Intramolecular cycloadditions isomiinchnones

A number of bridged heterocyclic compounds have been prepared using the intramolecular cycloaddition of rhodium( 11)-generated isomiinchnones [51-53, 84, 129], as exemplified by the complex structure 37 [49, 53] and the tricyclic derivatives 38 and 39 (Scheme... 

Kappe et al. (166) employed an isomilnchnone generation-trapping sequence to access conformationally restricted dihydropyrimidine derivatives as novel calcium channel modulators. For example, the conformationally restricted analogues 269 were prepared via intramolecular cycloadditions from the isomiinchnones generated from a-diazo imides 268. The structures of these cycloadducts were established by X-ray crystallography. 

Other cycloadditions were reported. The intramolecular cycloaddition of alkenylnitrones was 2q>phed to the synthesis of piperidines <99TL1397, 99JCS(P1)185>. Cycloaddition of an alkenyl azide afforded piperidines after reduction of the bicyclo triazole <99T1043, 99EJOC1407>. Similar to the cyclization of the diazo imide 2 in section 6.1.2.1, isomiinchnone intermediates can rearrange to functionalized piperidines <99JOCS56>. 

Several additional examples of the intramolecular cycloaddition of unactivated acetylenes with isomiinchnones were reported by Maier [30]. This cycloaddition approach represents an efficient method for providing rapid access to annulated furans present in several sesqui- and diterpenes, such as the panicu-lides [51],furanonaphthoquinones [52],furodysin,andfurodysinin [53,54].The decomposition of acyclic acetylenic diazoimides 102 and 103 with Rh2(OAc)4 resulted in cycloaddition and retro-Diels-Alder extrusion of methyl isocyanate to give annulated furans 104 and 105 in good yield. The overall transformation is closely related to the intramolecular Diels-Alder reactions of acetylenic oxa-zoles extensively studied by Jacobi and coworkers [55]. 

The first successful generation and trapping of isomiinchnones using this strategy was described independently by Maier et al. (36,37) and Padwa et al. (38,39). Maier and Evertz (36) were the first workers to report the intramolecular dipolar cycloaddition of isomiinchnones to alkenes, the reaction that Padwa would later exploit so spectacularly. Thus, diazo imide 62 was readily prepared from... 

Maier and Schoffling (37) extended this intramolecular isomiinchnone cycloaddition to a synthesis of fused furans by employing an alkyne dipolarophile (Scheme 10.9). Thus, the diazo acetylenes (66) are smoothly converted to furans (69) via isomtinchnones (67) with catalytic rhodium acetate. 

Padwa et al. (187,188) concisely summarized his domino cycloaddition/ A -acyliminium ion cyclization cascade process, which involves sequentially the generation of an isomiinchnone 1,3-dipole, intramolecular 1,3-dipolar cycloaddition reaction, 77-acyliminium ion formation, and, hnally, Mannich cyclization. Kappe and co-workers (189) utilized Padwa s cyclization-cycloaddition cascade methodology to construct several rigid compounds that mimic the putative receptor-bound conformation of dihydropyridine-type calcium channel modulators. 

We used this method as the key sequence in the synthesis of ( )-lycopodine (78). The intramolecular isomiinchnone cycloadduct 81 was envisaged as the precursor of the key Stork intermediate 79 (via 80) [42]. The heart of our synthetic plan was the formation of the latter intermediate by a Pictet-Spengler cyclization of the N-acyliminium ion derived from 81. Central to this strategy was the expectation that the bicyclic iminium ion originating from 81 would exist in a chair-like conformation [42,43]. Cyclization of the aromatic ring onto the iminium ion center should take place readily from the axial position. The readily available heptenoic acid 82 would serve as the precursor for the a-dia-zoimide, the direct progenitor of the isomiinchnone dipole. This extension of the tandem cycloaddition-cationic 1-cyclization protocol to the formal synthesis of ( )-lycopodine (78) is outlined below. 

The decomposition of suitably crafted diazoimides 181, in the presence of a transition metal catalyst, affords the metallo-carbenoids 182 that undergo intramolecular cycUzation onto the neighboring amide carbonyl oxygen to form the five-membered ring carbonyl yUdes (isomiinchnones) 183 (Scheme 58). Early examples of inter- and intramolecular 1,3-dipolar cycloaddition of the mesoionic ylides 183 have mainly emanated from the research groups of Ibata [149], Maier [150] and Padwa [151]. These reactive species (isomimchnones) can be trapped by various electron-rich and electron-deficient dipolarophiles [152] to furnish the cycloadducts in high yield. Much work has been reported in this area and for clarity of presentation is described here under various subheadings. 

Kappe and co-workers have extended their intermolecular isomiinch-none cycloaddition reaction (see Scheme 26) to an intramolecular version to obtain the conformationally rigid polyheterocycles 206, which mimic the putative receptor-bound conformation of dihydropyrimidine-type calcium channel modulators [159]. The key step in the synthesis involves the regio- and diastereoselective intramolecular 1,3-dipolar cycloaddition reaction of a dihydropyrimidine-fused isomiinchnone dipole. The diazoimides... 

Given the success in forming novel azabicyclic systems derived from an intramolecular isomiinchnone cycloaddition/iV-acyliminium ion cyclization... 

The intramolecular 1,3-dipolar cycloaddition of isomiinchnones with alkyl vinyl ethers has been shown to proceed with complete diastereoselectivity. The cyclodehydration of cyclic A-acyl-a-amino acids yields bicyclic mesoionic compounds which react with A-(phenylmethylene)benzenesulfonamides to produce a new class of spiro-cyclic -lactams possessing biological activity. 

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