The Preparation of Pure N-Acetyl-L-leucine and L-Leucine<sup>1</sup>

DeWitt, H. D.; Ingersoll, A. W.

doi:10.1021/ja01151a108

Cited by 45 publications

(15 citation statements)

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“…(1R,2R) 1,2 Diphenylethane 1,2 diamine (ee 99%, Aldrich) and (S) proline (high purity grade) with [α] D -53.0 (c 0.5, 0.5N HCl) were used without additional purification; N acetyl (R) leucine was prepared according to a known procedure. 74 Sodium and potassium (S) prolinates were synthesized by treatment of (S) proline with an equimolar amount of NaOH or KOH in methanol at 20 °C. After removal of the solvent, the residue was thoroughly dried in vacuo.…”

Section: Methodsmentioning

confidence: 99%

Asymmetric exchange of cyclopalladated ligands: A new route to optically active phosphapalladacycles

et al. 2006

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An asymmetric version of the cyclopalladated ligand exchange reaction was developed. This procedure involves the use of prochiral phosphines in an aprotic medium. A benzylaminate palladacycle bearing the primary amino group and the bulky Bu t substituent at the C* stereo center serves as a chirality inductor.Key words: asymmetric induction, C-H bond activation, cyclopalladated ligand exchange, optically active phospha and azapalladacycles, X ray diffraction analysis.Although the idea of asymmetric C-H bond activa tion by transition metals is attractive, examples of this process are scarce. In a special case of cyclopalladation, two versions of asymmetric C-H bond activation under control of either external sources of chirality (bases) 1-7 or inner sphere sources are known. Bidentate N,N 8,9 and P,P donor 10,11 ligands were tested as the latter sources. The chirality transfer from chelated ligands proved to be highly efficient in the closure of C*O 9 and C*C palladacycles (see Refs 8, 10, and 11), whereas an attempt to generate planar chirality upon the formation of a CN palladacycle with the use of an optically active monodentate S* donor ligand (sulfoxide) in a metallating agent failed. 12 Chelation of phosphino P ylides giving rise to PC* palladacycles with diastereoselectivity of ~70% de (see Refs 13 and 14) is the only example of the use of CN palladacycles as chirality inductors. However, con figurational lability of such systems substantially limits their use.The aim of the present study was to develop a new method of asymmetric C-H bond activation based on cyclopalladated ligand exchange (CLE ) 15,16 (Scheme 1). Scheme 1Although the starting palladacycle in the CLE reac tion can serve not only as the metallating agent but also as the source of chirality, only achiral versions of this reac tion have been examined. The only attempt to perform asymmetric CLE has been unsuccessful. 17 High efficiency of cyclopalladated complexes in optical resolution 18,19 and enantioselective catalysis, 20-23 as reagents for the enantiomeric purity determination, 24,25 and as matrices for asymmetric synthesis 26-28 was documented. This stimulated the estimation of their potential as chirality inductors in CLE reactions. The preliminary results of our investigations in this field have been published re cently. 29 Results and DiscussionWe chose a series of benzylaminate CN dimers (1a,b and 2a-7a), which differ in the nature of the amino The asymmetric atom directly bound to the metal atom is marked with an asterisk.The more laconic term transcyclometallation has been pro posed 16 for the description of such reactions; however, this term does not reflects the essence of the process, in which ligands rather than metal atoms (transmetallation) are exchanged.The number of the complex corresponds to the superscript n in the code of the starting ligand HL n , and the letters stand for different derivatives of this palladacycle.

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Section: Methodsmentioning

confidence: 99%

Asymmetric exchange of cyclopalladated ligands: A new route to optically active phosphapalladacycles

et al. 2006

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“…N-Acetyl-L-phenylalanine (NAP) was prepared according to the method of DeWitt and Ingersoll (13). 14C-labeled NAP and PAP were prepared by the same methods.…”

Section: Methodsmentioning

confidence: 99%

Potential use of biaromatic L-phenylalanyl derivatives as therapeutic agents in the treatment of sickle cell disease.

Votano¹,

Altman²,

Wilchek³

et al. 1984

Proc. Natl. Acad. Sci. U.S.A.

