Nitrones in 1, 3-dipolar cycloadditions

An optically active cyclic nitrone in 1,3-dipolar cycloaddition was first reported by Vasella in 1985. 81A variety of optically active cyclic nitrones have been devised since then. Some typical chiral nitrones described in Ref. 63c are shown in Scheme 8.17. Applications of these nitrones are also presented in this review. 

The present procedure serves as a model for the generation and use in situ of unstable nitrones in 1,3-dipolar cycloaddition reactions. 

Nitrile oxides are generally more reactive than nitrones in 1,3-dipolar cycloadditions. Nitrile oxides are most often generated in situ by dehydrochlorination of hydroximoyl chlorides. Similar to nitrones, the oxygen preferentially adds to the more substituted ethylenic carbon. 

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. 

Various kinds of chiral acyclic nitrones have been devised, and they have been used extensively in 1,3-dipolar cycloaddition reactions, which are documented in recent reviews.63 Typical chiral acyclic nitrones that have been used in asymmetric cycloadditions are illustrated in Scheme 8.15. Several recent applications of these chiral nitrones to organic synthesis are presented here. For example, the addition of the sodium enolate of methyl acetate to IV-benzyl nitrone derived from D-glyceraldehyde affords the 3-substituted isoxazolin-5-one with a high syn selectivity. Further elaboration leads to the preparation of the isoxazolidine nucleoside analog in enantiomerically pure form (Eq. 8.52).78... 

Alkyl and silyl nitronates are, in principle, /V-alkoxy and /V-silyloxynitrones, and they can react with alkenes in 1,3-dipolar cycloadditions to form /V-alkoxy- or /V-silyloxyisoxaz.olidine (see Scheme 8.25). The alkoxy and silyloxy groups can be eliminated from the adduct on heating or by acid treatment to form 2-isoxazolines. It should be noticed that isoxazolines are also obtained by the reaction of nitrile oxides with alkenes thus, nitronates can be considered as synthetic equivalents of nitrile oxides. Since the pioneering work by Torssell et al. on the development of silyl nitronates, this type of reaction has become a useful synthetic tool. Recent development for generation of cyclic nitronates by hetero Diels-Alder reactions of nitroalkenes is discussed in Section 8.3. 

These experimental findings, as well as earlier data on alkylidenecyclopropanes, clearly disclose a peculiar effect of a cyclopropylidene system both on reaction rates and regioselectivity. In fact, the parent MCP as well as its derivatives exhibit a high reactivity in 1,3-dipolar cycloadditions with nitrones. In contrast, the related open chain isobutene and its derivatives are well known to enter 1,3-dipolar cycloadditions sluggishly [51c-d, 70]. For example, there is no chance to obtain a cycloadduct from 256 and an open chain trialkyl or tetraalkylethylene, as was obtained in the reaction of 256 with 270 and 271. 

To study asymmetric induction from the nitrone part in 1,3-dipolar cycloaddition to styrene, D-erythrose derived nitrones (479 a-c) have been used. Cycloaddition of nitrones (479 a-c) to styrene, in boiling toluene for 10 h, affords a mixture of four diastereomeric 3,5-disubstituted isoxazolidines (481 a-c-484 a-c) in high yields (82%-94%) (Scheme 2.237) (208). 

Recently, an example of green chemistry in the formation of a nitrone in aqueous medium, using a surfactant, was reported in 1,3-dipolar cycloadditions to ethyl acrylate (776). The control of regioselectivity in this reaction favors the formation of trans -5-substituted isoxazolidines. 

Dipolarophile D7. Recently, dipolarophiles D7 (Fig. 2.39) have been widely used in 1,3-dipolar cycloadditions to various nitrones (Fig. 2.40) (72, 781-787). 

In the frequency of their use in 1,3-dipolar cycloadditions to nitrones, alkynes constitute the second group of dipolarophiles after alkenes. They are of particular interest due to the fact that isoxazolines, the products of initial cycloadditions,... 

The use of nitriles as dipolarophiles in 1,3-dipolar cycloaddition reactions is scarce because of their relative inertness in such reactions. Indeed, nitriles with electron-donor substituents do not react with nitrones even under harsh conditions. Hence, an additional activation of the reactants is required. This can be achieved, either by activating the nitrile (dipolarophile) or the nitrone (dipole), or both of them. For example, the reaction of electron-difficient nitriles such as... 

Synthesis of Dialkylboryl Nitronates Approaches to the synthesis of boryl nitronates are similar to the strategy for the synthesis of silyl nitronates developed in more detail (see Section 3.2.3). However, only four studies have dealt with the synthesis of boryl nitronates (217, 229-231). The absence of interest in this class of compounds is apparently attributed to the fact that they are not involved in 1,3-dipolar cycloaddition reactions and, consequently, are unlikely to find use in organic synthesis. 

Oxidation of amines to nitrones.1 Secondary amines can be oxidized to nitrones by 30% H202 in the presence of a catalytic amount of Se02. The reaction is applicable to acyclic and cyclic amines. The products can be used without isolation in 1,3-dipolar cycloadditions. 

The above-mentioned complexes are the sole iridium derivatives applied to DCR, and the cycloaddition of nitrones to enals or methacrylonitrile, the unique process studied. We think that iridium-based catalysts are underrepresented in 1,3-dipolar cycloaddition chemistry. For example, no iridium (1) systems have been developed to this end. It can be anticipated that the (bidentate ligand)lr(l) fragment could be active (and stereoselective if chiral bidentate ligands are used) in DCR such as those involving azomethine ylides. 

