Diastereoselectivity nitrile oxides

A series of 3-substituted-2-isoxazoles are prepared by the following simple procedure in situ conversion of nitroalkane to the silyl nitronate is followed by 1,3-dipolar cycloaddition to produce the adduct, which undergoes thermal elimination during distillation to furnish the isoxazole (Eq. 8.74). 5 Isoxazoles are useful synthetic intermediates (discussed in the chapter on nitrile oxides Section 8.2.2). Furthermore, the nucleophilic addition to the C=N bond leads to new heterocyclic systems. For example, the addition of diallyl zinc to 5-aryl-4,5-dihydroi-soxazole occurs with high diastereoselectivity (Eq. 8.75).126 Numerous synthetic applications of 1,3-dipolar cycloaddition of nitronates are summarized in work by Torssell and coworker.63a... 

Recently, silicon-tethered diastereoselective ISOC reactions have been reported, in which effective control of remote acyclic asymmetry can be achieved (Eq. 8.91).144 Whereas ISOC occur stereoselectively, INOC proceeds with significantly lower levels of diastereoselection. The reaction pathways presented in Scheme 8.28 suggest a plausible hypo thesis for the observed difference of stereocontrol. The enhanced selectivity in reactions of silyl nitronates may he due to 1,3-allylie strain. The near-linear geometry of nitrile oxides precludes such differentiating elements (Scheme 8.28). 

High diastereomeric ratios were observed in the 1,3-DC of various nitrile oxides to the chiral acryloylhydrazide 38. For example benzonitrile oxide afforded the isoxazoline 40 in 98% de <00TL1453>. The levels of facial selectivity obtained in the same 1,3-DC with the chiral 3-acryloyl-2-oxazolidinone 39 was very low (dr 43 57), but in the presence of MgBr2 (1 equiv) the reaction proceeded with high diastereoselectivity to give preferentially the isoxazolidine 41 in 92% de <00TL3131>. 

Cycloaddition of 2-alkoxy-l,3-butadienes, H2C=C(OAlk)CH=CH2, and nitrile oxides to give isoxazolines 51 proceeds with the participation of only one of the conjugated C=C bonds. With benzonitrile oxide, only the vinyl group in alkoxydienes participates in cycloaddition reactions while in the case of phenyl-glyoxylonitrile oxide both double bonds react (222). Nitrile oxides RC=NO react with iron complexed trienes 52. The reaction proceeds with good yield and diastereoselectivity ( 90/10) to give isoxazolines 53 (223). 

Regio- and diastereoselectivity in 1,3-dipolar cycloadditions of nitrile oxides to 4-substituted cyclopent-2-enones was studied (238, 239). The reactions are always regioselective, while the diastereofacial selectivity depends on the nature of the substituents. Thus, 4-hydroxy-4-methylcyclopent-2-enone (75) gives preferably adducts 76a, the 76a 76b ratio warying from 65 35 to 85 15 (Scheme 1.22). 

Optically active 3-arylisoxazoline-5-carboxylic acid derivatives 403 or 404 have been, prepared by the reaction of (S)- or (/ )-3-acryloyl-4-benzyl-5,5-dimethyloxazolidin-2-one (405 or 406) with nitrile oxides, obtained from benzo-hydroximoyl chloride and its substituted derivatives in the presence of a catalytic amount of metal salt, for example, Yb(OTf)3 (445). This procedure improves the diastereoselectivity of compounds 403 or 404, which are industrially useful as intermediates for various drugs and agrochemicals. It also enables the amount... 

Intramolecular cycloaddition of nitrile oxides, prepared from 1,2-isopropy-lidene-protected ether-linked oligo-pentoses leads to the diastereoselective formation of chiral isoxazolines fused to 10-16-membered oxa-cycles (456). 

Diastereoselective intermolecular nitrile oxide—olefin cycloaddition has been used in an enantioselective synthesis of the C(7)-C(24) segment 433 of the 24-membered natural lactone, macrolactin A 434 (471, 472). Two (carbonyl)iron moieties are instrumental for the stereoselective preparation of the C(8)-C(ii) E,Z-diene and the C(i5) and C(24) sp3 stereocenters. Also it is important to note that the (carbonyl)iron complexation serves to protect the C(8)-C(ii) and C(i6)-C(i9) diene groups during the reductive hydrolysis of an isoxazoline ring. 

A strategy based on the diastereoselective dipolar cycloaddition reaction of nitrile oxides and allylic alcoholates, has been applied to the synthesis of bis-(isoxazolines) that are precursors to polyketide fragments. These intermediates can be elaborated into protected polyols, for example, 439, by sequential chemos-elective reductive opening of each isoxazoline or, alternatively, by simultaneously, providing access to all stereoisomers of this carbon skeleton (479). 

