Michael reaction/ketalization

Mukaiyama reaction (Lewis acid-catalyzed Michael reaction) with electron-poor olefins, ketals and acetals, and enones 32... 

A possible biogenesis of the macroline-cabucraline dimers derives from a Michael reaction of the nucleophilic C(IO ) of cabucraline (299) with the unsaturated aldehyde 300 (which may be regarded as an opened form of talcarpine) to give an addition product 301, which on subsequent hemiketalization or ketalization furnishes the dimeric compounds 296 and 297 [83]. 

An intramolecular counterpart of the photochemical step used in the formation of (6) has been successfully applied to the synthesis of 12-epi-lycopodine (14). Photolysis of (10) yielded the intermediate (11) which was converted into the diketone (12). The latter compound gave the aldol product (13) which, in four steps, produced 12-epi-lycopodine (14). An amazing simplification of the overall route resulted when it was found that the diketolactam corresponding to the ketal (15) underwent a stereospecific Michael reaction to give (13) directly in 30% yield. 

Hydrogenation was carried out at O to minimize decarboxylation of the saturated 3-keto acid product 18. Mannich reaction proceeded with in situ decarboxylation to afford a-methylene ketone 19, which on Michael reaction with ketal 3 keto ester 20 -" yielded adduct 21. Saponification, B ring closure, and decarboxylation then led to ketalenone 23 in high yield, which was converted into ( + )-19-nortestosterone 24 and thence to ( + )-19-norandrostenedione 25 in 50% yield from 18 or 27% overall yield from 12. However, ketal hydrolysis, A ring closure, oxidation at C-17, and isomerization by the Roussel procedure (acetyl bromide-acetic anhydride in methylene chloride at 20°) should yield (-f )-estrone 26 efficiently. 

A variant in the production of an intermediate in the Robinson synthesis, the tricyclic ABC diketone (18), was developed by Banerjee and co-workers [635, 636] (Scheme 58). The triester (22) was obtained from a-ethoxycarbonylcyclohexanone (21) by the Michael reaction with methyl acrylate, alkaline cleavage, and esterification, and it was then cyclized by Dieckmann s method with subsequent bromination and dehydrogenation to give the unsaturated keto diester (23). The addition of cyanoacetic ester gave compound (26) from which the keto triester (25) was obtained by methylation, acid hydrolysis, and esterification. The latter, by Dieck-mann cyclization and hydrolysis, gave the BC fragment (24). Selective ketalization, reduction, and hydrolysis of the ketal led to the hydroxy-ketone (27). The trans-B/C linkage present in it required the protection... 

Stork and Livingston have also employed a Michael reaction methodology in a concise synthesis of alloyohimbone 247 (Scheme 3.37). In this sequence, the Schilf base 243, prepared from tryptamine and 4-methoxybenzaldehyde, underwent sequential Birch reduction and acylation to afford the cyclo-hexadiene 244. Hydrolysis provided the corresponding a, ) -unsaturated ketone. Under basic conditions, the key Michael addition took place to yield the cis-fused bicyclic lactam 245. Decarboxylation and ketalization afforded 246 which underwent Bischler-Napieralski cyclization and subsequent deke-talization to afford alloyohimbone 247. All in all. Stork has shown that Michael addition methodologies can be successfully employed to construct the pentacyclic yohimbine alkaloid skeleton in an eflBcient stereoselective manner. 

The mercaptol alcohol rac-14 undergoes facile Michael addition reaction with quinone ketal 13 which is commercially available or can be readily prepared. 

An interesting use of the nickel-catalyzed allylic alkylation has prochiral allylic ketals as substrate (Scheme 8E.47) [206]. In contrast to the previous kinetic-resolution process, the enantioselectivity achieved in the ionization step is directly reflected in the stereochemical outcome of the reaction. Thus, the commonly observed variation of the enantioselectivity with respect to the structure of the nucleophile is avoided in this type of reaction. Depending on the method of isolation, the regio- and enantioselective substitution gives an asymmetric Michael adduct or an enol ether in quite good enantioselectivity to provide further synthetic flexibility. 

Another concise route to 107 featured the facile construction of the cyclohexanone derivative 109 via the Michael addition of triply deprotonated methyl dioxohexanoate to the nitrostyrene (108 (Scheme 9) (115). Ketalization of 109 followed by hydrogenation of the nitro function and then cyclization of the resulting amino ester by thermolysis in refluxing xylene furnished the lactam 110, which was reduced LiAlH4 to the amine 111. All attempts to cyclize 111 via a Pictet-Spengler reaction led to complex mixtures of products. However, when the unstable enone 112, which was obtained by acid-catalyzed hydrolysis of 111,... 

In the lactone acylations discussed above, there was never any evidence for a competing side reaction due to break down of the hemiketal moiety and Michael addition of the alcohol to the newly formed pro-pargylic ketone. This may be taken as filler evidence for the stability of the ketal-alkoxide intermediate however, hemiketal ring opening and intramolecular Michael addition would provide an... 

At 0.8 GPa pressure and in the presence of trimethyl orthoformate as water scavenger, various saturated cyclic and acyclic ketones 177 were converted nearly quantitatively into the corresponding dimethyl ketals 178 under essentially neutral conditions. Under the same reaction conditions, several a, 3-unsaturated cyclic and acyclic ketones 179 have given the oxy-Michael/ ketal derivatives 180 in good to excellent yields (Scheme 7.45). 

Unless otherwise noted, the reaction was carried out using 1.0 mmol of Michael acceptors and donors (1 1) in 1.0 mL of solvent. The molar ratio of acceptor donor ruthenium is 50 50 1 (S/C = 50). Isolated yield after flash chromatography on the silica gel. Determined by HPLC analysis. dS/C = 100. eNot determined. -Determined by 13C NMR of the ketals derived from the products and (2R,3 )-butanediol. 

Chiral iy -2,3-disubstituted 2,3-dihydro-l,4-benzoxathiins 73 are available from the reaction of enantio-enriched mercaptoethanols with quinone ketals. An initial Michael addition is followed by cyclisation and aromatisation <04TL5429>. 

The steroidal a-(isocyanomethyl)phosphonates (130) and (133) have been synthesized by methylation of the carbanions (129) and (132), respectively.66 Compounds (130) and (133) behave as N,P-ketals in that they can be hydrolysed to the corresponding ketones (131) and (134) (Scheme 10). A range of a-substituted a-aminophosphonic acids (136) have been prepared in moderate to excellent yield by the alkylation of the protected a-aminophosphonate (135) with alkyl and aryl halides and Michael acceptors under phase transfer catalysis (Scheme 11).67 The reactions of the lithium carbanion of diethyl prop-2-enyIphosphonate (137) with a,P-unsaturated ketones and esters have been investigated.6S Attack can be at the a- or y-positions in the phosphonate although in all cases Michael addition to the a, p-unsaturated carbonyl is preferred to attack at carbonyl carbon. In some examples simple adducts (138) are formed, but in more complex cases addition is followed by cyclisation to give (139) (Scheme 12). The bisphosphonate (141), which is a potent inhibitor of myo-inositol monophosphatase, has been prepared with the phosphonylation of the carbanion of (140) as a key step.6 9... 

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