Synthesis thienamycin

Merck s thienamycin synthesis commences with mono (V-silylation of dibenzyl aspartate (13, Scheme 2), the bis(benzyl) ester of aspartic acid (12). Thus, treatment of a cooled (0°C) solution of 13 in ether with trimethylsilyl chloride and triethylamine, followed by filtration to remove the triethylamine hydrochloride by-product, provides 11. When 11 is exposed to the action of one equivalent of tm-butylmagnesium chloride, the active hydrogen attached to nitrogen is removed, and the resultant anion spontaneously condenses with the electrophilic ester carbonyl four atoms away. After hydrolysis of the reaction mixture with 2 n HC1 saturated with ammonium chloride, enantiomerically pure azetidinone ester 10 is formed in 65-70% yield from 13. Although it is conceivable that... 

Table 4.29 Summary of reaction metrics and synthesis tree parameters for thienamycin synthesis plans ranked according to overall kernel (maximum) RME. ...

Recently Ikegami used the thiol addition reaction in the preparation of optically pure 4-phenylthioazetidin-2-one, the starting material for an elegant ( + )-thienamycin synthesis (58). When 4-phenylsulfonylazetidin-2-one was treated with cinchonidine and thiophenol, the intermediate azetinone underwent a thiol addition reaction and the 4-phenylthioazetidin-2-one was obtained in 54% optical and 96% chemical yield (eq. [13]). Recrystallization of the optically active aze-tidinone allows isolation of the pure enantiomer from the mother liquor. The phenylthio group is eliminated later in the synthesis of thienamycin. 

Methylcorrinoids are competent for the efficient methylation of alkyl radicals. Thermolysis of 2 -bis(ethoxycarbonyl)propylcobalamin and methylcobalamin at 70 °C led to formation of cob(II)alamin and the organic products 2-ethyl-2-methylmalonic acid diethyl ester and 2,2-dimethylmalonic acid diethyl ester. The former product was generated with quantitative deuterium incorporation from CDsCobjllljalamin. The proposed mechanism involves homolytic substitution on methylcob(III)alamin by the 2 -bis(ethoxycarbonyl)propyl radical, resulting in net methyl-radical abstraction, a process calculated to be highly exothermic (A7/ -201 kJmoK ). The stereochemical course of the reaction should result in net inversion at the methyl carbon, although this has not been demonstrated. The reaction may serve as a precedent for several biosynthetic methylations, such as the antibiotic thienamycin synthesis. ... 

In spite of the existing methods to carry out the ring closure [5c], the carbene insertion reaction developed by the Merck group [7] for the thienamycin synthesis (Scheme 1), seems to be the most efficient procedure for the construction of bicyclic p-lactam compounds. Thermolysis of diazoketone 7 in the presence of rhodium acetate provides the cyclized P-ketoester 8 in excellent yield which can be converted into thienamycin 3 in three steps. 

In another penem building block synthesis, a functionalised azetidinone is reacted with benzyl 2-bromopropionate in the presence of diethylaluminium chloride in hexane/THF. A mixture of epimers is obtained, which has to be separated chromatographically. Afterwards, the lactam nitrogen is protected, and the benzyl residue reductively cleaved. The next steps bear a close resemblance to those of the thienamycin synthesis construction of a jS-ketoester, diazo transfer and rhodium-catalysed insertion of a carbenoid into the lactam N-H bond. Finally, the jS-keto-ester is activated with diphenyl chlorophos-phonate. [60]... 

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