Nitrones 3+2 -cydoadditions

Dipolar cydoadditions are one of the most useful synthetic methods to make stereochemically defined five-membered heterocydes. Although a variety of dia-stereoselective 1,3-dipolar cydoadditions have been well developed, enantioselec-tive versions are still limited [29]. Nitrones are important 1,3-dipoles that have been the target of catalyzed enantioselective reactions [66]. Three different approaches to catalyzed enantioselective reactions have been taken (1) activation of electron-defident alkenes by a chiral Lewis acid [23-26, 32-34, 67], (2) activation of nitrones in the reaction with ketene acetals [30, 31], and (3) coordination of both nitrones and allylic alcohols on a chiral catalyst [20]. Among these approaches, the dipole/HOMO-controlled reactions of electron-deficient alkenes are especially promising because a variety of combinations between chiral Lewis acids and electron-deficient alkenes have been well investigated in the study of catalyzed enantioselective Diels-Alder reactions. Enantioselectivities in catalyzed nitrone cydoadditions sometimes exceed 90% ee, but the efficiency of catalytic loading remains insufficient. 

Among the J ,J -DBFOX/Ph-transition(II) metal complex catalysts examined in nitrone cydoadditions, the anhydrous J ,J -DBFOX/Ph complex catalyst prepared from Ni(C104)2 or Fe(C104)2 provided equally excellent results. For example, in the presence of 10 mol% of the anhydrous nickel(II) complex catalyst R,R-DBFOX/Ph-Ni(C104)2, which was prepared in-situ from J ,J -DBFOX/Ph ligand, NiBr2, and 2 equimolar amounts of AgC104 in dichloromethane, the reaction of 3-crotonoyl-2-oxazolidinone with N-benzylidenemethylamine N-oxide at room temperature produced the 3,4-trans-isoxazolidine (63% yield) in near perfect endo selectivity (endo/exo=99 l) and enantioselectivity in favor for the 3S,4J ,5S enantiomer (>99% ee for the endo isomer. Scheme 7.21). The copper(II) perchlorate complex showed no catalytic activity, however, whereas the ytterbium(III) triflate complex led to the formation of racemic cycloadducts. 

Absolute configurations of the isoxazolidines obtained in the nitrone cydoaddition reactions described in Schemes 7.21 and 7.22 were determined to be 3S,41 ,5S structure by comparison of the optical rotations as well as retention times in a chiral HPLC analysis with those of the authentic samples. Selection of the si face at C/ position of 3-crotonoyl-2-oxazolidinone in nitrone cydoadditions was the same as that observed in the Diels-Alder reactions of cyclopentadiene with 3-croto-noyl-2-oxazolidinone in the presence of the J ,J -DBF0X/Ph-Ni(C104)2-3H20 complex (Scheme 7.7), and this indicates that the s-cis conformation of the dipolaro-phile has participated in the reaction. 

Nitrones are a rather polarized 1,3-dipoles so that the transition structure of their cydoaddition reactions to alkenes activated by an electron-withdrawing substituent would involve some asynchronous nature with respect to the newly forming bonds, especially so in the Lewis acid-catalyzed reactions. Therefore, the transition structures for the catalyzed nitrone cydoaddition reactions were estimated on the basis of ab-initio calculations using the 3-21G basis set. A model reaction indudes the interaction between CH2=NH(0) and acrolein in the presence or absence of BH3 as an acid catalyst (Scheme 7.30). Both the catalyzed and uncatalyzed reactions have only one transition state in each case, indicating that the reactions are both concerted. However, the synchronous nature between the newly forming 01-C5 and C3-C4 bonds in the transition structure TS-J of the catalyzed reaction is rather different from that in the uncatalyzed reaction TS-K. For example, the bond lengths and bond orders in the uncatalyzed reaction are 1.93 A and 0.37 for the 01-C5 bond and 2.47 A and 0.19 for the C3-C4 bond, while those in... 

