Acetals protecting groups, removal

The carbonyl group can be deprotected by acid-catalyzed hydrolysis by the general mechanism for acetal hydrolysis (see Part A, Section 7.1). A number of Lewis acids have also been used to remove acetal protective groups. Hydrolysis is promoted by LiBF4 in acetonitrile.249 Bismuth triflate promotes hydrolysis of dimethoxy, diethoxy, and dioxolane acetals.250 The dimethyl and diethyl acetals are cleaved by 0.1-1.0 mol % of catalyst in aqueous THF at room temperature, whereas dioxolanes require reflux. Bismuth nitrate also catalyzes acetal hydrolysis.251... 

Difficulty removing acetate protecting group from amide 29... 

Acetals Removing the acetal protecting group is easily achieved by acid-catalyzed hydrolysis, although catalytic hydrogenolysis is better for acid-sensitive compounds. The oxygen connected to the... 

Dave and co-workers have reported a successful synthesis of 2,2,4,4-tetranitroadamantane (117) which uses the mono-protected diketone (113) as a key intermediate. In this synthesis (113) is converted to the oxime (114) and then treated with ammonium nitrate and nitric acid in methylene chloride to yield the em-dinitro derivative (115). This nitration-oxidation step also removes the acetal-protecting group to leave the second ketone group free. Formation of the oxime (116) from ketone (115), followed by a similar nitration-oxidation with nitric acid and ammonium nitrate, yields 2,2,4,4-tetranitroadamantane (117). In this synthesis the protection strategy enables each carbonyl group to be treated separately and thus prevents the problem of internal nitroso dimer formation. 

Hydrolysis procedures have been, developed for the removal of the acetal protecting groups without accompanying crosslinking of polydiene backbones. Dilute solution hydrolyses are preferred over bulk methods ( ). (Eq. 6-9). 

The bis-diethylacetal of di-(4-oxo-n-butyl)amine (182) was obtained from y-aminobutyraldehyde diethylacetal (180) and y-chlorobutyral-dehyde acetal (181) and, after removal of acetal protecting groups, converted into 1-formylpyrrolizidine (183) without isolation of the intermediates. The final condensation was achieved by Babor et oZ.,109 who isolated 1-formylpyrrolizidine in ca. 10-15% yield at pH 4—4.5. Hydrogenation of the compound over platinum afforded 1-hydroxymethylpyrrolizidine, which they claimed to be ( + )-isoretronecanol. Leonard and Blum123 carried out the same condensation at pH 7 and reduced the resultant aldehyde, without isolation, with sodium boro-... 

Although we were able to obtain the desired 29 in this way, there were several aspects of the last few steps that troubled us. One flaw was the requirement for azeotropic removal of H20 in two consecutive steps the dehydration of 26 to 5 and the acetalization of 5 to 27. Another flaw was that the acetal protecting group, discarded immediately after its use here, needed to be reinstalled before the last step of the synthesis (see below). Although ethylene glycol was very inexpensive, it seemed that this duplication of effort should have been avoided, if possible. 

Our retrosynthetic analysis for lipid I is presented below [Scheme 2], Our protected version of lipid I employed acetate protective groups for the carbohydrate hydroxyls, methyl esters for each of the carboxyl groups in the pentapeptide side chain, and trifluoroacetate for the terminal amino group of the lysine residue. These base-cleavable protective groups could be removed in a single operation in the final step of our synthesis and would not subject the sensitive diphosphate linkage to acidic reagents or reaction conditions. 

ACSH thiol acetic acid will be added in 1,6 addition to the double bond, acidic media will remove the ethylene acetal (protecting group and CiO] will oxidize aldehydic group into COOH with spontaneous cyclization. 

The hydrolysis of the epoxide to the diol was accomplished with acid and water (see Section 10.10). This step also removed the acetal protective group. 

For the same reason, reaction of the keto aldehyde with one equivalent of ethylene glycol selectively forms the acetal of the aldehyde functional group. The ketone can then be reduced with NaBFLj and the acetal protecting group can be removed. 

Keto aldehyde 191 (Scheme 2.87) was prepared as a common precursor in the synthesis of a series of isoprenoid pheromones. One of the synthetic options required the selective reduction of a ketone carbonyl in this compound. Under mild conditions of acetalization (weak acid, methanol), only the aldehydic function of 191 was affected to form a mono-protected derivative, 192. Reduction of the keto group in the derivative with sodium borohydride and subsequent removal of the acetal protecting group gave the desired hydroxy aldehyde 193. ... 

SCHEME 3.23 Examples of regioselective removal and opening of acetal protecting groups. 

Liberation of the 4-ammo function requires selective reduction of the azido group in the presence of the double bond. This has been achieved by first gaining water solubility by removal of the acetate protecting groups with... 

One problem with the use of the ketal or acetal protecting group for 05,6 protection is the removal of the ketal or acetal without concomitant hydrolysis of the 2-sulfate. Sulfation of free ascorbic acid has been reported to aflFord mixtures or sulfated products (23,26,30). Seib et al. (26) oflEered a rational solution to the problem of regioselective sulfation of ascorbic acid with his observation that the di-anion of ascorbic acid reacts exclusively at the 02 position affording 18 in high yield. The formation of 03 sulfated derivatives of ascorbic acid has not been observed, possibly due to the lability of the 3-0-sulfates to intermolecular hydrolysis or rearrangement to the more stable 18 (2). 

We can then remove both of the acetal protecting groups to reveal the tetraol 151. The stereochemistry of both the diols in 151 demands the use of AD-mix-P on 152. 

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