Conversion to enol ethers

Finally, production of tricyclic array 153 (Scheme 24) required cyclization of bicyclic ester 151 in which additional oxygenation was present in the olefinic appendage. The successful conversion to enol ether 152 demonstrated further the power of the method and led to the JKF fragment 153 [34b]. 

Allyl ethers can be removed by conversion to propenyl ethers, followed by acidic hydrolysis of the resulting enol ether. 

The efficacy of the procedure for the synthesis of highly complex systems, and the utility of the enol ether functionality obtained in the reaction is demonstrated by the conversion of the intricate polyether 134 to enol ether 135 and its subsequent elaboration to the hexacyclic system 138 (Scheme 20) [34a]. 

Conversion of Carboxylic Esters to Enol Ethers Methylene-de-oxo-bisubstitution... 

Particularly useful for conversion of lactones and esters to enol ethers... 

Like enamines, dihalocarbenes add smoothly to enol ethers and in many cases it is possible to isolate the dihalocyclopropyl intermediates which are valuable synthons for chloroenones (cf. Section 4.7.3.7.1). The earliest example of the addition of a dihalocarbene to an enol ether was provided by Parham,6,79 who studied the addition of dichlorocaibene to dihydropyran (equation 22). An example which illustrates the synthetic potential of the process is the conversion of the cyclohexanone enol ether (6) to the dichlorocy-clopropane (7 equation 23).80 The latter served as a useful intermediate in a stereospecific synthesis of Prelog-Djerassi lactonic acid. 

The conversion of enol ether 80 to cyclic ketal 83 in water in 12% yield exemplifies the chemoselectivity possible with 14D9.79 Although 83 is the normal product of the acid-catalyzed hydrolysis of 80 in organic solvents, it is never observed in water because the highly reactive oxocarbenium intermediate is rapidly trapped by the solvent to give ketone 82 (via hemiacetal 81) as the sole product. The ability of the antibody to protect the reactive oxonium ion intermediate from hydrolysis and partition it toward a product that is not typically observed under these conditions (i.e., 83) mimics the capabilities of rather sophisticated enzymes. Extension to other reactions involving reactive, water-incompatible intermediates can be easily imagined. 

In the present context, the term electron rich alkenes refers primarily to enol ethers, enol sulfides, and A-vinylamides or A-vinylamines. Such alkenes are typically much more readily ionizable than are simple alkenes. The conversion of these substrates to the corresponding (highly electron deficient) cation radicals represents a sharp Umpolung. The Diels-Alder additions of tra j -anethole, phenyl vinyl ether, phenyl vinyl sulfide, 1,3-dioxole, and A-methylindole to 1,3-cyclohexadiene have been reported (Scheme 22) [49, 52]. 

Ketones and aldehydes can also be converted to enol ethers if, after the loss of H2O, the carbocation fragments with loss of H+ to give the alkene. Because enol ethers are extremely reactive toward H+, they are usually isolated only when the double bond is conjugated to an electron-withdrawing group, as in the conversion of /3-diketones to vinylogous esters. 

Deoxyloganin (24) has previously been synthesized by Tietze and coworkers, utilizing an intramolecular hetero-Diels-Alder reaction to construct the iridoid core (Scheme 10). The synthesis commenced with conversion of (5)-citronellal (47) to enol ether 48 in seven steps. Knoevenagel condensation of the aldehyde with Meldrum s acid, followed by in situ intramolecular hetero-Diels-Alder reaction afforded pyran 49, with all the carbons required for the natural product core installed. Conversion of 49a, via methanolysis and a reduction/elimination sequence, to lactol acetate 50, was achieved in four steps. Finally, glycosylation and deprotection provided the natural product in a total of 14 steps. 

Syntheses of 5,6- and Other Unsaturated Cyclic Compounds - A general approach to enol ethers, illustrated by conversion of nitro-alkene 37 into 38 by treatment with tetrabutylammonium hydrogen sulfate-potassium fluoride, has been described. The reaction was also found to be applicable to a wide range of acyclic sugars (see Section 4 below). 

As noted in Section 2.5 above, a general approach to enol ethers from nitro-alkenes, as depicted by the conversion of 37 into 38, has also been applied to the preparation of a range of acyclic derivatives. Here, the pyranose rings (of 37 and 38) were replaced with various benzyl or cyclohexylidene protected L-glycero-... 

To avoid oligomer formation, Roberts and Rainier utilized an internal rather than a terminal olefin as a precursor to the cychzation reaction (Scheme 3.57) [62]. To this goal, internal olefin 303 was synthesized and subjected to enol ether formation but with the titanium efhylidene rather than the methylidene reagent for the acyclic enol ether forming reaction. Surprisingly, this relatively minor modification resulted in the conversion of 303 into cyclic enol ether 300 [63]. No acyclic enol ether was observed. The authors argued that the relatively moderate yield was due to the instability of the products and was not necessarily a result of an inefficient reaction. 

The most recent, and probably most elegant, process for the asymmetric synthesis of (+)-estrone appHes a tandem Claisen rearrangement and intramolecular ene-reaction (Eig. 23). StereochemicaHy pure (185) is synthesized from (2R)-l,2-0-isopropyhdene-3-butanone in an overall yield of 86% in four chemical steps. Heating a toluene solution of (185), enol ether (187), and 2,6-dimethylphenol to 180°C in a sealed tube for 60 h produces (190) in 76% yield after purification. Ozonolysis of (190) followed by base-catalyzed epimerization of the C8a-hydrogen to a C8P-hydrogen (again similar to conversion of (175) to (176)) produces (184) in 46% yield from (190). Aldehyde (184) was converted to 9,11-dehydroestrone methyl ether (177) as discussed above. The overall yield of 9,11-dehydroestrone methyl ether (177) was 17% in five steps from 6-methoxy-l-tetralone (186) and (185) (201). 

By using the directed aldol reaction, unsymmetrical ketones can be made to react regioselectively. After conversion into an appropriate enol derivative (e.g. trimethylsilyl enol ether 8) the ketone reacts at the desired a-carbon. 

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