Ketals 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). 

The second step in acetal and ketal hydrolysis is conversion of the hemiacetal or hemiketal to the carbonyl compound. The mechanism of this step is similar to that of the first step. Usually, the second step is faster than the initial one. Hammett a p plots and solvent isotope effects both indicate that the transition state has less cationic character than... 

The method of choice for preparing tropone (45) is to treat the initial mixture of monoadducts (43a) and (43b) with methanolic 1 TV hydrochloric acid to complete ketal hydrolysis and then carry out the pyridine rearrangement to give 3-bromo-4-methoxy-A-homo-estra-2,4,5(10)-trien-17-one (44) as described above for monoadduct 17-ketone (43b). 

D. 1,4-Di-O-benzyl-L-threitol. The crude ketal is dissolved in methanol (300 mL), 0.5 N hydrochloric acid (30 idL) is added, and the resulting mixture Is heated to reflux. Acetone and methanol are slowly distilled off (Note 29). Additional methanol (50 mL) and 0.5 N hydrochloric acid (20 mL) are added and the mixture Is kept at room temperature until ketal hydrolysis Is complete. The mixture Is diluted with saturated sodium bicarbonate solution (500 mL) and extracted with ether (3 x 500 mL). The ether extracts are combined, dried over anhydrous magnesium sulfate, and filtered. Removal of volatile material under reduced pressure gives crude l,4-di-0-benzy1-L-threitol as a pale yellow solid. This solid is recrystallized twice from chloroform/hexanes, to provide 59-65 g (195-215 mmol, 57-63% yield) of pure diol, up 54-55 C (Notes 30 and 31). Concentration of the mother liquors from the recrystallizations gives a yellow solid which is chromatographed on 70-230 mesh silica gel 60 (500 g) (Note 32), and eluted with 50% ethyl... 

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... 

Figure 28 Triamcinolone acetonide ketal hydrolysis under acidic conditions.

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).

FruA is stereoselective and stereocenter 2 is created with the SNuclear Overhauser Effects (NOEs) observed, and the coupling constants measured, the configurations found for compound 11 were IS, 2S, 3R, and 6R. AH the substituents are equatorially positioned on the cyclohexane ring. The (2S,3R)-configurations are consistent with the usually observed diastereoselectivity of FruA In a second exploration [20], the racemic aldehyde 10 was condensed with DHAP after ketal hydrolysis of rac-14 under acidic conditions. In this case, two major isomers 12 and 13 were isolated in 35 and 29% yields after flash chromatography purification. 

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. 

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