Selective protection

3 SELECTIVE PROTECTION METHODOLOGIES (REGIOSELECTIVE PROTECTION OF HYDROXYL GROUPS) 

In spite of recent developments, efficient regioselective glycosylations are only rarely possible. Therefore, one major part of oligosaccharide synthesis is the regioselective protection of saccharides. Several techniques have been developed over the years [39], and the most common are discussed below. 

Direct one-step protection (acylations, etherifications) of an unprotected saccharide is sometimes possible to produce a derivative with only one hydroxyl free. However, since the reactivity difference between the secondary hydroxyl groups is not that large, usually a complex mixture of differently protected compounds is obtained. Needless to say, given the need for extensive chromatographic separations and subsequent characterizations, this approach is rarely used in protecting group strategies. 

SCHEME 3.10 Examples of selective protection of primary hydroxyl groups. 

SCHEME 3.13 Examples of stannyl activated regioselective protection. 

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Metal hydrides reduce preferably polar double bonds, whereas catalytic hydrogenation is somewhat selective for non-polar double bonds. Selective protection of amino groups in amino acids. 

Pentafiuoropyridine—hexafiuorobenzene working fiuids show the requisite stabiUty at 382°C for automotive Rankiae-cycle power units (427). Hydroxyl and related functions ia steroids can be selectively protected as tetrafiuoro-4-pyridyl ethers by pentafiuoropyridine (428). 

Skin exposure should be avoided and must be considered when selecting protective equipment and clothing. 

Acetates. Because of the significant interest in selective acetylation reactions of sucrose, the need for a convenient and unambiguous method of identification has been recognized (34,35). The position of an acetyl group in a partially acetylated sucrose derivative can be ascertained by comparison of its H-nmr acetyl methyl proton resonances after per-deuterioacetylation with those of the assigned octaacetate spectmm. The synthesis of partially acetylated sucroses has generally been achieved either by way of selectively protected derivatives such as trityl ethers and cychc acetals or by direct selective acetylation and deacetylation reactions. 

Methylation of avermectins B and B2 leads to the corresponding derivatives of the A series (49). A procedure involving the oxidation of the 5-methoxy group with mercuric acetate and NaBH reduction of the 5-keto-intermediate allows the conversion of the A to the B components (50). The 23-hydroxy group of the "2" components, after selective protection of the other secondary hydroxy groups, is converted to a thionocarbonate, which can be elirninated to give the 22,23-double bond of the "1" components alternatively it can be reduced with tributyltin hydride to the 22,23-dihydro derivatives (= ivermectins) (51). 

Since a few protective groups cannot satisfy all these criteria for elaborate substrates, a large number of mutually complementary protective groups are needed and, indeed, are becoming available. In early syntheses the chemist chose a standard derivative known to be stable to the subsequent reactions. In a synthesis of callistephin chloride the phenolic —OH group in 1 was selectively protected as an acetate. In the presence of silver ion the aliphatic hydroxyl group in 2 displaced... 

Some of the original work in the carbohydrate area in particular reveals extensive protection of carbonyl and hydroxyl groups. For example, a cyclic diacetonide of glucose was selectively cleaved to the monoacetonide. A summary describes the selective protection of primary and secondary hydroxyl groups in a synthesis of gentiobiose, carried out in the 1870s, as triphenylmethyl ethers. 

M HCl at room temperature. Little, if any, use of these groups has been made by the general synthetic community, but the wide range of selectivities observed in their acidic hydrolysis should render them useful for the selective protection of poly functional molecules. 

Me2NC5H5NCPh3 Cr, CH2CI2, 25°, 16 h, 95% yield. In this case a pri-maiy alcohol is cleanly protected over a secondary alcohol. The reagent is a stable isolable salt. If the solvent is changed from CH2CI2 to DMF, the amine of serine can be selectively protected. 

Since a secondary alcohol is oxidized in preference to a primary alcohol by Ph3C BF,i , this reaction results in selective protection of a primary alcohol. 

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... 

The trimethoxy derivative is too labile for most applications, but the mono and diderivatives have been used extensively in the preparation of oligonucleotides and oligonucleosides. The monomethoxy derivative has been used for the selective protection of a primary allylic alcohol over a secondary allylic alcohol (MMTr, Pyr, -10°). ... 

