Stereochemistry of 1,3-dipolar cycloaddition

To control the stereochemistry of 1,3-dipolar cycloaddition reactions, chiral auxiliaries are introduced into either the dipole-part or dipolarophile. A recent monograph covers this topic extensively 70 therefore, only typical examples are presented here. Alkenes employed in asymmetric 1,3-cycloaddition can be divided into three main groups (1) chiral allylic alcohols, (2) chiral amines, and (3) chiral vinyl sulfoxides or vinylphosphine oxides.63c... 

Dipolar addition to nitroalkenes provides a useful strategy for synthesis of various heterocycles. The [3+2] reaction of azomethine ylides and alkenes is one of the most useful methods for the preparation of pyrolines. Stereocontrolled synthesis of highly substituted proline esters via [3+2] cycloaddition between IV-methylated azomethine ylides and nitroalkenes has been reported.147 The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and L-proline alkyl esters with various nitroalkenes has been reported. Cyclic and acyclic nitroalkenes add to the anti form of the ylide in a highly regioselective manner to give pyrrolizidine derivatives.148... 

The stereochemistry of 1,3-dipolar cycloadditions of azomethine ylides with alkenes is more complex. In this reaction, up to four new chiral centers can be formed and up to eight different diastereomers may be obtained (Scheme 12.4). There are three different types of diastereoselectivity to be considered, of which the two are connected. First, the relative geometry of the terminal substituents of the azomethine ylide determine whether the products have 2,5-cis or 2,5-trans conformation. Most frequently the azomethine ylide exists in one preferred configuration or it shifts between two different forms. The addition process can proceed in either an endo or an exo fashion, but the possible ( ,Z) interconversion of the azomethine ylide confuses these terms to some extent. The endo-isomers obtained from the ( , )-azomethine ylide are identical to the exo-isomers obtained from the (Z,Z)-isomer. Finally, the azomethine ylide can add to either face of the alkene, which is described as diastereofacial selectivity if one or both of the substrates are chiral or as enantioselectivity if the substrates are achiral. 

In order to control the stereochemistry of 1,3-dipolar cycloadditions involving this type of nitrone, the Cu(OTQ2-BOX complex 238 was found to be the most suitable catalyst (Scheme 12.81) (367). The 1,3-dipolar cycloaddition of 256 with the electron-rich ethyl vinyl ether 232a as the dipolarophile in the presence of 25 mol% of 258 proceeded at room temperature to give a high conversion, an exo/ endo ratio of 84 16, and exo-251 was obtained with up to 93% ee. 

R. P. Litvinovskaya, V A. Khripach, Regio- and Stereochemistry of 1,3-Dipolar Cycloaddition of Nitrile Oxides to Alkenes, Russ. Chem. Rev. 2001, 70, 464—485. 

The Stereoselectivity of 1,3-Dipolar Cycloadditions. The exo or endo stereochemistry of 1,3-dipolar cycloadditions is not as straightforward as it is for Diels-Alder reactions. Stereoselectivity, more often than not, is low, as shown by the nitrone reactions that we saw on p. 335 when we were looking only at regiochemistry. We now see that the major regioisomer 6.344 from the reaction of CVV-diphcnylnitronc with methyl acrylate is a mixture of exo and endo isomers, exo- and endo-6.344. Similarly, the only regioisomer 6.346 from the reaction of A-benzyl-C-ethylnitrone with methyl crotonate is a mixture of exo-6.346 and endo-6.346. In both cases, the reaction is a little in favour of the exo product.867... 

Regio- and stereochemistry of 1,3-dipolar cycloaddition of nitrile oxides to alkenes 01UK464. 

Nitrones were the first as well as the most widely used dipoles in asymmetric cycloadditions. The first report on the use of enantiomerically pure vinylsulf-oxides as dipolarophiles was due to Koizumi et al. [153], who described in 1982 the reaction of (-R)-vinyl p-tolyl sulfoxide 1 with acyclic nitrones 191. The reactions required 20 h in refluxing benzene to be completed, yielding a mixture of only two compounds, 192 and 193 (Scheme 91). They exhibited identical endo or exo stereochemistry (which was not unequivocally assigned), deduced from the fact that their reduction yielded enantiomeric thioethers. The major component, 192, exhibits (S) configuration at C-3, determined by chemical correlation. The authors claim this paper [153] to be the first example of 1,3-dipolar cycloaddition using chiral dipolarophiles. 

