2-Methylbutanoic acid preparation

The 3-(2-hydroxy-4,6-dimethylphenyl)-3-methylbutanoic acid shown in Fig. 8.23, as well as another phenylpropanoic derivative presented below, have been used as pro-moieties to prepare a number of prodrugs of therapeutic peptides [169] [238], Of interest here is that the pro-moiety is linked to the peptide by both amide and ester bonds to form a cyclic, double prodrug, the two-step activation of which is schematized in Fig. 8.24. Briefly, enzymatic hydrolysis of the ester bond unmasks a nucleophile (in this case, a phenol) that carries out an intramolecular attack on the amide bond, resulting in cy-clization of the pro-moiety and elimination of the peptide. [Leu5]enkephalin was one of the therapeutic peptides used to validate the concept, as illustrated in Fig. 8.25 [241],... 

Problem 16.67 Prepare 2-methylbutanoic acid from 2-butanol. ... 

Problmn 17.13 Use malonic ester to prepare (a) 2-ethylbutanoic acid, (b) 3-methylbutanoic acid, (c) 2-methylbutanoic acid, (d) trimethylacetic acid. M... 

Figure 10.10 The synthesis of 2R-methylbutanoic acid, illustrating the use of a chiral auxiliary. The chiral auxiliary is 2S-hydroxymethyltetrahydropyrrole, which is readily prepared from the naturally occurring amino acid proline. The chiral auxiliary is reacted with propanoic acid anhydride to form the corresponding amide. Treatment of the amide with lithium diisopropyla-mide (LDA) forms the corresponding enolate (I). The reaction almost exclusively forms the Z-isomer of the enolate, in which the OLi units are well separated and possibly have the configuration shown. The approach of the ethyl iodide is sterically hindered from the top (by the OLi units or Hs) and so alkylation from the lower side of the molecule is preferred. Electrophilic addition to the appropriate enolate is a widely used method for producing the enantiomers of a-alkyl substituted carboxylic acids...

The halolactonization reaction can be utilized to synthesize enantiomerically pure ot-hydroxy acids. In fact, cyclization of the (S)-/V-(a,/ii-unsaturated acyl)proline 1, prepared by the condensation of ( S )-pi oline and ( )-2-methyl-2-butenoyl chloride in 86 % yield, proceeds stereoselec-tively. The halolactonization, carried out by stirring the unsaturated amide with an equivalent of jY-bromosuccinimide in dimethylformamide for 20 hours, provides the bromolactone 2 in 84% yield and a diastereomeric ratio of 94.5 5.5. Debromination with tributyltin hydride in benzene affords the crude lactone 3 which is hydrolyzed with 36% hydrochloric acid at reflux to give (R)-2-hydroxy-2-methylbutanoic acid (4)1,2,4b. 

A chiral 2-alkyl-4,5-dihydrooxazole 7 is obtained by the use of (+)-( 5, 2 S)-1-phenyl-2-aminopropane-1,3-diol, available from the chiral pool (see p 115). From this, the methyl ether 8 is prepared using sodium hydride and iodomethane. As a result of internal asymmetric induction, the alkylation of its lithium derivative occurs diastereoselectively. In the case of = Me, = Et, hydrolysis yields the (+)-( S)-enantiomer of 2-methylbutanoic acid 9, with ee = 67 %, as the main product ... 

The Hell-Volhard-Zelinsky reaction has been used to prepare the amino acid valine from 3-methylbutanoic acid by the following procedure. 

Explain why an amino acid cannot be prepared from phthalimide and the ethyl ester of 2-bromo-2-methylbutanoic acid. 

A different approach to hydroxy amino acids used the allylic bromination of 3-methyl-2-butenoic acid to give a mixture of 2.62 and 2.63, as shown in reaction 6.3 Reaction of this mixture with ammonium hydroxide led to formation of lactam 2.64, which was hydrolyzed to 4-amino-2,3-dihydroxy-3-methylbutanoic acid, 2.65. Hydroxylactams can be converted to functionalized amino acids other than hydroxy amino acids. An example is shown in reaction 7, where 5-fIuoromethyl-2-pyrroli-dinone [2.67) was prepared from 5-hydroxymethyl-2-pyrrolidinone ( .66) by reaction with chlorotrifluorodiethylaminoethane.37 Hydrolysis gave 4-amino-5-fluoropentanoic acid, 2.68. 

What is the structure of valine When isolated from proteins, natural valine has a specific rotation [a] of +26°. What is the rotation of valine prepared via halc enation of 3-methylbutanoic acid ... 

Andrushko N, Andrushko V, Thyrann T, Kdnig G, Bomer A. Synthesis of enantiopure (R)-2-(4-methoxy-3-(3-methoxy-propoxy)-benzyl)-3-methylbutanoic acid-a key intermediate for the preparation of Aliskiren. Tetrahedron Lett. 2008 49(41 ) 5980-5982. 

Effectively, addition of bromine (1 equivalent) to 3-methyl-l,2-bis(trimethylsiloxy)cy-clobutene, prepared by sodium induced acyloin cyclization of methyl 2-methylbutanoate in the presence of chlorotrimethylsilane, followed by treatment with sodium hydroxide and acidification, gave cfs-l-hydroxy-2-methylcyclopropanecarboxylic acid (9) quantitatively (dia-stereoselectivity > 96%). ... 

A heterogeneous tartaric acid modified nickel catalyst was used in the synthesis of methyl (S,.S )-3-hydroxy-2-methylbutanoate. necessary for the preparation of the sex-attractant of the pine sawfly. A syntanti ratio of 75 25 was obtained69. 

Synthesis. Polyampholytes are most readily prepared by the direct statistical copolymerization of anionic and cationic monomers typically in aqueous media, via conventional free radical pol3unerization. Examples of such materials were first reported in the 1950s (240-244). Using this approach a wide range of copolymers and terpolymers, often with a neutral hydrophilic monomer such as acrylamide, have been reported. For example, early reports of statistical polyampholytes include the methacrylic acid-stat-2-(dimethylamino)ethyl methacrylate copolymers (245), from IZ and 2Z with 6Z and the iV,A(-diethylallylamine-stat-acrylic acid copolymers from IZ and 6Z (246). More recently, synthesis and properties of novel polyampholytic terpol5uners have been described (247-250). For example, the aqueous solution properties of novel ampholytic terpolymers of acrylamide, sodium 3-acrylamido-3-methylbutanoate 5Z and 3-(acrylamidopropyl)trimethylammonium chloride 8Z have been studied in detail (187). 

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