Dihydrothiazine structure

There are several naturally occurring variations on the lactam-thiazolidine or lactam-dihydrothiazine structures, leading to other useful antibiotics or to inhibitors of the (5-lactamases, enzymes that hydrolyze the (5-lactam unit. One group, termed carbapenems 5 has a five-membered ring in which the thiazolidine sulfur is replaced with CH2- Such compounds may still contain sulfur in a thioethylamine side chain (derived from L-cysteine) as in thienamycin 6, originally isolated from Streptomyces cattleya (Scheme 2). 

By 1959, Rolinson and coworkers completed the isolation of the penicillin nucleus, 6-aminopenicil-lanic acid, (Figure 1) in quantity. At about the same time the p-lactam-dihydrothiazine structure for the cephalosporin C was proposed [2] and confirmed subsequently by X-ray crystallographic analysis. In 1962, Morin and coworkers established a chemical method for the production of 7-aminocephalosporanic acid (Figure 1) from cephalosporin C in quantity. These developments opened the way to the preparation of... 

Cephalosporins consist of a six-membered dihydrothiazine ring fused to a /3-lactam ring. Thus, the cephalosporins (A -cephalosporins) are structurally related to the penicillins (section 2.1). The position of the double bond in A -cephalosporins is important, since A -cephalosporins (double bond between 2 and 3) are not antibacterial irrespective of the composition of the side-chains. 

In the 1-carbacephems (Fig. 5.5G), the sulphur in the six-membered dihydrothiazine ring ofthe cephalosporins (based on the cephem structure, see Fig. 5.4) is replaced by carbon. Loracarbef (Fig. 5.5U) is a new oral carbacephem which is highly active against Gram-positive bacteria, including staphylococci. 

Penicillins and cephalosporins both have a [1-lactam ring joined to an S-containing ring structure (penicillins a thia-zolidine ring cephalosporins a dihydrothiazine ring). Because of their structural likeness, allerginicity between... 

The (5-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, 8-(L-a-aminoadipyl)-L-cysteinyl-D-valine 1, ACV or Arnstein tripeptide . ACV is converted to a (5-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 (5-lactam biosynthesis.18,19... 

Penicillin and cephalosporin antibiotics are usually classed as P-lactam antibiotics, since their common feature is a lactam function in a four-membered ring, typically fused to another ring system. This second ring takes in the P-lactam nitrogen atom and also contains sulfur. In the case of penicillins, e.g. benzylpenicillin, the second ring is a thiazolidine, and in the cephalosporins, e.g. cephalosporin C, this ring is a dihydrothiazine. What is not readily apparent from these structures is that they are both modified tripeptides and their biosyntheses share a common tripeptide precursor. 

Deprotonation of a dihydrothiazine ring, followed by a reaction with an electrophile, is most straightforward in benzothiazin-3-ones (general structure 35), which are deprotonated at the 2-position by lithium diisopropyl amide (LDA). The enolate can then react with a variety of electrophiles including deuterium oxide, methyl iodide, and aldehydes <1982T3059>. Compound 70 was prepared in this manner from 2,4-dimethyldihydro-l,4-benzothiazin-3-one (Equation 27) <1985T569>. 

Compounds of the general structure 284 undergo a cycloaddition with dienophiles (Scheme 66) <1991S543> and those with general structure 285 react with dielectrophiles to give dihydrothiazines (Equation 88) <1998T2459>. 

Lactam antibiotics are natural or semisynthetic compounds whose basic nuclear structure consists of a -lactam ring coupled to a thiazolidine (five-membered) or a dihydrothiazine (six-membered) ring to form the penicillin or cephalosporin nucleus, respectively. To those nuclei, various side chains that determine most of the properties of the different -lactams are attached. All members of this group of antibiotics are readily attacked at the -lactam nitrogen by nucleophilic reagents such as hydroxyl ions, alcohols, and primary amines, as well as by secondary amines. They are also susceptible to electrophilic attack at both the... 

A was supported by a 3D X-ray structure of the inhibitor at the closely related porcine elastase (Navia, 1987) (Figure 13.12). After initially reversible inhibition (Figure 13.12, top two rows), time-dependent irreversible inhibition through covalent bonding of the dihydrothiazine ring of the inhibitor to the His-57 residue of the active site of the enzyme increasingly takes over (Figure 13.12, bottom row). Peptidyl chloromethyl ketones, known unspecific inhibitors, act in similar fashion. 

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

Bis-imines (117) have been used far less than the monoimines as dienophiles. However, there are enough examples of these cycloadditions to indicate clearly that they are regioselective and, provided at least one electron-withdrawing group is present on nitrogen, that they proceed under mild reaction conditions. As with the monoimines, little is known with regard to the establishment of sulfur stereochemistry in the dihydrothiazine imines (118). Equations (55)," (56) and (57) demonstrate both the regio-selectivity of the process and some of the structural types of bis-imino compounds which have been... 

An intramolecular version of this methodology was further applied to construction of amino sugars, such as the unnatural C-5 epimer of desosamine (399) (84JOC3243) and deoxyaminopentose (406) (85T1143). When ( , )-diene carbamate 393 was treated with thionyl chloride/pyridine between 0°C and room temperature, a single Diels-Alder adduct (395) was formed in 80% yield. The structure and stereochemistry of this dihydrothiazine oxide were... 

A consequence of the development of the large number of cephalosporins is that the molecular structures have become more and more complex. Alterations in the cephalosporin molecule have resulted in differences between cephalosporins in spectrum of activity, protein binding, peak serum level, serum half-life, route of excretion, cerebrospinal fluid levels and toxicity. Cephalosporins are semi-synthetic antibiotics derived from 7-aminocephalosporanic acid, which is also called the cephalosporin nucleus. The cephem ring ( nucleus") is composed of a (3-lactam ring fused with a dihydrothiazine ring (Figure 1). 

The structure of cephalosporin C (Fig. 10.41) has similarities to that of penicillin in that it has a bicyclic system containing a four-membered (3-lactam ring. However, this time the 3-lactam ring is fused with a six-membered dihydrothiazine ring. This larger ring relieves the strain in the bicyclic system to some extent, but it is still a reactive system. 

Dihydrothiazines may be prepared by the action of elemental sulfur and aziridine upon ketones " the outcome of the reaction is markedly dependent upon the structure of the ketone. Thus with symmetrical ketones of type 62, e.g., pentan-3-one, heptan-4-one, cyclopentanone, cyclohexanone, and cyclooctanone, dihydrothiazines of type 63 were obtained in high yields symmetrical thiazolidines of type 64 were also formed as minor by-products. 

---