Protective groups for acetals

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. 

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). 

Six protective groups for alcohols, which may be removed successively and selectively, have been listed by E.J. Corey (1972B). A hypothetical hexahydroxy compound with hydroxy groups 1 to 6 protected as (1) acetate, (2) 2,2,2-trichloroethyl carbonate, (3) benzyl ether, (4) dimethyl-t-butylsilyl ether, (5) 2-tetrahydropyranyl ether, and (6) methyl ether may be unmasked in that order by the reagents (1) KjCO, or NH, in CHjOH, (2) Zn in CHjOH or AcOH, (3) over Pd, (4) F", (5) wet acetic acid, and (6) BBrj. The groups may also be exposed to the same reagents in the order A 5, 2, 1, 3, 6. The (4-methoxyphenyl)methyl group (=MPM = p-methoxybenzyl, PMB) can be oxidized to a benzaldehyde derivative and thereby be removed at room temperature under neutral conditions (Y- Oikawa, 1982 R. Johansson, 1984 T. Fukuyama, 1985). 

A benzylidene acetal is a commonly used protective group for 1,2- and 1,3-diols. In the case of a 1,2,3-triol the 1,3-acetal is the preferred product. It has the advantage that it can be removed under neutral conditions by hydrogenolysis or by acid hydrolysis. Benzyl groups and isolated olefins have been hydrogenated in the presence of 1,3-benzylidene acetals. Benzylidene acetals of 1,2-diols are more susceptible to hydrogenolysis than are those of 1,3-diols. In fact, the former can be removed in the presence of the latter. A polymer-bound benzylidene acetal has also been prepared." ... 

The p-methoxybenzylidene acetal is a versatile protective group for diols tl undergoes acid hydrolysis 10 times faster than the benzylidene group. ... 

Acetals are useful because they can act as protecting groups for aldehydes and ketones in the same way that trimethylsilyl ethers act as protecting groups for alcohols (Section 17.8). As we saw previously, it sometimes happens that one functional group interferes with intended chemistry elsewhere... 

Acetal (Section 19.10) A functional group consisting of two -OR groups bonded to the same carbon, R2C(OR )2-Acetals are often used as protecting groups for ketones and aldehydes. 

Protective Groups for Diols. Diols represent a special case in terms of applicable protecting groups. 1,2- and 1,3-diols easily form cyclic acetals with aldehydes and ketones, unless cyclization is precluded by molecular geometry. The isopropylidene derivatives (also called acetonides) formed by reaction with acetone are a common example. 

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... 

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... 

Benzyl acetal protecting groups were hydrogenolyzed over Pd/C,159 over 20% Pd(OH)2/C in AcOEt for 2 hours,160 and over 10% Pd/C in AcOEt in the presence of NaHC03 for 30 minutes.161... 

Although many examples of this type of ring system are known in the literature, the vast majority of these are cyclic acetals, which have been used as protecting groups for diols. These have not been included in this chapter. Otherwise, the majority of the compounds which fall into this category are either natural products or derivatives of, or precursors to, the natural products. 

---