Highly hindered esters

As a catalyst for ester and amide formation from acyl chlorides or anhydrides, 4-(di-methylamino)pyridine has been recommended (DMAP G. Hdfle, 1978). In the presence of this agent highly hindered hydroxyl groups, e.g. of steroids and carbohydrates, are acylated under mild conditions, which is difficult to achieve with other catalysts. 

Halogenation of the 7 position also proves compatible with good antiinflammatory activity. Construction of this compound, aclomethasone dipropionate (80), starts by introduction of the required unsaturation at the 6,7 position by dehydrogenation with DDQ (76). The highly hindered nature of the hydroxyl at position 17 requires that a roundabout scheme be used for formation of the corresponding ester. Thus treatment of 76 with ethyl orthoformate affords first the cyclic orthoformate This then rearranges to the 17 ester on exposure to acetic acid. Acylation of the 21 alcohol is accomplished in straightforward fashion with... 

The anions derived from racemic alkyl and benzyl tert-butyl sulfoxides undergo 1,4-addition to a,/J-unsaturated esters to give adducts with high product diastereoselection (>5 1)10,11. Alkyl 4-methylphenyl sulfoxides were found to be less diastereoselective. In the case of 2-methyl-2-(methylsulfinyl)propanc the highly hindered 2,6-di-rer7-butyl-4-methylphenyl ester was required to prevent a competing acylation reaction. 

Additional acceleration of acylation can be obtained by inclusion of cupric salts, which coordinate at the pyridine nitrogen. This modification is useful for the preparation of highly hindered esters.122 Pyridine-2-thiol esters can be prepared by reaction of the carboxylic acid with 2,2 -dipyridyl disulfide and triphenylphosphine123 or directly from the acid and 2-pyridyl thiochloroformate.124... 

A number of these alkylation reactions are illustrated in Scheme 9.2. Entries 1 and 2 are typical examples of a-halo ester reactions. Entry 3 is a modification in which the highly hindered base potassium 2,6-di-f-butylphenoxide is used. Similar reaction conditions can be used with a-halo ketones (Entries 4 and 5) and nitriles (Entry 6). Entries 7 to 9 illustrate the use of diazo esters and diazo ketones. Entry 10 shows an application of the reaction to the synthesis of an amide. 

This procedure illustrates a general method for the selective splitting of a carbomethoxy group in the presence of easily hydrolyzed esters of other alcohols, such as the easily hydrolyzed equatorial acetoxy group. The specificity of the reaction is not affected by steric hindrance, and a highly hindered methyl ester can be split in the presence of other less hindered esters of secondary alcohols. Normal alkaline saponification goes in exactly the opposite way. 

Ordinarily, alkyl nitrate esters will not nitrate amines under neutral conditions. However, Schmitt, Bedford and Bottaro have reported the use of some novel electron-deficient nitrate esters for the direct At-nitration of secondary amines. The most useful of these is 2-(trifluoromethyl)-2-propyl nitrate, which nitrates a range of aliphatic secondary amines to the corresponding nitramines in good to excellent yields. Nitrosamine formation is insignificant in these reactions. 2-(Trifluoromethyl)-2-propyl nitrate cannot be used for the nitration of primary amines, or secondary amines containing ethylenediamine functionality like that in piperazine. Its use is limited with highly hindered amines or amines of diminished nucleophilicity due to inductive or steric effects. 

The reaction of azide with A-chlorohydroxamic esters has proved to be an excellent source of highly hindered esters . The rearrangement of 82 to 83 (Scheme 16), apart from being highly favourable energetically, is characterized by an early transition state with little disruption to the carbonyl. In these HERON reactions, the N—C 0) bond... 

Simple alkyl esters show rather low stereoselectivity. However, highly hindered esters derived from 2,6-dimethylphenol or 2,6-di-/-butyl-4-methylphenol provide the anti stereoisomers. 

The propargyl alcohols react with trivalent phosphorus halides to give allenic phosphorus esters as described in Scheme 3 and Table VI. In the case of aryl-substituted alkynols or highly hindered t-propargyl alcohols which contain no free acetylenic —H, thionyl halides or phosphorus trihalides yield bromo- or chloroallenes [74d], Thionyl chloride also reacts in a similar fashion with a wide variety of unhindered secondary alcohols (structure XV) to give a mixture of the chloroallene and chloroalkyne [74a-d]. 

The preparation of furans by acid catalyzed dehydration of 1,4-diketones followed by cyclization of the monoenol has been comprehensively reviewed (69RCR389). This method of furan preparation is useful for all 1,4-diketones which are not sterically hindered with the highly hindered l,4-bis(2,4,6-triisopropylphenyl)-l,4-butanedione no cyclization occurs (50JA5754). Although sulfuric acid is normally used for cyclization, hydrochloric acid was employed in the conversion of a 1,2-diacylethylene to a furylacrylic acid derivative (59MIP31200). Other reagents used for this purpose include polyphosphoric acid, phosphorus trichloride, zinc chloride and DMSO. Both DMSO and phosphoric esters provide neutral... 

As has been clearly demonstrated by X-ray studies (Section III,B), complexation of a salt by a cryptand results in cation-anion separation or dissociation. This enhances anionic reactivity and may effect solubilization of the salt in organic solvents. For example the highly hindered ester methyl mesitoate, 13, may be smoothly hydrolyzed by powdered potassium hydroxide in dry benzene in the presence of [2.2.2] (98). Indeed cryptands have proved particularly useful in phase-trans-... 

Some observations by Hammett et al. (28) on solutions of carboxylic acids in concentrated sulfuric acid had led to a procedure which served in the esterification of hindered weak acids and in the hydrolysis of their esters 28, 29). It had been found that most carboxylic acids dissolved in concentrated sulfuric acid to give the monoprotonated species. However, some highly hindered carboxylic acids reacted further to give the much less hindered acylium ion ... 

OL-Glycosyl esters.1 The anomeric lithium alkoxide of 2,3,4,5-tetra-O-benzyl-D-glucopyranose (2) reacts with 1 to form mainly an a-glycosyl ester (3, a/p = 16 1). This reaction is generally strongly a-selective, even with highly hindered... 

Protection of phosphates as 2-(trimethylsilyl)ethyl esters was first developed by the Masamune group as part of their efforts to synthesise Calyculin A with its highly hindered phosphate monoester.77 A diallyi phosphate was evaluated in a model compound, but it was rejected because of incomplete deprotection under Pd(0)-catalysis, The corresponding bis-[2-(trimethylsilyl)ethyl] ester 37 1, on the... 

In 1998, methoxy and halogen substituents meta to a highly hindered benzoate ester were found to increase the rate of displacement of the sandwiched ortho methoxy leaving group. (equation 28) In 2001, weta-alkoxy rate enhancement was found applicable also to displacement of a methoxy group para to a benzoate ester. ... 

Cleavage of esters. Lithium or sodium in ethereal ammonia cleaves esters to the alcohol in 70-95% yield. The method is not useful for highly hindered esters and for esters of allylic alcohols (which are converted to the corresponding hydrocarbons by alkyl-oxygen cleavage). ... 

The phorphorus betaine method is recommended for inversion of the stereochemistry of acyclic di- and Irisubstituted alkencs. Highly hindered epoxides react very slowly with LDP and alkenes arc not obtained in good yield. Keto groups interfere with the sequence owing to enolate formation unless 2 eq. of reagent is used. Epoxy esters cannot be dcoxygenated in practical yield. 

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