Cyclization bicyclic keto ester from

The diazo function in compound 4 can be regarded as a latent carbene. Transition metal catalyzed decomposition of a diazo keto ester, such as 4, could conceivably lead to the formation of an electron-deficient carbene (see intermediate 3) which could then insert into the proximal N-H bond. If successful, this attractive transition metal induced ring closure would accomplish the formation of the targeted carbapenem bicyclic nucleus. Support for this idea came from a model study12 in which the Merck group found that rhodi-um(n) acetate is particularly well suited as a catalyst for the carbe-noid-mediated cyclization of a diazo azetidinone closely related to 4. Indeed, when a solution of intermediate 4 in either benzene or toluene is heated to 80 °C in the presence of a catalytic amount of rhodium(n) acetate (substrate catalyst, ca. 1000 1), the processes... 

The unexpected products 18 and 19 were formed by further oxidation of the major product 14, which occurred at 60 °C, but not at room temperature. Tandem oxidative cyclization of P-Keto ester 13 with 4 equivalents of Mn(OAc)3 and 1 equivalent of Cu(OAc>2 in acetic acid at room temperature provided only 14-16. However 18 was the major product from oxidation of 13 with 4 equivalents of Mn(OAc)3 and 1 equivalent of Cu(OAc)2 at 60 °C. The intermediacy of 14 was established by oxidation of 14 with 2 equivalents of Mn(OAc)3 and 1 equivalent of Cu(OAc)2 in AcOH at 60 °C to provide 70% of a 10 1 mixture of 18 and 19. Oxidation of 14 will afford a-keto radical 17, which will be oxidized to give 19 or cyclize to give a bicyclic radical that will be oxidized by Cu(II) to give 18. The formation of 18 and 19 in the Mn(III)-mediated electrochemical oxidation of 13 thus results solely from the necessity of using a higher reaction temperature to obtain a reasonable rate of reaction at the lower Mn(III) concentration of Mn(III)-mediated electrochemical oxidative cyclization. 

Oiganocatalysts can also be used to prepare polycyclic systems. Professor Jorgensen has found (Chem. Commun. 2008, 3016) that condensation of 14 with acetone dicarboxylate 17, again using catalyst 3a, gave the bicyclic P-keto ester 18. Matthew J. Gaunt of the University of Cambridge observed (J. Am. Chem. Soc. 2008,130,404) that for the cycliza-tion of 19, catalyst 3b was superior to catalyst 3a. The power of desymmetrization of prochiral intermediates was illustrated by the report (J. Am. Chem. Soc. 2008,130, 6737) from Benjamin List of the Max-Planck-lnstitute, Mulheim of the cyclization of 21 to 23. 

The acid (67) has also been obtained from an intermediate in the synthesis of the ketone (53), the bicyclic acid (52). Compound (52) was converted by the diazomethane method into the corresponding bromoketone (62), the condensation of which with sodiomalonic ester and decarboxylation led to the keto acid (63). Cyclization of the latter under the action of sulfuric acid led to they-lactone (64), which has also been obtained by the lactonization of acid (67) [197, 198, 200]. All these methods have also been applied to the synthesis of the acid analogous to (67) not containing the 3-methoxy group [195, 201]. 

The main starting material for the majority of syntheses of these compounds is )S-(m-anisyl)ethyl bromide (78), obtained in ten stages from m-aminophenol with an over-all yield of 22% [209]. The successive condensation of the bromide (78) with sodiomalonic ester and the chloride of glutaric semiester led to the keto triester (79), which by cyclization, saponification, and methylation was converted into the bicyclic diester (80) [188, 209]. In another variant, the bromide (78) was condensed with the diester of p -oxo-pimelic acid to form the keto diester (73) from which the diester (80) was again obtained by cyclization, hydrolysis, and methylation [210]. 

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