Reaction ketal hydrolysis

In acid solution, the double bond of (203) is hydrogenated to the trans-fused sulfone (204). Presumably, this hydrogenation goes through a cis-fused intermediate that is rapidly epimerized to (204) under the acidic conditions of the reaction. Condensation of the sodium salt of 7,7-ethylenedioxy-3-oxooctanoate (205) with (204) produces (206). Cmde (206) is cyclized, hydroly2ed, and decarboxylated, producing the tricycHc compound (207). Hydrogenation of (207) followed by ketal hydrolysis and cyclization affords (208) in an overall yield of 35% from hydrindandione (203). 

Formation of hemiacetals and acetals, as well as of hemiketals and ketals, is reversible under acidic conditions, as we already have noted for acid-catalyzed esterification. The reverse reaction is hydrolysis and the equilibrium for this reaction can be made favorable by having an excess of water present ... 

A criterion of mechanism based on the Hammett acidity function, H0 (Section 3.2, p. 130),has long been used to decide the type of question raised by the choice between Mechanisms I and II in Scheme 8. Since in strongly acidic media the concentration of the protonated substrate should be proportional to h0, the reaction rate for a unimolecular decomposition of this protonated substrate (Mechanism I) should also be proportional to h0, whereas if a water molecule is required (Mechanism II), the rate should follow H30+ concentration instead. This test, known as the Zucker-Hammett hypothesis,76 when applied to acetal and ketal hydrolysis, appears to confirm the A-l mechanism, since a linear relationship is found between rate constant and h0 at high acidity.77 Inconsistencies have nevertheless been found in application of the Zucker-Hammett hypothesis, for example failure of the plots of log k vs. — H0 to have the theoretical slope of unity in a number of cases, and failure to predict consistent mechanisms for forward and reverse reactions the method is therefore now considered to be of doubtful validity.78 Bunnett has devised a more successful treatment (Equation 8.45), in which the parameter to measures the extent of... 

Scheme 1. Endgame to the immunosuppressive natural product sanglifehrin A (1) from Streptomyces Jlaveolus. Nicolaou et al. and Paquette et al. connect the same building blocks 2 and 3 by Stile coupling reactions, followed by ketal hydrolysis. Strategic connections for the synthesis of 2 and 3 are given (see following Schemes).

Figure 10.13 Ketal hydrolysis overview. The most likely reaction path is boxed.

In further work, Johnson investigated the interception of ketal hydrolysis by a transannular amine reaction. The debenzylated protected intermediate (61) was cyanomethylated in 85% yield [Eq. (21)]. Because of the reduced... 

The rate determining step is the formation of a carbonium ion and as expected, substituents that are able to stabilize the carbonium ion will strongly accelerate the hydrolysis reaction. This effect is shown in Table 1. However, as also shown in Table 1, this is not true for ortho esters where substituent effects are much smaller than would be predicted by analogy with acetal or ketal hydrolysis, and in some cases are in the opposite direction. These data are consistent with the hypothesis that in ortho ester hydrolysis, there is very little carbonium ion character in the transition state and that in the hydrolysis of ortho esters, addition of a proton is concerted with the breaking of a C-O bond. 

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 related reaction type is the high pressure (6.2 kbar) Diels-Alder reaction of 2-pyrones with cyclopropenone ketals 16 to give isolable bicycloadducts 17, which then undergo cycloreversion, electrocyclic rearrangement, and ketal hydrolysis leading to tropones. Tropolones also have been formed in this way. This tropolone annulation chemistry was the partial subject of a review in 1990, and it was exploited in the syntheses of some naturally occurring tropoloisoquinolines 18-20. ... 

It was pointed out in the mechanistic discussion concerning acetal and ketal hydrolysis that general acid catalysis occurs only for acetals and ketal having special structural features. Usually, specific acid catalysis operates. The question of whether general acid catalysis could be observed in intramolecular reactions has been of interest because intramolecular general acid catalysis is postulated to play a part in the mechanism of action of the enzyme lysozyme, which hydrolyzes the acetal linkage present in certain polysacharides. One group of molecules that has been examined as a model system are acetals derived from o-hydroxybenzoic acid (sali-... 

I- ol, and elaborated by conjugate addition of nitrile, ketal formation, conversion with diisobutylaluminium hydride to the hydroxyaldehyde (129) and then the sequence Wittig reaction, alcohol oxidation with chromium trioxide—sulphuric acid in dimelhylformamide, ketone reduction and ketal hydrolysis to give (1)-... 

The synthesis continued with reduction of the cyclohexanone to the alcohol oxidation state, taking it out of play for a series of reactions that constructed the sidechain (49 54). The sidechain ketone was then protected as an acetal, and the cyclohexanone was reinstalled by deprotection and oxidation of the cyclohexanol. Regioselective acylation of 55 under conditions of thermodynamic control, followed by reduction of the intermediate /3-ketoester, gave 56 (for comparison see 3 —> 14 on Steroids-3). Formation of the tosylate, a /3-elimination, and ketal hydrolysis completed the synthesis of 14. 

Pos twe-Tone Photoresists. The ester, carbonate, and ketal acidolysis reactions which form the basis of most positive tone CA resists are thought to proceed under specific acid catalysis (62). In this mechanism, illustrated in Figure 22 for the hydrolysis of tert-huty acetate (type A l) (63), the first step involves a rapid equihbrium where the proton is transferred between the photogenerated acid and the acid-labile protecting group ... 

As chemists proceeded to synthesize more complicated stmctures, they developed more satisfactory protective groups and more effective methods for the formation and cleavage of protected compounds. At first a tetrahydropyranyl acetal was prepared, by an acid-catalyzed reaction with dihydropyran, to protect a hydroxyl group. The acetal is readily cleaved by mild acid hydrolysis, but formation of this acetal introduces a new stereogenic center. Formation of the 4-methoxytetrahy-dropyranyl ketal eliminates this problem. 

Zn/EtOAc or THF, reflux, 3-12 h, 40-100% yield. It is more efficient to prepare this ketal by an exchange reaction with the dimethyl or diethyl ketal than directly from the carbonyl compound. Hydrolysis can eilso be effected by acid catalysis. 

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