Aminoacid derivatives

Fig. 1-7. Racemic aminoacid derivatives resolved and chiral selector used as foaming agent.

Replacement of the p-aminoacyl moiety with an a-aminoacid derivative such as isoleucyl or cyclohexylglycyl led to a 2- to 4-fold decrease in potency. This was the first indication that SAR between this series and the a-amino acid series was distinct. Early on it was discovered that the "right hand side" amide could be replaced with an ester or acid moiety. This result led to a more systematic exploration of acid substitutions. Ortho-, meta- and para-substituted phenylacetic acid derivatives were prepared, and the latter analog (11, Figure 5) proved to be the first submicromolar inhibitor prepared in this series (IC50 = 510 nM). Grati-fyingly, 11 was devoid of thrombin inhibitory activity [31]. 

As the latter were not easily accessible by chemical synthesis at that time, new methods of preparing these ferrocene derivatives were developed and introduced in 1969. It was then proved that the U-4CRs of chiral a-ferrocenyl-alkylamines can form diastereomeric a-aminoacid derivatives stereo-selectively, and it was further shown that after the reaction the a-ferrocenyl groups of the products can be replaced by protons, thus resynthesizing the chiral a-ferrocenyl-alkylamines simultaneously." Later, the development of this ferrocene chemistry was given up since such syntheses cannot form the products in sufficient quantity and stereoselective purity. ... 

A few years later Goebel and Ugi formed a-aminoacid derivatives by the U-4CR with tetra-6)-aIkyl-l-glucopyranosylamines, 58, where any carboxylic acid component can participate. Lehnhoff and Ugi used the U-4CR with 1-amino-2-deoxy-2-Al-acetylamino-3,4,6-tri-6)-acetyl- 3-D-glucopyranose, 59, whose large variety of products could be formed stereoselectively in excellent yields. The desired selective cleavage of the auxiliary groups of these products was equally unefficient. 

Ross and Ugi" prepared l-amino-5-deoxy-5-thio-2,3,4-tri-6)-isobutanoyl-P-D-xylopyranose 61a from xylose via the 5-desoxy-5-thio-D-xylopyranose. The U-4CRs of this amine form a-aminoacid derivatives stereoselectively and in excellent yields. These products have the advantage that their products are stable and their auxiliary group 5-desoxy-5-thio-D-xylopyranose can be cleaved off selectively by mercury(II) acetate and trifluoroacetic acid. The expected steric structure of the corresponding U-4CR product was confirmed by X-ray measurement. 

CS133 Imperato, F. N-P-coumarylglutamic acid, an unusual hydroxy cinnamic acid-aminoacid derivative from black CS143 tea. Chem Ind (London) 1980 388. 

Aminoacid derivs malvngamides Lyngbya majuscula Gomont, Cyanobact. from Curasao, Caribbean Wu 1997 and the C6te d Azur, Mediterr. Mesguiche 1999). 

Substitution of one of the two alkylthio-leaving groups of bis-alkyl-thioacrylonitriles (60) by aminoacid derivatives yielded substituted enam-inonitriles (61), which cyclized to 3-aminopyrroles (62) when heated in ethanol in the presence of triethylamine (88JPR1015) (Scheme 16). 

Aminoacids occur in plants and animals, both in the free state and as the basic units of proteins and other metabolites. Aminoacid derivatives have been reported in marine environment, such as from marine sponges of the genus Jaspis sp. [371,372], from Suberea creba, a Coral Sea marine sponge [373], and the marine ascidian Leptoclinides dubius [374], Some of these compounds have been shown to possess interesting biological properties, e g., cytostatic activity exhibited by axinastatin-4, an aminoacid derivative isolated from a marine sponge [375],... 

