Intramolecular carbenoid insertion

For 5-(2-diazo-l,3-dioxobutyl)-l-oxa-5-azaspiro[5,5]undecane (313), intramolecular carbenoid insertion into a (N)C—H bond represents quite an unusual way of constructing a P-laetam ring 285). 

Table 21. Rh2(OAc)4-catalyzed intramolecular carbenoid insertion into the N—H bond of JJ-lactams.

The Cu(acac)2-promoted transformation 368 - 369 represents an intramolecular carbenoid insertion into the penicillin C5—S bond 347). The original report did not mention the low-yield formation of a second product to which the tricyclic structure 370 was assigned 348,349 >. In both 369 and 370, the original stereochemistry at C-5 of 368 has been inverted this is seen as a consequence of intramolecular nucleophilic a-face attack in a presumed azetidinium enolate intermediate. Attempts to realize a more flexible intermediate which then would have a chance to undergo p-face attack centered on the chain-extended diazoketone 371. Its catalytic decomposition led to the tricycle 372 exclusively, however, C7/N rather than C5/S insertion having taken place 349). 

Cyclic epoxides such as 124 can react in two ways with strong bases (a) via abstraction of a /3-proton to form allylic alcoholates 125 or (b) by deprotonation at the epoxide carbon atom forming the intermediate 126 and, after electrophilic substitution, the epoxides 128. If there is a suitable C—H bond in the vicinity of the C-Li moiety, intramolecular carbenoid insertion reactions to 127 may take place (equation 27) ° . ... 

Since the observation that Rh(II) carboxylates are superior catalysts for the generation of transient electrophilic metal carbenoids from a-diazocar-bonyls compounds, intramolecular carbenoid insertion reactions have assumed strategic importance for C-C bond construction in organic synthesis [1]. Rhodium(ll) compounds catalyze the remote functionalization of carbon-hydrogen bonds to form carbon-carbon bonds with good yield and selectivity. These reactions have been particularly useful in the intramolecular sense to produce preferentially five-membered rings. 

The intramolecular carbenoid insertion into the N — H bond of j8-lactams is frequently used for constructing the l-azabicyclo[4.2.0]octane ring system. Thus, in the synthesis of (-)-homothienamycin, the crucial ring closure was effected by refluxing compound 160 in a benzene solution containing Rh2(OAc)4 (80TL1193). Such an approach was used to advantage in... 

Diazetidinones 487 were obtained in high yield (75-100%) by the decomposition of diazo compounds 488 in the presence of Rh2(OAc)4 in refluxing benzene. This result is rationalized in terms of an intramolecular carbenoid insertion into the y-NH bond [85TL3171 87JCS(P1)899],... 

In the laboratory of J.D. White, the asymmetric total synthesis of the non-natural (+)-codelne was accomplished via intramolecular carbenoid insertion In the late stages of the total synthesis It was necessary to Install a 6-membered piperidine moiety. This transformation was accomplished utilizing a Beckmann rearrangement of the cyclopentanone oxime portion of one of the intermediates. Later the 6-membered lactam was reduced to the corresponding amine with LAH. To this end, an oxime brosylate (Bs) was prepared, which underwent a smooth Beckmann rearrangement in acetic acid to provide a 69% yield of two isomeric lactams in an 11 1 ratio in favor of the desired isomer. 

The asymmetric total synthesis of (+)-codeine, the unnatural enantiomer, was accomplished by J.D. White and coworkers using an intramolecular carbenoid insertion as the key step. The first stereogenic center that directed all subsequent stereochemical events was installed by the asymmetric hydrogenation of an alkylidene succinate that was obtained using the Stobbe condensation. Dimethyl succinate and isovanillin were reacted in the presence of excess sodium methoxide at reflux and the resulting reaction mixture was acidified to obtain the monomethyl ester. 

White, J. D., Hrnciar, P., Stappenbeck, F. Asymmetric Total Synthesis of (+)-Codeine via Intramolecular Carbenoid Insertion. J. Org. Chem. 1999,64, 7871-7884. 

The Cu(acac)2-promoted transformation 368 - 369 represents an intramolecular carbenoid insertion into the penicillin C,—S bond The original report did not mention the low-yield formation of a second product to which the tricyclic structure 370 was assigned in both 3 and 370, the original stereochemistry at C-5... 

Two groups have reported syntheses of the bicyclo[3.2.1]octane ring system found in certain tetracyclic diterpenes in which the key step is an intramolecular carbenoid insertion reaction. Thus decomposition of the diazoketone (4) in the presence of copper(II) sulfate gives the cyclopropyl ketone (5) in 48% yield. Acid hydrolysis of the acetal grouping is accompanied by concomitant fragmentation to the substituted bicyclo[3.2.1]octanone derivative (6).3... 

Oxatricyclo[3.2.1.0 ]octane. Treatment of the gem-dibromocyclo-propane (1) with methyllithium in ether for 10 min. gives a mixture of (2) and (3). The origin of (3) is not understood, but evidence has been obtained that (2) arises by an unusual intramolecular carbenoid insertion into the O-H bond. 

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... 

Intramolecular carbenoid insertion into NH bonds of diazohydrazides of type 8.142 is also possible, as shown by Lawton et al. (1987). In boiling benzene, diazetidine-l,2-diones (8.143) are obtained in good yield (87-93 <7o), if dirhodium tetraacetate is used as catalyst (8-61). 

A New Approach to the Synthesis of Ring E of the Diterpene Alkaloids. An intramolecular carbenoid insertion as a means of introducing the C-20 functionality has been employed by Ghatak and Chakrabarty in work related to their general diterpenoid syntheses. 

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