Dipolar addition is closely related to the Diels-Alder reaction, but allows the formation of five-membered adducts, including cyclopentane derivatives. Like Diels-Alder reactions, 1,3-dipolar cycloaddition involves [4+2] concerted reaction of a 1,3-dipolar species (the An component and a dipolar In component). Very often, condensation of chiral acrylates with nitrile oxides or nitrones gives only modest diastereoselectivity.82 1,3-Dipolar cycloaddition between nitrones and alkenes is most useful and convenient for the preparation of iso-xazolidine derivatives, which can then be readily converted to 1,3-amino alcohol equivalents under mild conditions.83 The low selectivity of the 1,3-dipolar reaction can be overcome to some extent by introducing a chiral auxiliary to the substrate. As shown in Scheme 5-51, the reaction of 169 with acryloyl chloride connects the chiral sultam to the acrylic acid substrate, and subsequent cycloaddition yields product 170 with a diastereoselectivity of 90 10.84... 

A study of the regioselectivity of the 1,3-dipolar cycloaddition of aliphatic nitrile oxides with cinnamic acid esters has been published. AMI MO studies on the gas-phase 1,3-dipolar cycloaddition of 1,2,4-triazepine and formonitrile oxide show that the mechanism leading to the most stable adduct is concerted. An ab initio study of the regiochemistry of 1,3-dipolar cycloadditions of diazomethane and formonitrile oxide with ethene, propene, and methyl vinyl ether has been presented. The 1,3-dipolar cycloaddition of mesitonitrile oxide with 4,7-phenanthroline yields both mono-and bis-adducts. Alkynyl(phenyl)iodonium triflates undergo 2 - - 3-cycloaddition with ethyl diazoacetate, Ai-f-butyl-a-phenyl nitrone and f-butyl nitrile oxide to produce substituted pyrroles, dihydroisoxazoles, and isoxazoles respectively." 2/3-Vinyl-franwoctahydro-l,3-benzoxazine (43) undergoes 1,3-dipolar cycloaddition with nitrile oxides with high diastereoselectivity (90% de) (Scheme IS)." " ... 

Substituted 1,2,4-oxadiazoles were prepared by addition of nitrile oxides to imines or hydrazones. It has been reported that interaction of hydroximoyl chlorides 262 with chiral hydrazones 263 in the presence of EtsN leads to intermediates 264 with diastereoselectivity up to 97%. A subsequent N-N bond cleavage to remove chiral auxiliary by formic acid leads to 1,2,4-oxadiazolines 265 with ee up to 91% (equation 113). ... 

The convergence of the nitronate and nitrile oxide cycloadditions has allowed for the direct comparisons of yields and stereoselectivities of the two processes. For intramolecular reactions, the nitronate dipole typically required longer reaction times and/or elevated temperatures (22,98,135), however, the nitronate cycloaddition shows considerably higher diastereoselectivity (Table 2.42). Interestingly, the diastereoselectivity is dependent on the placement of a substituent on the tether. In the case of the silyl nitronate derived from 172, the diastereoselectivity is controlled by the substituent at C(l), while cyclization of the analogous nitrile oxide is governed by the substituent at C(l ) (Scheme 2.10) (124). 

TABLE 2.42. DIASTEREOSELECTIVITIES OBSERVED WITH NITRONATES AND NITRILE OXIDE CYCEOADDITIONS... 

The use of chiral auxiliaries to induce (or even control) diastereoselectivity in the cycloaddition of nitrile oxides with achiral alkenes to give 5-substituted isoxazolines has been investigated by a number of groups. With chiral acrylates, this led mostly to low or modest diastereoselectivity, which was explained in terms of the conformational flexibility of the vinyl-CO linkage of the ester (Scheme 6.33) (179). In cycloadditions to chiral acrylates (or acrylamides), both the direction of the facial attack of the dipole as well as the conformational preference of the rotamers need to be controlled in order to achieve high diastereoselection. Although the attack from one sector of space may well be directed or hindered by the chiral auxiliary, a low diastereomer ratio would result due to competing attack to the respective 7i-faces of both the s-cis and s-trans rotamers of the acrylate or amide. 

Extensive work has been done to determine and understand the factors controlling diastereoselectivity in the cycloaddition of nitrile oxides to alkenes but very little is known about nitrile ylides in this regard. Work on their reactions with alkenes that are geminally disubstituted with electron-withdrawing groups (e.g., 187) has illustrated some of the difficulties in such studies. When the imidoyl chloride-base route was used to generate the nitrile ylides it was found that the products 188 epimerized under the reaction conditions. When the azirine route was used, the reaction was complicated by the photochemical isomerization of the dipolarophiles (96,97). Thus, in both cases, it proved impossible to determine the kinetic product ratio. 

