Intramolecular nitrile oxide cycloaddition INOC

Intramolecular 1,3-cycloadditions of nitrile oxides (INOC) provide a useful tool for the construction of fused cyclic ring systems. The stereochemical outcome of this reaction is presumed to be a consequence of reaction through the transition state that minimizes allylic 1,3 strain (Scheme 8.19).103... 

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. 

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. 

AW, Acid-washed Choi, Cholesterol DMAP, 4-(Dimethylamino)pyridine DMF, N,/V-Dimethylformamide DMTr, Di(p-niethoxyphenyl)phenyl methyl GalNAc, N-Acetylgalactosamine, 2-acetamido-2-deoxy-D-galactose HMF, 5-Hydroxymethylfur-fural, 5-(hydroxymethyl)-2-furaldehyde INOC, Intramolecular nitrile oxide-alkene cycloaddition Lea, Lewisa Lex, Lewisx MOM, Methoxymethyl MP, p-Methoxyphe-nyl MS, Molecular sieves NIS, N-Iodosuccinimide PCC, Pyridinium chlorochromate PDC, Pyridinium dichromate PMA, Phosphomolybdic acid PMB, p-Methoxybenzyl ... 

R = h, Me, Ph. INOC intramolecular nitrile oxide cycloaddition. Scheme 3.140... 

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). 

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... 

The formation of compound (16) is proposed to proceed through the nitrile oxide (15) as an intermediate to undergo intramolecular nitrile oxide-olefin cycloaddition (INOC). On the contrary, the generation of (18) is proposed to proceed through intramolecular alkoxycarbonyl nitronate-olehn cycloaddition (lAOC) step because only the trans isomers are formed. 

Either intramolecular nitrile oxide cycloadditions (INOC) or intramolecular silylnitroate cycloadditions (ISOC) of /3-nitrosulfides 477 gives isomeric thieno[3,4-c]isoxazolines 478 and 479 (Equation 17) <1997SC1865>. 

Pyranoisoxazoles 425 have been prepared by intramolecular 1,3-dipolar cycloaddition of nitrile oxides obtained by treatment of nitrooxaheptynes with -BuLi and AC2O (Scheme 102) <2003H(59)685>. The coupling of the Ugi multicomponent reaction with the intramolecular T-oxide cyclization (Ugi/INOC) provided access to novel fused isoxazoles 426 in two steps from easily available starting materials in moderate to good overall yields... 

INOC Intramolecular nitrile oxide-olefln cycloaddition... 

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]. 

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. 

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