Hindered Esters

Hiadered esters are also produced from and Cg a-olefias. These olefias are coaverted iato C —C fatty acids by the oxo process the acids are thea treated with polyols such as peataerythritol and trimethylol propane to produce hindered esters, which find use ia lubricants for jet engines and other high performance appHcations. 

The r-butyl ester is a relatively hindered ester, and many of the methods reported below should be—and in many cases are—equally effective for the preparation of other hindered esters. The related 1- and 2-adamantyl esters have been used for the protection of aspartic acid. ... 

Boronic esters are easily prepared from a diol and the boronic acid with removal of water, either chemically or azeotropically. (See Chapter 2 on the protection of diols.) Sterically hindered boronic esters, such as those of pinacol, can be prepared in the presence of water. Boronic esters of simple unhindered diols are quite sensitive to water and hydrolyze readily. On the other hand, very hindered esters, such as the pinacol and pinanediol derivatives, are exceedingly difficult to hydrolyze and often require rather harsh conditions to achieve cleavage. 

The stereochemistry of this reaction is consistent with transition state 2 in which the ethoxycar-bonyl unit adopts an equatorial position. The same result could occur, however, via boat-like transition state 3 with an axial ethoxycarbonyl group47. The reactions of 2-oxopropanoate esters and 9-(2-butenyl)-9-borabicyclo[3.3.1]nonane occur at — 78°C, reflecting the greater reactivity, but stereoselectivity is generally poor except in cases where a very hindered ester is employed3811. 

A similar result has been found for certain sterically hindered esters.This reaction is similar to 10-44, with OCOR as the leaving group. 

Entry 2 shows an E-enolate of a hindered ester reacting with an aldehyde having both an a-methyl and (3-methoxy group. The reaction shows a 13 1 preference for the Felkin approach product (3,4-syn) and is controlled by the steric effect of the a-methyl substituent. Another example of steric control with an ester enolate is found in a step in the synthesis of (-t-)-discodermolide.99 The E-enolate of a hindered aryl ester was generated using LiTMP and LiBr. Reaction through a Felkin TS resulted in syn diastereoselectivity for the hydroxy and ester groups at the new bond. 

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... 

One such agent is prepared by NBS and peroxide bromination of ethyl 4-chiorophenylacetate (108) to give 109. This is converted by sodium hydride to the benzylic carbene, which is inserted into the double bond of ethyl acrylate to give cis-cyclopropane 110. Partial saponification cleaves the less hindered ester moiety to give 111. This is next converted to the alkoxyimide (112) on reaction with diethyl carbonate and diammonium phosphate. Stronger base (NaOEt)... 

This is a typical representative example of an enhanced microwave-specific effect related to the difficulty of the reaction, which presumably proceeds via a later and later TS. Whereas essentially thermal effects are observed (around 200 °C) with methyl and octyl benzoate, a microwave-specific effect is increasingly apparent with hindered esters and becomes optimal with mesitoyl octanoate (Eq. (43) and Tab. 3.18) [95]. 

The earliest example of the increased reactivity of the potassium hydroxide complex of dicyclohexyl- 18-crown-6 ((20] + [21]) was presented by Pedersen (1967b), who found that the sterically hindered esters of 2,4,6-trimethyl-benzoic acid [136], which are inert towards KOH in protic solvents, are readily... 

Solid-liquid phase systems with no added solvent produce esters in high yield [e.g. 2, 3] and are particularly Useful when using less reactive alkyl halides [e.g. 15], for the preparation of sterically hindered esters [16], or where other basic sites within the molecule are susceptible to alkylation, e.g. anthranilic acid is converted into the esters with minimal A-alkylation and pyridine carboxylic acids do no undergo quat-emization [17]. Excellent yields of the esters in very short reaction times (2-7 minutes) are also obtained when the two-phase system is subjected to microwave irradiation [18]. Direct reaction of the carboxylic acids with 1,2-dichloroethane under reflux yields the chloroethyl ester [19], although generally higher yields of the esters are obtained under microwave conditions [20]. 

For the cleavage of less hindered esters, the lower-boiling 2,6-lutidine (b.p. 143°) can be used as the solvent. 

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. 

Even esters can be ortholithiated, provided the electrophile is present in situ during the hthiation. Neopentyl ester 160 gives, on treatment with LDA in the presence of triisopropylborate, the boron derivative 161, which can be deprotected and used in Suzuki coupling reactions (Scheme 79) . Less hindered esters can also be successfully orthohthiated in the presence of a boron electrophile (Scheme 80) . ... 

