INOC reaction

A substituent effect on the rate and stereoselectivity of INOC reaction has been observed (Eq. 1) [13]. Thus, gem-dicarboalkoxy and gem-dithioalkoxy groups were found to have profound accelerating effect on the cyclization (Entries g and h, Table 1). When C-3 in 2 was monosubstituted, good diastereoselectivity was observed depending on the relative size of the substituents (Ph > Me > C02Me). 

Aldoximes can be oxidatively dehydrogenated to nitrile oxides using a variety of oxidants such as lead tetraacetate [16a], alkali hypohalites [lla],NBS in DMF followed by base treatment [16b], chloramine-T [11b], 1-chlorobenzotriazole [16c], mercuric acetate [ 16 d], etc. However, we employed either NaOCl or chloramine-T for most of our INOC reactions. For instance, a piperidine ring fused to an isoxazoline as in 14 was constructed using the INOC methodology (Scheme 3) [17]. Monoalkylation of N-tosylallylamine 10 with the bromoacetal... 

The regioisomer 18 of isoxazoline 14 was also synthesized by an INOC reaction (Eq. 2). Homoallylamine 16 prepared by displacement of 4-bromo-l-butene... 

The versatility of the INOC reaction is evident from the synthesis of tetrahy-drofurans fused to an isoxazoline 22a-f (Eq. 3) [181. a-Allyloxyaldoximes 21, formed by the reduction of jS-nitrostyrenes 19 with SnCl2 2H2O in the presence of an unsaturated alcohol 20, are transformed to isoxazolines 22 in high yield on treatment with NaOCl via stereoselective ring closure of a nitrile oxide intermediate (Table 2). 

A nitrile oxide generated from a sugar derived aldoxime 30 underwent INOC reaction to the chiral pyranoisoxazoline 31 (Eq. 4) [20]. Reductive cleavage of isoxazoline 31 followed by acetylation provided the tetrasubstituted pyran 32. 

A highly stereocontrolled synthesis of (+) testosterone 49 was accomplished wherein the A/B ring system was constructed via INOC reaction of 47 to isox-azoline 48 (Scheme 6) [24]. The cycloaddition was assumed to be taking place via a chair-like TS 47 providing isomerically pure isoxazoline 48 in 87 % yield. 

Table 5. Experimental and MM2 Calculation Results of the INOC Reaction of Unsaturated Oximino Ethers 58 ...

Calculations reveal that both ground and TS energies are lower for 99 b and 99d, which are formed readily in the INOC reaction, than for 99a, 99c, and 99e for which ring closure was not observed (Table 10). Furthermore, a large energy difference between cis- and trans-iused rings in 99 b and 99 d in favor of the ds-fused isomers is obvious from the calculations. Raney Ni cleavage of the isox-... 

Table 10. Molecular mechanics calculations on the INOC reactions of nitrile oxides 98 (energies in kcal/mol)...

A regio- and stereospecific INOC reaction of unsymmetrical silaketals 114, synthesized in one pot from unsaturated alcohols, nitro ethanol, and dichloro-silanes, via the nitrile oxide 115 to isoxazolines 116 has been described (Scheme 14) [37a]. The intermolecular version of the cycloaddition, under similar conditions, proceeds with poor regio and stereoselectivity. 

A high level of diastereoselectivity was reported despite the length of the tether in the INOC reaction of silaketals (e.g., 118) possessing an allylic substituent (Eq. 12) [37b]. 

Although the unsaturated nitrile oxides 124 can be prepared via the aldoxime route (see Scheme 8), the older procedure suffers from the disadvantage that a tenfold excess of allyl alcohol and two additional steps are required when compared to Scheme 15. Therefore, unsaturated nitro ether 123 that can be prepared by condensation of an aldehyde 120 and a nitro alkane followed by Michael addition of alcohol 122, was a useful precursor to nitrile oxide 124 [381. The nitrile oxide 124 spontaneously cyclized to ether 125. This procedure is particularly suitable for the synthesis of tetrahydrofurans (125a-h) and tetrahydropyrans (125i-k) possessing Ar substituents in 72-95% yield (Table 12). The seven-membered ether 1251 was obtained only in 30% yield on high dilution. The acetylenic nitro ether 126 underwent INOC reaction to provide the isoxazole 127. 