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N-Phenylacetyl-L-phenylalanine (PAP) and L-phenylalanyl-3-aminopyridine (PAPA) are biaromatic agents with properties that make them suitable candidates for the development of a useful therapeutic agent for the treatment-of sickle cell disease. PAP and PAPA are taken up by the erythrocyte to give intra-/extracellular concentration ratios of 2.2 and 1.5, respectively, after a 2-hr exposure period. The intracellular buildup of PAP and PAPA produces moderate decreases in the mean corpuscular hemoglobin concentration (MCHC) of 6 and 10%, respectively, at 3 mM and a further decline in MCHC with increased concentration. Both PAP and PAPA increase the deoxy-Hb S solubility, C,. If Many of the approaches and rationales (1, 2) aimed at the development of chemical agents for the treatment of sickle cell disease have centered on agents that can interact covalently or noncovalently with the Hb S tetramer to increase the delay time of Hb S gelation. With respect to the latter, in vitro studies of small peptides, alkylureas, and amino acids (3-6), aryl-substituted alanines (7), and halogenated aryl derivatives of oxy acids (8) have revealed several general stereochemical criteria associated with antigelation activity for a noncovalent inhibitor. Biaromatic and bicyclic compounds are more effective than monocyclic compounds and aromatic moieties, more so than aliphatic groups. With regard to aromatic nuclei, the higher the degree of ring polarizability and hydrophobicity of the compound, the greater is its antigelation activity. However, little is known of erythrocyte penetration by these compounds except for amino acids and peptides.Another result was found with noncovalent binding compounds in the study of aromatic amino acid esters including L-phenylalanyl benzyl ester (9) and Cetiedil (10, 11), a tricyclic ester. Both of these compounds induce water uptake by the erythrocyte. The exact mechanism by which the benzyl ester can cause water uptake is not known whereas Cetiedil has been shown to alter cation permeability so as to induce water gain by the cell. The net effect of water uptake, of course, is a reduction in the mean corpuscular hemoglobin concentration (MCHC), with an attendent increase in the delay time for intracellular gelation (12).Drawbacks to the benzyl ester of L-phenylalanine are its low solubility and gradual hydrolysis in the cell. We have addressed these problems by synthesizing biaromatic derivatives of L-phenylalanine that are held together by a stable amide bond rather than an ester bond. We report on two such antisickling agents, one of which is N-phenylacetyl-Lphenylalanine (PAP), where the linkage is through the a-amino group of L-phenylalanine. The other is L-phenylalanyl-3-aminopyridine (PAPA), which has a linkage through the carboxyl group of L-phenylalanine. In this paper, we describe properties of both compounds as they relate to their permeability in the erythrocyte, their antigelation activity as measured by deoxy-Hb S solubility, and their effects on the MCHC. In addition, these e...

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“…The requisite N-acetyl-L-leucine and Lvaline were prepared using the method of H. D. DeWitt and A. W. Ingersoll [11].…”

Section: Preparation Of Optically Active N-acetyl-α-amino Acidsmentioning

confidence: 99%

“…The N-acetyl-L-alanine and N-acetyl-L-phenylalanine were commercially available. The requisite N-acetyl-L-leucine and Lvaline were prepared using the method of H. D. DeWitt and A. W. Ingersoll [11].…”

Section: Jul-aug 2001 919mentioning

confidence: 99%

Synthesis and NMR spectroscopic studies of optically active derivatives of γ‐aminobutenoic acids and 2‐amino‐pyrrolin‐4‐ones

Petroliagi

Igglessi‐Markopoulou

2001

Journal of Heterocyclic Chem

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The Preparation of Pure N-Acetyl-L-leucine and L-Leucine¹

Cited by 45 publications

References 1 publication

Asymmetric exchange of cyclopalladated ligands: A new route to optically active phosphapalladacycles

Asymmetric exchange of cyclopalladated ligands: A new route to optically active phosphapalladacycles

Potential use of biaromatic L-phenylalanyl derivatives as therapeutic agents in the treatment of sickle cell disease.

Synthesis and NMR spectroscopic studies of optically active derivatives of γ‐aminobutenoic acids and 2‐amino‐pyrrolin‐4‐ones

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The Preparation of Pure N-Acetyl-L-leucine and L-Leucine1

Cited by 45 publications

References 1 publication

Asymmetric exchange of cyclopalladated ligands: A new route to optically active phosphapalladacycles

Asymmetric exchange of cyclopalladated ligands: A new route to optically active phosphapalladacycles

Potential use of biaromatic L-phenylalanyl derivatives as therapeutic agents in the treatment of sickle cell disease.

Synthesis and NMR spectroscopic studies of optically active derivatives of γ‐aminobutenoic acids and 2‐amino‐pyrrolin‐4‐ones

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The Preparation of Pure N-Acetyl-L-leucine and L-Leucine¹