Pyrrolidines nitrone 1,3-dipolar cycloadditions

Since Huisgen s definition of the general concepts of 1,3-dipolar cycloaddition, this class of reaction has been used extensively in organic synthesis. Nitro compounds can participate in 1,3-dipolar cycloaddition as sources of 1,3-dipoles such as nitronates or nitroxides. Because the reaction of nitrones can be compared with that of nitronates, recent development of nitrones in organic synthesis is briefly summarized. 1,3-Dipolar cycloadditions to a double bond or a triple bond lead to five-membered heterocyclic compounds (Scheme 8.12). There are many excellent reviews on 1,3-dipolar cycloaddition, in particular, the monograph by Torssell covers this topic comprehensively. This chapter describes only recent progress in this field. Many papers have appeared after the comprehensive monograph by Torssell. Here, the natural product synthesis and asymmetric 1,3-dipolar cycloaddition are emphasized.630 Synthesis of pyrrolidine and -izidine alkaloids based on cycloaddition reactions are also discussed in this chapter. 

Dipolar cycloaddition reactions between three A-benzyl-C-glycosyl nitrones and methyl acrylate afforded key intermediates for the synthesis of glyco-syl pyrrolidines. It was found that furanosyl nitrones (574) and (575) reacted with methyl acrylate to give mixtures of all possible 3,5-disubstituted isoxazolidines (577) and (578). On the other hand, the reaction with pyranosyl nitrone (576) was much more selective and cycloaddition at ambient temperatures afforded only one of the possible Re-endo adducts (579a). The obtained isoxazolidines were transformed into the corresponding (V-benzyl-3-hydroxy-2-pyrrolidinones (580—582) on treatment with Zn in acetic acid (Scheme 2.264) (773). 

An impressive enantiopure synthesis of Amaryllidaceae alkaloids has been achieved through the formation of sugar-derived homochiral alkenyl nitrone 265 (Fig. 1.7).[280] While this reagent required lengthy preparation, it underwent an intramolecular dipolar cycloaddition to establish the required stereochemistry of the polycyclic pyrrolidine skeleton of (—)-haemanthidine (266), which was converted to (+)-pretazettine and (+)-tazettine by established procedures (281). 

The dipolar cycloaddition of nitronates has been applied to the synthesis of several natural products in the context of the tandem [4+2] / [3 + 2] nitroalkene cycloaddition process. All of these syntheses have focused on the construction of pyrrolidine, pyrrolizidine, and indolizidine alkaloids. For example, the synthesis of ( )-hastanecine (316), a necine alkaloid, involves the elaboration of a p-benzoy-loxynitroalkene 311 via [4 + 2] cycloaddition with a chiral vinyl ether (312) in the presence of a titanium based Lewis acid, to provide the nitronate 313 with high diastereo- and facial selectivity (Scheme 2.30) (69). The dipolar cycloaddition of... 

Nitrogen heterocycles continue to be valuable reagents and provide new synthetic approaches such as NITRONES FOR INTRAMOLECULAR -1,3 - DIPOLAR CYCLOADDITIONS HEXAHYDRO-1,3,3,6-TETRAMETHYL-2,l-BENZISOX AZOLINE. Substituting on a pyrrolidine can be accomplished by using NUCLEOPHILIC a - sec - AM IN O ALKYL ATION 2-(DI-PHENYLHYDROXYMETHYL)PYRROLIDINE. Arene oxides have considerable importance for cancer studies, and the example ARENE OXIDE SYNTHESIS PHENANTHRENE 9,10-OXIDE has been included. An aromatic reaction illustrates RADICAL ANION ARYLATION DIETHYL PHENYLPHOSPHONATE. 

The Cl sequence introduced in Chap. 2.2 represents a mild and catalytic access to chalcones. l,3-Diarylprop-2-en-l-ones are bifunctional electrophilic Michael-systems and per se important three-carbon building blocks in synthetic heterocyclic chemistry [33]. Among many classes of five-, six-, and seven-membered heterocycles the underlying principle is always the Michael-addition-cyclocondensation sequence of chalcones and bifunctional nucleophiles [176-181, 222-229]. Furthermore, chalcones can also participate in cycloadditions, as dienophiles and dipolar-ophiles and furnish in the case of 1,3-dipolar cycloadditions with diazo alkanes pyrazolines [230, 231], with azides triazolines [232], with nitrones isoxazolidines [233] with azomethinylides pyrrolidines [234], or with nitriloxides isoxazolines [235]. Therefore, the mild, catalytic access to chalcones by the CIR excellently sets the stage for the development of consecutive MCRs based upon cyclocondensation strategies. 

Various oxidants have been used to convert pyrrolidine and piperidine into nitrones (imine oxides), of value for 1,3-dipolar cycloadditions in one method hydrogen peroxide is the oxidant in the presence of a catalyst/... 

Abstract This review is devoted to the stereoselectivity of intermolecular (intramolecular cycloadditions are not included) 1,3-dipolar cycloadditions of sugar-derived nitrones. Stereoselective cycloaddition (transformation of isoxazolidine followed by reduction of the N O bond to produce both an amino and a hydroxy function) allows the synthesis of tailor-made products of possible biological interest such as pol>4iydroxylated pyrrolidines, pyrrolizidines, indolizidines, fi-aminocarbonyl compounds, and disaccharides. Attention is focused on the preparation of isoxazolidinyl nucleosides and to the catalysis of the cycloaddition by Lewis acids. This review has concentrated on the new developments achieved from 1999 to February 2007. 

The 1,3-dipolar cycloaddition of a variety of nitrile oxides, nitrones, ethyl diazoacetate, and azomethine ylide to the chiral furanone 174a was studied with respect to the present regio- and diastereoselectivity (93T8899). In the case of the azomethine ylide addition, three stereoisomeric adducts were obtained. However, in the case of the other dipoles only two stereoisomeric adducts were isolated the major product proved to be the an//-facial isomer. In this way, a number of multifunctional (lactone-annulated) isoxazolines 241 and 242, isoxazolidines 243 and 244, pyrazolines 245a,b, and pyrrolidines 248a,b,c could be synthesized (Scheme 65) (93T8899). 

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