Penem synthesis

Fig. 2. Reaction scheme for the first penem synthesis where V = CgH OCH2CONH.

An analogous preparation of thioxopenams from dithiocarbonates (75, R = t-C4H2(CH2)2Si, R = OC H ) has also been described (115). Additionally, an iatramolecular Michael addition reaction to form the [2,3] bond has been exploited ia penem synthesis to prepare FCE 22101 (69) (116). 

Only one successful penem synthesis involving a [nitrogen, C-3] ring closure has been described (119). Cyclization of the ketomalonate (79) usiag hydrofluoric acid-pyridine afforded the penams (80) which were converted to the penem (81). Attempts to adapt the versatile diazoketoester-carbapenem cyclization for penem synthesis failed (120). 

Scheme 53 Woodward s penem synthesis from a penicillin precursor.

Scheme 54 Dicarbonyl reductive coupling for penem synthesis from a penam precursor.

Scheme 56 Penem synthesis from enolizable penam precursors.

This is an example of a penem synthesis by intramolecular reaction of an ylide with an oo-trithiocarbonate group... 

Woodward s Phosphorane Route. The first penem synthesis, shown in Figure 2, utilized an intramolecular Wittig reaction to form the [2,3] double bond of the thiazoline ring (84). Reductive acylation of the penicillin derived disulfide (44) gave the thioester (45). Ozonolysis of the latter provided the oxalimide (46) which on mild methanolysis gave the azetidinone (47). Well established methods were applied to convert (47) to the phosphorane (48) which underwent thermal cydization to the penem ester (49). Catalytic hydrogenation gave the penem acid [64370-39-4] (50) which was shown to possess antibacterial activity in spite of its rather limited stability. 

Scheme 1. Outline of strategies for obtaining azetidinones useful in penem synthesis. R,R , prospective penem Cg and C2 sidechains or precursors thereof L, leaving group (e.g., OCOR", SO2R", Cl) (L), leaving group precursor (e.g., CO2R", COR", SR", CH=CHR", C=CR") P, removable activating or protecting group...

Miller s hydroxamate method [41], widely used for the preparation of mono-bactams, surprisingly scores a single application useful for penem synthesis [42]. Chiral 0-butyl hydroxamate 91 was prepared by aldol reaction of crotonalde-hyde with synthon 90a (Sn(OTf )2/iV-ethylmorpholine), followed by temporary 0-TBDMS protection of obtained 90b and displacement with butoxyamine. Lactamization of 91 under Mitsunobu conditions (PPh3/DEAD) afforded 92, an equivalent (by alkene oxidative cleavage and deprotection) of enantiomerically pure 4-acetoxyazetidinone. 

By two important methodologies, chlorinolysis and mercury acetate oxidation, penams are converted to 1,5-secopenicillanates useful for penem synthesis in both reactions, initial formation of sulfonium salt 98 (X = Cl or HgOAc X = Cl" or AcO") is followed by fragmentation to a resonance-stabilized azetin-ium ion. Trapping of the latter by its counterion and P-elimination, spontaneous under the reaction conditions or promoted by exposure to triethylamine, leads to the stable iV-butenoate 99. 

Even if temporary stereocontrol at C4 and acceptable yields could be achieved on protected 6-hydroxyethylpenicillanates by Nayler s or Denerley s protocol, for penem synthesis obtained thioethers 125 needed further elaboration, ultimately implicating loss of the penicillanic sulfur atom and new stereo-controlled chemistry at C4. These and other drawbacks were overcome by an innovative penam cleavage promoted by the co-operative effect of thiophilic metal salts and strong, non-nucleophilic bases, which was devised at Farmitalia-Carlo Erba by Alpegiani et al. [81]. 

A final mention of Kamiya disulfides in penem synthesis relates to their use as intermediates for 4-chloroazetidinones these in turn can be converted to 4-thioesters [55]. However, chlorinolysis of azetidinone-4-sulfides and -disulfides finds its most important application in the 1,5-ring closure strategy to penems, so that it will be discussed at a later point in this review. 

While 1,2-cleavage of penams by base-promoted P-elimination requires activation with thiophiles, penam sulfones readily react with DBN to give azetidinone sulfinic acids by an ElcB mechanism [98]. Stoodley et al., who discovered this reaction, also developed the sulfinic acid chemistry necessary for application to penem synthesis, namely the conversion of the ring-opened products into either 4-alkylsulfonyl- or 4-acyldithioazetidinone derivatives. 

The alternate use of sulfinic acids for penem synthesis entails as the key step a reductive acylation to acyldithioazetidinones 147 [93]. When treated with 3 mol equiv. of a thioacid RCOSH, the sulfinyl chlorides derived from 159... 

The li -hydroxyethyl substituent at the 6a-position of penems and carbapenems imparts microbiological properties which have remained unrivalled through the last decade s research. Consequently, insertion of this essential group (when not present in the starting material, e.g. L-threonine) into penam or azetidinone intermediates is an integral part of penem synthesis today. 

Formation of the thiazoline ring, the crucial step of penem synthesis, has been obtained by several methods they will be critically compared on the basis of the classification outlined in Scheme 3. The different ring formation strategies... 

The other way to generate thioesters at the penultimate step of penem synthesis is acylation of silver thiolates 226. These compounds are conveniently obtained by cleavage of the corresponding trityl sulfides 225 with silver nitrate and methanol [51a, 144] trityl methyl ether and nitric acid (trapped by pyridine or, better, imidazole) are liberated in the process. Tetrahydropyranylthioethers 227 [145] and acetyl thioesters 228 [51a, 52] were also reported to be cleavable to the corresponding argentiothio-phosphoranes of general formula 226. 

The high degree of antibacterial activity associated with 2-alkylthiopenems and the ease by which these compounds could be obtained from a common 2-thioxopenam precursor made the 6-hydroxyethyl-2-thioxopenam 290b a major target of penem synthesis. To prepare this intermediate, the tritylthio-azetidinone 102c was selected as starting material at Schering s [174]. 

Similar rearrangements were observed on related substrates in the preparation of bis-norpenicillins [188a]. Competition from the sulfur atom in the nucleophilic intramolecular attack of the nitrogen atom to the carbenoid species could be repressed by oxidation to the sulfoxide or sulfone derivatives [188]. Unfortunately, these findings were of no use in penem synthesis. 

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