Penicillin 6-methoxy

Substitution of penicillins by 6a-methoxy was found to be compatible with an a-acidic side chain in terms of antibacterial activity, but less beneficial when the side chain contained an a-acyl or a-ureido substituent. However, analogues of the ureido penicillin VX-VC-43 (Table 2) containing a 6a-methoxy substituent (10) were found to combine good stabiUty to P-lactamase and relatively high antibacterial activity (37). Following an extensive program to identify other 6a-substituents that would stabilize the acyl and ureido series of penicillins, the 6a-formamido series (11) represented by formidacillin (BRL 36650) (Table 2) was developed (38). 

The early chemistry leading to these derivatives was originally carried out via the 6a-(methylthio) derivative (17) which was prepared by way of a Schiff s base (39). The 6a-thiomethyl group could then be displaced by various nucleophiles giving rise to 6a-methoxy or other 6a-substituted penicillins. A stereo-specific one-step introduction of a methoxy group at C-6 in penicillins provided a simple entry to 6a-methoxy penicillins (40) in yields ranging from 50—62%. 

After formation of the acylimine (12), methanol adds to the less sterically hindered a-face of the molecule with high selectivity to provide (13). A further direct incorporation of a 6a-methoxy group (41) and subsequendy a 6a-formamido group into penicillin has been achieved using ttiduoromethanesulfonamides of type (14) (42). 

Another route to a certain class of 6a-methoxypenicillanates (77TL3831) also probably involves the intermediacy of a 6-imino species. As shown in Scheme 46, 6/3-ketenimino intermediates are readily formed with penicillins having this kind of side chain. Chlorination followed by treatment with methoxide affords the 6a-methoxy-6/3-ketimine, probably involving the intermediates shown. 

Fig. 5.2 (Opposite) Examples of the side chain R in various penicillins (the numbers 1-19 correspond to those in Table 5.1). Numbers 20 (mecillinam) and 21 (pivmecillinam) are 6-/3-amidinopenicillanic acids (mecillinams). Number 11 (temocillin) has a methoxy (—OCH3) group at position 6a this confers high /3-lactamase stability on the molecule.

The last procedure is important as it can be used for the synthesis of 6- and 7-methoxy penicillins or cephalosporins which are potent antibiotics against Gramnegative bacteria (Eq. (55))... 

Further, the discovery of 7-a-methoxy cephalosporins [5] from Streptomyces in 1971, carbapenems [6], thienamycin [7], clavulanic acid [8], sulbactum [9] as well as the totally synthetic oxapenems [10], oxacephams [11], and other bicyclic (3-lactams stimulated the search for novel antibiotics. More recent dedicated efforts to find new active molecules and modify the penicillin and cephalosporin structure have resulted in the discovery of simple monocyclic (3-lactams such as norcardicins and monobactams [12, 13]. Yet another dimension has been added to the (3-lactam research with the recent discovery of tricyclic (3-lactam antibiotics called trinems [14]. Thus, (3-lactam antibiotics in general can be classified into several groups based on their structures (Fig. 1). 

EDC FDPP Fmoc HOBt LiHMDS MAMP MCPBA MeOPEG NCA NMP PAL PASP PBP PEG SASRIN TEA TFA TMAD N-Ethyl-N - [ 3 - (dimethy lamino)propy 1] -c arbodiimide hydrochloride Pentafluoro phenyldiphenyl phosphate 9 -Fluoreny lme thoxy c arbony 1 Hydroxybenzotriazol Lithium hexamethyldisilazane Merrifield, alpha methoxy phenyl resin w-Chloroperbenzoic acid Methoxy polyethylene glycol /V-Carboxv a-aminoacid anhydride /V - M e t h v 1 pyrrol i do n e Peptide amide linker Polymer assisted solution phase Penicillin-binding proteins Polyethylene glycol Super acid sensitive resin Triethylamine Trifluoroacetic acid Tetramethylamine azodicarboxylate. 

The first highly stereocontrolled total synthesis of a natural penicillin was reported 2 years later by Baldwin et al. <1976JA3045>. In this case, the methodology relies on the formation of the fi-lactam ring before the thiazolidine ring closure, via the sulfenic acid intermediate 97 (Rz = OH), which gives electrophilic attack on the double bond to produce a penam sulfoxide 98 (see Section 2.03.5.3) (Scheme 52). A similar route has been developed independently by Kishi for the total synthesis of 6cr-methoxy penicillin derivatives <1975JA5008>. 

Hydroxy- and alkoxyisothiazoles are readily available by direct ring synthesis12,18,28, 38,44,52 125 (see Section I) and, therefore, other methods have been little explored. However, 3-hydroxy-5-phenyl-isothiazole has been prepared from the corresponding diazonium compound,18,118 and 4-cyano-3-methoxy-5 phenylisothiazole from 3-chloro-4-cyano-5-phenylisothiazole and sodium methoxide.57 3-Iso-thiazolones have been obtained from penicillin sulfoxide128 and 1,4-thiazepines which are related to penicillins (Scheme 35).127... 

The preferred route, which involves diazotization of the C-6(7) amino group is useful to functionalize C-6(7) by the introduction of methoxy and other groups [189]. The 7a-methoxycephalothin (R=T) (99) end-product exhibits cephalothin-like activity and an enhanced resistance against cephalosporinase. At the same time, it is curious that the inhibiting-ability of 6a-methoxypenicillin G (100) is 15% that of penicillin G [189], while the activity of 6/8-methoxypenicillin G (101) is at most only 1% of that of... 

The appropriate energy content and reactivity of the /8-lactam 0=C-N bond (cf. the problem of 6(7)a-methyl and methoxy substitution and 2-substituted derivatives). Although the molecular orbital calculations on penicillins and cephalosporins [271,272,293] are not enough to yield exact conclusions, it is likely that a parabolic relationship exists between the electron population of the 0=C-N bond and the antimicrobial activity. 

One approach has been to modify the structure of the yS-lactam antibiotic so as to increase its stability and thus confer resistance to yS-lactamases, whilst retaining its inhibitory activity against transpeptidases. This was achieved by introducing sterically crowded 6-acyl substituents, as in methicillin (1) and the isoxazolyl penicillins (2) and (3) [20], or by the introduction of a methoxy substituent to the a-face of the -lactam, as in cefoxitin (9) [21] and temocillin (11) [22]. The two latter compounds were a direct result of the discovery of the y5-lactamase stable cephamycins (10), isolated by fermentation of Streptomyces in 1970 by Merck and Lilly [23]. 

The ab nce of the benzylmethylene group of penicillin Gand the sieric protection afforded by the 2- and 6-methoxy poops make this compound particularly re.sistant to enzymatic hydrolysis. 

Deprotection. Treatment with AlClj leads to selective cleavage of an isopropyl aryl ether without affecting a coexisting methoxy substituent. A combination with ethanethiol is effective for the deprotection of p-methoxybenzyl ethers. Penicillin esters attached to... 

Methoxylation of penicillin derivatives. Oxidation of the anhydropenicillin (I) with f-butyl hypochlorite in methanol containing sodium perborate (1, 1102) as buffer gives the 6-methoxy derivative (2) in nearly quantitative yield.5 The thiazolidine sulfur atom can be protected either as the sulfone or sulfoxide. 

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