2-r-butyl-2- esters

The carboxamidomethyl ester was prepared for use in peptide synthesis. It is formed from the cesium salt of an A-protected amino acid and a-chloroacetamide (60-85% yield). It is cleaved with 0.5 M NaOH or NaHCOa in DMF/H2O. It is stable to the conditions required to remove BOC, Cbz, Fmoc, and r-butyl esters. It cannot be selectively cleaved in the presence of a benzyl ester of aspartic acid. ... 

Mel, CH3CN morpholine or diethylamine, methanol, 76-95% yield. These conditions also cleave tlie 4 -pyridyl derivative. The Pet ester is stable to the acidic conditions required to remove the BOC and r-butyl ester groups, to the basic conditions required to remove the Fmoc and Fm groups, and to hydrogenolysis. It is not recommended for use in peptides that contain methionine or histidine since these are susceptible to alkylation with methyl iodide. 

Note that a cumyl ester can be selectively cleaved in the presence of a r-butyl ester and a/3-lactam. ... 

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. ... 

Diphenylmethyl esters are similar in acid lability to r-butyl esters and can be cleaved by acidic hydrolysis from 5-containing peptides that poison hydrogenolysis catalysts. 

Thiol esters, which are more reactive to nucleophiles than are the corresponding oxygen esters, have been prepared to activate carboxyl groups for both lactoniza-tion and peptide bond formation. For lactonization S-f-butyl and S-2-pyridyP esters are widely used. Some methods used to prepare thiol esters are shown below. The S-r-butyl ester is included in Reactivity Chart 6. 

The TCBOC group is stable to the alkaline hydrolysis of methyl esters and to the acidic hydrolysis of r-butyl esters. It is rapidly cleaved by the supemucleophile lithium cobalt(I)phthalocyanine, by zinc in acetic acid, and by cobalt phthalocy-anine (0.1 eq., NaBH4, EtOH, 77-90% yield). 

Alkali metal alkoxides, r-butyl acetate neat, 45°, 30 min, 98% yield of r-butyl ester from methyl benzoate. The rate constant for the reaction increases with increasing ionic radius of the metal and with decreasing polarity of the solvent. Equilibrium for the reaction is achieved in <10 sec. Other examples eire presented. " ... 

KOH, 18-crown-6, toluene, 100°, 5 h, 94% yield. These conditions were used to cleave the r-butyl ester from an aromatic ester they are probably too harsh to be used on more highly functionalized substrates. 

This tertiary ester was developed to reduce aspartimide and piperidide formation during the Fmoc-based peptide synthesis by increasing the steric bulk around the carboxyl carbon. A twofold improvement was achieved over the the standard Fbutyl ester. The Mpe ester is prepared from the acid chloride and the alcohol and can be cleaved under conditions similar to those used for the r-butyl ester. ... 

The dibenzosuberyl ester is prepared from dibenzosuberyl chloride (which is also used to protect -OH, -NH, and -SH groups) and a carboxylic acid (Et3N, reflux, 4 h, 45% yield). It can be cleaved by hydrogenolysis and, like r-butyl esters, by acidic hydrolysis (aq. HCl/THF, 20°, 30 min, 98% yield). ... 

Amination. Three laboratories2-4 have reported use of esters of azodicarbox-ylic acid for amination of chiral substrates to provide a synthesis of optically active a-hydrazino and a-amino acids. The di-r-butyl ester is particularly useful because the diastereoselectivity improves with increasing size of the ester group, and in addition these esters are hydrolyzed by TFA at 25°. Two laboratories21 used the lithium enolates of chiral N-acyloxazolidones (2) as the chiral precursors. A typical procedure is outlined in equation (I). Thus reaction of the lithium enolate of 2... 

Method C The malonic ester (15 mmol) is stirred with aqueous NaOH (50%, 30 ml) and TEBA-CI (3.54 g, 15 mmol). The alkylating agent (0.25 mmol) is then added and the mixture is stirred for 1 h at room temperature. The mixture is diluted with H,0 (75 ml) and extracted with Et,0 (3 x 25 ml). The dried (MgS04) extracts are evaporated to give the alkylated ester. Acidification of the aqueous phase with cone. HCI and extraction with Et,0 (3 x 25 ml) yields the alkylated malonic acid or r-butyl ester. 

