A-Azido acids

A 0.05-0.10 M solution of (45,2S)-3-(2-azidoacyl)-4-benzyl-l, 3-oxazolidin-2-one in THF/H20 3 1 stirred at 0 rC under N2 is treated with 2.0 equiv of solid LiOH. After stirring for 20 min. excess 0.5 N aq NaHCO, is added and the THF is removed in vacuo. The residual mixture is extracted with four portions of CH2C12. The organic extracts are combined, dried with Na,S04, and evaporated in vacuo to afford the recovered chiral auxiliary in 95-100% yield. The aqueous phase is acidified to pH 1 -2 with 3 N aq HC1 and extracted successively with four portions of EtOAc. The combined organic extracts arc dried over Na2S04 and evaporated in vacuo to afford the a-azido acid 8 yield 90 100%. 8 is generally found to be pure by H-NMR spectroscopy and combustion analysis. If necessary, 8 can be purified by Hash chromatography (silica gel hexane/F.tOAc/HOAc 50 50 1). [The azido acid 8 (R = C H5) racemizes to the extent of 5-10% under these conditions.]... 

Whereas the saponification of the a-azidocarboximides proceeds in high yields, the hydrolysis of the sterically demanding (S)-7 (R = -Bu), however, proved to be problematic, since cleavage occurs predominantly at the endocyclic oxazolidinone carbonyl. A dramatic improvement has been achieved in the lithium hydroperoxide mediated hydrolysis of this substrate. The desired cnantiomerically pure a-azido acid (S)-8 (R = r-Bu) is thereby obtained in 98 % yield along with a 98% recovery of the chiral auxiliary. 

A stirred solution of 1.0 mmol of the (45,2 5)-3-(2 -azidoacyl)-4-benzyl-1,3-oxazolidin-2-one 7 in 15 mL of THF and 4.6 mL of H20, cooled to 0 "C, is treated with 0.40 mL (4.1 mmol, 4 equiv) of 31 % H202 followed by 48 mg (2.00 mmol, 2.0 equiv) of solid LiOH. After stirring at 0 "C for 30 min, the reaction is treated with a solution of 0.55 g (4.4 mmol) of Na,S03 in 3 mL of H20 followed by 10 mL of 0.5 N aq NaHCOj. After removal of the THF in vacuo on a rotary evaporator, the residue is diluted to 80 mL with H2G and extracted with four portions of CH2C12 (200 mL total). The aqueous phase is acidified to pH 1 -2 with 5 N aq HC1 and extracted with four portions of F.tOAc (400 mL total). The EtOAc extracts arc combined, dried over Na2S04, evaporated in vacuo to yield the pure a-azido acid 8. The CH,C12 extracts are combined, dried over Na2S04, and evaporated in vacuo to afford the chiral auxiliary 10, which can be purified further, if necessary, by recrystallization or chromatography. 

This hydrolysis of the chiral imide auxiliary in the presence of other potentially vulnerable ester groups has proved to be very successful. A lucid example is given in the synthesis of the cyclic tripeptide OF4949-III 14. The complex a-azidocarboximide 11 is transformed into the corresponding a-azido acid 12 by means of lithium hydroperoxide in 89% yield. 

Soellner MB, Nilsson BL, Raines RT. Staudinger ligation of a-azido acids retains stereochemistry. Staudinger ligation of a-azido acids retains stereochemistry. J. Org. Chem. 2002 67 4993-4996. 

Due to the lack of efficient protecting groups and the difficult accessibility of natural amino acids, the use of amino acid precursors for the synthesis of peptides was thoroughly investigated during the earliest periods of peptide chemistry. For this purpose a-halo acids, a-azido acids,and a-oxo acidsf - were used (for a comprehensive review of the older literature on this subject, see reft 1). 

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 ... 

Optically active a-azido acids as versatile a-amino acid synthons are obtained by diaste-reoselective halogenation of chiral auxiliary-based enols or enolatest followed by stereospecific azide displacement by A(A(A, A -tetramethylguanidinium azide or alternatively... 

Azido-2-methylpropanoic Add a-Azido Acids from a-Bromo Adds and NaN3 i i 2-Bromo-2-methylpropanoic acid (4.96 g, 29.7 mmol) and NaNj (2.88 g, 44.3 mmol) were mixed in dry DMF (50mL) and stirred under argon for 2d. The mixture was concentrated, redissolved in HjO (30 mL) and acidified to pH 2 with 3 M HCl. The aqueous phase was extracted with CHCI3 (3 x 30 mL) and the organic phase was dried, concentrated, and purified by vacuum liquid chromatography (VLCI " ) (AcOH/EtOAc/heptane 5 20 75) yield 2.68 g (70%). 

Since azides are smoothly reduced on solid supports with SnCybenzenethiol/TEA (5 mmol/ 25 mmol/25 mmol for 1 mmol resin-bound azide rt, 2 this alternative procedure has been exploited for the synthesis of oligoureas on resin using a-azido acids.Similarly, azides are efficiently reduced to amines with dithiothreitol (DTT),P 1 a procedure that was successfully transferred to the reduction of a-azidoacyl peptides on resin for the SPPS with a-azido acids.In the case of sterically hindered azides, addition of small amounts of 2-sulfanylethanol to the DTT/DIPEA mixture or the use of DBU as a base enhances the reaction rates (Scheme Other reductions of azides include the use of H2S/pyridine/... 

As a-azido acids are readily reduced to a-amino acids, the problem of a-amino protection is fully bypassed with the highly reactive a-azido acid chlorides (see also Section 2.1.1.10.2). The quantitative reduction of a-azido acids to the corresponding amino acids is accomplished by treatment with DTT/DIPEA/DMF at 50°C.P Chiral a-azido acid chlorides can be used under solid-phase conditions without loss of configuration, but since the reduction process is slow, the method is not attractive for standard peptide synthesis. Compatibility of the a-azido acids with Fmoc- and Boc-chemistry and acid chloride activation, however, makes a-azido amino acid chlorides highly useful for incorporation of very sterically hindered amino acids such as C -disubstituted glycines. 

Azido-2-propylpentanoic Add Chloride Typical Procedure for a-Azido Acids ... 

Azido-2-propylpentanoic acid (95.6 mg, 0.516 mmol) was dissolved in freshly distilled thionyl chloride/dry CH2CI2 (0.8 mL, 1 1) and heated at 50 °C. After 3 h, the soln was taken up in toluene (3 mL) in an inert atmosphere and the a-azido acid chloride was diluted with anhydr CHjCb (1 mL). 

The a-azido acid chlorides 113, on reaction with amines, are assumed to form the extremely labile a-azidoketenes 114 which niay be trapped as lactams 116 when the reaction is carried out at — 60° in the presence of Schiff bases Only the nitriles 115 were isolated fol-... 

Intermediate (5)-l is simply yV-benzyl-4-fluorophenylglycine that has been capped with an ethylene unit. The original synthesis in which 4-fluorophenylacetic acid was transformed to the corresponding chiral oxazolidinone 6 is depicted in Scheme 2. Masked a-azido acid 7 was formed diastereoselectively from this intermediate. Hydrolysis and azide reduction afforded enantiomerically pure (5)-4-fluorophenyl glycine (8). Reductive amination with benzaldehyde introduced the V-benzyl unit and subsequent A, 0-dialkylation with ethylene dibromide provided chiral oxazinone 1. 

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