Ketal Claisen reaction

A very elegant stereoselective synthesis of juvenile hormone has been achieved by Johnson and co-workers,who employed the olefinic ketal Claisen reaction to great advantage. Thus, the hydroxy-ester (15), on treatment with the olefin-ketal (16) in acidic medium was converted into the ester (17). Sodium borohydride reduction to the corresponding allylic alcohol and a second Claisen-reduction sequence as described above yielded the trienol-ester (18). Chlorination under Sni conditions and selective reduction of the resultant primary allylic chloride produced the well-known triene-ester (19) which was converted to juvenile hormone (11). 

A soln. of the startg. m. and 4 equivalents ketal heated ca. 8 hrs. at 100° in toluene containing 2,4-dinitrophenol as catalyst, and the intermediate ketone treated at 0° with NaBH4 in methanol > product. Y up to 81% purity 98%. -This olefinic ketal Claisen reaction is useful for preparing trans-disubst as well as trans-trisubst. olefinic bonds. The above producure is the last of a succession of 3 similar steps. F. e. and catalysts s. W. S. Johnson et al., Am. Soc. 92, 4463 (1970) Proc. Natl. Acad. Sci. U.S. 67, 1462, 1465, 1810, 1824 (1970) geospecific synthesis of ethylene derivs., review, s. J. Reucroft and P. G. Sammes, Quart. Rev. 25,135 (1971). 

Ozonolysis of diketone carbonate 417 in methanol afforded an almost quantitative yield of the bicyclic diene triketone hydroxy-ester 418 (119). This remarkable transformation can also be readily explained. Ozonolysis of 417 produces the tetraketone intermediate 419 followed by methanol addition to produce the hemi-ketal 420 which undergoes a retro-Claisen reaction to 421. Then, loss of carbon dioxide from 421 yields 418. Again, 420 could also undergo a Grob type fragmentation to yield 418 directly. 

Diethyl acetals and ketals. Claisen showed that triethyl orthoformate reacts with aldehydes and ketones to form diethyl acetals and diethyl ketals. The reaction... 

Two moles of this ketone (K) were then condensed by Claisen reaction in 5% ethanolic potassium hydroxide with crocetindial (ref.52) and the terminal ketal groups in the product then removed by refluxing with acetone containing 4-toluenesulphonic acid. The resultant... 

Ethylene ketals. The exchange reaction between dialkyl acetals or dialkyl ketals and 1,2-glycols as a route to cyclic acetals and ketals was first described by Delepine. This method in combination with Claisen s orthoester ketalization procedure (1, 1206) constitutes a convenient route to ethylene ketals (1, 376). The mixed orthoester 1 is probably the actual reagent involved in the Delepine method. It is convenient to prepare and use for ketalization of carbonyl compounds under mild conditions. A striking example is the ready conversion of the acid-sensitive 2 into 3, a reaction that proceeds by other known methods in yields of only 30%. 

Ketals are converted to allyl vinyl ethers after Wittig olefination [14]. Wittig reactions permit the incorporation of various substituents into the allyhc terminal of the ether. Enol ethers have been conveniently prepared by cleavage of acetals with various Lewis acids. Cleavage of the ketals with the Lewis acid, for example, triethylsilyl triflate, in the presence of diisopropylethylamine in refluxing 1,2-di-chloroethane afforded the enol ethers (Eq. 3.1.9). The resulting enol ethers were then heated to effect the Claisen rearrangement without isolation. 

An electrochemical oxidative decarboxylation in combination with an ester enolate Claisen rearrangement was reported by Wuts et al. (Scheme 5.2.26) [51]. A variety of allylic esters such as 97 was subjected to an Ireland-Qaisen rearrangement, and the resulting acids (98) obtained were submitted to electrolytic decarboxylation in a divided cell to afford ketals 99. The use of the divided cell was necessary to suppress side reactions such as alkene reduction. 

The Claisen rearrangement of vinyl allyl ethers is a powerful reaction for the preparation of yS-unsaturated carbonyl compounds. The regioselectivity of the ketal version of this reaction has been studied, the results aiding the understanding and prediction of products formed from ketals of unsymmetrical ketones [equation (34)]. The allyl vinyl ether may also be formed by proto-... 

Similar to the mechanism described in Scheme 2.16, a Knoevenagel reac-tion/ketalization cascade of hydroxyacetone with 1,3-dicarbonyl compounds is assumed. In Scheme 2.16, a Knoevenagel condensation/ketalization reaction is depicted. This sequence allows a subsequent oxa-Michael addition, which yields the corresponding C-glycosides. In contrast, a Knoevenagel addition/ketalization occurs under the reaction condition described in Scheme 2.28, which is followed by an intramolecular retro-Claisen step. As a result of that, the corresponding esters were obtained (Scheme 2.29). 

This transformation was successfully extended to reactions of unprotected dihy-droxyacetone 141 with acetylacetone 5 or benzoylacetone 138. The expected products derived from a Knoevenagel/ketalization/retro-Claisen cascade were isolated in high yields (Scheme 2.30). 

To explain the high selectivity, which is detected in these cascade reactions, the possible products and reaction paths for reaction with L-erythrulose 146 and acety-lacetone 5 are depicted in Scheme 2.32. The stereoselective Knoevenagel addition to intermediate Q is favored and determines simultaneously the configuration of the tertiary alcohol. A subsequent ketalization step to ketone S followed by the final intramolecular retro-Claisen step yields the isolated product 147 as a single stereoisomer. 

In the amine-catalyzed reactions, a Knoevenagel addition/ketalization/ intramolecular retro-Claisen cascade is detected (Scheme 2.32). The retro-Claisen step is enabled by the ketalization of the Knoevenagel addition product Q. The ketalization of the Knoevenagel product (Q S) is initiated by the hydroxyl groups of the carbohydrate moiety, as in-house NMR-experiments suggest (formation of intermediate ketal structure K in Knoevenagel condensation/ketalization/oxa-Michael cascade reaction Scheme 2.16). Products derived from this reaction sequence (Scheme 2.16)... 

Model studies have demonstrated that the approach of Mariano and his coworkers does indeed permit rapid construction of the pentacyclic yohimbine skeleton (Scheme 129) (41, 42). For example, Diels-Alder reaction of dihydropyridine 193 with methyl vinyl ketone (194) afforded isoquinuclidene 195 which was sequentially ketalized, the nitrogen deprotected, and trypto-phylated to yield the model substrate 196. Treatment of 196 with t-butyl propiolate effected the crucial zwitterionic amino-Claisen rearrangement to efficiently provide the hexahydroisoquinoline 197 having the crucial cis-DE-ring fusion in place. Treatment of 197 under the Wenkert cyclization condi-... 

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