Protecting groups, primary hydroxyl secondary hydroxyls

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. 

Dihydro-2f/-pyran (167) is well known in organic chemistry as a reagent employed for the temporary protection of primary and secondary hydroxyl groups. Addition reactions to the double bond of 167 afford compounds that fall into the category of 3,4-dideoxypentoses. 

A. Hasegawa, T. Nagahama, H. Ohki, K. Hotta, H. Ishida, and M. Kiso, Reactivity of glycosyl promoters in a-glycosylation of W-acetylneuraminic acid with the primary and secondary hydroxyl groups in the suitably protected galactose and lactose derivatives, J. Carbohydr. Chem. 70 493 (1991). 

Monomolar benzylation of methyl 2,3-di-0-benzyl-a-D-galactopyranoside in DMF gave 2,3,6-tri-O-benzyl derivative in 73% yield [52], The primary 6-benzyl ether also forms the major part of the monobenzyl fraction obtained from methyl a-D-galactopyranoside or from its p-anomer [53]. Interestingly, position 6 becomes less reactive than position 2 if 3,4-0-isopropylidene acetals is used to protect the other two secondary hydroxyl groups. The ratio of 2- and 6-benzyl ethers was found to be 11 1 in the a-anomer and 2.5 1 in the p-anomer [53] (see also, Ref. [54]). Uridine [55], cyti-dine [56], and 4-(methylthio)uridine [56] also prefer OH-2 over the primary position when benzylated in dimethyl sulfoxide (for other benzylations in this solvent, see Refs. [35, 57]). 

NT0-Bis(terf-butyldimethylsilyl)acetaniide silylates tertiary and hindered secondary alcohols in the presence of a catalytic amount of TBAF or another source of fluoride anion [Scheme 4.67].113 Protection of primary hydroxyl groups in the presence of secondary ones and secondary in the presence of tertiary is possible but the monoprotection of 1,2-diols fails due to the migration of the silyl group caused by the presence of basic fluoride anion. 

Alcohol protection. Primary and secondary hydroxyl groups are esterified by 1 in the presence of pyridine (71-92% yield). The usual selectivity for acylation of primary versus secondary hydroxyl functions obtains. The resulting 2-di-bromomethylbenzoates 2 are deprotected under neutral conditions by silver perchlorate mediated hydrolysis to 2-formylbenzoate esters 3 (2,6-lutidine or 2,4,6-collidine is added to maintain a virtually neutral reaction medium). Addition of morpholine then leads to rapid dcacylation with release of the alcohol in high yield... 

Acid Catalyst. Camphorsulfonic acid (CS A) has been used extensively in synthetic organic chemistry as an acid catalyst. It has particularly been used in protecting group chemistry. For example, hydroxyl groups can be protected as tetrahydropyranyl (THP) ethers using dihydropyran and a catalytic amount of CSA (eq 1). Both 1,2- and 1,3-diols can be selectively protected by reaction with orthoesters in the presence of camphorsulfonic acid to form the corresponding cyclic orthoester (eq 2) This method of protection is particularly useful in that reduction of the orthoester with Diisobutylaluminum Hydride forms the monoacetal, which allows for preferential protection of a secondary alcohol in the presence of a primary alcohol. Ketones have also been protected using catalytic CSA (eq 3). ... 

Imidazole carboxylic esters of secondary or tertiary alcohols, such as 1053 and 1054,, form carbonates exclusively with primary alcohols (Scheme 253). Thus, 1054 is a useful reagent for the BOC-protection of primary hydroxyl groups < 19990L933>. In some cases, 1054 offers better selectivity than pivaloyl chloride in the protection of carbohydrates <1998S1787>. Similarly, l-(methyldithiocarbonyl)imidazole 1055 and its methyl triflate salt convert alcohols to ri -methyldithiocarbonates <1997SL1279> and amines to 6 -methyldithiocarbamates or thioureas <2000T629>. 

The reagent is prepared by reaction of /3,/3,/1-tribromoethanol with phosgene in benzene. It reacts with primary and secondary hydroxyl groups of nucleosides to give /3,/8,/8-tribromoethoxycarbonyl compounds (I). The protective gronp is removed by /3-elimination with a zinc-copper couple.1... 

No acetolyses appear to have been performed on methylene acetals of aldoses or aldosides. The use of the trifluoroacetic anhydride-acetic acid sequence would be one way of protecting a primary hydroxyl group and freeing a particular secondary one. 

Heating a tertiary alcohol with l-(trimethylsilyl)iniidazole (abbreviated TMSIM. by-product imidazole) at 100 °C accomplishes O-trimethylsilylation even in the presence of a trisubstituled oxirane [Scheme 4.10].Tetrabutylammonium fluoride (TBAP) catalyses the 0-silylation of alcohols with various silazanes, including l-(trimethylsilyI)imidazole, so that silylation takes place at room temperature in DMF [Scheme 4.11]. In the absence of TBAF, no silylation occurs. The use of more hindered silazanes such as the bissilyl derivative of 5,5-dimethyIhy-dantoin allows regioselective TMS or TBS protection of primary hydroxyl groups in the presence of secondary and tertiary ones. Hydrosilanes and disilanes can be used instead of silazanes in TBAF-caialysed protection of primary and secondary alcohols. ... 

The protected butane-1,2,3,4-tetraol 15, easily available in three steps from D-tartaric add diethyl ester, was the starting material for the synthesis of (+)-phomopsohde B (Scheme 2.4). Thus, IBX (2-iodoxybenzoic acid) oxidation of the primary alcohol followed by HWE olefination with a chiral phosphonate derived from L-lactic add (not depicted) gave a,fi-enone 16. Stereoselective reduction of the ketone carbonyl and acidic deavage of the acetal moiety furnished triol 17. Selective protection of the two secondary hydroxyl groups was achieved through triple silylation with subsequent selective desilylation of the primary OTBS group. 

Primary and secondary hydroxyl groups can be fluorinated by reaction with di-ethylaminosulfiir trifluoride (DAST) [103]. The reaction of asymmetric secondary alcohols produces inversion of the configuration. Thus, the reaction of the protected diacetone allose with DAST, followed by removal of the protective groups, gives 3-deoxy-3-fluoro-D-glucose [104] (reaction 4.100). 

The tritylone ether is used to protect primary hydroxyl groups in the presence of secondary hydroxyl groups. It is prepared by the reaction of an alcohol with 9-phenyl-9-hydroxyanthrone under acid catalysis (cat. TsOH, benzene, reflux, 55-95% yield).It can be cleaved under the harsh conditions of the WolfT-Kishner reduction (H2NNH2, NaOH, 200°, 88% yield), " and by electrolytic reduction (-1.4 V, LiBr, MeOH, 80-85% yield). It is stable to 10% HCl, 55 h. ... 

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. 

Among the tasks remaining is the replacement of the C-16 hydroxyl group in 16 with a saturated butyl side chain. A partial hydrogenation of the alkyne in 16 with 5% Pd-BaS04 in the presence of quinoline, in methanol, followed sequentially by selective tosylation of the primary hydroxyl group and protection of the secondary hydroxyl group as an ethoxyethyl ether, affords intermediate 17 in 79% overall yield from 16. Key intermediate 6 is formed in 67 % yield upon treatment of 17 with lithium di-n-butylcuprate. 

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