More recently, MacMillan has introduced the amine catalysts 42 and 45, readily available from L-phenylalanine, methylamine, and acetone or pivalaldehyde, respectively (Schemes 4.15 and 4.16). The broad potential of these materials in enan-tioselective organocatalysis was first proven in Diels-Alder reactions [28] and nitrone cydoadditions [29]. In 1,4-addition of C-nudeophiles MacMillan et al. later showed that Friedel-Crafts reactions of pyrroles with enals can be made highly enantioselective (Scheme 4.15) [30]. 

Goti, Brandi and coworkers developed an effective synthesis of (-)-rosmarinecine (4-357) via a domino cydoreversion-intramolecular nitrone cydoaddition of 4-355, which led to 4-356 (Scheme 4.79) [125]. 

A new type of rigid polymer of 1,1-binaphthols was developed recently [41-43]. The 3,3 -crosslinked polymeric binaphthol ligand 18 in combination with AlMe3 was applied as the catalyst for the 1,3-dipolar cydoaddition (Scheme 6.16) [44]. Very high selectivities were obtained when the aluminum catalyst of 18 (20 mol%) was applied to the 1,3-dipolar cydoaddition reaction between nitrone la and al-kene 8a. The only observable diastereomer resulting from the reactions was exo-9a... 

Holmes et al. used another interesting pericyclic domino reaction in the synthesis of (-)-histrionico-toxine 116 (scheme 23).1631 In a not fully understood sequence 113 at 190 °C generates the cydoadduct 115 in 80% yidd with loss of styrene. It can be assumed that the process consists of a retro-13-dipolar and a 13-dipolar cydoaddition with the intermediary formation of the nitrone 114. Overall, three new stereogenic centers, necessary for the natural product, have been efficiently created. An... 

This 1,3-dipolar cydoaddition not only gave excellent results but was also found to be very general with regard to the nitrone component. Several types of aryl- and alkyl-substituted nitrone have been applied successfully. Irrespective of the substitution pattern, high diastereomeric ratios and enantioselectivity were obtained (see Scheme 8.9, products 35a,d,f,g). Variation of the N-alkyl group is also possible. As can be see from Scheme 8.9 (see, e.g., products 35a-c), the reactions also proceed well when an N-allyl and N-methyl-substituted nitrone is used. Acrolein, 32b, and crotonaldehyde, 32a, were used as the aldehyde component. It is noteworthy that this reaction is also suitable for use on a larger scale, as has been demonstrated by the 25 mmol-scale preparation of endo-35a (98% yield, 94% ee) starting from nitrone 31a and crotonaldehyde. 

It is assumed that, after the initial formation of the oxime 2-634, a Michael addition occurs to give 2-635 with formation of a nitrone moiety which then can undergo a 1,3-dipolar cydoaddition to give 2-636. 

Enantioenriched (-)-rosmarinedne, which belongs to the group of pyrrolizidine alkaloids [413], has been synthesized by Goti, Brandi and coworkers applying an intramolecular 1,3-dipolar cydoaddition as the key step [414], The required nitrone was obtained in situ from L-malic acid. Moreover, 1,3-dienes as precursors for a cy-... 

The key step in the synthesis of4-354 is the retro-1,3-dipolar cydoaddition of the isoxazolidine 4-351 to give the nitronate 4-352, which underwent an intramolecular 1,3-dipolar cydoaddition. The obtained cydoadduct 4-353 can be transformed in a few steps into the desired target 4-354 (Scheme 4.78). 

A first example of (chiral) Lewis acid-catalyzed 1,3-dipolar cydoaddition of nitrones with electron-rich ketene acetals has been reported by ... 

The [3 + 2J Nitrone-Olefin Cydoaddition Reaction Pat N. Confalonc and Edward M. Huic... 

