Isomiinchnone cycloadduct

It is assumed that the intermediate N-acyliminium ions formed from the Lewis acid-assisted ring opening of the isomiinchnone cycloadducts undergo rapid proton loss to produce tetra-substituted enamides. In the case of 65, this process is clearly evident as witnessed by the stereochemical outcome observed... 

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. 

When l-[diazo(methoxycarbonyl)acetyl]-2-oxopyrrolidine derivative 231 was treated with Rh2(pfm)4 (pfm = per-fluorobutyro amidate) in the presence of W-phenylmaleimide, none of the desired dipolar cycloadduct was formed but instead the acidic proton at C-3 in the isomiinchnone intermediate 232 was transferred, and the fused oxazoli-dinone 3-oxo-2,3,5,6-tetrahydropyrrolo[2,l- ]oxazole-2,7-dicarboxylic acid dimethyl ester 233 was isolated in 77% yield (Scheme 33) <1997JOC6842>. 

Mathias and Moore (30-33) described a new synthesis of isomiinchnones 55 via the thermal cyclization of A-(chloroacetyl)lactams (54) (Scheme 10.7). These isomiinchnones can be captured by NPM to give fused 2-pyridones in moderate yields. Cycloadducts from the reaction with DMAD are produced in much lower yields (<17%), and other olefinic dipolarophiles (fumarate, maleate, acrylate, and dicyanocyclobutene) are unreactive. Reaction of 7/-(chloroacetyl)benzamide (57) in the presence of NPM gave 58 in low yield. 

Doyle et al. (39) expanded the rhodium-catalyzed generation of isomiinchnones from diazoacetacetamides and subsequent trapping with dipolarophiles (38). As shown in Scheme 10.12, in the case of diazoacetoacetyl urea (79) the derived isomtinchnone 80 reacts with methyl propiolate to give a 2 1 mixture of cycloadducts 81. The resulting regiochemistry is successfully rationalized using frontier molecular orbital (FMO) theory as being isomiinchnone-HOMO controlled. This result represents one of the few reactions in which the cycloadducts from isomiinchnones and alkynes are stable. 

Kato et al. (113) have had much better success in performing 1,3-dipolar cycloadditions with isomiinchnones than with miinchnones (see above). Thus, the room temperature union of isomiinchnone 51a with benzocyclopropene (249) leads to a syn-cycloadduct 250. The latter is remarkably stable and is recovered unchanged upon heating to 300°C. It is also impervious to the action of tributylpho-sphine, in Kato s abortive attempt to excise the bridging oxygen, which would have led to a methanooxonine. 

Regitz and co-workers (143) found that 2,3,4-tri-tert-butylazete reacts with isomiinchnones to give relatively labile cycloadducts. This group (153) has employed the cycloaddition of isomiinchnones 256 with phosphaalkynes 257 to prepare 1,3-oxaphospholes 258 (Scheme 10.35). This sequence is clearly the method of choice for the synthesis of the relatively little investigated 1,3-oxaphosp-holes. The presumed bicyclic intermediates could not be detected by NMR. 

Whereas 260 does not react with electron-rich dipolarophiles, the more delocalized isomiinchnone 261 does react with both electron-rich and -deficient dipolarophiles (154). A detailed FMO analysis is consistent with these observations and with the regiochemistry exhibited by diethyl ketene acetal and methyl vinyl ketone as shown in Scheme 10.36. The reaction of 261 with the ketene acetal to give 262 is LUMO-dipole HOMO-dipolarophile controlled (so-called lype III process). In contrast, the reaction of 261 with methyl vinyl ketone to give 263 is HOMO-dipole LUMO-dipolarophile controlled (so-called lype I process). In competition experiments using a mixture of A-phenylmaleimide and ketene acetal only a cycloadduct from the former was isolated. This result is consistent with a smaller energy gap for... 

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. 

Ibata was the first to show that the masked carbonyl ylide embedded within the isomiinchnone framework would readily undergo 1,3-dipolar cycloaddition with various dipolarophiles [34], The isolable isomiinchnone 4 was observed to react with dimethyl fumarate to produce cycloadduct 7 which possesses the 7-oxa-2-azabicyclo[2.2.1]heptane skeleton. When the reaction of 1 was carried out using catalytic amounts of Cu(acac)2 in the presence of various dipolarophiles, smooth dipolar cycloaddition was observed to occur giving mixtures of endo and exo isomers. In most cases, the exo isomers were favored. All of Ibata s isomiinchnone cycloadditions contain aromatic substituent groups, presumably selected to facilitate dipole formation. The synthetic utility of the cycloaddition reaction is diminished, however, because of the low reactivity of the aromatic substituents toward further manipulation. 

Lengthening the alkenyl tether by one carbon atom was observed to have no effect on the ability of the isomiinchnone to cycloadd across the olefmic 1-bond. This was shown in a study of the cycloaddition behavior of diazoimide 46 which afforded cycloadduct 47 in 86% yield as a single diastereomer [28]. 

Our group has also encountered success in cycloadding an isomiinchnone dipole across an indole double bond [28]. Cycloadduct 91 was generated in high yield as a single diastereomer from the Rh2(OAc)4-catalyzed reaction of diazoimide 90. The assignment was unequivocally established by an X-ray crystal structure. The ready construction of these poly-heterocycles in one step and in... 

An interesting feature of isomiinchnones is their ability to undergo 1,3-dipo-lar cycloaddition with carbonyl compounds, a reaction which is unprecedented with miinchnones [56]. This is illustrated by the reaction of diazoimide 106 with Cu(acac)2 in the presence of several different aldehydes and ketones which resulted in the formation of cycloadducts of type 107 -109. When benzil was used as the dipolarophile, the regioselectivity was reversed giving rise to cycloadduct 110 as the only regioisomer. 

Rhodium(Il) perfluoiobutyramidate catalyses the formation of the mesoionic isomiinchnone 96 from the diazo compound 95. In the presence of A -methylmaleimide, the 1,3-dipolar cycloadduct is isolated as the exolsyii isomer 97. The analogue 98 is similarly obtained it affords mainly the exoluiui product 99 With /V-methylmaleimide (Scheme 5) <97JOC6842>. 

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. 

An isomiinchnone-based strategy has also been deployed to gain access to a new class of 5-functionalized adenosines [158]. Elaboration of the 5 -aminoadenosine 201 employing amine protection, amide formation with methyl malonyl chloride and the usual diazotransfer reaction led to the a-di-azoimide 202. The Rli2(pfbm)4-catalyzed reaction of the diazoimide 202 in the presence of ethyl vinyl ether yielded the endo-selective cycloadducts 203a... 

StereocontroUed [3-i-2]-cycloadditions using various amino acid-derived chiral isomiinchnone dipoles provide access to the enantiopure cycloadducts [163]. Decomposition of the amino acid-derived diazoimide 209 with rhodiiun(II) perfluorobutyramidate [Rh2(pfm)4] in the presence of NPM resulted in the formation of the cycloadducts 210a and 210b with nearly complete exo/endo selectivity and high 7T-facial selectivity (Scheme 66). 

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