Extensive studies on diastereoselectivity in the reactions of 1,3-dipoles such as nitrile oxides and nitrones have been carried out over the last 10 years. In contrast, very little work was done on the reactions of nitrile imines with chiral alkenes until the end of the 1990s and very few enantiomerically pure nitrile imines were generated. The greatest degree of selectivity so far has been achieved in cycloadditions to the Fischer chromium carbene complexes (201) to give, initially, the pyrazohne complexes 202 and 203 (111,112). These products proved to be rather unstable and were oxidized in situ with pyridine N-oxide to give predominantly the (4R,5S) product 204 in moderate yield (35-73%). 

Yamamoto and co-workers (135,135-137) recently reported a new method for stereocontrol in nitrile oxide cycloadditions. Metal ion-catalyzed diastereoselective asymmetric reactions using chiral electron-deficient dipolarophiles have remained unreported except for reactions using a-methylene-p-hydroxy esters, which were described in Section 11.2.2.6. Although synthetically very useful and, hence, attractive as an entry to the asymmetric synthesis of 2-isoxazohnes, the application of Lewis acid catalysis to nitrile oxide cycloadditions with 4-chiral 3-(2-aIkenoyl)-2-oxazolidinones has been unsuccessful, even when > 1 equiv of Lewis acids are employed. However, as shown in the Scheme 11.37, diastereoselectivities in favor of the ffc-cycloadducts are improved (diastereomer ratio = 96 4) when the reactions are performed in dichloromethane in the presence of 1 equiv of MgBr2 at higher than normal concentrations (0.25 vs 0.083 M) (140). The Lewis acid... 

Only a few reports have described the application of optically active nitrile oxides in 1,3-dipolar cycloadditions (65-70). A general trend for these reactions is that moderate-to-poor diastereoselectivities are obtained when it is attempted to control the stereoselectivity using a chiral nitrile oxide. In one of the few recent examples, the chiral nitrile oxide 43, derived from Al-formylnorephenedrine and 3-methylnitrobutene, was subjected to reaction with diethyl fumerate (Scheme 12.16) (69). Compound 44 was obtained as the major product of this reaction as a 75 25 mixture with its diastereomer. 

Nitrile imines are related to azomethine imines, in the same manner as nitrile oxides are related to nitrones. In a single and recent report, the reactions of D-galactose derived chiral nitrile imines have been described (104). However, in reactions with nonchiral alkenes, no diastereoselection was obtained. 

For alkenyl nitrile oxides having the alkene in a cyclic structure, such as compound 141, high diastereoselectivities can be obtained (Scheme 12.47). Compound 141 is formed in situ, and undergoes a spontaneous cyclization to furnish 142 as the sole diastereomer. Toyota et al. (239) used the tricyclic isoxazoline 143 in the synthesis of (+)-pumiliotoxin C. 

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. 

The reactions of nitrones with 165 have been described (277-279). In the approach described by Koskinen and co-workers (279), the bulky nitrone 166 was used in a reaction with 165 to give a 20 1 mixture of 167 and an unidentified diastereomer (Note Opposite enantiomers are shown here). Reactions of less bulky nitrones gave lower selectivities (277,278). Kim et al. (280,281) described reactions of 165 with silyl nitronates (Scheme 12.52). The configuration of the direct isoxazolidine products was not determined. Instead, diastereoselectivities of 66-88% de of 169 were found after elimination of the silyloxy group. The reaction of various nitrile oxides proceeded to give the same isoxazoline products 169 as obtained for nitronates (Scheme 12.52). For the reactions of 165 with various alkyl and aryl nitrile oxides 170, the products 169 were obtained with diastereoselectivities of 62-90% de (282-286). In a theoretical study, it was proposed that the... 

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 amino acid derived chiral oxazolidinone 188 is a very commonly used auxiliary in Diels-Alder and aldol reactions. However, its use in diastereoselective 1,3-dipolar cycloadditions is less widespread. It has, however, been used with nitrile oxides, nitrones, and azomethine ylides. In reactions of 188 (R = Bn, R =Me, R = Me) with nitrile oxides, up to 92% de have been obtained when the reaction was performed in the presence of 1 equiv of MgBr2 (303). In the absence of a metal salt, much lower selectivities were obtained. The same observation was made for reactions of 188 (R = Bn, R = H, R = Me) with cyclic nitrones in an early study by Murahashi et al. (277). In the presence of Znl2, endo/exo selectivity of 89 11 and up to 92% de was observed, whereas in the absence of additives, low selectivities resulted. In more recent studies, it has been shown for 188 (R =/-Pr, R = H, R =Me) that, in the presence of catalytic amounts of Mgl2-phenanthroline (10%) (16) or Yb(OTf)3(20%) (304), the reaction with acyclic nitrones proceeded with high yields and stereoselectivity. Once again, the presence of the metal salt was crucial for the reaction no reaction was observed in their absence. Various derivatives of 188 were used in reactions with an unsubstituted azomethine ylide (305). This reaction proceeded in the absence of metal salts with up to 60% de. The presence of metal salts led to decomposition of the azomethine ylide. 

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