Wagner [71] performed 1,3-dipolar cydoaddition of nitrones 95 with trans-[PtCl2(PhCN)2] (94) and showed that microwave irradiation enhances the rate of the cydoaddition substantially and also favors selectivity towards the monocycloadduct 96, compared with thermal conditions (Scheme 5.28). Both cycloadditions can be performed at room temperature overnight, indicating that the difference between reactivity is not dramatic, although it is sufficient to achieve high selectivity. The progress of the reaction with time is shown in Fig. 5.20. The nitrone... 

The 1,3-dipolar cycloaddition reaction between nitrones and unsaturated systems under the action of microwave irradiation has been shown to be a powerful method for the synthesis of a wide variety of novel five-membered heterocycles. In 2002, several nitrone-mediated 1,3-dipolar cydoaddition reactions were reported by de la Hoz in the original edition of this book [3jj. Most of the examples provided had been described between 1995 and 2001 [9a, 13b, 84, 92]. 

Bashiardes et al. [94] described an intramolecular cydoaddition reaction of unprotected carbohydrates 126, involving a nitrone ylide dipole 127 derived from the 1-aldehydic position, and an co-olefinic moiety constructed from the 6-hydroxyl function (Scheme 11.32). In this enantiomeric synthesis of novel bicyclic oxazoli-dines bearing a quaternary bridgehead, 128, a comparative study was performed of classical heating conditions and microwave-assisted cydoaddition, both in the same reaction medium, aqueous ethanol. All the examples provided products in yields which were improved from approximately 60% to 90%, basically because of the cleaner reactions. The reaction times were reduced from 48 h to just 1 h. 

The [3+2] cycloaddition of nitrones to organonitriles bound to Pt(II), Pt(IV), or Pd(II), by use of a combination of the Lewis acidity of the transition metals and microwave irradiation, has been described in three independent reports. In the first example, Wagner et al. [95] reported that the [3+2] cydoaddition of N-methyl-C-phenylnitrone 130 to transition metal coordinated ( )-cirmamonitrile 129 occurred exclusively at the nitrile C=N bond, leading to bis-oxadiazoline complexes 132 in high yield (Scheme 11.33). In contrast, reaction of the nitrone 130... 

Some excellent results for cycloadditions involving nitrones were observed by Merino et al. [99] using a solvent-free [3+2] cydoaddition of N-berrzyl-C-glycosyl nitrones to methyl acrylate. Microwave irradiation for 0.1 h was sufficient to afford a 100% yield of the isolated isoxazolidine whereas thermal heating under reflux conditions (80 °C) required 0.5 h and produced the same yield and the same stereoisomeric ratio. 

Fig. 7 1,3-Dipolar cydoaddition of v-threo nitrone with methyl acrylate...

Fig. 19 1,3-Dipolar cydoaddition of o-xylo nitrone with vinyl nudeobases...

Keywords 1,3-dipolar cydoaddition Isoxazolines Nitrile oxide Silyl nitronate... 

Stereoselectivity of l S-Dipolar Cydoaddition. The stereoselectivity of the intermolecular cycloaddition of an acyclic nitrone to an alkene is difficult to predict, and wotdd appear to be susceptible to minor structural changes in either component (13). The chiral 2,2-dimethyl-l,3-dioxolan-4-yl nitrone showed only modest astereoface selectivity in its addition to methyl crotonate (14). However, the more hindered tetramethyl-l,3-dioxolan-4-yl nitrone was more selective. 

Stereoselectivity of 1,3-Dipolar Cydoaddition. The anti-isoxazolidines 15 arise from cycloaddition of Z-nitrone through endo transition state, or the E-nitrone in an exo-mode. Conversely the syn-isoxazolidines 16 could be formed by the Z-nitrone reacting in the exo-fashion or the E-nitrone in an endo-mode (Scheme VH). 

Y. Yu, H. Fujita, M. Ohno, S. Eguchi, 1,3-dipolar cydoaddition of nitrile functions with nitrones under high pressure conditions. A new and direct synthesis of 2,3-dihydro-l,2,4-oxadiazole derivatives. Synthesis (1995) 498-500. 

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