Ligand exchange has proved to be very successful in the separation of several enantiomers. Davankov and Rogozhin (41) used chiral copper complexes bonded to silica. The enantiomeric separation is based essentially on the formation of diastereomeric mixed complexes with different thermodynamic stabilities. It is generally accepted that chiral discrimination proceeds via the substitution of one ligand in the coordination sphere of the metal ion. Ligand exchange technique is especially effective for the enantiomeric resolution of aminoacids, aminoacids derivatives, and hydroxy acids (42). 

Sauvagnat, B., Lamaty, F., Lazaro, R. and Martinez, J., Poly(ethylene glycol) as solvent and polymer support in the microwave assisted parallel synthesis of aminoacid derivatives, Tetrahedron Lett., 2000, 41, 6371. 

V-/ -methoxyphenyl protected a-imino ethyl glyoxalate 169 in the presence of L-proline as catalyst resulted in the formation of enantioselective p-formyl a-aminoacid derivatives 170 in excellent yields. 

The authors have demonstrated for the first time the use of a,a-disubstituted aldehydes in the Mannich reaction to generate all-carbon quaternary stereocenters. The enantioselective p-formyl a-aminoacid derivatives 170 were further transformed to spiro- p-lactams 171 using oxidation followed by basic hydrolysis and acidification. 

In 1987 Kunz [32] reported the use of 2,3,4,6-tetra-0-pivaloyl-/ -D-galactopyrano-sylamine 27 as chiral auxiliary in the preparation of a-aminoacid derivatives via the Strecker reaction with aldehydes and trimethylsilyl cyanide. One year later he reported [33, 34] the use of the same chiral auxiliary in the Ugi reaction, where trimethylsilyl cyanide was replaced by an isocyamde and a carboxylic acid (Scheme 1.12). 

A comparison between aminoalcohol and aminoacid derivatives F-I reveals that the latter have equal potency in locomotive activity and muscles tests. They have prolonged ethanol anesthesia and are active only in the tonic phase of corazole convulsion tests. Methiodide H is highly effective against hypoxia.511... 

Because of their efficiency in natural systems in giving supramolecular aggregates, aminoacids have been implemented extensively in calix[4]arene scaffolds. Di- and tetrasubstitution with aminoacid derivatives have been investigated observing different behaviors depending on the orientation of the chiral residues attached to the calix[4]arene scaffold. Derivatives compris-... 

The mildness of the conditions of reaction and the regioselectivity of the /V-arylation of imidazoles allowed the A-arylation of the azolic nitrogen of a protected histidine 87, even with the organolead reagent 88 derived from tyrosine, thus realizing the link between two aminoacid derivatives moieties (Equations (89) and (90)).1... 

Sulfinyl sultam 82 was also used in the synthesis of enantiopure sulfinimines 85, useful precursors in the synthesis of enantiomerically pure amine, as well as a- and P-aminoacid derivatives.109 Interestingly, the addition of one equivalent of water to the sulfinylated HMDS 84 prior to the addition of the aldehyde was necessary to convert enolizable aldehyde into enantiomerically pure sulfinimines 85, which cannot be obtained by the Davis procedure. Thus, both enolizable and noneno-lizable aldehydes can afford enantiomerically pure aryl and alkyl sulfinimine 85 in good yield (Scheme 26). 

Diaryl ether aminoacid derivatives, (IV), prepared by Weaver (4) were effective in inhibiting or preventing ictogenesis and epileptogenesis and used in the treatment of seizure disorders. 

A method for converting the Step 8 product of the current invention into a piperidinyl-methylcyclopentyl aminoacid derivatives is illustrated in Eq. 2 and described by the author in the current invention. 

Cyclic hydroxyimides 482 react with carbodiimides to form the expected isourea derivative, which undergoes further reaction with the starting material to give the isolated aminoacid derivative 483. 

Several studies were undertaken in order to investigate in more detail the nature of the antiviral compounds and their mechanisms of action. Structures of active pure compounds have been determined as PS, steroids, aminoacid derivatives, diterpenes, lipids and alkaloids. 

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