Protective groups for

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). 

Primary and secondary amines are susceptible to oxidation and replacement reactions involving the N—H bonds. Within the development of peptide synthesis numerous protective groups for N—H bonds have been found (M, Bodanszky, 1976 L.A. Carpino, 1973), and we shall discuss five of the more general methods used involving the reversible formation of... 

The only acid-resistant protective group for carbonyl functions is the dicyanomethy-lene group formed by Knoevenagel condensation with malononitrile. Friedel-Crafts acylation conditions, treatment with hot mineral acids, and chlorination with sulfuryl chloride do not affect this group. They have, however, to be cleaved by rather drastic treatment with concentrated alkaline solutions (J.B. Basttis, 1963 H. Fischer, 1932 R.B. Woodward, 1960, 1961). 

It is widely recognized that an allyl group is a useful protecting group for acids, amines, and alcohols. Facile formation of a Tr-allylpalladium complex from... 

Fig. 23. Representative protecting groups for phenolic and carboxylic acid-based systems, (a) The polymer-based protecting groups are fisted in order of increasing activation energy for acid-catalyzed deprotection, (b) Acid-labile monomeric dissolution inhibitors, a bifunctional system based on protected bisphenol A. (c) Another system that combines the function of dissolution inhibitor and PAG in a single unit.

These were originally prepared by Khorana as selective protective groups for the 5 -OH of nucleosides and nucleotides. They were designed to be more acid-labile than the trityl group because depurination is often a problem in the acid-catalyzed removal of the trityl group. Introduction of p-methoxy groups increases the rate of hydrolysis by about one order of magnitude for each p-methoxy substituent. For 5 -protected uridine derivatives in 80% AcOH, 20°, the time for hydrolysis was... 

This substantial group was developed as a fluorescent, acid-labile protective group for oligonucleotide synthesis. It has properties very similar to those of the DMTr group except that it can be detected down to 10 M on TLC plates with 360-nm ultraviolet light. 

See also Chapter 5, on the preparation of esters as protective groups for carboxylic acids. 

The prevalence of diols in synthetic planning and in natural sources (e.g., in carbohydrates and nucleosides) has led to the development of a number of protective groups of valuing stability to a substantial array of reagents. Dioxolanes and diox-anes are the most common protective groups for diols. The ease of formation follows the order ... 

Some of the protective groups for diols are listed in Reactivity Chart 3. 

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. ... 

A comparison has been made with several other common protective groups for tyrosine, and the degree of side-chain alkylation decreases in the order Bn >... 

The 1,3-dioxolane group is probably the most widely used carbonyl protective group. For the protection of carbonyls containing other acid-sensitive functionality, one should use acids of low acidity or pyridinium salts. In general, a molecule containing two similar ketones can be selectively protected at the less hindered carbonyl, assuming that neither or both of the carbonyls are conjugated to an al-kene. ... 

The related 2-/-butyl derivative has also been prepared and used to advantage as a temporary protective group for the stereogenic center of amino acids during alkylations. ... 

The phenyl group became a practical protective group for carboxylic acids when Sharpless published a mild, effective one-step method for its conversion to a carboxylic acid. It has recently been used in a synthesis of the amino acid statine, where it served as a masked or carboxylic acid equivalent. ... 

Carbamates can be used as protective groups for ammo acids to minimize race-mization in peptide synthesis. Raccmi/ation occurs during the base-catalyzed coupling reaction of an W-protected, catboxyl-uc ivated amino acid, and takes place in the intermediate oxazolone that foro S readily from an N-acyl protected amino... 

This work has been carried out in association with Professor Elias J. Corey, who suggested the study of protective groups for use in computer-assisted synthetic analysis. 1 appreciate his continued help and encouragement. I am grateful to Dr. 

The dimethyl ketal function (51) is one of the most suitable base stable protecting groups for saturated 5a- and 5/i-3-ketones. It is formed by reaction of the ketone (50) with methanol in the presence of a suitable catalyst. Good selectivity can also be achieved with this group since 2-, 6-, 11-, 12-, 17- and 20-ketones do not form dimethyl ketals under these conditions. The 2-ketone is converted in part to the dimethyl ketal in the presence of homogeneous rhodium catalyst. "" y -Toluenesulfonic acid is the catalyst of... 

The 3-methoxime (74) provides a base-stable protecting group for A " -3-ketones. It is removed in low yield by conversion to the corresponding semicarbazone. 

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