Aspartic acid intermediate

Precursors in the biosynthesis of pantothenic acid include a-ketoiso valeric add (pantoic acid), uracil (/J-alanine), and aspartic acid. Intermediates in the synthesis include ketopantoic acid, pantoic acid, and -alanine. 

Polyanionic polyamides are available by the condensation of polycarboxyamino acids such as glutamic acid and aspartic acid. Though both homopolymers are known and claimed as biodegradable, L-aspartic acid is more amenable to a practical industrial thermal polymerization since it has no tendency to form an internal N-anhydride as is the case with glutamic acid. An alternative synthesis for poly(aspartic acid) is from ammonia and maleic acid via an unisolated D,L-aspartic acid intermediate. 

Q The enzyme active site contains an aspartic acid, a histidine, and a serine. First, histidine acts as a base to deprotonate the -OH group of serine, with the negatively charged carboxylate of aspartic acid stabilizing the nearby histidine cation that results. Serine then adds to the carbonyl group of the triacylglycerol, yielding a tetrahedral intermediate. 

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. 

The HIV-1 protease, like other retroviral proteases, is a homodimeric aspartyl protease (see Fig. 1). The active site is formed at the dimer interface, with the two aspartic acids located at the base of the active site. The enzymatic mechanism is thought to be a classic acid-base catalysis involving a water molecule and what is called a push-pull mechanism. The water molecule is thought to transfer a proton to the dyad of the carboxyl groups of the aspartic acids, and then a proton from the dyad is transferred to the peptide bond that is being cleaved. In this mechanism, a tetrahedral intermediate transiently exists, which is nonconvalent and which is mimicked in most of the currently used FDA approved inhibitors. 

The type of intermediate that is formed in the slow inhibition with D-gly-cals was identified, with the aid of the ) -D-glucosidase A3 from Asp. wentii, as an ester of 2-deoxy-D-araA/ o-hexose with an aspartic acid side-chain. The same aspartoyl residue had already been shown, by labeling with con-duritol B epoxide (see Section 111,1), to be essential for -D-glucoside hydrolysis. In addition, this aspartate was found to form a glycosyl -enzyme... 

Radkiewicz, J. L., H. Zipse, S. Clarke, and K. N. Houk. 1996. Acclerated Racemization of Aspartic Acid and Asparagine Residues via Succinimidine Intermediates An ab initio Theoretical Exploration of Mechanism. J. Am. Chem. Soc. 118,9148. 

A number of P-chirogenic diaminophosphine oxides (DIAPHOXs) 275 derived from aspartic acid were prepared via hydrolysis of triaminophosphine intermediate 274, generated in a fully diastereoselective reaction of triamines 273 with phosphorus trichloride (Scheme 65) [102, 103],... 

Thus, the best compromises for Boc and Fmoc chemistries seem to be cyclohexyl and 2,4-dimethylpent-3-yl (Dmpn), which is of intermediate stability, and the removal of which by trifluoromethanesulfonic acid with the aid of thioanisole (see Section 6.22) leads to minimal imide formation (see Section 6.13). Points to note are that acidolysis of esters by hydrogen fluoride can lead to fission at the oxy-car-bonyl bond instead of the alkyl-oxy bond, thus generating acylium ions that can react with nucleophiles (see Sections 6.16 and 6.22), and that benzyl esters may undergo transesterification if left in methanol. The side reactions of cyclization (see Section 6.16) and acylation of anisole (see Section 6.22) caused by acylium ion formation do not occur at the side chain of aspartic acid.47-51... 

A. A. Kossiakoff, S. A. Spencer, Direct Determination of the Protonation States of Aspartic Acid-102 and Histidine-57 in the Tetrahedral Intermediate of the Serine Proteases Neutron Structure of Trypsin , Biochemistry 1981, 20, 6462-6474. 

After formation of the aldimine, numerous factors in the enzyme facilitate deprotonation of the a-carbon (Fig. 3, Step II). The lysine liberated by transimi-nation is utilized as a general base and is properly oriented for effective deprotonation [11]. Furthermore, the inductive effects of the ring system are tuned to increase the stabilization of the quinoid intermediate. For example, the aspartate group that interacts with the pyridyl nitrogen of the co enzyme promotes proto-nation to allow the ring to act as a more effective electron sink. In contrast, in alanine racemase, a less basic arginine residue in place of the aspartic acid is believed to favor racemization over transamination [12]. 

If aspartic acid-52 acts as a nucleophile in lysozyme reactions a glycosyl enzyme intermediate will be formed [60]. There is no evidence, kinetic or otherwise, for substituted enzyme intermediates, but rapid breakdown might preclude attainment of detectable concentrations. Formation of a substituted enzyme could explain the observed retention of configuration at the anomeric carbon in transglycosidation reactions, provided backside attack in a subsequent reaction is chemically reasonable. It has therefore been important to attempt to understand the chemistry of acylal hydrolysis so as to assess the properties that would be expected of an acylal intermediate in reactions catalysed by the enzyme. 

The alternative role for direct involvement of aspartic acid-52 is electrostatic stabilization of an oxocarbonium ion, a reasonable expectation in view of the steric situation in the active site, the poor internal stabilization of a glycosyl carbonium ion, and the apparent need for some kind of stabilization if general acid catalysis by glutamic acid-35 is to occur. Nevertheless, this assignment is questionable since electrostatic stabilization has not been demonstrable with o-methoxymethoxyisophthalic acid (Dunn and Bruice, 1970) and benzaldehyde disalicyl acetals (Anderson and Fife, 1973). In the former example, such stabilization should be favourable because the carbonium ion intermediate is unstable. 

Joseph P.A. Harrity of the University of Sheffield has reported (J. Org. Chem. 2005, 70, 207) a complementary approach to enantiomerically-pure piperidines. Alkylated azridines such as 17 are readily available from aspartic acid. Pd-catalyzed condensation of 17 with the Trost reagent 18 was found to be most effectively mediated by bis-phosphines such as dppp , 1,3-bis-diphenylphosphinopropane. The piperidine 19 was the key intermediate for the preparation of several of the Nuphar alkaloids, including 20. 

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