Carbapenem synthesis

Formal syntheses of thienamycin (2) from precursors such as carbohydrates (43—45), amino acids (46,47), isoxa2ohdines (48), and tricarbonyliron lactam complexes (49) have also been reported. Many other methods for carbapenem synthesis have been widely reviewed (10,50—52). 

Alternatively, the acidity of the aldehyde-derived CH or CH2 group can be enhanced by converting the isocyanide derived amide into an ester. According to this principle, tandem Ugi-Dieckmann was exploited in the context of carbapenem synthesis, where the first 4-membered ring was built through an intramolecular Ugi reaction of p-amino acid 66. Then, after a three-step manipulation of the carboxylic appendages, a Dieckmann cyclization afforded, stereoselectively, the desired carbapenem skeleton 67 [79]. 

Other synthetic routes to the carbapenem ring system include photolytic Wolff rearrangement (73JCS(P 1)2024), aldol condensation (78JA313), addition-cyclization (80JOC1135) and /3-lactam formation (78JOC4438,79TL4359). An excellent review of carbapenem synthesis has recently appeared (82H(17)463). 

The Tadano group extended the use of the sugar-based chiral templates for the l 8-methyl carbapenem synthesis. As concerns the chemical synthesis of 1/3-methyl carbapenems such as 1 /S-methyl thienamycin, the most common approach is a late-stage ring closure for bicyclic skeleton construction using a C-4 functionalized azetidin-2-one, such as 113, namely (35, 45)-3-[(R)-l-(r-butyldimethylsilyloxy)ethyl]-4-[(R)-l-carboxyethyl]azetidin-2-one, which may be constructed via the Mannich-like reaction of commercial (3R,4R)-4-acetoxy-3-[(R)-l-(r-... 

Induced stereoselectivity can also be obtained with chiral ketenes. Since most studies have been directed toward the synthesis of /1-lactam antibiotics, cycloadditions of protected aminoketenes have been extensively explored to produce intermediates for penicillin and cephalosporin synthesis and cycloadditions of protected hydroxyethylketenes have been used to produce intermediates for carbapenem synthesis. 

Chlorosulphonylisocyanate has also found application in the preparation of other valuable 3-lactams for carbapenem synthesis which have also been previously reviewed [5c, f ]. For instance, the 4-vinylazetidinone 52, obtainable from CSI and 1,3-butadiene [28], has been widely utilized in P-lactam chemistry [5]. The most recent application of the p-lactam 52 in carbapenem synthesis has been reported by Stoodley and coworkers [29] for the synthesis of ethoxy-carbonyl derivatives of carbapen-l-em-3- xo-carboxylates (Scheme 8). These... 

Several groups have shown that azetidine-2,3-diones are useful synthetic targets for the construction of p-lactams with the cephamycin [48], aspareno-mycin [49] and nocardicin [50] type side chains. Azetidine-2,3-diones like 93, have been utilized by us (Scheme 14), for the preparation of appropriately substituted P-lactam intermediates in carbapenem synthesis. 

In this context the Reformatsky type reaction of Gilman and Specter between a-bromoesters and imines, the lithium enolate-imine condensation and the use of silyl ketene acetals, boron enolates and tin(II) enolates have been successfully utilized in the synthesis of appropriately substituted P-lactams for carbapenem synthesis. 

The first report on the synthesis of P-lactams through an ester enolate-imine condensation was reported by Gilman and Specter close to 45 years ago [68]. The method involved reaction between an a-bromoester and an imine in the presence of zinc and iodine as catalyst to give P-aminoesters or P-lactams, depending on the reaction conditions employed. The mechanistic and stereochemical features of this reaction have been widely studied [69], however its utility in the preparation of valuable P-lactams for carbapenem synthesis has received very little attention. Recently we [70a] demonstrated the utility of this reaction for the preparation of 3-alkyl-4-acetoxyazetidin-2-ones as precursors for the synthesis of ( ) PS-5 and ( ) PS-6 antibiotics. 

As mentioned above the use of organometallic reagents for the construction of both the azetidinone ring and the bicyclic system has already been reviewed [118]. An interesting new contribution on carbapenem synthesis has been introduced by Liebeskind and Prasad [130] (Scheme 50). They found that 4-allenylazetidinones 337 upon treatment with silver ion furnished the A -carbapenem system 338. When this reaction (Scheme 51), was performed on 4-(2-propynyl)-azetidinones 339 the desired A -carbapenem 340 was produced in yields in the range 20%-45%. 

Intramolecular nucleophilic substitution by an active methylene linked to the nitrogen atom of a-substituted carboxamides was first utilized in azetidinone synthesis by Sheehan and Bose in 1950 [27]. When 3-hydroxyethylazetidinones became an important research target, it was realized that L-threonine or D-allo-treonine, easily converted to bromohydrins 57,61 or to epoxyacid 64, are by this method one of the most convenient natural chiral source for penem and carbapenem synthesis. Shiozaki et al. [28] at Sankyo s laid down the fundaments of the threonine route . Early works from D-a//o-threonine-derived 2R-bromo-3R-hydroxybutyric acid 57 were run using malonate anions as the nucleophilic moiety, as shown in amide 58, which in presence of DBN cyclized to azetidinone 59a with complete inversion of configuration [28a, c]. 

Lactone L is a synthetic equivalent of amino acid K its homo-analog has gained popularity in carbapenem synthesis as Melillo s lactone [36]. Its precursor, butenolide 82a, easily accessible by condensation (LDA) of methyl... 

Other C2-C3 bond formation strategies for the preparation of penam compounds susceptible to elimination to penems are represented overleaf. Route A has found application in carbapenem synthesis [Aldol-type approach 178] but failed on substrate 300, probably owing to mercaptide expulsion [29b]. Route B failed as well [29b], since the expected product, 303, would undergo retro-aldol reaction to the starting material 302 [84b]. If this possibility is precluded, as in... 

Homocarbapenems with a sulphur (at various oxidation levels) at C-3 were prepared [89] according to a strategy developed earlier for carbapenem synthesis [94]. The key intermediate was the 3-chlorohomocarbapenem 181 (Scheme 52). In spite of their similarity with the thienamycin antibiotics, compounds 182, 184 to 186 exhibit no antibacterial activity. 

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