For the first time, DFT theory has been applied to a study of diastereofacial selectivity in 1,3-dipolar cycloadditions of nitrones to di-3,4-dimethylcyclobutene. ° The stereochemical outcome of the INAC reactions of nitrones (49) and (52) derived from 3-(9-allyl-D-hexoses is dependent only on the relative configuration at C(2,3), and thus 3-(9-allyl-D-glucose (48) and -o-altrose (threo configuration) afford oxepanes (50) selectively whereas 3-O-allyl-D-allose (51) and -D-mannose (erythro configuration) give tetrahydrofurans (53) and (54) selectively (Scheme 18). frani-2-Methylene-... 

Other nitrones (21-23) having the chiral moiety located at the carbon atom have been applied in reactions with various alkenes (Scheme 12.10) (33-35). Nitrone 21 offered poor discrimination in 1,3-dipolar cycloadditions with benzyl crotonate, as all four diastereomers were obtained in both reactions (33). The fluorinated nitrone... 

Mukai et al. (36,37) applied the chiral tricarbonyl(r -arene)chromium(0)-derived nitrone 24b in 1,3-dipolar cycloadditions with various alkenes, such as styrene 25 (Scheme 12.11). The analogous nonmetallic nitrone 24a was used in a reference reaction with 25, giving the isoxazohdine 26a with an endo/exo ratio of 82 18. By the apphcation of nitrone 24b in the 1,3-dipolar cycloaddition with 25, the endo/exo-selectivity changed significantly to give exo-26b as the only observable product. The tricarbonylchromium moiety effectively shielded one face of the nitrone, leading to high diastereofacial selectivity. The product exo- 26b was obtained with 96-98% de. 

Another type of chiral alkene applied in 1,3-dipolar cycloadditions are vinyl groups attached to chiral phosphine oxides or sulfoxides. Brandi et al. (150,151) used chiral vinyl phosphine oxide derivatives as alkenes in 1,3-dipolar cycloadditions with chiral nitrones. This group also studied reactions of achiral nitrones with chiral vinyl phosphine oxide derivatives. Using this type of substrate, fair endo/exo-selectivities were obtained. In reactions involving optically pure vinyl phosphine oxides, diastereofacial selectivities of up to 42% de were obtained. Chiral vinyl... 

The auxihary acrylates 161 and 162 have been used in 1,3-dipolar cycloadditions with nitrile oxides. The camphor-derived acrylate 161 underwent a 1,3-dipolar cycloaddition with benzonitrile oxide with up to 56% de (Scheme 12.51) (263). The auxiliary in acrylate 162 is derived from naturally occurring L-quebrachitol, and provided an effective shielding of the re-face of the alkene in the reaction with benzonitrile oxide, as 90% de was obtained (273). Compound 163 was used in a reaction with the nitrone 1-pyrrole-1-oxide, and the reaction proceeded to give a complex mixture of products (274). 

The a,p-unsaturated amides 180-188a have all been used in 1,3-dipolar cycloadditions with nitrile oxides, and some of them represent the most diastereoselective reactions of nitrile oxides. The camphor derivative 180 of Chen and co-workers (294), the sultam 181 of Oppolzer et al. (295), and the two Kemp s acid derived compounds 186 (296) and 187 (297) described by Curran et al. (296) are excellent partners for diastereoselective reactions with nitrile oxides, as very high diastereos-electivities have been observed for all of them. In particular, compound 186 gave, with few exceptions, complete diastereoselection in reactions with a wide range of different nitrile oxides. Good selectivities were also observed when using compounds 183 (298) and 184 (299-301) in nitrile oxide cycloadditions, and they have the advantage that they are more readily available. Curran and co-workers also studied the 1,3-dipolar cycloaddition of 187 with silyl nitronates. However, compared to the reactions of nitrile oxides, lower selectivities of up to 86% de were obtained (302). 

The use of chiral vinyl ethers in 1,3-dipolar cycloadditions with nitrones allows for the subsequent removal and recovery of the chiral group. Using the chiral vinyl ether 197 and the cyclic nitrone 77, the cycloaddition proceeded with high diastereoselectivity (Scheme 12.56). The endo/exo-selectivity was not given in this communication by Carmthers et al. (313), but this is of minor importance for the final outcome of this work, since one of the chiral centers was destroyed in the conversion of 198 into the final product 199. The chiral auxiliary can by recovered in this reaction sequence, and 199 was obtained with an optical purity of >95% ee. 

The direct cycloaddition adduct was oxidized, resulting in the hydroxylated isoxazoline product (316). Better selectivities were obtained in 1,3-dipolar cycloadditions of 204 with nitrile oxides (317,318). The 1,3-dipolar cycloadditions proceeded with concomitant loss of the boron group to give the isoxazoline products in up to 74% ee (318). The alkene 204 was also tested in reactions with nitrones. The reactions proceeded with poor yields, but high selectivities were observed in two cases (318). Gilbertson et al. (319) investigated the use of chiral ot,p-unsaturated hexacarbonyldiiron acyl complexes 205 as dipolarophiles in reactions with nitrones. Selectivities of up to >92% de were observed. The iron moiety was removed oxidatively after the cycloaddition and the thioester was hydrolyzed. 

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