene provided an 86 14 ratio of cis- and frans-fused isomers.61... 

Gibberellin A5 (C H Os) has a melting point of 260-61° and forms a methyl ester (m.p. 190-91°). The infrared spectra of Nujol mulls of the acid and ester (see Table II) show the presence of alcoholic hydroxyl, hydroxyl of carboxylic acid, unconjugated five-ring lactone, carboxyl (or ester) carbonyl, exocyclic methylene group, and a cis-disubstituted double bond. Catalytic hydrogenation of the methyl ester confirmed the presence of two double bonds. 

When the propargyl phosphate 225 was heated in the presence of Pd2(DBA)3-CHCl3 and sodium acetate in THF, the central sp carbon atom of the (j-allenylpalladium complex, formed from the propargyl alcohol ester and Pd(0), was attacked by the lactam nitrogen atom to yield the carbapenam 226 with an exocyclic methylene group <2001TL4869>. 

Phenylthiomethyllithium was also used for ketone methylenation, - mainly in the case of hindered ketones which do not react with the usual Wittig reagent. This is a three-step sequence the reagent (2a) is added, then the resulting alcohol is acylated, and finally the exocyclic methylene is formed by reduction with lithium in ammonia (Scheme 17). 

In the late stages of the total synthesis of dihydroclerodin, A. Groot and co-workers used the Chugaev elimination reaction to install an exocyclic double bond on ring Before employing the xanthate ester pyrolysis, the authors tried several methods that failed to convert the primary alcohol to the exocyclic methylene functionality. The corresponding xanthate ester was prepared followed by heating to 216 °C in n-dodecane for 2 days to afford the desired alkene in 74% yield. 

The presence of an exocyclic methylene group in ignavine is indicated by the IR spectrnm (1645 and 892 cm i) and by formation of formaldehyde on ozonization. That the exocyclic methylene is involved in a secondary allylic alcohol system as in atisine was demonstrated by catalytic isomerization to a methyl ketone (1692 cm i) and by oxidation to a conjugated enone (1615, 1687 cm i) (72). 

Tricyclic ketone 215 was converted by previously reported procedures to the ketoacid 218, which was treated with methylenetriphenylphosphorane to introduce the exocyclic methylene on the D ring (219) (Scheme 25). The ester was then converted to the aldehyde (220), treated with isopropenylmagnesium bromide to yield the allylic alcohol, subjected to Claisen rearrangement with methyl or thioacetate, and the resulting aldehyde converted to the tetramethyl allylic alcohol 208 by the previously described sequence (210 — 212, Scheme 24). The polyolefinic precursor to the serratene skeleton was obtained in overall yield of 3.1% from m-methoxycinnamic acid. 

Evidently, these or closely related intermediates are accessible and reactive, since the synthesis was successfully achieved as outlined in Scheme 13.28. In addition to the key cationic cyclization in Step D, interesting transformations were carried out in Step E, where a bridgehead tertiary alcohol was reductively removed, and in Step F, where a methylene group, which was eventually reintroduced, had to be removed. The endocyclic double bond, which is strained because of its bridgehead location, was isomerized to the exocyclic position and then cleaved with Ru04/I04. The enolate of the ketone was then used to introduce the C(12) methyl group in Steps F-3 and F-4. 

The late stages of the synthesis (Scheme 1.17) proceeded with Wittig methylenation of ketone 144 with Ph3P=CH2 at 70 °C to furnish exocyclic alkene 145 in 77 % yield. Finally, the alcohol was installed via a Se02-mediated allylic hydroxylation [57] of the exocyclic alkene 145 to afford ( )-nominine (1) in 66 % and 7 1 dr. The structure of nominine (1) was verified via an X-ray crystal structure determination, thereby completing the racemic total synthesis of ( )-nominine (1). 

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