Aminolysis intramolecular

In this series of amides, hydrolysis or aminolysis of a simple ester, cleavage of a silyl groups a cis/trans isomerization, or reduction of a quinone to a hydro-quinone exposes an alcohol that then induces deprotection by intramolecular addition to the amide carbonyl. 

Intramolecular general base catalysed reactions (Section II, Tables E-G) present less difficulty. A classification similar to that of Table I is used, but since the electrophilic centre of interest is always a proton substantial differences between different general bases are not expected. This section (unlike Section I, which contains exclusively unimolecular reactions) contains mostly bimolecular reactions (e.g. the hydrolysis of aspirin [4]). Where these are hydrolysis reactions, calculation of the EM still involves comparison of a first order with a second order rate constant, because the order with respect to solvent is not measurable. The intermolecular processes involved are in fact termolecular reactions (e.g. [5]), and in those cases where solvent is not involved directly in the reaction, as in the general base catalysed aminolysis of esters, the calculation of the EM requires the comparison of second and third order rate constants. 

G.3 Intramolecular general base catalysis of aminolysis by the amino-group... 

BF Gisin, RB Merrifield. Carboxyl-catalyzed intramolecular aminolysis. A side reaction in solid-phase peptide synthesis. J Am Chem Soc 94, 3102, 1972. 

FIGURE 7.34 Decomposition of the symmetrical anhydride of A-methoxycarbonyl-valine (R1 = CH3) in basic media.2 (A) The anhydride is in equilibrium with the acid anion and the 2-alkoxy-5(4//)-oxazolone. (B) The anhydride undergoes intramolecular acyl transfer to the urethane nitrogen, producing thelV.AT-fcwmethoxycarbonyldipeptide. (A) and (B) are initiated by proton abstraction. Double insertion of glycine can be explained by aminolysis of the AA -diprotected peptide that is activated by conversion to anhydride Moc-Gly-(Moc)Gly-0-Gly-Moc by reaction with the oxazolone. (C) The A,A -diacylated peptide eventually cyclizes to the IV.AT-disubstituted hydantoin as it ejects methoxy anion or (D) releases methoxycarbonyl from the peptide bond leading to formation of the -substituted dipeptide ester. 

Cephalosporins are mostly degraded via intramolecular aminolysis (see above, Fig. 5.8). However, high drug concentrations may also favor degradation via oligomer formation [119]. In the case of loracarbef (5.44, Fig. 5.16), which is not subject to intramolecular aminolysis, the formation of dimeric structures becomes predominant under moderately acidic conditions [120],... 

A. G. De Oliveira, M. S. Nothenberg, I. M. Cuccovia, H. Chaimovich, Micellar Catalysis of the Intramolecular Aminolysis of the /3-Lactam Antibiotic Cephaclor , J. Phys. 

M. I. Page, D. Render, G. Bemath, Stereochemical Studies. Part 112. Geometrical Dependence of Intramolecular Catalysis in the Hydrolysis and Aminolysis of Aryl Esters , J. Chem. Soc., Perkin Trans. 2 1986, 867-871. 

Carboxy-catalyzed intramolecular aminolysis of the dipeptide ester. ... 

The intramolecular aminolysis reaction was also shown to be involved in the formation of (Gly-Gly) and the biosynthetic pathway of the biologically active cyclic dipeptide cyclo(His-Pro), found throughout the CNS, peripheral tissue, and body fluids. ... 

The diastereomerically related keto esters 53 and 55, activated for removal of the chiral auxiliary, were obtained from 5 and 9. The requisite nitrogen atom was introduced by an azide displacement of chloride and at an opportune stage of the synthesis an intramolecular aminolysis of the carboxylic ester provided the enantiomerically related keto lactams 54 and 56. Although shorter routes to these popular synthetic targets have been reported in recent years, the conversion of 9 to (—)-iso-nitramine (ten steps, 50% overall yield) clearly illustrates the efficiency of the asymmetric Birch reduction-alkylation strategy for construction of the azaspiroundecane ring system. 

The kinetics of the aminolysis reactions of the a-effect nucleophiles hydrazine and hydroxyiamine with Y-phenyl X-benzoates (8) have been reported." The results demonstrated that the magnitude of the a-effect decreases with increasing electron-withdrawing ability of the acyl substituents. The authors propose that hydrazine stabilizes the transition state (9) by intramolecular H-bonding. ... 

