Lactams y-lactam

The most commonly used cyclic derivatives of L-aspartic acid are p-lactams (eq 4). For example, excellent regioselec-tivity and diastereoselectivity are observed in the alkylation of the dianion of (3). Other compounds related to (3) have been prepared from L-aspartic acid and used in highly di-astereoselective alkylations en route to a variety of natural and nonnatural products including p-lactams, y-lactams, and dihydroisocoumarin derivatives. ... 

The tributyltin hydride-mediated carbon-carbon bond formation via radical addition and cyclization of alkyl halides with alkenes has often been a choice for construction of various organic molecules [1], However, the requirement for high-temperature initiators or photo initiation and the difficulties associated with purification of the products from tributyltin halides tend to limit the widespread use of these methods, despite the efforts to make the methods easier [Ic, 2], Recently, nickel-mediated radical additions and cyclizations have been introduced as promising alternatives to the tributyltin hydride methods. These are the nickel powder-acetic acid method for cyclization of haloamides to y-lactams, y -lactams and in-dolones, the borohydride exchange resin-nickel boride method for radical addition, nickel-catalyzed electroreductive cyclization and nickel-catalyzed Kharasch addition of polyhalo compounds. 

Formation of Lactams Five-membered lactams (y-lactams) and six-membered lactams (6-lactams) often form upon heating or adding a dehydrating agent to the appropriate y-amino acids and 8-amino acids. Lactams containing smaller or larger rings do not form readily under these conditions. 

The heating of y- and 8-amino acids leads to intramolecular condensation and the formation of N-analogues of lactones, termed lactams. y-Lactams (butane-4-lactams or pyrrolidine-2-ones) form from y-amino acids (Figure 2.45), while 8-amino acids yield 8-lactams (pentane-5-lactams or piperidine-2-ones) (Figure 2.46). 

Tertiary amiqe P Lactams Y Lactams Alkvl carbonate ... 

In his cephalosporin synthesis methyl levulinate was condensed with cysteine in acidic medium to give a bicyclic thiazolidine. One may rationalize the regioselective formation of this bicycle with the assumption that in the acidic reaction mixture the tMoI group is the only nucleophile present, which can add to the ketone. Intramolecular amide formation from the methyl ester and acid-catalyzed dehydration would then lead to the thiazolidine and y-lactam rings. The stereochemistry at the carboxylic acid a-... 

Polyfluorinated a-diketones react with 1,2-diainino compounds, such as ortlio-phenylenediamine, to give 2,3-substituted quinoxalmes [103] Furthermore, the carboxyl function of trifluoropyruvates offers an additional electrophilic center. Cyclic products are obtained with binucleophiles [13, 104] With aliphatic or aromatic 1,2-diamines, six-memhered heterocycles are formed Anilines and phenols undergo C-alkylation with trifluoropyruvates in the ortho position followed by ring closure to form y-lactams and y-lactones [11, 13, 52, 53, 54] (equation 23). 

Compounds of types 69 and 70 are classified as reductones. Nonaromatic reductones, such as 71 and 72, exist entirely in the lactam or lactone form, but an appreciable proportion of aromatic reductones is in the y-oxo form (cf. 73) at equilibrium. These conclusions are largely based on studies of 3,4-dihydroxythiacouma-rinio7-io8a a nd 3,4-dihydroxycoumarin (70, Z = S and O, respec-... 

Nevertheless, the adjacent position of the amide and acetylenic groups was used in another type of heterocyclization. The nitrogen atom in the amide group is a weak nucleophile. Therefore, the N anion should be generated by potassium ethoxide. There are two possible variants of nucleophilic addition to the triple bond. Only one takes place, i.e., the formation of y-lactam. After 7 h of heating in EtOH in the presence of KOH, amide 72 isomerized into the known isoindoline 73 in 80% yield (Scheme 128). 

