Penam derivatives synthesis

Acylketenes, derived from Meldrum s acid, add to esters of (R)-4,5-dihydrothiazolin-4-catboxylic acid to give 81 <00OL2065>. A solid-phase synthesis of 2P-methyl substituted penam derivatives utilises a tether through an ester group <99TA3893>. 

The synthesis of penams has been reported to be conveniently prepared from Meldrum s acid [55] and thiazoline [56]. The substrates were reacted in dry benzene containing dry HC1 (gas) at reflux to afford a series of penam derivatives with aryl, n-hexyl. and cyclohexyl substituents (Scheme 9), [57]. 

Mata et al. also described a new and robust protocol for the solid-phase synthesis of 2(3-methyl substituted penam derivatives using Merrifield resin as support [210]. The work begins with immobilization of 6,6-dibromopenicillanic acid (171) onto Merrifield resin followed by oxidation with m-chloroperbenzoic acid (MCPBA) to obtain the resin-bound sulfoxide (173). The key-step involves the thermal rearrangement of the corresponding penicillin sulfoxide (Scheme 49). 

Scheme 49 Solid-phase synthesis of 2-P-methyl substituted penam derivatives...

Scheme 50 Last step of Sheehan s total synthesis of penam derivatives.

The first preliminary studies towards the synthesis of penam derivatives by the Ugi reaction were carried out roughly 30 years ago. 3-Thiazoline derivatives (153) were allowed to react with isocyanides in the two-phase system water/petroleum ether to yield up to 95% of the penam derivatives (154). 

Schutz and Ugi129 developed the synthesis of penam derivatives (155 R = Me) - (159 R4 = Bu ). This penam synthesis was improved by the use of R = All and R4 = All or CHzCChEt.122 In these recent 3-lactam syntheses the Ugi reaction was executed in trifluoroethanol, a magic solvent for such conversions.73125 In a recent carbacephem synthesis ethylene glycol/glycerol gave very good results as the solvent."811... 

The addition of thiyl radicals to alkenes and alkynes can also occur in an intramolecular fashion to lead to sulfur heterocycles. Surzur and co-workers [33, 34] have shown that the pent-4-enylthiyl radical yields both five- and six-mem-bered rings. The six-membered rings were formed in much higher yield than the five-membered rings (ca. 10 1). Since these cyclizations are reversible, the product distribution reflects a thermodynamic control (Scheme 5). The same type of reactions can be initiated by photolysis of disulfides, as demonstrated by Maki and Sako in the synthesis of cepham and penam derivatives [35]. The photoreaction of (5) is concentration dependent at low concentrations cepham derivatives are formed almost exclusively via 6-endo cyclization, whereas at high concentrations penam derivatives predominate. 

The possibilities of transformations at the C-2 position are relatively poor. Nonetheless, penicillins can be converted into clavulanic-like derivatives <1983TL2563, 1987TL2283> by changing the hybridization of C-2 from sp3 to sp2. Indeed, 2-carboxylate penam /3-sulfoxides, readily obtained from penicillin V, enable a decarboxylative Pummerer reaction to provide 2-exomethylene penams 13, as well as penems, their endocyclic tautomers (Scheme 9) <1987CC81>. On the other hand, 2-oxo-, 2-thioxo-, and 2-iminopenams <1996CCA1367> could be obtained by total synthesis (see Section 2.03.11.4) and further used for the preparation of 2-heterosubstituted penems (see Section 2.03.6.4). 

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>. 

Carbodiimides are also used in the enantioselective synthesis of 3-substituted 4-(alkoxy-carbonyl)-2-azetidinones from malic acid. DCC is used in the the synthesis of nocardicin Penam, 4-thiazabicyclo[3.2.0]heptan-7-one, and 2,3-disubstituted derivatives utilize EDCCl in the cyclization steps. ... 

The photo-Wolff rearrangement has proved of particular value in the synthesis of compounds containing four-membered rings. The first [4.4.4.5]fenestrane derivative (64) to be characterized was obtained in this way by irradiation of the diazocyclopentanone (65) in methanol, and the 4-diazopyrrolidine-2,3-diones (66) have similarly served as useful precursors in a novel approach to /3-lactams (67) and penams. " The related ring contraction... 

They demonstrated the effectiveness of the alkylation of enolates (160) + (161) - (162) for preparing precursors of penam and cepham derivatives. The penam synthesis by Schutz and Ugi, as well as the cepham synthesis (168) - U73) profited from Just et at. immensely. ... 

PCR m polymerase chain reaction, 226-227 Pechmann s 1,2,3-triazole synthesis, 151-152 Penam, 311 Penem derivative, 32... 

The synthesis of (6S)-cephalosporins from 6-aminopenicillanic acid derivatives 90 has been achieved by two routes. The Morin penam sulfoxide-cephem rearrangement was shown to be a practical method for the preparation of cephalosporins 91 with unnatural configurations <00T6053>. 

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. 

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