Push-pull carbonyl ylide cycloadditions

Prompted by our earlier work dealing with the internal dipolar cycloaddition reaction of mesoionic oxazolium ylides of type 74, we subsequently studied the rhodium(II) catalyzed reactions of the related a-diazo ketoamide system 154 97JOC2001 04OL3241 05JOC2206 . Attack of the amido oxygen at the rhodium carbenoid produces a push-pull carbonyl ylide dipole (i.e., 155) that is isomeric with the isomiinchnone class of mesoionic betaines. 

Tandem carbonyl ylide generation from the reaction of metallo carbenoids with carbonyl continues to be of great interest both mechanistically and synthetically. Effective carbonyl ylide formation in transition metal catalyzed reactions of diazo compounds depends on the catalyst, the diazo species, the nature of the interacting carbonyl group and competition with other processes. The many structurally diverse and highly successful examples of tetrahydrofuran formation cited in this mini-review clearly indicate that the tandem cyclization/cycloaddition cascade of metallo carbenoids has evolved as an important strategy in both carbo- and heterocyclic synthesis. 

I am indebted to my excellent coworkers for their commitment and considerable contributions in the form of ideas and experiments. Their names can be found in the references. I am particularly grateful to the National Science Foundation for generous financial support. 

Kanuma, T. Kato, Chem. Pharm. Bull. 1982, 30, 1315. 

Ishibashi, K. Sato, M. Ikeda, H. Maeda, S. Akai, Y. Tamura, J. Chem. Soc. Perkin. Trans. 1 1985, 605. 

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Lycorine is an alkaloid that has attracted attention from both the synthetic community and pharmacologists. Prior synthetic approaches have included inter-and intramolecular Diels-Alder cycloaddition. Based on a similar retrosynthetic disconnection, Padwa and co-workers (106,109) chose to use a push-pull carbonyl ylide cycloaddition with a disubstituted pyrrolidinone core to generate a tricyclic substrate. The major difference for this synthetic smdy was the availability of a labile proton a to the carbonyl moiety (Scheme 4.53). 

In more recent work, Chiu and co-workers [167, 168] have reported an intramolecular 1,3-dipolar cycloaddition approach toward the pseudolaric acids 85, in which the di-polarophile is an unactivated 1,1-disubstituted alkene. Hence, treatment of the diazo ketone 86 with catalytic Rh2(OAc)4 furnished a mixture of tricyclic products 87 and 88 in nearly equal proportions (Scheme 19.13). The synthesis of 2-pyridones [169] and their application to the ipalbidine core [170] has been described. The pentacyclic skeleton of the aspidosperma alkaloids was prepared via the cycloaddition of a push-pull carbonyl ylide [171]. The dehydrovindorosine alkaloids 89 have also been investigated, in which the a-diazo-/ -ketoester 90 undergoes a facile cycloaddition to furnish 91 in... 

Padwa and co-workers (60,106,107) have been highly active in using carbonyl ylides for the synthesis of a number of bioactive alkaloids (Scheme 4.51). In an approach to the aspidosperma alkaloids, a push-pull carbonyl ylide was used to generate a bicyclic ylide containing a tethered indole moiety. This strategy ultimately allowed for the synthesis of the dehydrovindorosin skeleton (108). Starting from a quaternary substimted piperidone (200), elaboration of the 3-carboxylic acid provided p-ketoester amide 201. Addition of the indole tethered side chain provided a very rapid and efficient method to generate the cycloaddition precursor 203. 

Mejla-Oneto and Padwa have explored intramolecular [3+2] cycloaddition reactions of push-pull dipoles across heteroaromatic jr-systems induced by microwave irradiation [465]. The push-pull dipoles were generated from the rhodium(II)-cata-lyzed reaction of a diazo imide precursor containing a tethered heteroaromatic ring. In the example shown in Scheme 6.276, microwave heating of a solution of the diazo imide precursor in dry benzene in the presence of a catalytic amount of rhodium I) pivalate and 4 A molecular sieves for 2 h at 70 °C produced a transient cyclic carbonyl ylide dipole, which spontaneously underwent cydoaddition across the tethered benzofuran Jt-system to form a pentacyclic structure related to alkaloids of the vindoline type. 

Carbonyl ylides derived from nitrogen-substituted carbonyl moieties provided for the synthesis of very stable push-pull dipolar intermediates. Although these compounds are quite stable, they still have sufficient reactivity to engage in cycloaddition and related processes. Carbonyl ylides derived from amides have been trapped in intermolecular cycloadditions to give aminals (Scheme 4.34) (56). 

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