Thienamycin, carbene synthesis

There are several examples of intramolecular reactions of monocyclic /3-lactams with carbenes or carbenoids most of these involve formation of olivanic acid or clavulanic acid derivatives. Thus treatment of the diazo compound (106) with rhodium(II) acetate in benzene under reflux gives (107), an intermediate in the synthesis of thienamycin (80H(14)1305, 80TL2783). 

NH insertions were already known at the time of the exclusive use of copper catalysts for metal-carbene transformations, but, like CH insertions, they became important in synthesis only at the time of growing interest in rhodium catalysts. A breakthrough was the intramolecular carbenoid insertion into the NH bond of azetidin-2-one, catalyzed by [Rh2(OCOCH3)4] (8.127), as it was first described for the synthesis of thienamycin (8.140) by the group of Salzmann (1980) in the Merck laboratories. This synthesis (8-60) opened the way for many related pharmaceutical products of the carbapenem and the carbacephem type (see Maas, 1987, Table 21, p. 201). At an early date, the NH insertion of the parent compound 8.141 was studied... 

Insertion of carbenes into other bonds, particularly O—H and N—H bonds, has found worthwhile application in organic synthesis. Both inter- and intramolecular reactions are possible to give ethers, amines or amides. Intramolecular O—H insertion of the carbene, generated from the diazoketone 105, gave rise to the seven-membered cycUc ether 106 (4.84). In a synthesis of the -lactam antibiotic thienamycin, intramolecular N—H insertion of the carbene, formed from the diazoketone 107, was a key step to give the -lactam 108 (4.85). 

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 the synthesis of thienamycin, the Merck group used an insertion reaction by carbene to form a C-N bond. Application of this method to construct the 1-oxa-... 

Trapping by nucleophiles such as alcohols, which can also be drawn as insertion into the O-H bond, is a useful process. Cyclic ethers can be formed under very mild conditions (Scheme 8.136). Similarly, amines and other nitrogen derivatives can be employed to trap the carbene, most notably in the commercial synthesis of the antibiotic thienamycin in which a five-membered ring is annulated onto an existing p-lactam 8.507 (Scheme 8.137). °... 

An early report that showcased the power of C-H activation approaches in steroid synthesis can be found in the work of Yoshikoshi (Equation 26) [87]. Irradiation of diazoketone 148 in the presence of CuO led to the generation of a putative carbene intermediate that underwent chemoselective insertion at the proximal, suitably positioned, methine C-H to give tetracycle 149. Another noteworthy example can be found in the synthesis of thienamycin (152), a novel / -lactam antibiotic, reported by workers at Beecham (Scheme 15.15) [16]. This transformation may constitute the first use of a rhodium catalyst to effect a C-H insertion. In the experiment, treatment of 150 with Rh2(OAc)4 furnished the key trans- -lactam 151 in 25% yield. Curiously, the investigators noted that conducting the C-H insertion process under irradiation furnished product in higher yields. Both of these early examples clearly illustrate the power of C-H insertion as a strategy for rapid introduction of molecular complexity onto a scaffold. 

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