2- bromo-4-methylpentanoic acid

When it is required to prepare an a-bromo acid from a carboxylic acid which is not particularly readily available commercially, but which can be synthesised by the malonic acid route (Section 5.11.6, p. 680), advantage may be taken of the ease of bromination in the a-position of the intermediate alkylmalonic acid. The substituted bromomalonic acid undergoes ready decarboxylation on heating to yield the a-bromo acid (e.g. 2-bromo-3-methylpentanoic acid, Expt 5.166). 

DL-Isoleucine (2-amino-3-methylpentanoic acid). Allow 65 g (0.33 mol) of 2-bromo-3-methylpentanoic acid (Expt 5.166) to react with 400 ml of concentrated ammonia solution as for valine. Concentrate the resulting solution to about 130 ml, filter off a first crop of crude product and wash with 20 ml of ethanol. Further concentrate the aqueous filtrate to about 60 ml to obtain a second crop of crude product, and wash it with 10 ml of water followed by... 

JV,0,S -Triacetyl-Cys(ol) (21 1.50 g, 6.44 mmol) was hydrolyzed with 1.7 M HC1 (60 mL) at 90 °C under an atmosphere of N2 for 72 h. The solvent was removed under reduced pressure and residual H20 was removed by azeotropic distillation with absolute EtOH. The crude H-L-Cys(ol)-HCl was dissolved in absolute EtOH (20 mL) containing NaOEt (17.34 mmol). To this soln was added (f )-2-bromo-4-methylpentanoic acid (24 0.38 g, 4.46 mmol) in absolute EtOH (5mL). The mixture was stirred for 72 h at rt followed by removal of the solvent. The residue was dissolved in H20, acidified with 6 M HC1, and extracted with Et20. The aqueous portion was neutralized with 2 M NaOH and diluted to 150 mL with deionized H20. This soln was desalted on a column of Dowex 1X8 (2 x 20 cm), according to the procedure of Dreze et a I.1441 The ninhydrin-positive fractions were pooled and the solvent was removed under reduced pressure. The residue was recrystallized (47.5% EtOH) to give 25 yield 0.70 g (70%) mp 179-180 °C [ex]25 D -53.7 (c 2.5, H20). 

D-Leucine (100.0 g, 0.76 mol) and potassium bromide (317.5 g, 2.67 mol) were dissolved in aqueous acid (150 ml concentrated sulfuric acid in 500 ml of water). The solution was cooled to -2°C and sodium nitrite (69.6 g, 0.95 mol in water) was added over 1 h taking care to maintain the temperature between -1°C and -2°C. After addition was complete the mixture was kept at 0°for a further hour, then DCM was added and the mixture stirred for a few minutes. The layers were separated and the aqeous phase was washed with further portions of DCM (5 x 250 ml). The combined organic layers were dried over magnesium sulfate then the solvent removed to give the 2R-bromo-5-methylpentanoic acid as a pale yellow oil (123.1 g, 0.63 mol, 83%). 

R-Bromo-5-methylpentanoic acid (123.0 g, 0.63 mol) was dissolved in DCM (400 ml) and the solution cooled to -40°C while isobutene was condensed in to roughly double the volume. Maintaining the temperature at -40°C concentrated sulfuric acid (4 ml) was added dropwise. When the addition was complete the reaction was allowed to warm to room temperature overnight. The resultant solution was concentrated to half the volume by removing the solvent at reduced pressure, then the DCM was washed twice with an equal volume of 10% sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and the solvent removed under reduced pressure to leave the t-butyl 2R-bromo-5-methylpentanoate as a yellow oil (148.1 g, 0.59 mol, 94%). 

If methanol rather than water is added at the end of a Hell-Volhard-Zelinskii tion, an ester rather than an acid is produced. Show how you could prepare metl l 2-bromo-3-methylpentanoate from 3-methylpentanoic acid, and propose a med nism for the ester-forming step. 

Parent compound pentane (becomes pentanoic acid) Position of —COOH carbon-1 (Must be ) Substituents 2-bromo and 4-methyl Name 2-Bromo-4-methylpentanoic acid... 

Problem 15.36. Draw a structural formula for each of the following compounds (a) 3-chlorobutanoic acid, ib) 4-methylpentanoic acid, (c) 2-bromo-4-methylbenzoic acid, id) 3-methylcyclopentanecar-boxylic acid. 

The four diastereomers of 2-bromo-3-hydroxy-4-methylpentanoic acid are shown below, with the configuration of each stereocenter identified. 

Optically active acids. The a-bromo acid obtained from L-alloisoleucine by di-azotization (s. Synth, Meth. 13, 492) added to an aq. dispersion of Zn-dust, and stirred or refluxed overnight -> (R)-3-methylpentanoic acid. Y ca. 100%, overall 50% optical purity 92%. - This route is recommended if alkaloid resolution fails. C. G. Overberger and I. Cho, J. Org. Chem. 33, 3321 (1968). 

An alternative approach used phthalimido-ketone 4.121, which was converted to an N-phthalimidoyl alcohol under Reformatsky conditions, but removal of the phthalimidoyl group led to formation of lactam 4.J22.55 Treatment with acid led to conjugated lactam 4.123 rather than the amino acid. If 4.121 was reacted with bromo f-butyl acetate and zinc, alcohol 4.124 was obtained after hydrolysis of the ester.55 Removal of the phthalimidoyl group with hydrazine then led to 5-amino-3-hydroxy-3-methylpentanoic acid, 4.125. 2-Aryl-3-hydroxy derivatives such as... 

Hydroxyleucine is an amino acid (Chapter 26) that is a key component in the structures of many depsipeptide medicinal agents, such as sanjoinine (below), (a) Find the part of the sanjoinine molecule that is derived structurally from (2S,3S)-3-hydroxyleucine. (b) Although many depsipeptide antibiotics occur in nature, the quantities available are too small to be useful pharmaceutically thus these molecules must be synthesized. (25,35)-3-Hydroxyleucine, which is also not available in quantity from nature, must be synthesized as well. Possible starting materials are the four diastereomers of 2-bromo-3-hydroxy-4-methylpentanoic acid (below). Draw structural formulas for each of these diastereomers and identify which of the four should be the best starting material for a preparation of (25,35)-3-hydroxyleucine. 

Problem 51 of Chapter 6 presented a strategy for the synthesis of the amino acid (25,35 )-3-hydroxyleucine, requiring as the starting material a specific stereoisomer of 2-bromo-3-hydroxy-4-methylpentanoic acid. Addition of bromine... 

Ethanolic Na-ethoxide added slowly at 5-10 to a mixture of ethyl 2-bromo-3-methylpentanoate and thiophene-2-carboxaldehyde with stirring, whidi is continued 0.5 hr. at the same temp, and 3 hrs. while the mixture is allowed to warm to room temp., water added, stirred 3 hrs. in a steam bath, cooled to room temp., and dil. phosphoric acid added to bring the pH to 3, whereby COg-evolution occurs l-(2-thienyl)-3-methyl-2-pentanone. Y 82%. F. e. s. J.D. Belcher, Jr., et al., J. Chem. Eng. Data 20, 206 (1975). 

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