Cycloaddition intramolecular nitrile oxide

Hassner and coworkers have developed a one-pot tandem consecutive 1,4-addition intramolecular cycloaddition strategy for the construction of five- and six-membered heterocycles and carbocycles. Because nitroalkenes are good Michael acceptors for carbon, sulfur, oxygen, and nitrogen nucleophiles (see Section 4.1 on the Michael reaction), subsequent intramolecular silyl nitronate cycloaddition (ISOC) or intramolecular nitrile oxide cycloaddition (INOC) provides one-pot synthesis of fused isoxazolines (Scheme 8.26). The ISOC route is generally better than INOC route regarding stereoselectivity and generality. 

Intramolecular Cycloaddition Intramolecular nitrile oxide cycloaddition (INOC) is widely used in the synthesis of various compounds, particularly, natural products. This field is reviewed in detail in Chapter 6 of the mono-graph/Reference 5 and also in Reference 400 limited to nitrile oxides generated from nitroalkenes. Some features of INOC are illustrated in this subsection by new data and those omitted in Reference 5. 

R = h, Me, Ph. INOC intramolecular nitrile oxide cycloaddition. Scheme 3.140... 

Intramolecular nitrile oxide cycloaddition. The conjugate addition of t-butyl isocyanide to a nitroalkene can generate a nitrile oxide, which can be trapped intramolecularly by a double bond to form an isoxazoline. 

Intramolecular [3+2] dipolar cycloadditions have also been employed as a post-Ugi transformation to generate heterobicyclic structures, namely fused isoxazolines [130], isoxazoles [130] and triazoles [131] (Fig. 31). Isoxazoles were obtained through intramolecular nitrile oxide cycloaddition. The precursor of the nitrile oxide (a nitro group) was introduced into the carboxylic component, while a triple bond was positioned in the starting amine. Treatment of 152 with POCl3/Et3N gave the intermediate nitrile oxide, which spontaneously cyclized to isoxazoles 153. 

Regio- and Stereoselectivity in Intramolecular Nitrile Oxide Cycloadditions. 407... 

Intramolecular Nitrile Oxide Cycloadditions Applications in Synthesis. 437... 

Syntheses with Intramolecular Nitrile Oxide Cycloaddition and... 

REGIO- AND STEREOSELECTIVITY IN INTRAMOLECULAR NITRILE OXIDE CYCLOADDITIONS... 

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). 

Many aspects of intramolecular nitrile oxide cycloadditions are similar to those of the intermolecular ones. Due to the proximity of the reacting groups, however, there are also several items that differ significantly. While HOMO-LUMO interactions and steric effects direct the intermolecular nitrile oxide cycloaddition to 1-alkenes to produce 5-substituted isoxazolines, the intramolecular cases often show a different behavior. With most of them, regioselectivity is determined by geometric constraints and cycloadditions occur in the exo mode to furnish the annulated bicycle (Scheme 6.42). 

INTRAMOLECULAR NITRILE OXIDE CYCLOADDITIONS APPLICATIONS IN SYNTHESIS... 

An intramolecular nitrile oxide cycloaddition also served as the key step in the stereoselective assemblage of the skeleton of angular triquinane sesquiterpenes of the isocomene series. Tetracyclic isoxazoline 203 was obtained from oxime 202 [derived from tetrahydroindandione 201] and on treatment with sodium hypochlorite... 

The sesquiterpene skeleton has also been assembled by the intramolecular nitrile oxide cycloaddition sequence. Oxime 238 (obtained from epoxy silyl ether 237), on treatment with sodium hypochlorite gave isoxazoline 239, which was sequentially hydrolyzed and then subjected to the reductive hydrolysis conditions-cyclization sequence to give the furan derivative 240 (330) (Scheme 6.93). In three additional steps, compound 240 was converted to 241. This structure contains the C11-C21 segment of the furanoterpene ent-242, that could be obtained after several more steps (330). 

A stereoselective synthesis of testosterone (261) was advanced by Fukumoto and co-workers (331), where ring B was joined to the C/D part by an intramolecular nitrile oxide cycloaddition. The key nitrile oxide dipole was generated in situ from oxime 258, which in turn was derived from the optically active tetrahydroin-danone 257. Tetracyclic isoxazoline (259) was obtained as a single stereoisomer... 

Shibasaki and co-workers used an intramolecular nitrile oxide cycloaddition to prepare the skeleton of phorbol (272) (Scheme 6.99), a tumor promoter that activates protein kinase C (PKC) (333). Nitroalkene 268 was elaborated in several steps from (+)-3-carene (267) and was subjected to cycloaddition by means of -chlorophenyl isocyanate-triethylamine to give cycloadduct 269 in 88% yield. Reductive hydrolysis employing Raney Ni and boric acid afforded hydroxyketone 270, that was subsequently used for the construction of the optically active derivative 271, which contains the phorbol skeleton (333). 

One of the very first uses of the intramolecular nitrile oxide cycloaddition involved the synthesis of macrocyclic lactones. Asaoka et al. (238) conceived this approach to the 16-membered ring antibiotic A26771B (277). Nitro compound 274 [obtained from 11-acetoxydodecanal (273)] was dehydrated with 4-chlorophenyl isocyanate-triethylamine and this was followed by dipolar cycloaddition, which gave isoxazoline 275 as a 4 1 mixture of diastereomers (Scheme 6.100). 

Few examples of total syntheses have been reported that involve an intramolecular nitrile oxide cycloaddition and ensuing reduction to an aminoalcohol. The very first example was reported by Confalone et al. (334) and involved a synthesis of the naturally occurring vitamin biotin (287). The nitro precursor 284 was easily prepared from cycloheptene. When treated with phenyl isocyanate-triethylamine, cycloaddition led to the all-cis-fused tricyclic isoxazoline 285 with high stereoselectivity (Scheme 6.102). Reduction with LiAlFLj afforded aminoalcohol 286 as a... 

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