Aspartic protection

Erbeldinger, Mesiano, and RusseU carried out a thermolysin-catalyzed reaction of L-aspartate, protected with a carboxybenzoxy group with L-phenylalanine methyl ester, in order to synthesize Z-aspartama [5]. The thermolysin-catalyzed condensation reaction is reported in Scheme 10.3. 

Cyclic anhydddes aie formed readily from Al-protected aspartic and glutamic acids. 

The carboxamidomethyl ester was prepared for use in peptide synthesis. It is formed from the cesium salt of an A-protected amino acid and a-chloroacetamide (60-85% yield). It is cleaved with 0.5 M NaOH or NaHCOa in DMF/H2O. It is stable to the conditions required to remove BOC, Cbz, Fmoc, and r-butyl esters. It cannot be selectively cleaved in the presence of a benzyl ester of aspartic acid. ... 

The r-butyl ester is a relatively hindered ester, and many of the methods reported below should be—and in many cases are—equally effective for the preparation of other hindered esters. The related 1- and 2-adamantyl esters have been used for the protection of aspartic acid. ... 

The p-bromobenzyl ester has been used to protect the /3-COOH group in aspartic acid. It is cleaved by strong acidic hydrolysis (HF, 0°, 10 min, 100% yield), but is stable to 50% CF3COOH/CH2CI2 used to cleave /-butyl carbamates. It is 5-7 times more stable than a benzyl ester. ... 

Oxazolidines are prepared to allow selective protection of the ct- or aj-C02H groups in aspartic and glutamic acids. 

This ester was designed as a base-labile protective group. Monoprotection of aspartic acid was achieved using the DCC/DMAP protocol. Cleavage is... 

Relative Lability of Aspartic Acid )8-Carboxyl Protective Groups ... 

Dimethyl-3-pentanoL DCC, DMAP, CH2CI2, 4 h. This group was developed as an improvement over the use of cylcohexanol for aspartic acid protection during peptide synthesis. ... 

A more general method for preparation ofa-amino acids is the amidotnalmatesynthesis, a straightforward extension of the malonic ester synthesis (Section 22.7). The reaction begins with conversion of diethyl acetamidomalonate into an eno-late ion by treatment with base, followed by S 2 alkylation with a primary alkyl halide. Hydrolysis of both the amide protecting group and the esters occurs when the alkylated product is warmed with aqueous acid, and decarboxylation then takes place to vield an a-amino acid. For example aspartic acid can be prepared from, ethyl bromoacetate, BrCh CCHEt ... 

Intermediate 10 must now be molded into a form suitable for coupling with the anion derived from dithiane 9. To this end, a che-moselective reduction of the benzyl ester grouping in 10 with excess sodium borohydride in methanol takes place smoothly and provides primary alcohol 14. Treatment of 14 with methanesulfonyl chloride and triethylamine affords a primary mesylate which is subsequently converted into iodide 15 with sodium iodide in acetone. Exposure of 15 to tert-butyldimethylsilyl chloride and triethylamine accomplishes protection of the /Mactam nitrogen and leads to the formation of 8. Starting from L-aspartic acid (12), the overall yield of 8 is approximately 50%, and it is noteworthy that this reaction sequence can be performed on a molar scale. 

In the published synthesis the ozonolysis is performed on the protected product (9) and aldehyde (10) isolated before oxidation, hydrolysis and decarboxylation give aspartic acid. 

Treatment of the disaccharide derivative, 2,3,6-tri-0-acetyl-4-0-(2,3,4,6-tetra-O - acetyl -fi-D- galactopyranosyl) -fi-D- glucopyranosyl-amine (46), with 71 also gave50 a mixture of protected L-aspart-1- and -4-oyl disaccharide derivatives (77 and 78). The almost identical yields of... 

Ibogaine protects the N-methyl-D-aspartate neuron receptors against excessive release of excitatory amino acids and represents, therefore, a potential therapeutic agent for the treatment of Alzheimer s disease, Huntington s chorea, and other... 

In a comparable approach, Roques and coworkers [15] converted the aspartic acid derivative 7-23, which bears a protected thiol in the 3-position, into unsaturated compounds 7-27 and 7-28, respectively (Scheme 7.9). 

Longbottom, D., Redmond, D.L., Russell, M., Liddell, S., Smith, W.D. and Knox, D.P. (1997) Molecular cloning and characterisation of an aspartate protease associated with a highly protective gut membrane protein complex from adult Haemonchus contortus. Molecular and Biochemical Parasitology 88, 63-72. 

Nonaka S, Chuang DM. Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N -methyl-D-aspartate receptor-mediated calcium influx. Proc Natl Acad Sci USA 1998 95 2642-2647. 

The volume concludes with the preparation of four useful starting materials. The highly electrophilic tricarbonyl reagent DIMETHYL MESOXALATE finds application as a two-electron component in various pericyclic processes. 9-BROMO-9-PHENYL-FLUORENE is becoming increasingly used for the protection of primary amines, particularly amino acids and amino esters. Two methods for introducing the 9-phenylfluorenyl group are illustrated in the preparations of (S)-N-(9-PHENYLFLUOREN-9-YL)ALANINE AND (S)-DIMETHYL N-(9-PHENYLFLUOREN-9-YL)ASPARTATE. 

Cyclocondensation processes of p-dicarbonyl derivatives or their analogues are still widely employed for the synthesis of new isoxazoles. Non-proteinogenic heterocyclic substituted ct-amino acids have been synthesised using the alkynyl ketone functionality as a versatile building block ynone 2, derived from protected L-aspartic acid 1, reacted with hydroxylamine hydrochloride affording the isoxazole 3 with enantiomeric purity greater than 98% ee <00 JCS(P 1 )2311 >. 

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