2-Methylbutanoic acid reactions

It has been confirmed that isoleucine but not 3-hydroxy-2-methylbutanoic acid is a precursor for the tiglic acid which is the esterifying acid in some tropane alkaloids [e.g., meteloidine (77) (735)]. In the biosynthesis of meteloidine (77) from 3a-hydroxytropane (1), the hydroxyl groups at C-6 and C-7 are most probably introduced after esterification at C-3 (5) (Scheme 23). In this connection we would point out that scopolamine (89) is a well-known 2,3) metabolite of hyoscyamine (27) and that the reaction proceeds via 6-hydroxyhyoscyamine [(—)-anisodamine (63)] and 6,7-dehydrohyoscyamine (211) (Scheme 26). 

Compound 24 (0.5 g, 1.75 mmol) was dissolved in THF/H20 (3 1, 30 mL). The soln was cooled in ice and LiOH (88 mg, 3.7 mmol) was added. After lh, further LiOH (36 mg, 1.5 mmol) was added and the reaction was stirred for a further 20 min. The THF was removed in vacuo and the resultant aqueous residue washed with CH2C12. The aqueous layer was adjusted to pH 2 with 2M HC1 and then extracted (CH2C12). The extracts were combined, dried (Na2S04), and concentrated to afford (R)-4-cyano-2-methylbutanoic acid yield 0.163 mg (73%). 

Similarly to the hydroformylation, under certain reaction conditions the formation of the intermediate palladium-alkyl complex can be practically irreversible as shown by the different prevailing chirality of the 2-methylbutanoic acid ester obtained from 1-butene and (Z)-2-butene, as well as from ( )- and (Z)-2-butene. Therefore, re-gioselection and enantioface selection must occur, as in hydroformylation, during or before the formation of the postulated palladium-alkyl intermediate (see Scheme IV). 

The synthesis of 2-methylbutanoic acid (Expt 5.129) is illustrative of the method. Other organometallic reagents undergo a similar carboxylation reaction, and examples of the use of organolithium and organosodium reagents are included in the section on the synthesis of aromatic carboxylic acids (Section 6.13.3, p. 1069). 

The base-catalysed acyl transfer (Baker-Venkataraman reaction) of enantiopure 2-acetyl-l-hydroxyanthraquinone esters of 2-methylbutanoic acid or of O-allyllactic acid produces the respective 1,3-diketones, precursors of anthra[l,2-fc]pyran antibiotics, without any racemization.9... 

To convert 3-methylbutanoic acid to valine, a leaving group must be introduced at the a carbon prior to displacement by ammonia. This is best accomplished by bromination under the conditions of the Hell-Volhard-Zelinsky reaction. 

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. 

If the Cannizzaro reaction of racemic 2-methylbutanal is catalyzed by H4Ru4(CO)8(R,7 -DIOP)2, an enantiomeric selection takes place for 2-methylbutanoic acid... 

The volatile compounds of these samples were analyzed using SPME-GC-MS. 15 of the compounds included in Table 1 were identified in most samples of at least a group and underwent statistical analysis butane-2,3-dione, acetic acid, 3-methylbutanal, pentanal, hexanal, butanoic acid, hex-( )-2-enal, 3-methylbutanoic acid, heptan-2-one, hept-( -2-enal, octanal, oct-( )-2-enal, 1-octen-3-ol, and non-( )-2-enal. The effect of sodium chloride content, sodium nitrite, added amino acids and reaction time on these compounds is shown below. None of the esters, sulfur and nitrogen containing compounds included in Table 1 could be statistically analyzed. 

The effect of sodium nitrite addition on the volatile compounds was barely related to reaction time no significant interaction appeared, although a slight effect (p < 0.1) was found for hexanal and 3-methylbutanoic acid. However, the effect of sodium nitrite was closely related to sodium chloride content significant interaction (p < 0.05) appeared for pentanal, hexanal, heptanal and oct-( )-2-enal, and a slight effect (p < 0.1) for hept-(E)-2-enal and octanal. 

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

Botteghi C, Bona DD, Paganelli S, Marchetti M, Sechi B (1996) Studies on the synthesis of chiral 2-(p-chlorophenyl)-3-methylbutanoic acid, a key precursor of Fenvalerate, by hydro-carbonylation reactions. An Quim Int Ed 92 101-107... 

NaAMB Series. 3-Acrylamido 3-methylbutanoic acid (AMBA) was synthesized via a Ritter reaction involving acrylonitrile and 3,3-dimethylacrylic acid in the presence of water and an excess of sulfuric acid. The synthesis basically followed the procedure set forth by Hoke and Robins. The crude product was twice recrystallized from a mixture of methyl ethyl ketone and petroleum ether prior to use (m.p. 89-91 C). The product was analyzed by elemental analysis and FTIR. Acrylamide was twice recrystallized from acetone prior to use. 

The same isocyanate derivative is also seen in the Hofmann rearrangement (Scheme 10.36). TTiat is, if the carboxylic acid chloride from the 2-methylbutanoic acid is first converted to the corresponding amide by reaction with ammonia (NH3) and the latter treated with bromine (Br2) and sodium hydroxide (i.e.,NaOBr formed from reaction of the two reagents), the corresponding A -bromo compound forms. 

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. 

Reactions 1-4 use N-chlorosulfonyl isocyanate (2.8S CSI) in reactions with various alkene moieties. When CSI reacted with 3-chloro-2-methylpropene in reaction 1, p-lactam 2.93 was produced.49 Deprotection of the nitrogen was followed by hydrolysis to give 3-amino-4-chloro-3-methylbutanoic acid (2.94). 

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