Correction lactams

Since a knowledge of the correct tautomeric form of the pyrimidines is a requisite for understanding the mode of binding to active sites, as well as nucleic acid structure and modification, the formulae of the conventionally-named 2- and 4-hydroxypyrimidines are presented in the correct lactam, or pyrimidone, form in this chapter. Other physical properties of the pyrimidines, such as dissociation constants, protonation sites, and distribution coefficients, are presented in cases where there is a known relation to drug activity. Biogenesis and enzyme control mechanisms are discussed where they relate to an understanding of inhibitor action. 

At Smith Kline French a general approach to cephalosporin and penicillin nuclear analogs was developed that utilizes a monocyclic /3-lactam (59) with the correct cis stereochemistry as a key intermediate. This is prepared by reaction of the mixed anhydride of azidoacetic acid and trifluoroacetic acid with imine (58) followed by oxidative removal of the dimethoxybenzyl group. This product could be further elaborated to intermediate (60) which, on reaction with a -bromoketones, provides isocephalosporins (61). These nuclear analogs displayed antibacterial properties similar to cephalosporins (b-79MI51000). 

The last comprehensive review of the chemistry of oxazolones covered the literature through 1954. Most of the studies up to that time stemmed from either interest in the role of azlactones as precursors of a-amino acids and peptides or the monumental studies on penicillin, which, for a time, was thought to possess an oxazolone ring, rather than the correct jS-lactam moiety. 

Several degradation reactions were performed with ene lactams. The Hofmann degradation of fumaridine (113) methiodide led to des base 153 (131), the correct structure of which and consequently of fumaridine (113) was... 

This is not the first time that the kinetics of bulk polymerizations has been analysed critically. Szwarc (1978) has made the same objection to the identification of the rate constant for the chemically initiated bulk polymerization of tetrahydrofuran as a second-order rate constant, k, and he related the correct, unimolecular, rate constant to the reported by an equation identical to (3.2). Strangely, this fundamental revaluation of kinetic data was dismissed in three lines in a major review (Penczek et al. 1980). Evidently, it is likely to be relevant to all rate constants for cationic bulk polymerizations, e.g., those of trioxan, lactams, epoxides, etc. Because of its general importance I will refer to this insight as Szwarc s correction and to (3.2) as Szwarc s equation . 

In natural bioactive peptides the modes of cyclization described previously may be prevented either by the lack of suitable side-chain functionalities for lactamization or because these as well as the amino and carboxy termini are crucially involved in the bioactivity itself, and thus cannot be modified. In order to overcome these potential limitations, the concept of backbone cyclization has been proposed.129 According to this, the cyclization is performed by a covalent interconnection of two backbone amides by artificial spacers or of one backbone amide by a correctly functionalized spacer with side-chain functions or with the N- and C-terminus of the peptide (Scheme 21). This type of strategy significantly increases the diversity of possible ring structures (see Scheme 22) and of their related libraries (see Section 6.8.4). Its potential for enhancing the stability of the related peptide derivatives toward proteolytic digestion,[417 419 potency,141942" and selectivity,11417-419 is well-established. 

Immediate sodium borohydride (NaBfLt) reduction gave lactam 44. Bischler-Napieralski cyclization of 44 followed by NaBfLt reduction yielded ( )-methyl-0-acetyl-isoreserpate (45). The correct stereochemistry at C-3 was obtained by first lactonizing compound 45 epimerization with pivalic acid then resulted in ( )-reserpic acid lactone (47). Treatment with base followed by acylation with TMBCI yielded racemic reserpine. The stereochemical considerations involved in the epimerization reaction will be discussed later. 

A large exothermal effect resulting from chemical reactions is typical of these processes. When using oligomeric initial components, for example, formulations based on urethane prepolymers, epoxy resins, and lactams, self-heating may cause thermal decomposition. For this reason the correct choice of the initial solidification temperature is very important. 

The enol acetate 77 of 3,4-dihydro-7-methoxy-5-methyl-l-(2l/)-naphthalenone was converted to the acid 78 by ozonolysis and hydrolysis and this by a Wittig reaction with a-methoxyethyltriphenyl-phosphonium chloride gave 79. Compound 79 was converted into 80 by a series of reactions, five in number, which in turn was converted into 81 by reaction with potassium in -butanol. The methyl ester of compound 81, one isomer of which was recognized as that having the correct stereo structure, was converted to 82 by heating with acetic anhydride and 10-camphorsulfonic acid. Subsequent steps involved ozonization, reaction with V,iV -carbonyldiimidazole, lactam formation, reaction with pyridinium bromide perbromide, reaction with sodium hydride, and a further series in which (+ )-oxodendrobine (83) was ultimately obtained. Reduction of the latter to ( )-dendrobine... 