Intramolecular addition of the amide group to the triple bond in pyrazoles is more difficult, and results in closure of the 5-lactam rather than the y-lactam ring. The reaction time of the 4-phenylethynylpyrazole-3-carboxylic acid amide under the same conditions is extended to 42 h (Scheme 129) (Table XXVII). The cyclization of l-methyl-4-phenylethynyl-l//-pyrazole-3-carboxylic acid amide, in which the acetylene substituent is located in the 7r-electron-rich position of the heterocycle, is the only one complete after 107 h (Scheme 130) (90IZV2089). 

Schemes 15 and 16 summarize the syntheses of intermediates that represent rings A and D of vitamin Bi2 by the Eschenmoser group. Treatment of lactam/lactone 51, the precursor to B-ring intermediate 8 (whose synthesis has already been described, see Scheme 8), with potassium cyanide in methanol induces cleavage of the y-lac-tone ring and furnishes intermediate 76 after esterification of the newly formed acetic acid chain with diazomethane. Intermediate 76 is produced as a mixture of diastereomers, epimeric at the newly formed stereocenter, in a yield exceeding 95%. Selective conversion of the lactam carbonyl in 76 into the corresponding thiolactam...

There is an analogous preparation of y-lactams from y-amino-substituted iron-acyl complexes46. 

Lactame ergeben mit Hydriden den Carbonsaure-amiden ahnliche Reduktionspro-dukte (s. S. 230). Der cyclischen Struktur entsprechend werden cyclische a-Hydroxy-amine und Amine, sowie unter Aufspaltung des Lactam-Ringes co-Amino-alde-hyde und [Pg.244]

Azabicyclo[2.2.1]hept-5-en-3-one, a bicyclic y-lactam, is an intermediate for the synthesis of antiviral carbocyclic nucleosides (Figure 6.41). This compound was resolved using a cloned lactamase in an industrial-scale process [106,107]. 

As in 10-55 hydrazides and hydroxamic acids can be prepared from carboxylic esters, with hydrazine and hydroxylamine, respectively. Both hydrazine and hydroxylamine react more rapidly than ammonia or primary amines (the alpha effect, p. 445). Imidates, RC(=NH)OR, give amidines, RC(=NH)NH2. Lactones, when treated with ammonia or primary amines, give lactams. Lactams are also produced from y- and 5-amino esters in an internal example of this reaction. 

Treatment of compounds 44 with a catalytic amount of sodium ethoxide in ethanol led to a smooth intramolecular reaction, which resulted in the formation of y-lactams 45 in good yields [45] (Scheme 35). The stereochemical course of this ring expansion was unambiguously established by an X-ray analysis of product 45 [45]. Clearly an intramolecular Sn2 reaction has taken place. 

The results of inhibition studies with aldonolactones and 5-amino-5-deoxyaldonolactams may be summarized as follows y -D-glycosidases are inhibited by 1,5-lactones and the lactams some 100- to > 10,000-fold better than by the parent aldoses, with Kj values from 200 //Mto <0.1 nM. Al-dono-1,4-lactones are probably no better inhibitors than aldoses or polyols of comparable structure, with the possible exception s of 2-acetamido-2-deoxy-D-glucono-1,4-lactone. 

Bode and co-workers have extended the synthetic ntility of homoenolates to the formation of enantiomerically enriched IV-protected y-butyrolactams 169 from saccharin-derived cyclic sulfonylimines 167. While racemic products have been prepared from a range of P-alkyl and P-aryl substitnted enals and substitnted imi-nes, only a single example of an asymmetric variant has been shown, affording the lactam prodnct 169 with good levels of enantioselectivity and diastereoselectivity (Scheme 12.36) [71], As noted in the racemic series (see Section 12.2.2), two mechanisms have been proposed for this type of transformation, either by addition of a homoenolate to the imine or via an ene-type mechanism. 

Under the conditions of the Wacker oxidation, 4-trimethylsilyl-3-alkyn-l-ols give 7 -lactones. Similarly, A-carbamoyl or A-acetyl 4-trimethylsilyl-3-alkynamines cyclize to y -lactams. Formulate a mechanism for these reactions. (Hint In DzO,... 

Joyeau, R. Dugenet, Y. Wakselman, M. Synthesis of fused P-lactams by copper promoted intramolecular aromatic substitution. J. Chem. Soc. Chem. Common. 1983, 431 432. 

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