A secondary alcohol was selectively protected in the presence of a secondary allylic alcohol with TBDMSOTf, 2,6-lutidine at —78°. ... 

The 2-hydroxyl of methyl 4,6-0-benzylidine-o -glucopyranoside was selectively protected/... 

Li2C03, Mel, DMF, 55°, 18 h, 54-90%. This method selectively protects phenols with pK < 8 as a result of electron-withdrawing ortho- or para-substituents. 

Catechols can be protected as diethers or diesters by methods that have been described to protect phenols. However, formation of cyclic acetals and ketals (e.g., methylenedioxy, acetonide, cyclohexylidenedioxy, diphenylmethylenedioxy derivatives) or cyclic esters (e.g., borates or carbonates) selectively protects the two adjacent hydroxyl groups in the presence of isolated phenol groups. 

AC2O, FeCl3, It, <30 min, 60-93% yield. These conditions will selectively protect an aldehyde in the presence of a ketone. This combination also converts r-butyldimethylsilyl (TBDMS) ethers to acetates. 

In the first example selective protection was more successful with 1,3-pro-panediol than with ethylene glycol. ... 

HS(CH2) SH, BF3-Et20, CH2CI2, 25°, 12 h, high yield, n = 2, n = 3. In a,/3-unsaturated ketones the olefin does not isomerize to the /3,7-position as occurs when an ethylene ketal is prepared. Aldehydes are selectively protected in the presence of ketones except when steric factors force the ketone to be protected as in the example below." A TBDMS group is not stable to these conditions. ... 

Me3SiSCH2CH2SSiMe3, Znl2, Et20, 0-25°, 12-24 h, high yields. Less hindered ketones can be selectively protected in the presence of more hin-i dered ketones. o , 3-Unsaturated ketones are selectively protected (94 1, 94 4) in the presence of saturated ketones by this reagent. ... 

HS(CH2) SH, S0Cl2-Si02, 88-100% yield. Aldehydes are selectively protected in the presence of ketones. 

Dimethyl-2-sila-l,3-dithiane, BF3 Et20, CH2CI2, 0°, 82-99% yield. This method was reported to be superior to the conventional synthesis because cleaner products are formed. Aldehydes are selectively protected in the presence of ketones, which do not react competitively with this reagent. 

MONOPROTECTION OF DICARBONYL COMPOUNDS Selective Protection of a- and /3-Diketones... 

In an attempt to synthesize the macrolide antibiotic chlorothricolide, an unhindered —COOH group was selectively protected, in the presence of a hindered —COOH group, as a MEM ester that was then reduced to an alcohol group. ... 

Ph2CHO)3PO, CF3COOH, CH2CI2, reflux, 1-5 h, 70-87% yield. Free alcohols are converted to the corresponding Dpm ethers. This reaction has also been used for the selective protection of amino acids as their tosylate salts (CCI4, 15 min-3 h, 63-91% yield). ... 

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. ... 

Oxazolidines are prepared to allow selective protection of the ct- or aj-C02H groups in aspartic and glutamic acids. 

The sulfhydiyl group in cysteine can be selectively protected in the presence of the amino group by reaction with 2,4-dinitrophenol at pH 5-6. ... 

The base-catalyzed reaction of thiothreitol with methyl dithiobenzoate selectively protects a thiol group as an 5-thiobenzoyl derivative in the presence of a hydroxyl group.-... 

A copper chelate selectively protects the q -NH2 group in lysine. The chelate is cleaved by 2 A HCl or by EDTA (H02CCH2)2NCH2CH2N(CH2C02H)2. ... 

In practice the 3-ketone in both 5a- and 5i -steroids is the least hindered and most reactive carbonyl group, whereas the 11-ketone is the most hindered and least reactive. The 6-ketone is less reactive than the 3-ketone but it can be selectively protected in the presence of a 17- or 20-ketone. The 7-ketone is more reactive than a 12-ketone. 

The reactivity of various steroid alcohols decreases in the order primary > secondary (equatorial) > secondary (axial) > tertiary. The only systematic investigation relating to the selective protection of steroidal hydroxyl functions has been carried out with the cathylate (ethyl carbonate) group. Since only equatorial hydroxyl groups form cathylates this ester has been used as a diagnostic tool to elucidate the configuration of secondary alcohols. 

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