Nitrile oxide, cycloaddition synthesis

Isoxazolines are good precursors of a,(3-unsaturated ketones.63,94 This transformation is useful for synthesis of polyenes. For example, nitrile oxide cycloaddition chemistry is used to prepare 4-oxo-2-alkenylphosphonates, which are useful to synthesize a long polyethylenic unit via Woodworth-Emmons olefination (Eq. 8.66).101... 

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. 

Intramolecular Cycloaddition Intramolecular nitrile oxide cycloaddition (INOC) is widely used in the synthesis of various compounds, particularly, natural products. This field is reviewed in detail in Chapter 6 of the mono-graph/Reference 5 and also in Reference 400 limited to nitrile oxides generated from nitroalkenes. Some features of INOC are illustrated in this subsection by new data and those omitted in Reference 5. 

An expedient and fully stereocontrolled synthesis of epothilones A (435, R = H) and B (435, R = Me) has been realized (473, 474). The routes described, involve an extensive study of nitrile oxide cycloadditions, as substitutes for aldol addition reactions, leading to the realization of a highly convergent synthesis, based on the Kanemasa hydroxyl-directed nitrile oxide cycloaddition. 

Two stereoselective aldol reactions, followed by a nitrile oxide cycloaddition and a stereoselective late-stage epoxidation are the key steps in the total synthesis of myriaporones 1, 3, and 4 (436, 437, and 438). The synthesis allows... 

Three novel stereo- and regioselective schemes for the total synthesis of (+ )-brefeldin A 440 have been accomplished. Each of them exploit intermolec-ular nitrile oxide cycloaddition for constructing the open chain and introducing substituents, but differ in subsequent stages. The first (480) and the second (481) use intramolecular cycloaddition for the macrocycle closure. However, in the second scheme INOC is followed by C=C bond cis-trans-isomerization. In the third scheme (481) intermolecular cycloaddition is followed by ring closing metathesis as the key step. 

The synthesis of the spiroisoxazoline natural product (+ )-calafianin 447 has been reported, using asymmetric nucleophilic epoxidation and nitrile oxide cycloaddition as key steps. Syntheses and spectral analyses of all calafianin stereoisomers lead to unambiguous assignments of relative and absolute stereochemistry (494). 

Intramolecular Nitrile Oxide Cycloadditions Applications in Synthesis. 437... 

The chemistry of nitrile oxides, in particular their application in organic synthesis, has been continuously developed over the past two decades and represents the main theme of this chapter. The parent compound, fulminic acid (formonitrile oxide), has been known for two centuries, and many derivatives of this dipole have been prepared since that time. Several simple and convenient methods for the preparation of nitrile oxides have evolved over the years. Dehydrochlorination of hydroximoyl chlorides was first introduced by Werner and Buss in 1894 (1). A convenient synthesis of isoxazoles was reported by Quilico et al. (2 ), and then the discovery of nitrile oxide cycloadditions to alkenes was subsequently noted by the same group (5). 

From the 1980s on, many efforts were directed toward asymmetric induction of nitrile oxide cycloadditions to give pure (dia)stereoisomeric isoxazolines, and acyclic products derived from them (17,18,20-23). The need to obtain optically active cycloaddition products for use in the synthesis of natural products was first served by using chiral olefins, relying on 1,2-asymmetric induction, and then with optically active aldehydes or nitro compounds for the nitrile oxide part. In the latter case, insufficient induction occurs using chiral nitrile oxides, a problem still unsolved today. Finally, in the last 5 years, the first cases of successful asymmetric catalysis were found (29), which will certainly constitute a major area of study in the coming decade. 

Intramolecular nitrile oxide cycloadditions were first studied by Garanti and coworkers (24) in 1975, employing 0-allyl derivatives of salicylic aldehyde. The first example of a carbocycle-forming process was reported in 1977 (25). This process (sometimes referred to as INOC) has seen many extensions and applications for the synthesis of natural and unnatural products alike, notably by the groups of Kozikowski, Curran, Fukumoto, and Shishido (see Section 6.4). 

Eully hydroxylated 1,4-iminopolyols have been obtained using cis-4-oxyisoxa-zolines. This synthesis involves nitrile oxide cycloaddition to furan followed by various oxidative transformations of the C2 enol ether portion of the resulting furoisoxazoline cycloadducts (21,82,293,294) (see Section 6.4.3). 