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... 

Thermal decomposition of symmetrical hydrazines (212a-d) according to equation 30 resulted in excellent yields of hindered esters (231a-d). The hydrazines leading to the esters were generated as intermediates by the oxidation of Af-alkoxyamides using ceric ammonium nitrate or Ni02.H20 (Scheme 31). 

Yields of hindered esters formed by HERON decomposition of the 1-acyl-l-alkoxy-diazene intermediates from treatment of A-alkoxy-Al-chloroamides with sodium azide in aqueous acetonitrile according to Scheme 16 are presented in Table 3 (Section III.C.4). 

Esterases have a catalytic function and mechanism similar to those of lipases, but some structural aspects and the range of substrates differ 7-11). Most important, they lack the so-called lid prominent in almost all lipases. Nevertheless, one can expect that the lessons learned from the directed evolution of lipases also apply to esterases. So far, few efforts have been investigated in the directed evolution of enantioselective esterases, although earlier work by Arnold 17,32,139) had shown that the activity of esterases as catalysts in the hydrolysis of achiral esters can be enhanced. The first example involving the improvement of enantioselectivity concerned the hydrolytic kinetic resolution of the sterically hindered ester rac-19 catalyzed by the esterase from P. fluorescens (PFE) 140). 

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. 

Especially for large-scale work, esters, may be more safely and efficiently prepared by reaction of carboxylate salts with alkyl halides or tosylates. Carboxylate anions are not very reactive nucleophiles so the best results are obtained in polar aprotic solvents54 or with crown ether catalysts.55 The reactivity for the salts is Na+ < K+ < Rb+ < Cs+. Cesium carboxylates are especially useful in polar aprotic solvents. The enhanced reactivity of the cesium salts is due both to high solubility and to the absence of ion pairing with the anion.56 Acetone has been found to be a good solvent for reaction of carboxylate anions with alkyl iodides.57 Cesium fluoride in DMF is another useful combination.58 Carboxylate alkylation procedures have been particularly advantageous for preparation of hindered esters that can be relatively difficult to prepare by the acid-catalyzed esterification method (Fischer esterification) which will be discussed in Section... 

Pedersen (1) noted that the sterically hindered esters of 2, 4, 6-trimethylbenzoic acid, although resistant to saponification by KOH in hydroxylic solvents, are saponified by the KOH complex of dicyclohexyl-18-crown-6 in aromatic hydrocarbons. 

An initial stndy demonstrated that Josiphos and its inverted analogue 11 were very effective in promoting the Cu-catalyzed conjugate addition of EtMgBr to unsaturated crotonates (Scheme 5). It is noteworthy that the use of sterically hindered esters, which nsnally helps to avoid nndesired 1,2-additions, or alternatives for esters such as an oxa-zolidinone, are not reqnired. Indeed, the highest conversions and stereoselectivities are obtained with methyl crotonate. ... 

In macrobicyclic cryptate complexes where the cation is more efficiently encapsulated by the organic ligand these ion pair interactions are diminished and the reactivity of the anion is enhanced. This effect is seen in the higher dissociation constant, by a factor of 104, of Bu OK in Bu OH when K+ is complexed by [2.2.2]cryptand (12) compared to dibenzo[18]crown-6 (2). The enhanced anion reactivity is illustrated by the reaction of the hindered ester methyl mesitoate with powdered potassium hydroxide suspended in benzene. 

Hydrolysis of esters,1 KOH crushed with neutral alumina effects hydrolysis of even hindered esters at room temperature (4-48 hours). 

The iV-aminopyrrole - benzene ring methodology has been applied to a synthesis of the 9,10-dihydrophenanthrene juncusol (218) (81TL1775). Condensation of the tetralone (213) with pyrrolidine and reaction of the enamine with ethyl 3-methoxycarbonylazo-2-butenoate gave pyrrole (214). Diels-Alder reaction of (214) with methyl propiolate produced a 3 1 mixture of (215) and its isomer in 70% yield. Pure (215) was reduced selectively with DIBAL to the alcohol, reoxidized to aldehyde, and then treated with MCPBA to generate formate (216). Saponification to the phenol followed by O-methylation and lithium aluminum hydride reduction of the hindered ester afforded (217), an intermediate which had been converted previously to juncusol (Scheme 46). 

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