Enol ethers, hydrolysis

An interesting synthesis of enantiopure cu-decahydroquinolines, which involves enol ether hydrolysis, double bond isomerization, and intramolecular 1,4-addition of an amino group across a cyclohexenone has been reported <06T9166>. The process is stereoselective, with the exclusive formation of both cu-isomers 176 (43% over 3 steps) and 177 (17% over 3 steps) of the decahydroquinoline ring. 

Step 2 Mild acid catalyzes the enol ether hydrolysis without subsequent 3, y to a, (3 alkene isomerization. 

On the other hand, in view of important analogies in kinetic behaviour between enol ketonisation and enol ether hydrolysis, the HA [HA,] terms cannot correspond to a concerted mechanism. Lienhard and Wang (1969) and this author (Dubois and Toullec, 1969b Toullec and Dubois, 1974) have pointed out that the rate-limiting step of enol ketonisation is closely similar to that of enol ether hydrolysis if the two-step mechanism for acid-catalysed enolisation is valid. The two reactions occur by rate-limiting proton transfer to the double bond with formation of either a hydroxycarbenium ion (19) or an alkoxycarbenium ion (20). However, in the latter reaction, in contrast to the... 

Recent data from Tidwell and coworkers (Koshy et al., 1979) made it possible to estimate the ratio between enol ketonisation and enol ether hydrolysis rate constants. It was observed that when the rate constant for hydronium-promoted protonation of the double bond in X—CH=CH2 are... 

Protonation and hydrolysis of the extended enol ether to release the enone may occur during work-up and the stable enone is the first compound that can be isolated. The 50% yield of this compound represents a much better yield in four steps fragmentation, olefin cyclization, addition of formic acid, and enol ether hydrolysis. 

To obviate 0-alkylation, the readily accessible l,5-dimethoxy-l,4-cyclohexa-diene surrogate derived from Birch reduction of 1,3-dimethoxybenzene can be used. Enol ether hydrolysis affords the alkylated 1,3-cyclohexadiones in excellent yields. " ... 

Why must the diketone tautomerize to the keto-enol before the addition of EtOH can occur By the principle of microscopic reversibility, both enol ether formation and enol ether hydrolysis must proceed by the same sequence of steps (only in reverse of one another). Protonation of the enol ether, the first step in its hydrolysis, would certainly occur on the carbonyl O, not on C, so enol ether formation must proceed through the same intermediate. 

EtOH, RhCli, reflux, 86% yield. Cleavage proceeds by isomerization and enol ether hydrolysis. See the section on alkyl allyl ether cleavage for other methods to perform the isomerization. 

We pointed out in chapter 27 that Schultz s asymmetric Birch reduction can be developed with iodolactonisation to remove the chiral auxiliary and set up new chiral centres. Now we shall see how he applied that method to alkaloid synthesis.1 The first reaction is the same as in chapter 27 but the alkyl halide is now specified this gave diastereomerically pure acetate in 96% yield and hydrolysis gave the alcohol 4. Mitsunobu conversion of OH to azide and enol ether hydrolysis gave 5, the substrate for the iodolactonisation. Iodolactonisation not only introduces two new chiral centres but cleaves the chiral auxiliary, as described in chapter 27. Reduction of the azide 6 to the amine with Ph3P leads to the imine 7 by spontaneous ring closure. 

If the retrosynthesis follows route I (addition of water to the fiiran C-2/C-3 bond followed by bond opening O/C-2, i.e. an enol ether hydrolysis according to steps a-c), then the 1,4-dicarbonyl system 8 is obtained as the first suggested educt. Starting from 8, the fiiran system should be formed by a cyclic dehydration. Further retroanalysis of 8 leads via f to the ar-halocarbonyl compound 10 and to the enolate of the carbonyl compound 11. The latter should be convertible into the 1,4-dicarbonyl system 8 by alkylation with 10. 

The first industrial synthesis of ) -carotene by Hoffmann-La Roche followed the Ci9 + C2 + Ci9 principle. With the Ci4-aldehyde from the Vitamin A synthesis as the starting point, the sequence of acetal formation, Lewis acid-catalysed insertion of an enol ether, hydrolysis and elimination of ethanol, produces initially a Cjg-aldehyde. Repetition of this sequence with ethyl 1-propenyl ether gives the Cjg-aldehyde. 

Danishefsky also investigated the development of a trans Diels-Alder reaction in seeming violation of the inherent stereoselectivity of the reaction mechanism. The key to this process was the use of 1-nitrocyclohexene (80) as the dienophile. After a standard intermolecular Diels-Alder reaction with diene 79, cis cycloadduct 81 could be transformed preferentially into trans-fused product 82 upon radical denitration and enol ether hydrolysis. ... 

This transformation, referred to as the 2-oxonia-Cope/Prins cascade has been successfully utilized to prepare, quite efficiently, the C18-C25 segment of lasonolide a sponge metabolite with potent activity against A-549 human lung carcinoma. In contrast to the previous example, the resulting oxocarbenium generated from the oxonia-Cope rearrangement of 188 is trapped by the enol ether, hydrolysis of whieh results in ketone 189. 

According to route I (addition of water to the furan C-2/C-3 bond followed by disconnection O/C-2, that is, an enol ether hydrolysis according to steps a-c), the... 

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