Aldehydes nitrile oxide intramolecular cycloadditions

Intramolecular nitrile oxide-alkene cycloadditions also provide efficient access to six-membered rings such as cyclohexanes or decalins that are heavily adorned with functional groups and side chains. For example, this strategy was used to prepare racemic hemaldulcin (213), which is a 3,6-disubstituted cyclohexenone found in a Mexican plant that possesses a strong sweet taste. Starting from (2Z,6E)-famesal (209) (328) (Scheme 6.88), the aldehyde was treated with hydroxylamine... 

Intramolecular nitrile oxide cycloadditions were first studied by Garanti and coworkers (24) in 1975, employing 0-allyl derivatives of salicylic aldehyde. The first example of a carbocycle-forming process was reported in 1977 (25). This process (sometimes referred to as INOC) has seen many extensions and applications for the synthesis of natural and unnatural products alike, notably by the groups of Kozikowski, Curran, Fukumoto, and Shishido (see Section 6.4). 

For intramolecular 1,3-dipolar cycloadditions, the application of nitrones and nitrile oxides is by far most common. However, in increasing frequency, cases intramolecular reactions of azomethine ylides (76,77,242-246) and azides (247-259) are being reported. The previously described intermolecular approach developed by Harwood and co-workers (76,77) has been extended to also include intramolecular reactions. The reaction of the chiral template 147 with the alkenyl aldehyde 148 led to the formation of the azomethine ylide 149, which underwent an intramolecular 1,3-dipolar cycloaddition to furnish 150 (Scheme 12.49). The reaction was found to proceed with high diastereoselectivity, as only one diaster-eomer of 150 was formed. By a reduction of 150, the proline derivative 151 was obtained. 

Modifying the aldehyde function in the pyrroles 1162 into 1,3-dipoles 1163 (nitrone) and 1167 (nitrile oxide) furnished tricyclic heterocycles 1164 and 1168 via intramolecular 1,3-dipolar cycloaddition reactions (Scheme 226) <2000T3013>. None of the isomeric bridged product 1165 is produced despite the preference for that regiochem-istry in the intermolecular reaction. Generated in situ (from the oximes 1166) nitrile oxides 1167 cyclized spontaneously to the dihydroisooxazole 1168 in quantitative yield at room temperature. 

Another synthesis of (-)-allosamizoline (8) was also carried out using the glucoseamine derivative 44 by an intramolecular cycloaddition of a nitrile oxide to an olefin as a key step (Scheme 5). ° lodination of 44 followed by reductive 3-elimination using zinc in THF afforded the 5-enofuranose 46, whose reaction with ethanethiol in cone. HCl followed by silylation with TBSOTf afforded 47. Dethioacetalization of 47 with HgCl2-CaC03 followed by treatment of the resulting aldehyde with NH2OH afforded the oxime 50, which underwent intramolecular cycloaddition to produce the isoxazoline 51. Alternatively, treatment... 

The routes leading from lactone A have the advantage of a chiral source of starting materials. With the two chiral centers at C24 and C25 set, the problem reduces down to elaborating the B ring with the appropriate substituents. An early solution was provided in an unusual cyclization of the B ring via an intramolecular Michael addition to the unsaturated aldehyde formed from a nitrile oxide 1,3-dipolar cycloaddition to the allyl methyl ketal of lactone A [76]. This clever use of relative stereocontrol provided by the highly constrained and predictable transition states of both key reactions unfortunately resulted in a low yield. A more conventional approach conceptualized the addition of a sulfoxide [77] to 2 to yield a masked diol-ketone precursor which cyclizes under acidic catalysis. Elimination of the sulfoxide permitted the introduction of the hydroxy substituent at C19 of the spiroketal. 

Zanze and co-workers recently reported an Ugi reaction followed by intramolecular nitrile oxide cycloaddition for the synthesis of novel isoxazo-hnes 130 (Scheme 34) [135]. The substrates required for INOC were synthesized by a multicomponent Ugi reaction utilizing aldehyde 125, aUyl amine 126, isocyanide 128 and -nitro carboxylic acids 127. 

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