P-Lactam structure

Studies using PM3 calculations of the alkaline hydrolysis of bicyclic P-lactam structures 82 (X = NNHCHO, 0, S) have shown that cleavage of the X-CO bond is the energetically favoured pathway both in the gas and solution phase <99MI287>. 

The synthesis of oxaspiro-p-lactam structures containing five- and six-membered rings was explored through RCM reaction. Unfortunately, dienes 26-29 having a... 

Treatment of isonicotinamide with LDA at 40°C and addition of an acylating or alkylating agent were reported in 2005 to form in good yield, a dearomatized product with spirocyclic p-lactam structure (Scheme 88), [195]... 

Demain AL, Solomon NA (1983) (eds) Antibiotics containing the P-lactam structure, parts 1 2. Springer, Berlin... 

Coll M, Frau J, Vilanova B, Donoso J, Munoz F, Garcia Blanco F. Theoretical study of the alkaline hydrolysis of an oxo-P-lactam structure. J Phys Chem A 1999 103 8879-8884. 

Cephalosporins contain the P-lactams structure, like the penicillins, but instead of a five-membered thiozolidine ring, cephalosporins contain a six-membered dihydrothiazine ring. 

Nor are the contributions to be made by p-lactam structures to the pharmaceuticals field over. The extraordinary developments of recent years in cholesterol absorption inhibitors (CAIs) based on the p-lactam ring deserve some mention, especially since Dr. T. K. Thiruvengadam in our chemical process development organization in Schering-Plough is the brilliant architect of one of the patented syntheses of this novel class of CAIs. His synthesis35 of Ezetimibe (Zetia), outlined in Scheme 13, serves to (a) introduce this new direction in the development of novel p-lactam medicinals and (b) end this excursion in the field of p-lactams. 

Examine Figure 6.1 and see if you can identify the P-lactam structure in the first four structures shown. 

Alcaide B, Almendros P, Alonso JM, Redondo MC (2003) Asymmetric synthesis of unusual fused tricyclic P-lactam structures via aza-cycloadditions/ring closing metathesis. J Org Chem 68 1426-1432, and references therein... 

In the period up to 1970 most p-lactam research was concerned with the penicillin and cephalosporin group of antibiotics (1). Since that time, however, a wide variety of new mono- and bicyclic p-lactam structures have been described. The carbapenems, characterized by the presence of the bicydic ring systems (1, X = CH2) originated from natural sources the penem ring (1, X = S) and its derivatives are the products of the chemical synthetic approach to new antibiotics. The chemical names are 7-oxo-(R)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid[78854-41-8], C H7N03, and 7-oxo-(R)-4-thia-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid[69126-94-9], C H NO S, respectively. 

IR s earliest recognition came during World War II when it provided a key clue to the unusual p-lactam structure of the miracle drug penicillin. 

The corresponding reaction of but-3-yn-l-ols or pent-4-yn-l-ols with primary or secondary alcohols in the presence of catalytic amounts of Ph3PAuBF4 and p-TsOH afforded tetrahydrofuranyl ethers (Scheme 4-76). This tandem 5-endo-cycloisomerization/hydroalkoxylation proceeds via 2,3-dihydrofurans, which then undergo an intermolecular Bronsted acid-catalyzed addition of the external alcohol. The transformation is not restricted to internal alkynols but can be applied to terminal acetylenes as well. Application of the method to the s thesis of bicyclic heterocycles with a P-lactam structure was reported recently.Under the same conditions, epoxyalkynes undergo a sequence of epoxide opening, 6-exo-cycloisomerization, and nucleophilic addition to afford tetrahydropyranyl ethers. In a closely related transformation, cyclic acetals were obtained from alk-2-ynoates bearing a hydroxy group in 6- or 7-position by treatment with AuCU and MeOH. ... 

The p-lactam antibiotics are now so extensively described that we cannot attempt to summarize the literature. Since our emphasis is on sulfur, we note that the sulfur atoms of the thiazolidine or dihydrothiazine rings derive from a common tripeptide, 5-(L-a-aminoadipyl)-L-cysteinyl-D-valine 1, ACV or Arnstein tripeptide . ACV is converted to a p-lactam structure, isopenicillin N 2 and thereafter, the two pathways diverge, i.e. to benzylpenicillin 3 or to cephalosporin C 4 (Scheme 1). There have been extensive studies of the genes and enzymes involved in p-lactam biosynthesis. ... 

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