Isoxazolines silyl nitronate cycloaddition

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. 

Hoveyda and co-workers employed nitroolefinic silanes 249 possessing a chiral center that bears a silicon substituent for the diastereoselective synthesis of isoxazolines 251 (Scheme 59) [160]. While the silyl nitronate cycloaddition provided the diastereomeric isoxazolines 251 in >20 1 ratio, the nitrile oxide route was much less selective (dr 1 2), in agreement with the findings by Hassner as shown in Scheme 49. The greater selectivity observed in the ISOC reaction was attributed to a possible 1,3-aUylic strain in the transition state leading to the minor isomer while no such strain was expected for nitrile oxides that have near-linear geometry. The authors also observed greater... 

Although nitrile oxide cycloadditions have been extensively investigated, cycloadditions of silyl nitronates, synthetic equivalent of nitrile oxides in their reactions with olefins, have not received similar attention. Since we found that the initial cycloadducts, hl-silyloxyisoxazolidines, are formed with high degree of stereoselectivity and can be easily transformed into isoxazolines upon treatment with acid or TBAF, intramolecular silylnitronate-olefin cycloadditions (ISOC) have emerged as a superior alternative to their corresponding INOC reactions [43]. Furthermore, adaptability of ISOC reactions to one-pot tandem sequences involving 1,4-addition and ISOC as the key steps has recently been demonstrated [44]. 

ISOC reaction was employed to synthesize substituted tetrahydrofurans 172 fused to isoxazolines (Scheme 21) [44b]. The silyl nitronates 170 resulted via the nitro ethers 169 from base-mediated Michael addition of allyl alcohols 168 to nitro olefins 167. Cycloaddition of 170 followed by elimination of silanol provided 172. Reactions were conducted in stepwise and one-pot tandem fashion (see Table 16). A terminal olefinic Me substituent increased the rate of cycloaddition (Entry 3), while an internal olefinic Me substituent decreased it (Entry 4). 

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. 

The use of silylketals derived from allylic alcohols and 1-substituted nitroethanols for the stereocontrolled synthesis of 3,4,5-trisubstituted 2-isoxazolines via intramolecular 1,3-dipolar cycloaddition has been demonstrated. Here again, the use of silyl nitronates (ISOC) increases the level of selectivity compared to INOC (Eq. 8.92).145... 

Several years later, Ioffe et al. (16) demonstrated that silyl nitronates also could be engaged in the dipolar cycloaddition with alkenes. These silylated isoxazolidine cycloadducts were then converted to the corresponding isoxazolines by treatment with sodium methoxide (Scheme 2.2). 

The [3 + 2] cycloaddition of silyl nitronates has been extensively investigated since the first pioneering studies by Ioffe et al. (16). This transformation is attractive because of the resulting isoxazolidine can be easily converted to the corresponding isoxazoline for which a myriad of transformations are known. Moreover, this procedure provides yields and selectivities different from those of the nitrile oxide [3 + 2] cycloaddition, which affords the isoxazoline directly. The reaction of silyl nitronates has been briefly reviewed in the context of the chemistry of nitronic acid derivatives (27,30). 

E) configuration. The dipolar cycloaddition of 141 with a silyl nitronate shows a slight increase of facial selectivity over 132 (Eq. 2.9). Because the cycloadducts are converted directly to the corresponding isoxazolines, only the facial selectivity can be determined. It is believed that the cycloaddition proceeds on the Re face of the dipolarophile due to shielding of the Si face by the auxihary. Both chiral auxiliaries can be liberated from the cycloadduct upon reduction with L-Selectride. 

The intramolecular cycloaddition of a silyl nitronate bearing a dipolarophilic appendage provides easy access to fused, bicyclic isoxazolidines (22). This process, in general, is very facile, and has allowed the use of unfunctionalized alkenes as dipolarophiles (Table 2.39) (106,124). Thus, a silyl nitronate bearing an allyl group will undergo the [3 + 2] cycloaddition at room temperature over 15 h to provide the corresponding isoxazoline upon acidic workup in moderate yield. 

The 3 + 2-cycloaddition of nitrile oxides to 2-crotyl-l,3-dithiane 1-oxides produces exclusively 5-acyldihydroisoxazoles.92 Lewis acid addition to 1,3-dipole cycloaddition reactions of mesityl nitrile oxide with a, /i-unsaturated 2-acyl-1,3-dithiane 1-oxides can reverse the sense of induced stereoselectivity.93 The 1,3-dipolar cycloaddition of 4-t-butylbenzonitrile oxide with 6A-acrylainido-6A-deoxy-/i-cyclodextrin (68) in aqueous solution favours the formation of the 4-substituted isoxazoline (69) rather than the 5-substituted regioisomer (Scheme 24).94 Tandem intramolecular cycloadditions of silyl nitronate, synthons of nitrile oxides, yield functionalized hydrofurans.95... 

Both nitrile oxide (eq 3) and silyl nitronate (eq 4) cycloadditions are highly diastereoselective processes. The use of either approach enables access to A -isoxazolines in good yield. 

Aside from the standard use of natural synthons and the routes via double umpolung, there is the possibility of enlisting 1,3-dipolar cycloadditions to form 7,5-difunctionalized molecular skeletons. Typical examples include the addition of nitrones, silyl nitronates [94], or nitrile oxides to alkenes. The initial products of the latter cycloaddition are isoxazolines, which may be refunctionalized in various ways (Scheme 2.52). When this generates sensitive functionalities, refunctionalization may be postponed until later in the synthesis sequence [95]. 

Nitronates, particularly silyl nitronates, are often superior to nitrile oxides in their 13DC with olefins in terms of their ease of generation from nitroalkanes, stability, and the observed selectivity during cycloaddition. Cycloaddition of alkyl or silyl nitronates with olefins generates N-alkoxy- or N-silyloxy-substituted isoxazolidines which then undergo spontaneous or acid catalyzed elimination of alcohol (or silanol) to produce isoxazolines (see Scheme 1, Sect. 2). 

Silyl nitronates 156, generated from a-halonitro compounds 155, undergo cycloaddition with a variety of olefins 157 such as styrene, acrylate, nor-bornene, cyclopentene etc to afford isoxazoline W-oxides 159 in good to high... 

Both nitrile oxide (eq 3) and silyl nitronate (eq 4) cycloadditions are highly diastereoselective processes. The use of either approach enables access to A -isoxazolines in good yield. Unfortunately, the corresponding nitrone cycloadditions are only slightly selective (dr = 78 22) The enantiomeric sultam was implemented effectively in azomethine ylide cycloadditions to gain access to bridged p)rrolidines with high levels of diastereos-election (eq 5). ... 

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