The kinetics of the alkaline hydrolysis of 2-methylpentyl salicylate (24) have been studied in various aqueous propanol and r-butanol mixtures and in mixtures of water and ethane-l,2-diol. ° Further smdies of the aminolysis of ionized phenyl salicylate (25) have been reported, in which it was observed that, in mixed acetonitrile-water solvents, glycine, 1,2-diaminoethane and 3-aminopropanol all reacted as did simple amines, via an intramolecular general-base-catalysed process. ... 

Kinetic studies of the unnatural 6-a -epimer of ampicillin, fi-ept-ampicillin (154), have revealed an intramolecular process not undergone by ampicillin (or other natural /3-substituted penicillins) At pH 6-9, intramolecular attack of the jS-lactam carbonyl group by the side-chain amino group of (154) yields a stable piperazine-2,5-dione derivative (155). Theoretical calculations show that the intramolecular aminolysis of 6-epi-ampicillin nucleophilic attack occurs from the a-face of the -lactam ring with an activation energy of 14.4kcalmor In other respects, the hydrolysis of the b-a-epimer is unexceptional. 

Highly efficient and stereoselective addition of tertiary amines to electron-deficient alkenes is used by Pete et al. for the synthesis of necine bases [26,27], The photoinduced electron transfer of tertiary amines like Af-methylpyrrolidine to aromatic ketone sensitizers yield regiospecifically only one of the possible radical species which then adds diastereospecifically to (5I )-5-menthyloxy-2-(5//)-furanone as an electron-poor alkene. For the synthesis of pyrrazolidine alkaloids in approximately 30% overall yield, the group uses a second PET step for the oxidative demethylation of the pyrrolidine. The resulting secondary amine react spontaneously to the lactam by intramolecular aminolysis of the lactone (Scheme 20) [26,27]. 

Aspartame is relatively unstable in solution, undergoing cyclisation by intramolecular self-aminolysis at pH values in excess of 2.0 [91]. This follows nucleophilic attack of the free base N-terminal amino group on the phenylalanine carboxyl group resulting in the formation of 3-methylenecarboxyl-6-benzyl-2, 5-diketopiperazine (DKP). The DKP further hydrolyses to L-aspartyl-L-phenyl-alanine and to L-phenylalanine-L-aspartate [92]. Grant and co-workers [93] have extensively investigated the solid-state stability of aspartame. At elevated temperatures, dehydration followed by loss of methanol and the resultant cyclisation to DKP were observed. The solid-state reaction mechanism was described as Prout-Tompkins kinetics (via nucleation control mechanism). 

In a similar manner, the thioester resin[363l is used only with Boc/Bzl chemistry, and the intramolecular aminolysis of the thioester by the amino group occurs upon deprotection and neutralization with DIPEA (3.0 equiv) and is catalyzed by DMAP (0.1 equiv) in DMA (cyclization time 2-7 d). 

Although 68e could not be prepared, the less reactive pivalic acid ester analogues 71a-d (Scheme 29) were synthesized. Hydrolysis rate constants at 40°C were pH independent from pH 1.0 to 7.0 and k i,s correlated with to give a of —6.0. The products derived from 71a-c are summarized in Scheme 29. These products are consistent with a nitrenium ion mechanism. In particular, the products and product ratios derived from the meta-hxomo ester 71b were consistent with those previously reported for 68e and the Bamberger rearrangement of N-(3-bromophenyl)hydroxylamine, with the exception of the rearrangement products. The rearrangement products 72 appear to be derived from intramolecular aminolysis of 73. These... 

Cycloalkylation (7, 148).2 Cycloalkylation of 2 with (Z)-l was used as one step in a total synthesis of (+ )-sesbanine (6), a constituent of Seshania drummondii seeds with antileukemic activity. The hydroxyl group was introduced into the cyclopentene ring of 4 by iodolactonization followed by reduction to give 5. Final steps included aminolysis of the lactone ring, intramolecular addition of the amide anion to the CN group, and hydrolysis to give 6. 

The synthesis described met some difficulties. D-Valyl-L-prolyl resin was found to undergo intramolecular aminolysis during the coupling step with DCC. 70% of the dipeptide was cleaved from the polymer, and the diketopiperazine of D-valyl-L-proEne was excreted into solution. The reaction was catalyzed by small amounts of acetic acid and inhibited by a higher concentration (protonation of amine). This side-reaction can be suppressed by adding the DCC prior to the carboxyl component. In this way, the carboxyl component is "consumed immediately to form the DCC adduct and cannot catalyze the cyclization. 

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