A-Amidations

AVP and OT are cyclic nonapeptides with a disulphide bridge between the cysteine residues 1 and 6, resulting in a six-amino acid ring and a COOH-terminal a-amidated three-residue tail. OT differs only in two amino acids from AVP lie in position 3, which is essential for OT recqrtor (OTR) stimulation and Leu in position 8. AVP has a Phe in position 3 and an Arg in position 8. Arg 8 is essential for acting upon vasopressin receptors (Fig. 1). Lysipressin, found in pigs and some marsupials, has a Lys in position 8 [1]. 

SOLUTION (a) Amide groups are present in the backbone, and so the polymer is a polyamide. Because the amide groups face in opposite directions, there are two different monomers, one with two acid groups and the other with two amine groups. We split each amide group apart and add a molecule of water to each amide link. 

FIG. 70. PAMAM can be modified with varied linkage functionalities thioureas (A) amides (B) heterobifunctional interspacing groups (C) and mixed sugars (D). 

The changes in the values of ks/kp observed for partitioning of the carbocations R-[14+] (Table 3) requires that the addition of a-ester, a-amide and a-thioamide substituents result in different changes in ks and kp for partitioning of the parent l-(4-methoxyphenyl)ethyl carbocation.33,41 42 The explanation for the changes in these ratios is complex, and is most easily understood by separate considerations of the effects of these substituents on ks and kp (Scheme 11). 

Substituent effects on ks. The replacement of an a-methyl group at the 4-methoxycumyl carbocation CH3-[14+] by an a-ester or a-amide group destabilizes the parent carbocation by 7 kcalmol-1 relative to the neutral azide ion adduct (Scheme 11 and Table 3) and results in 5-fold and 80-fold decreases, respectively, in ks for nucleophilic addition of a solvent 50/50 (v/v) methanol/water.33 These results follow the trend that strongly electron-withdrawing substituents, which destabilize a-substituted 4-methoxybenzyl carbocations relative to neutral adducts to nucleophiles, do not lead to the expected large increases in the rate constants for addition of solvent.28,33,92-95... 

The change from an a-methyl to an a-ester or a-amide substituent results in 2000-fold and 75 000-fold decreases, respectively, in kjkp for partitioning of the 4-methoxycumyl carbocation, due to both decreases in ks and increases in kp. The origins of these changes are complex. 

Fig. 50 Surface pressure/area isotherms for the compression and expansion cycles of first (solid line) and second (dashed line) eluting C-12 6,6 -A amide diacids on a pure water subphase at (A) 25°C, (B) 30°C, and (C) 35°C, carried out at a compression rate of 19.24 A2/molecule per minute. Arrows indicate the direction of compression and expansion.

Table 14 Equilibrium spreading pressures IF and surface excess free energies, entropies, and enthalpies of spreading for first and second eluting C-15 6,6 -A amide diacids. 

The effects of temperature and added achiral diluent to C-l5 6,6 -A amide diacids can also be due to differences in intermolecular interactions based on the molecule s configuration. The arguments given above are based on the assumption that the different configurations, the stereochemistry at the chiral... 

PAL peptidyl-a-hydroxyglycine a-amidating lyase Ptdlns 4P phosphatidylinositol 4-phosphate... 

PAM peptidylglycine a-amidating monooxygenase Ptdlns 4,5P2 phosphatidylinositol 4,5-bisphosphate... 

Peptidylglycine a-amidating monooxygenase (PAM) Pituitary, heart Oxidative A-dealkylation... 

Scheme 4. Use of diversification linkers for the synthesis of (a) amides, (b) amines, (c) aromatic, and (d) heteroaromatic compounds.

Figure 6.2 The polyesteramide structure proposed by Gaymans and co-workers E, ester group A, amide group [21]. Reprinted from Polymer, 38, van Bennekom, A. C. M. and Gaymans, R. J., Amide-modified polybutylene terephthalate structure and properties, 657-665, Copyright (1997), with permission from Elsevier Science...

For the primary and secondary a-alkoxy radicals 24 and 29, the rate constants for reaction with Bu3SnH are about an order of magnitude smaller than those for reactions of the tin hydride with alkyl radicals, whereas for the secondary a-ester radical 30 and a-amide radicals 28 and 31, the tin hydride reaction rate constants are similar to those of alkyl radicals. Because the reductions in C-H BDE due to alkoxy, ester, and amide groups are comparable, the exothermicities of the H-atom transfer reactions will be similar for these types of radicals and cannot be the major factor resulting in the difference in rates. Alternatively, some polarization in the transition states for the H-atom transfer reactions would explain the kinetic results. The electron-rich tin hydride reacts more rapidly with the electron-deficient a-ester and a-amide radicals than with the electron-rich a-alkoxy radicals. 

Fig. 5.5. Factors influencing the reactivity of the f-lactam bond a) amide resonance, and b) the nonplanar butterfly shape of penicillins...

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