INTRAMOLECULAR NITRILE OXIDE CYCLOADDITIONS APPLICATIONS IN SYNTHESIS... 

As was mentioned earlier, furoxans are often encountered as unwanted byproducts in nitrile oxide cycloadditions. There are, however, some efforts to exploit this facile C C forming dimerization for synthesis. In one case, an intramolecular hw(nitrile oxide) cycloaddition was used for a synthesis of biotin (322a). More recently, the intramolecular dimerization was employed for the construction of medium- and large-size rings. This was feasible if one of the two nitrile oxide functionahties was relatively hindered and stable (see Section 6.1.4). Unsymmetrical... 

A stereoselective synthesis of testosterone (261) was advanced by Fukumoto and co-workers (331), where ring B was joined to the C/D part by an intramolecular nitrile oxide cycloaddition. The key nitrile oxide dipole was generated in situ from oxime 258, which in turn was derived from the optically active tetrahydroin-danone 257. Tetracyclic isoxazoline (259) was obtained as a single stereoisomer... 

Synthesis of Macrocycles Employing Intramolecular Nitrile Oxide Cycloaddition and Aldol Cleavage... 

One of the very first uses of the intramolecular nitrile oxide cycloaddition involved the synthesis of macrocyclic lactones. Asaoka et al. (238) conceived this approach to the 16-membered ring antibiotic A26771B (277). Nitro compound 274 [obtained from 11-acetoxydodecanal (273)] was dehydrated with 4-chlorophenyl isocyanate-triethylamine and this was followed by dipolar cycloaddition, which gave isoxazoline 275 as a 4 1 mixture of diastereomers (Scheme 6.100). 

Few examples of total syntheses have been reported that involve an intramolecular nitrile oxide cycloaddition and ensuing reduction to an aminoalcohol. The very first example was reported by Confalone et al. (334) and involved a synthesis of the naturally occurring vitamin biotin (287). The nitro precursor 284 was easily prepared from cycloheptene. When treated with phenyl isocyanate-triethylamine, cycloaddition led to the all-cis-fused tricyclic isoxazoline 285 with high stereoselectivity (Scheme 6.102). Reduction with LiAlFLj afforded aminoalcohol 286 as a... 

The many successful applications of nitrile oxide cycloadditions in synthesis are intimately linked with theory, both the simple FMO variety as well as the more sophisticated ab initio treatment, where the work of Sustmann and subsequently of Houk and his group has been seminal. We, the practitioners, have thus been supplied with a consistent view on the nature of 1,3-dipoles, their reactivity toward dipolarophiles, and the origin and interpretation of stereoselectivity of cycloaddition chemistry. It is of course desirable that our understanding of the relative reactivities of alkenes as well as of many 1,3-dipoles would be also improved, thereby leading to simple, extended recipes for the chemist practicing synthetics. We hope that this account will stimulate further advances in this field of cycloaddition chemistry and promote further uses of nitrile oxides in organic synthesis. 

Carreira and co-workers (138) successfully applied the Mg(II) ion-mediated nitrile oxide cycloaddition method to the total synthesis of epothilones A and B (Scheme 11.36). The key step in the synthesis was a hydroxyl-directed syn-selective nitrile oxide cycloaddition using a phosphorus-functionalized aliphatic nitrile oxide. This cycloaddition step served not only to introduce a heterocycle-substituted appendage into the skeleton of the epothilones, but also to assemble two... 

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... 

Aliphatic nitro compounds are versatile building blocks and intermediates in organic synthesis,14 15 cf. the overview given in the Organic Syntheses preparation of nitroacetaldehyde diethyl acetal.16 For example, Henry and Michael additions, respectively, lead to 1,2- and 1,4-difunctionalized derivatives.14 18 1,3-Difunctional compounds, such as amino alcohols or aldols are accessible from primary nitroalkanes by dehydration/1,3-dipolar nitrile oxide cycloaddition with olefins (Mukaiyama reaction),19 followed by ring cleavage of intermediate isoxazolines by reduction or reduction/hydrolysis.20 21... 

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