Having identified the (+)-stereoisomer as the biologically active isomer, several independent enantioselective syntheses of this stereoisomer were developed. The initial synthesis developed in discovery chemistry employed the diastereoselective aldol condensation pioneered by Braun as the key component. Thus, treatment of aldehyde 13 from the racemic synthesis with the magnesium enolate of (5)-(+)-2-acetoxy-l,l,2-triphenylethanol at -70 °C, afforded 17 in 60% yield as a 97 3 mixture of the / ,5 5,5-diastereomers by HPLC (Scheme 3). Ester exchange employing sodium methoxide provided the methyl ester in quantitative yield. Reaction of this ester with three equivalents of lithio-f-butylacetate at -40 °C afforded the nearly enantiomerically pure r-butyl ester analog of racemic 14 in 75% yield. 

Quallich and Woodall described the first asymmetric synthesis utilizing a catalytic enantioselective reduction of the ketoester 35 with (S)-terahydro-l-methyl-3,3-diphenyl-lH,3W-pyrrolo[l,2-c][l,3.2]oxazaborole (CBS) to give the desired hydroxyester 36 (90% ee). After mesylation, Sn2 displacement with a higher-order cuprate derived from copper cyanide gave the diaryl r-butyl ester 37 with good chirality transfer. Intramolecular Friedel-Crafts cyclization gave the tetralone 31 in 90% ee (Scheme 7). ... 

Koga reports that a.P-unsaturated aldimines (89), derived from L-r-leucine r-butyl esters, undergo asymmetric additions with Grignard reagents which is due to formation of a highly ordered magnesium chelate (Scheme 29).75... 

Pyridinium trifluoroacetate is such a mild acidic catalyst that it can hardly affect acid-sensitive functionalities. Thus, for example the very acid-sensitive Boc-protected amines49 and r-butyl esters,50 as well as glycosides51 and acetals,52 remain unchanged under Pfitzner-Moffatt conditions. 

The alkylation of the [2-(l//-tetrazol-5-yl)benzyl]carbamic acid r/-butyl ester with Mel in DMF in the presence of K2C03 has been studied <2004JME2995>. A mixture of regioisomers was separated and purified by reverse-phase preparative ffPLC. 2-(l-Methyl-l//-tetrazol-5-yl)benzylamine hydrochloride and 2-(2-methyl-2//-tetrazol-5-yl)ben-zylamine hydrochloride formed under these conditions in a ratio 1 1.5 <2004JME2995>. 

Electron-poor alkenes are in general too susceptible to direct attack by alkyllithiums to be useful as traps in cyclisation reactions. For example, the unsaturated r-butyl esters 173 cyclise successfully to give four- or five-membered rings 174, but six-membered rings form in only very low yield, with the major side reaction being direct attack of BuLi on the unsaturated ester.84... 

Cyclisations of alkyllithiums onto E unsaturated phosphoranes or r-butyl esters are less stereoselective than the corresponding cyclisations onto unactivated alkenes, presumably because the additional stabilisation allows the transition state to become looser .86 With Z enoates 177, however, trans selectivity is high because of congestion in the transition state leading to the cis isomer of 178. With an alkoxy substituent (177, R = OMe), the stereoselectivity reverses, possibly due to Li-coordination. 

A number of oxazine-fused systems, including the pyrrolo[2,3-r/][l,3]oxazine (295 R = PhCH2), have been obtained by reacting dichlorotriphenylphosphorane with a 1,2-aminoester (e.g. (294 R = Et)) (Equation (105)). The r-butyl ester (294 R = Bu ) reacts with methyl pyruvate in the presence of acetic acid and sodium acetate to yield the pyrrolooxazine (295 R = Me) <90MI 707-05). 

The addition of a selenium-stabilized carbanion to an electrophile can be followed by another reaction as selenones are good leaving groups. a-Selenonylalkyl compounds 111 can be deprotonated using potassium tert-butoxide. Reactions with a,/ -unsaturated / r/-butyl esters lead to cyclopropane derivatives 112 in good yields (Scheme 26).197... 

The next step was to introduce the alkyl chain—this was best done by first oxidizing the sulfide to a sulfoxide, using sodium periodate. The sulfoxide was then deprotonated with -BuLi and alkylated with an alkyl iodide containing a carboxylic acid protected as its r-butyl ester. Reduction of the sulfoxide and hydrolysis back to the free acid gave biotin. 

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