Moxalactam is also amenable to the popular hydroxyl amine assay for g-lactam antibiotics. In this procedure the -lactam is reacted with hydroxyl amine to cleave the e-lactam moiety and form a hydroxamic acid. The hydroxamic acid will in turn react with acidified ferric ion to form a colored complex which is measured at 480 nm. A blank correction for non-e-lactam impurities which react with hydroxyl amine is incorporated by adding hydroxylamine to an acidified sample where the acid is used to destroy all e-lactam species. 

Alternatively, diltiazem (30) has been prepared using the Evans auxiliary derivative 31 derived from L-valine (Scheme 23.7).55 After dehydration of the adduct from the condensation of 31 with anisaldehyde through the mesylate, the enol ether was formed with a Z E ratio of 4 1. This imide was then treated with 2-aminothiophenol in the presence of 0.1 equiv. 2-aminothiophenoxide with no change in the isomer ratio. The auxiliary was removed with trimethylaluminum, with concomitant formation of the lactam. After separation by crystallization, the correct diastereoisomer was converted to diltiazem in >99%ee. 

The examination of Table XII shows that the theory correctly predicts (1) the continuous hypsochromic shift observed in the series of the lactam forms when passing from 2-hydroxy- to 6-hydroxy -and then to 8-hydroxypurine (2) the similar hypsochromic shift in the series of the lactim forms, when passing from 2-hydroxy- to 6-hydroxypurine (3) the hypsochromic shift when passing from the lactam to the lactim form in 2-hydroxy- and 6-hydroxypurines. A... 

These early findings, together with the ability to act as plant resistance factors towards pests, led to a cascade of some hundred papers dealing in an interdisciplinary manner with all aspects of benzoxazinoids. This name seems to be more correct than the name cyclic hydroxamic acids, which has often been used to name this class of compounds. However, it is not exact from the structural point of view, because it omits the fact that also a variety of acetal glucosides with lactam units was found in plants. They also may be split enzymatically to form lactam aglucones, but cannot undergo chemical decay into benzoxazolin-2(3H)-ones. Benzoxazinoids occur in Acanthaceae, Ranunculaceae, Scrophulariaceae,... 

Vertaline (61) was synthesized through two routes that involve an W-acylimin-ium ion cyclization (20) and an intermolecular [3 + 2] cycloaddition (21,22) as the key steps, respectively. Model studies (20, 24) for assembling the quinolizi-dine moiety by the W-acyliminium ion cyclization are shown in Scheme 7. The benzyl alcohol 65 was converted to glutarimide 66 by the Mitsunobu procedure in 55% yield. Reduction of imide 66 with diisobutylaluminum hydride afforded 67, which was subjected to V-acyliminium cyclization to give the lactam 68 in 40% overall yield from 66. Lactam 68 possesses the correct stereochemistry at all chiral centers required for vertaline (61). 

The formal synthesis56c of dihydrocorynantheine (Scheme 17), also by Takano s group, relies on the stereospecific addition of malonate to the unsaturated lactam (100) for the generation of the correct stereochemistry at positions 15 and 20. The... 

The correct answer is B (excretion depends on the kidney). Most of the p-lactam antibiotics depend on the kidney for excretion. Ceftazidime is predominantly eliminated by glomerular filtration. Thus in this patient the dose of ceftazidime would have to be modified due to the patient s renal status. A (effective on oral administration) is incorrect. Ceftazidime is only given par-enterally. C (interferes in vitamin K function to cause an anticoagulant effect) is incorrect. This property is peculiar to cefoperazone and cefamandole. D (causes ototoxicity at high serum levels) is not correct. E. Ceftazidine is administered IV or intramuscularly (IM). 

Lithium aluminum hydride reduction of pleiocarpinilam (CXLVI-D) and kopsinilam (CXLII-D) gave, respectively, N-methylkopsinyl alcohol (CXLVI-F) and kopsinyl alcohol (CXLII-F) and thus there was every likelihood that these alkaloids were the E-ring lactams derived from pleiocarpinine and kopsinine, respectively. The correctness of this view was shown by synthesis. Pleiocarpinilam was obtained by the direct permanganate oxidation of pleiocarpinine (CXLVI-A) in acetone, while kopsinilam could be prepared, in a similar manner, from N-acetyl-kopsinine (CXLIV-A) followed by acid hydrolysis of the acetyl group, or from pleiocarpine lactam A (CXLV-D) by hydrolysis and simultaneous decarboxylation of the X-carbomethoxyl followed by reesterification of the C-3 carboxylic acid. 

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