Protecting groups described

Protective group numbers in the Reactivity Charts are not continuous, since not all of the protective groups described in the text are included in the charts. The protective groups that are included in the Reactivity Charts are in general those that have been used most widely consequently, considerable experimental information is available for them. 

All the approaches for deblocking protective groups described earlier in this book have found application in the removal of protective groups from phosphorus derivatives. Because phosphate protection and deprotection are commonly associated with compounds that contain acid-sensitive sites (e.g., glycosidic linkages and DMTr-O- groups of nucleotides), the most widely used protective groups on phosphorus are those that are deblocked by base. 

Retinoids. Several routes have been described for the preparation of retinal and its derivatives. Two papers ° on the use of trimethylsilyl and triphenylsilyl protecting groups describe the preparation of the Ce intermediate -3-methyl-pent-2-en-4-yn-l-ol triphenylsilyl ether (100), and the four- or five-step synthesis of IIZ-retinal from this and the C14 aldehyde (101). A method for base-catalysed trans elimination of PhSOaH from the sulphone (102) affords retinyl acetate (103) in 86% yield. 

We shall describe a specific synthetic example for each protective group given above. Regiosdective proteaion is generally only possible if there are hydroxyl groups of different sterical hindrance (prim < sec < tert equatorial < axial). Acetylation has usually been effected with acetic anhydride. The acetylation of less reactive hydroxyl groups is catalyzed by DMAP (see p.l44f.). Acetates are stable toward oxidation with chromium trioxide in pyridine and have been used, for example, for protection of steroids (H.J.E. Loewenthal, 1959), carbohydrates (M.L. Wolfrom, 1963 J.M. Williams, 1967), and nucleosides (A.M. Micbelson, 1963). The most common deacetylation procedures are ammonolysis with NH in CH OH and methanolysis with KjCO, or sodium methoxide. 

Trichloro- and 2,2,2-tribromoethoxycarbonyl (Tceoc and Tbeoc) protecting groups are introduced with the commercially available 2,2,2-trihaloethyl chloroformates. These derivatives are stable towards CrOj and acids, but can smoothly be cleaved by reduction with zinc in acetic acid at 20 °C to yield 1,1-dihaloethene and CO. Several examples in lipid (F.R. Pfeiffer, 1968, 1970) and nucleotide syntheses (A.F. Cook, 1968) have been described. 

Synthesis of large heterocycles usually involves condensation reactions of two difunctional molecules. Such molecules tend to polymerize. So far two special techniques have been described above to avoid this important side-reaaion , namely high dilution and use of templates. The general procedure to avoid polymerizations in reactions between difunctional molecules is, of course, the application of protecting groups as described in sections 4.1.2 and 2.6. 

Photolytic cleavage reactions (e.g., of o-nitrobenzyl, phenacyl, nitrophenylsul-fenyl derivatives) take place in high yield on irradiation of the protected compound for a few hours at 254-350 nm. For example, the o-nitrobenzyl group, used to protect alcohols, amines, and carboxylic acids,has been removed by irradiation. Protective groups that have been removed by photolysis are described at the appropriate places in this book in addition, the reader may wish to consult five review articles. 

A number of standard synthetic reference books are available. A review article by Kossell and Seliger discusses protective groups used in oligonucleotide syntheses, including protection for the phosphate group, which is not included in this book, and a series of articles describe various aspects of protective group chemistry. 

The following miscellaneous esters have been prepared as protective groups, but they have seen little use since publication of the first edition. Therefore they are simply listed for completeness, rather than described in detail. 

Derivatives of carbonyl compounds that have been used as protective groups in synthetic schemes are described in this chapter some of the more important protective groups are listed in Reactivity Chart 5. ... 

Diphenylmethyl, substituted 5-diphenylmethyl, and 5-triphenylmethyl thioethers have often been formed or cleaved by the same conditions, although sometimes in rather different yields. As an effort has been made to avoid repetition in the sections that describe these three protective groups, the reader should glance at all the sections. 

Silyl-derived protective groups are also used to mask the thiol function. A complete compilation is not given here since silyl derivatives are described in the section on alcohol protection. The formation and cleavage of silyl thioethers proceed analogously to simple alcohols. The Si—S bond is weaker than the Si—O bond, and therefore sulfur derivatives are more susceptible to hydrolysis. For the most part silyl ethers are rarely used to protect the thiol function because of their instability. Silyl ethers have been used for in situ protection of the — SH group during amide formation. ... 

Sulfonamides (R2NSO2R ) are prepared from an amine and sulfonyl chloride in the presence of pyridine or aqueous base. The sulfonamide is one of the most stable nitrogen protective groups. Arylsulfonamides are stable to alkaline hydrolysis, and to catalytic reduction they are cleaved by Na/NH3, Na/butanol, sodium naphthalenide, or sodium anthracenide, and by refluxing in acid (48% HBr/cat. phenol). Sulfonamides of less basic amines such as pyrroles and indoles are much easier to cleave than are those of the more basic alkyl amines. In fact, sulfonamides of the less basic amines (pyrroles, indoles, and imidazoles) can be cleaved by basic hydrolysis, which is almost impossible for the alkyl amines. Because of the inherent differences between the aromatic — NH group and simple aliphatic amines, the protection of these compounds (pyrroles, indoles, and imidazoles) will be described in a separate section. One appealing proj>erty of sulfonamides is that the derivatives are more crystalline than amides or carbamates. 

These 108 reagents are used in the Reactivity Charts that have been prepared for each class of protective groups. The reagents and some of their properties are described on the following pages. 

A recent publication describes the protection of a S-keto-A" system via its eniminium salt, permitting enol acetylation of a 20-ketone, epoxidation, hydrolysis and finally removal of the A-ring protecting group. 

Polymer-supported esters are widely used in solid-phase peptide synthesis, and extensive information on this specialized protection is reported annually. Some activated esters that have been used as macrolide precursors and some that have been used in peptide synthesis are also described in this chapter the many activated esters that are used in peptide synthesis are discussed elsewhere. A useful list, with references, of many protected amino acids (e.g., -NH2, COOH, and side-chain-protected compounds) has been compiled/ Some general methods for the preparation of esters are provided at the beginning of this chapter conditions that are unique to a protective group are described with that group/ Some esters that have been used as protective groups are included in Reactivity Chart 6. 

The DMB carbamate can also be introduced through the 4-nitrophenyl carbonate. " It has been prepared from an isocyanate and 3, 5 -dimethoxybenzoin. The synthesis of a number of other substituted benzoins as possible protective groups has been described. ... 

The following sections primarily describe many of the methods used for the cleavage of some of the more common phosphate protective groups. Since most of these groups are introduced by either the phosphate or phosphite method, little information is included here about their formation. The cited references generally describe the means that were used to introduce the protective group. In some cases, methods of formation are described, but this is done only when alternative methods to the phosphate or phosphite procedure were used. 

---