Dihydrothiazine

Because the integrity of the dihydrothiazine ring and its C-4 carboxyl substituent is crucial to useful antimicrobial activity, reactions involving this part of the cephalosporin molecule are usually undesirable. The possibilities for sulfur oxidation or alkylation, substitution at C-2 which is adjacent to both sulfur and a double bond, double bond isomerization and addition reactions, and the influence of a free carboxylic acid must all be considered in designing reactions to selectively modify other cephalosporin functionalities. 

Woodward s total synthesis of cephalosporin C begins with L-cysteine (48) which establishes the chiral center at C-7. The cis geometry at C-6,7 is achieved in intermediate (49) which is cyclized to (50) by treatment with triethylaluminum. The dihydrothiazine ring is constructed by Michael addition to the condensation product of trichloroethyl glyoxylate... 

Thiazolidine-2,4-dione, 2-dialkylamino-bisimide synthesis, 5, 129 Thiazolidine-2,4-diones IR spectroscopy, 6, 242 tautomerism, 6, 270 Thiazolidine-2,5-diones synthesis, 5, 138 Thiazolidine-4,5-diones synthesis, 5, 129 6, 316-317 Thiazolidine-2,4-dithiones tautomerism, 6, 270 Thiazolidines "C NMR, 6, 243 conformation, 6, 242, 247 dihydrothiazines from, 2, 93 hydrolysis, 6, 273 IR spectra, 6, 242 ring fission, 5, 80 synthesis, 5, 118 6, 316-321 Thiazolidines, imino-tautomerism, 6, 273 Thiazolidines, methyl-conformation, 6, 242 Thiazolidine-2-thione, 3-acyl-reduction, 1, 469 Thiazolidine-2-thione, 4-alkyl-synthesis, 6, 318... 

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 dihydropyrimidinethione 30 has been obtained by microwave-induced rearrangement of a dihydrothiazine, using silicon carbide as a passive heating element <06JOC4651>. 

Also at Oxford, Abraham and Newton discovered the first cephalosporin, cephalosporin C, as a product of Acremonium chrysogenum (Cephalosporium acremonium).17 This new, sulfur-containing antibiotic was also a (5-lactam but the fused, sulfur-containing ring is a six-membered dihydrothiazine. 

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... 

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). 

Electron-withdrawing substituents at C(7) in cephalosporins decrease the rate of acid hydrolysis just as substituents at C(6) in penicillins do. However, in terms of acid-catalyzed hydrolysis cephalosporins are much less reactive than penicillins, even when the substituents on the side chains are similar [76], because cephalosporins do not show neighboring-group participation. The absence of neighboring-group participation in cephalosporins can be explained by the lower basicity of the N-atom of the dihydrothiazine ring compared to that of the thiazolidine ring of penicillins. 

Cephalosporins replacement of dihydrothiazine S-atom with CH2 (.carbacephalo-sporins) Decreased ca. 30-fold... 

Fig. 5.12. C(6)-Epimerization of the y-lactone degradation products of cefdinir and its 7-epi-mer (5.39a and b, Fig. 5.11). The mechanism involves deprotonation of the enamine N-atom, fission of the dihydrothiazine ring at the C-S bond, followed by reclosure with inversion of... 

Recently, a series of substituted dihydrothiazines such as (93) was reported by workers at Merrell Dow to display potent inhibition of partially purified rat neutrophil 5-LO (0.2-2.0 //M) [243], Substitution on the phenyl group or variation of the benzyl to other alkaryl had little effect on activity, but replacement of the benzyl by alkyl or hydroxyalkyl reduced potency about 10-fold. Replacement of the phenyl substituent by benzoyl reduced potency, while reduction of the trisubstituted double bond completely destroyed activity. No anti-inflammatory activity was reported for this series. 

A possible mechanism for the observed photochemical rearrangement of dihydrothiazine (56) to dihydrothiazine (59) is shown in Scheme 22. It involves a... 

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. 

The cephalosporin nucleus is synthesized with a beta-lactam ring attached to a six-membered dihydrothiazine ring. Unlike the penicillin nucleus, the cephalosporin nucleus is much more resistant to beta-lactamase. Moreover, it has large areas for possible modifications. Modifications Rj in the acyl side chain alter the antibacterial activity, while modifications of R2 are associated with changes in the pharmacokinetics and metabolic parameters of the drug. 

In addition, the last of the shown drugs, moxalactam, contains a hydrooxazine ring instead of the dihydrothiazine ring common to all other cephalosporins. A few cephalosporins contain an additional methoxy group at position C7 of aminocephalosporanic acid (cefotetan, cefaclor). 

As was already stated, and which is visible from the scheme of synthesis, moxalactam contains a dihydrooxazine ring instead of the dihydrothiazine ring common to all cephalosporins, and thus this compound cannot be formally numbered with cephalosporins, cephamicins, or penicillins however, in terms of pharmacological action, it is related to all three of the antibiotics listed above, and it is classified as a third-generation cephalosporin. 

Four regioisomeric dihydrothiazine 1,1-dioxides are possible depending upon the position of the double bond. The most common examples of this subclass include 5,6-dihydro-4//-l,2-thiazine 1,1-dioxides 5, 3,4-dihydro-2//-l,2-thiazine 1,1-dioxides 6, and 3,6-dihydro-2//-l,2-thiazine 1,1-dioxides 7. Scant interest has been paid to 5,6-dihy-dro-2/7-l,2-thiazine 1,1-dioxides 8 or their substituted derivatives. Related 3,6-dihydro-2//-l,2-thiazine 1-oxides 9 are also an important subclass of compounds due to their ease of preparation via [4-f2] cycloaddition reactions. 

Solvolysis of Diels-Alder adducts provides a useful means of preparing a variety of nitrogen-containing compounds. For instance, the hydrolysis of A Cbz or A -Ts bicylic sulfonamides 44 and 112 with NaOH affords the homoallylic carbamate 113 and sulfonamide 114, respectively (Scheme 12) <2000TL3743, 2002TA2407>. Related hydrolysis reactions have also been reported with monocyclic 1,2-dihydrothiazine oxides <2004JOC7198>. 

One notable advance in this chemistry since the publication of CHEC-II(1996) is the use of enantiomerically enriched 3,6-dihydro-l,2-thiazine 1-oxides in the rearrangement sequence. For instance, iV-Cbz-protected bicyclic 1,2-dihydrothiazine 44 undergoes ring opening upon treatment with phenylmagnesium bromide (Scheme 16). The synthesis of allylic amino alcohol 129 is completed in excellent yield upon exposure of the intermediate sulfoxide 130 to trimethyl phosphite and methanol at 80 °C <2002TA2407, 2000TL3743>. 

The discussion will follow the trend thiazines, thiazinones and thiones, dihydrothiazines, dihydrothiazinones and thiones, perhydrothiazines and perhydrothiazinones, and thiones. Discussion on 1,3-benzothiazines and 3,1-benzothiazines is incorporated within the appropriate section, depending on the oxidation state of the heterocyclic ring. 

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