A-Azido carboxylic acids

Evans, D. A., Britton, T. C., Ellman, J. A., Dorow, R. L. The asymmetric synthesis of a-amino acids. Electrophilic azidation of chiral imide enolates, a practical approach to the synthesis of (R)- and (S)-a-azido carboxylic acids. J. Am. Chem. Soc. 1990, 112, 4011-4030. 

Functionalization of alkenes. CAN oxidation is often employed in the generation of reactive species for addition to alkenes. Thus an azido radical created in the presence of a-methoxy a, -unsaturated nitriles is trapped. " The adducts are useful precursors of a-azido carboxylic acids, and thence a-amino acids. 

Azirine/oxazolone method, a synthetic method for the introduction of sterically highly hindered a,a-disubstituted a-amino acids into peptides. The synthesis of e.g., Aib-rich peptides requires either highly reactive coupling reagents (e.g., amino acid halides) or special derivatives (such as 3-amino-2H-azirines or a-azido carboxylic acid chlorides). The azirine/oxazolone method utilizes an amino component that... 

Scheme 12.60. The trichloromethyl ketone is reduced with catecholborane in the presence of the (5 )-oxazaborohdine catalyst. The resulting (i )-secondary alcohol (produced in high enantioselectivity) is treated with sodium hydroxide and sodium azide to yield the corresponding (5 )-a-azido carboxylic acid, and reduction then produces the amino acid (after Corey, E. J. Link, J. O. /. Am.Chem.Soc., 1992,114,1906).

A combination of N and CO activation was used by Vilarrasa to generate a range of medium-sized lactams 56. m-Azido carboxylic acids 54 were initially... 

This methodology provides a general synthesis of L-amino acids in 92-96% ee and in chemical yields of about 40-60%. Thus reaction of 3 (X = Br) with NaN3 under phase-transfer conditions provides 6, which is homologated to the 1-chloro-2-azidoboronate 7. This product is oxidized by sodium chlorite directly to an azido carboxylic acid (8). Hydrogenation of 8 provides L-amino acids (9). 

In general, the method of enzymatic cyanohydrin synthesis promises to be of considerable value in asymmetric synthesis because of the synthetic potential offered by the rich chemistry of enantiomerically pure cyanohydrins, including their stereoselective conversion into other classes of compounds such as a-hydroxy carboxylic acids or respective esters, w c-diols, / -aminoalcohols, aziridins, a-azido(amino/fluoro)nitriles, and acyloins [501, 516]. 

However, regiopure azido 1,2-diol 19 is converted to the corresponding azido carboxylic acid 22 by oxidative glycol cleavage with periodic acid in the presence of catalytic amounts of ruthenium trichloride. Interestingly, the use of sodium periodate instead of periodic acid resulted in a 10-15 % epimerization of the C-5 stereocenter. 

Racemic or achiral a-azido acids are synthesized by direct azide substitution on commercially available a-bromo carboxylic acids or by radical bromination of carboxylic acids followed by azide substitution. In general, azido acids are stored in the dark to avoid photolytic degradation with loss of nitrogen temperatures above 50 °C should be avoided. Radical a-bromination of a-branched carboxylic acids as required for the synthesis of a,a-dialkyl or a,a-diaryl amino acids is performed with A-bromosuccinimide. This is followed by nucleophilic substitution with sodium azide or other azide donors, e.g. tetrabutylannmonium azide, to produce achiral or racemic a-azido-a,a-diaIkyl or a-azido-a,a-diaryl carboxylic acids (Scheme 74).Synthesis of more sterically hindered a,a-disubstituted azido acids leads to hydroxy compounds when prolonged reaction times are required and not sufficient care is taken to operate under dry conditions and an inert atmosphere.t ... 

Esters of 2-(2-azidophenyl)ethyl alcohol are photolyzed under a high-pressure mercury lamp to a reactive nitrene intermediate which, following insertion into the alkyl side-chain, undergoes elimination to give the free carboxylic acid (up to 32%) and producing indole. The photochemical release was somewhat improved (65-80%) when 5-azido-4-(hydroxy-methyl)-l-methoxy naphthalene was used (see Scheme 27). 

FORMATION AND PHOTOCHEMICAL WOLFF REARRANGEMENT OF CYCLIC a-DIAZO KETONES D-NORANDROST-5-EN-3U-OL-16-CARBOXYLIC ACIDS, 52,53 FORMIC ACID, AZIDO, f-BUTYL ESTER, 50, 9... 

Types of compounds are arranged according to the following system hydrocarbons and basic heterocycles hydroxy compounds and their ethers mercapto compounds, sulfides, disulfides, sulfoxides and sulfones, sulfenic, sulfinic and sulfonic acids and their derivatives amines, hydroxylamines, hydrazines, hydrazo and azo compounds carbonyl compounds and their functional derivatives carboxylic acids and their functional derivatives and organometallics. In each chapter, halogen, nitroso, nitro, diazo and azido compounds follow the parent compounds as their substitution derivatives. More detail is indicated in the table of contents. In polyfunctional derivatives reduction of a particular function is mentioned in the place of the highest functionality. Reduction of acrylic acid, for example, is described in the chapter on acids rather than functionalized ethylene, and reduction of ethyl acetoacetate is discussed in the chapter on esters rather than in the chapter on ketones. 

To a solution of 5-methoxymethoxy-7-oxa-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid methyl ester (4.9 g, 22.9 mmol) in 8/l-Me0H/H20 (175 ml, v/v) was added sodium azide (7.44 g, 114.5 mmol) and ammonium chloride (2.69 g, 50.4 mmol) and the mixture was refluxed for 15 h. The reaction was diluted with water (75 ml) to dissolve precipitated salts and the solution was concentrated to remove methanol. The resulting aqueous phase containing a precipitated oily residue was diluted to a volume of 200 ml with water and was extracted with ethyl acetate (3 times 100 ml). The combined organic extracts were washed with saturated NaCI (100 ml), dried (MgS04), filtered and evaporated. The crude was purified on silica gel (1/1-hexane/ethyl acetate) to afford 5-azido-4-hydroxy-3-methoxymethoxy-cyclohex-l-ene-l-carboxylic acid methyl ester (5.09 g, 86%) as a pale yellow oil. Subsequent preparations of 5-azido-4-hydroxy-3-methoxymethoxy-cyclohex-l-ene-l-carboxylic acid methyl ester provided material which was of sufficient purity to use in the next step without further purification. 

C for 21 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (about 100 ml) and was filtered. The filtrate was evaporated and the residue was partitioned between diethyl ether (100 ml) and saturated NaCI (100 ml). The organic phase was washed again with saturated NaCI (100 ml), dried (MgS04), filtered, and was evaporated. Additional crude product was obtained from the aqueous washings by extraction with ethyl acetate and treated in the same manner as described above. The crude product was purified on silica gel (5% MeOH/CH2CI2) to afford 4-amino-5-azido-3-methoxymethoxy-cyclohex-l-ene-l-carboxylic acid methyl ester (2.95 g) as an oil which contained a small amount of triphenylphosphine oxide impurity from the previous step. 

To a solution of 4-acethylamino-5-azido-3-(l-ethyl-propoxy)-cyclohex-l-ene-1-carboxylic acid methyl ester (268 mg, 0.83 mmol) in THF (7.0 ml) was added aqueous KOH (1.60 ml of a 1.039 N solution) at room temperature. After stirring for 19 h at room temperature the reaction was acidified to pH 4.0 with Amberlite IR-120 (H+) acidic resin. The resin was filtered and washed with water and ethanol. Concentration in vacuo gave the crude 4-... 

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