Diazoketone insertion cyclization

C—H bond 280,281) comparison, only trace amounts of cyclopentane resulted from the CuSO -catalyzed decomposition of l-diazo-2-octanone or l-diazo-4,4-dimethyl-2-pentanone It is obvious that the use of Rh fOAc) considerably extends the scope of transition-metal catalyzed intramolecular C/H insertion, as it allows for the first time, efficient cyclization of ketocarbenoids derived from freely rotating, acyclic diazoketones. This cyclization reaction can also be highly diastereo-selective, as the exclusive formation of a /r< i5-2,3-disubstituted cyclopentane carboxylate from 307 shows The stereoselection has been rationalized by... 

Intramolecular C/H insertion by copper-catalyzed decomposition of a-diazoketones provides a convenient cyclization procedure which is limited, however, to diazo compounds which allow energetically favorable realization of the transition state leading to the cyclized product. 

Two type la syntheses of (3-hydroxypyrroles have appeared. An aza-Nazarov cyclization of l-azapenta-l,4-dien-3-ones produced (3-hydroxypyrroles including 2,2 -bipyrroles <06EJO5339>. A second approach to a (3-hydroxypyrrole involved an intramolecular N-H insertion into a rhodium carbene derived from the decomposition of a diazoketone <06JOC5560>. On the other hand, the photochemical decomposition of the diazoketone led to pyrrolidin-2-ones. 

Although most of the work with Rh-mediated intramolecular C-H insertion has focussed on five-membered ring construction, the first application to natural product synthesis, by Cane, involved establishment of a six-membered ring. Thus, on exposure to Rh2(OAc>4, diazoketone 2 was cyclized to the tricyclic lactone 3 [2. This product had previously been transformed by Paquette into pentalenolactone E (4) [3]. 

An unprecedented cyclopropanation reaction was observed during the reaction of ketene alkylsilyl acetals (191) with bromoform-diethylzinc. When monosubstituted acetals were used, cyclopropanecarboxylic esters (195) were formed by a novel C-H insertion. When disubstituted ketene acetals were used, byproducts such as a,)5-ethylenic esters (197) were also formed presumably via 196 (equation 49). This reaction provides a convenient method for the preparation of the bicyclo[3.1.0] hexane system and can be advantageously compared to the copper-catalysed intramolecular cyclization of unsaturated a-diazoketones . 

Methods for the formation of the six-membered ring of oxacephalosporins (336) include the intramolecular Wittig cyclization of azetidinonyl ylides (335) and the rhodium(II) acetate generation of carbene intermediates from 4-alkoxylactams (337) bearing a diazoketone unit in the side chain. Once formed, the carbenes insert into the N—H bond of the lactam unit thereby effecting ring closure (Scheme 95) <90H(3i)79i, 90H(3i)797>. 

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. 

A key observation by Wenkert proved vital in the subsequent popularity of rhodium as a highly effective catalyst for the generation of carbenes from diazoketones and their engagement in C-H insertion reactions (Equation 27) [15, 16, 88], In this experiment, treatment of diazoketone 153 with Rh2(OAc)4 led to a stereoselective C-H insertion reaction to generate ketone 154 in 59% yield [88], Importantly, no cyclization was observed in the presence of CuSO,. 

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