As we found that furan and thiophene substituted oximes can be used as substrates for the INOC reactions (Eq. 5) [29b] similarly, furan substituted nitro alkane 134 is also a good substrate for INOC reactions (Eq. 13) [40]. The furfuryl derivative 134, prepared via Michael addition of furfuryl alcohol to 4-methoxy- -nitrostyrene, was subsequently transformed without isolation of the intermediate nitrile oxide 135 to the triheterocyclic isoxazoline 136 as a 5 1 mixture of isomers in high yield. 

The key step in the diastereoselective synthesis of model insect antifeedant 152 starting from a-cyclocitral 148 was the INOC reaction of oxime 149 or nitro alkane 150 to the isoxazoline 151 (Eq. 15) [42]. 

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]. 

High levels of diastereocontrol in an ISOC reaction were induced by a stereogenic carbon center that bears a Si substituent (Scheme 23) [55]. For instance, conversion of nitro alkenes (e.g., 199) to j3-siloxyketones (e.g., 203) has been accomplished via a key ISOC reaction-reduction sequence with complete control of 1,5-relative stereochemistry. The generality of the ISOC reaction of a silyl nitronate with a vinylsilane was demonstrated with seven other examples. Corresponding INOC reaction proceeded with lower stereoselectivity. 

Akritopoulou Zanze I, Gracias V, Moore ID, Djuric SW (2004) Synthesis of novel fused isoxazoles and isoxazolines by sequential Ugi/INOC reactions. Tetrahedron Lett 45 3421-3423... 

The application of intramolecular dipolar cycloaddition reactions to the synthesis of complex natural products has recently come to be recognized as a very powerful synthetic tool, one equally akin to the intramolecular Diels-Alder reaction in its potential scope of application.69 This is particularly the case with nitrile oxides and the 1NOC reaction has been extensively utilized in total synthesis.70 The intramolecular nitrile oxide cycloaddition (INOC) generally displays exceptional regio- and stereo-chemical control which undoubtedly accounts for the popularity of this reaction. Internal cycloadditions of nitrile oxides have been found to offer a powerful solution to many problems in complex natural product synthesis.48 For example, Confalone and coworkers have utilized the INOC reaction for the stereospecific synthesis of the key amino alcohol (60), which was converted in five subsequent steps to ( )-biotin (61 Scheme 14).71... 

Kozikowski s group has been particularly active in the application of the INOC reaction toward the construction of a variety of natural products. One of the many examples from his laboratory involves the synthesis of tetracyclic compounds possessing suitably functionalized C rings for elaboration to a diverse number of ergot alkaloids via the INOC reaction. A total synthesis of chanoclavine I (65) was accomplished by this chemistry (Scheme 15). The key step in the synthesis involved the conversion of the nitro group of indole (62) into the corresponding nitrile oxide using the phenyl isocyanate procedure developed by Mukaiyama.57 The major product corresponded to isoxazoline (64). The isoxazoline nucleus was converted into chanoclavine I (65) in a series of subsequent steps. The application of nitrile oxide cycloaddition chemistry to the construction of other natural products can be expected to be an active area in future years. 

Intermolecular nitrile oxide cycloadditions have been known for a very long time.27 However, it was not until the mid-1970s that intramolecular nitrile oxide cycloaddition (INOC) reactions were studied.28... 

INOC reactions are occasionally synthetic alternatives to nitrone cyclizations. The isoxazolines produced can substitute for isoxazolidines in a number of further transformations. Thus, isoxazolines, like isoxazolidines, can be converted to 7-amino alcohols.31 Isoxazolines can be converted to isoxazolidines and vice versa.32... 

Nitroalkenes have also been used as cycloadduct precursors in the INOC reaction (Scheme 86). The nitroalkene (647 R1 = Me, R2 = COEt) was prepared by the addition of an unsaturated alkoxide (645) to the /3-nitroenone (646). Formation of the required nitrile oxide was accomplished by dehydration of the primary nitromethyl group with phenyl isocyanate and triethylamine. The resulting nitrile oxide underwent cycloaddition and gave the adduct (648 R1 = Me, R2 = COEt). 

---