Intramolecular nitrile oxide cycloaddition reaction

An intramolecular nitrile oxide cycloaddition reaction of a 1,3-dioxolane monocyclic precursor provided the construction of the two five-membered rings of the isoxazoline (32), a precursor to prostaglandin F2a (Equation (12)) <84JOC230l>. 

Intramolecular nitrile oxide cycloaddition reactions were found to have a widespread application in the syntheses of many different molecular frameworks. (For recent examples see references 388 397.) The stereochemical outcome of these reactions depends on ... 

There are few reports of intramolecular nitrile oxide cycloaddition reactions in which the stereochemical course is ruled by an allylic stereocenter outside the tether206 208. The following is one example207. 

Nitrile oxides are considerably more reactive than nitrones, and nitrile oxide dimerization is a prominent side reaction that can effectively compete with dipolar cycloaddition. To overcome this obstacle, nitrile oxides are typically generated in situ under conditions that lead to their participation in 1,3-dipolar cycloaddition reactions. The resulting isoxazolines constitute a versatile class of heterocycles, which are amenable to extensive manipulation. Confalone s synthesis of biotin (16) includes clever use of an intramolecular nitrile oxide cycloaddition reaction [46] that sei-ves to install the requisite relative configuration as well as the necessary side chain (Scheme 18.4) [47]. 

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. 

N. P. Peet, E. W. Huber, and R. A. Farr, Diastereoselectivity in the intramolecular nitrone, oxime, and nitrile oxide cycloaddition reactions, Tetrahedron 47 7537 (1991). 

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... 

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... 

Triannelation.2 A Diels-Alder reaction with a nitro diene such as 1 can be followed by an intramolecular nitrile oxide cycloaddition to afford multiply fused ring systems. 

Zanze and co-workers recently reported an Ugi reaction followed by intramolecular nitrile oxide cycloaddition for the synthesis of novel isoxazo-hnes 130 (Scheme 34) [135]. The substrates required for INOC were synthesized by a multicomponent Ugi reaction utilizing aldehyde 125, aUyl amine 126, isocyanide 128 and -nitro carboxylic acids 127. 

The enormous value of the intramolecular nitrile oxide cycloaddition (INOC) reaction has been further demonstrated by two syntheses from Kozikowski and his group. In one synthesis, that of ( )-sibirine (141) (Scheme 3), the reaction is used to form the spirocycle (140) in a modest 30% yield, a yield that is perhaps to be regarded as remarkably high when due account is taken of the unfavourable regio-directing character of the double bond and the... 

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]. 

An unusual solvent effect was observed in cycloadditions of aromatic nitrile N-oxides with alkyl-substituted p-benzoquinones in ethanol-water (60 40) the reaction rates were 14-fold greater than those in chloroform (148). The use of ion pairs to control nitrile oxide cycloadditions was demonstrated. A chiral auxiliary bearing an ionic group and an associated counterion provides enhanced selectivity in the cycloaddition the intramolecular salt effect controls the orientation of the... 

The study of the intramolecular nitrile oxide—allene cycloaddition shows, in particular, that dehydration of nitroallene 339 by PhNCO, generates a nitrile oxide in situ, which gives isoxazoline 340 (Scheme 1.36). Thus, the reaction of the more remote double bond with the formation of six-membered ring prevails (405). 

A total synthesis of the sesquiterpene ( )-illudin C 420 has been described. The tricyclic ring system of the natural product is readily quickly assembled from cyclopropane and cyclopentene precursors via a novel oxime dianion coupling reaction and a subsequent intramolecular nitrile oxide—olefin cycloaddition (463). 

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). 

Recently, the intramolecular nitrile oxide-alkene cycloaddition sequence was used to prepare spiro- w(isoxazolines), which are considered useful as chiral ligands for asymmetric synthesis (321). Reaction of the dibutenyl-dioxime (164) (derived from the diester 163) with sodium hypochlorite afforded a mixture of diastereomeric isoxazolines 165-167 in 74% combined yield (Scheme 6.80) (321). It was discovered that a catalytic amount of the Cu(II) complex 165-Cu(acac)2, where acac = acetylacetonate, significantly accelerated the reaction of diisopropylzinc... 

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