Carbapenems skeleton

Depending on the substituents of l,6-enynes, their cyclization leads to 1.2-dialkylidene derivatives (or a 1.3-diene system). For example, cyclization of the 1,6-enyne 50 affords the 1.3-diene system 51[33-35]. Furthermore, the 1.6-enyne 53, which has a terminal alkene, undergoes cyclization with a shift of vinylic hydrogen to generate the 1,3-diene system 54. The carbapenem skeleton 56 has been synthesized based on the cyclization of the functionalized 1,6-enyne 55[36], Similarly, the cyclization of the 1,7-enyne 57 gives a si -mem-bered ring 58 with the 1,3-diene system. 

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]. 

The strained structure of carbapenems confers a higher reactivity to the carbapenem skeleton than that of cephalosporin skeleton. It has been suggested that both p-lactam ring and the basicity of C-2 side play a major role in carbapenem-induced nephrotoxicify [70]. 

By warming ofthe diazo-compound with traces of rhodium acetate in toluene at 80°C, the carbenoid inserts smoothly into the neighbouring N-H bond. This reaction step is ofparticular importance, since it constitutes a new methodology for the construction ofthe carbapenem skeleton. Although investigations on comparable bicycUc -ketoesters showed that these exist almost entirely in their keto-form, reaction with diphenyl chlorophosphonate and Himig s Base leads to the enol phosphate. 

Carbacephem skeleton 86a can be constructed using enyne metathesis. Synthesis of carbapenem 86b has been reported, although the yield is moderate due possibly to high strain in the product (Scheme 35). ... 

In 1973, it was demonstrated that 1,2-epoxystannanes, produced from vinylstannanes and MCPBA, could be isolated and characterized,in comparison with 2,3-epoxystannanes (from allylstannanes), which are extremely reactive and have not been isolated (see Section 4.2.2.3). Subsequently, useful applications of 1,2-epoxystannanes have been reported, including the internal alkyne - ketone conversion, in the carbapenem and carbacephem ( -lactam antibiotic) skeletons. Ketone (10) should be of value in the construction of the biologically interesting l-caibapoi-2-ene ring system. Syndiesis of ketoacetates of potential use in the carbacephem system (e.g. 11 and 12) was also achieved by similar sequences shown in Scheme 11. ... 

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-... 

The j6-lactam (azetidin-2-one) skeleton is the core stmcture of commonly used antibiotics including penicillins, cephalosporins, carbapenems, and monobactams, and of... 

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