Thienamycin aldol reaction

This aldol reaction was employed for an asymmetric synthesis of the azetidinone 9 from the adduct (5) of acetaldehyde and l.5 Azetidinone 9 is a versatile precursor to the antibiotic thienamycin 10. The configurationally stable aldehyde 6, obtained by ozonolysis of the silyl ether of 5, undergoes addition with allylzinc chloride to afford 7, which on transamination is converted to the N-methoxy amide 8. This product is converted in several steps to the desired 9 in 34% overall yield. An interesting feature of this synthesis is the early incorporation of the hydroxyethyl side chain at C6, a step that is difficult to effect after formation of the (3-lactam ring. 

The medicinally important )3-lactam antibiotic thienamycin (34) has stimulated several investigations into the application of the aldol reaction for the introduction of the hydroxyethyl moiety with the indicated Cg and Cg stereochemistry (29,30). Low-temperature enolization (LDA, THF) of either 35 (29a,b) or 36 (30) and subsequent condensation with excess acetaldehyde afforded the illustrated kinetic aldol adducts (eqs. [22] and [23]). In both examples the modest levels of threo diastereoselection are comparable to related data for unhindered cyclic ketone lithium enolates. Related condensations on the penam nucleus have also been reported (31). 

A new efficient methodology for the preparation of a chiral 2-azetidinone intermediate applicable to the total synthesis of (+)-thienamycin and l)S-substituted carbapenems has been developed (86JAa673). This is based on the highly diastereoselective aldol-type reaction employing C4-chiral 3-acyl-l,3-thiazolidine-2-thiones and 4-acetoxy-2-azetidinones. 

The first synthesis 104, 105) of racemic thienamycin by the Merck group made use of the azetidinone (113) derived from acetoxybutadiene and chlorosulphonyl isocyanate (CSI). Reduction, hydrolysis and condensation with acetone gave the 1,3-tetrahydrooxazine (114). Introduction of the hydroxyethyl side chain by way of an aldol condensation produced predominantly the thermodynamically more stable tra s-P-lactam (115) as a mixture of R)- and (5)-isomers in the side chain. On removal of the acetone residue a proportion of the unwanted (5)-isomer crystallised from the mixture. The synthesis was continued with the mixture by way of the aldehyde (116) and the thio-acetal (117). Bromination, elimination and introduction of the iV(l) malonate residue gave (119) ready for an intramolecular alkylation reaction. 

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