There have also heen a few reports of 1,3-dipolar cycloaddition to dioxolane-containing dipolarophiles. The regioselectivity of nitrile oxide addition to give products 155 and 156 has been examined, in some cases using ultrasound <1995JCCS877, 1995JOC7701>, and the stereochemistry of mesitonitrile oxide addition to compounds... 

Stereochemical path of 1,3-dipolar cycloadditions as shown above. As the major secondary orbital interaction works on the substituents of dipoles, the stereochemistry of cycloadditions depends upon the ylide configuration. A more reliable methodology to control the stereochemistry of cycloadditions has been recently developed. In the cycloadditions of N-metallated azomethine ylides with carbonyl-activated olefins, the carbonyl oxygyen chelates the metal to allow the endo approach of olefinic dipolarophiles. 

Huisgen s general concept was not only fruitful for synthetic applications after 1960, but also for thorough evaluations of the mechanism of 1,3-dipolar cycloadditions, carried out simultaneously. Within three years, Huisgen came to quite remarkable conclusions (1963 a, b) with respect to stereochemistry and orbital control of these reactions they fitted very well to the principle of conservation of orbital symmetry (Hoffmann and Woodward, 1965). 

Some 1,3-dipoles, such as azides and diazoalkanes, are relatively stable, isolable compounds however, most are prepared in situ in the presence of the dipolarophile. Cycloaddition is thought to occur by a concerted process, because the stereochemistry E or Z) of the alkene dipolarophile is maintained trans or cis) in the cycloadduct (a stereospecihc aspect). Unlike many other pericycUc reactions, the regio- and stereoselectivities of 1,3-dipolar cycloaddition reactions, although often very good, can vary considerably both steric and electronic factors influence the selectivity and it is difficult to make predictions using frontier orbital theory. 

Sol 3. This reaction is regioselective because the diazo terminal carbon atom bonds exclusively to the (3-carbon of the ester. The retention of configuration in the product with respect to both the 1,3-dipole and the dipolarophiles is a characteristic feature of 1,3-dipolar cycloadditions. Thus, stereochemistry of the substituents on the resulting five-membered cyclic ring entirely depends upon stereochemistry of the substituents on the dipolarophiles. Such a stereospecificity provides strong support for a concerted mechanism. 

The stereochemistry of the 1,3-dipolar cycloaddition reaction is analogous to that of the Diels-Alder reaction and is a stereospecific syn addition. Diazomethane, for example, adds stereospecifically to the diesters 43 and 44 to yield the pyrazolines 45 and 46, respectively. 

The 1,3-dipolar cycloaddition reaction of nitrones with alkenes gives isoxazolidines is a fundamental reaction in organic chemistry and the available literature on this topic of organic chemistry is vast. In this reaction until three contiguous asymmetric centers can be formed in the isoxazolidine 17 as outlined for the reaction between a nitrone and an 1,2-disubstituted alkene. The relative stereochemistry at C-4 and C-5 is always controlled by the geometric relationship of the substituents on the alkene (Scheme 8.6). 

Among the many recent applications to natural products, syntheses of pyrrolizidine and indolizidine alkaloids that take advantage of the 1,3-dipolar cycloaddition methodology have been reviewed [8]. The regio- and stereochemistry [9] as well as synthetic appHcations [10] of nitrile oxide cycloadditions have also been discussed. 

Two issues are of essential for predicting the structure of 1,3-DCA products (1) What is the regiochemistry and (2) What is the stereochemistry Many specific examples demonstrate that 1,3-dipolar cycloaddition is a stereospecific syn addition with respect to the dipolarophile, as expected for a concerted process. 

Intermolecular Cycloaddition at the C=C Double Bond Addition at the C=C double bond is the main type of 1,3-cycloaddition reactions of nitrile oxides. The topic was treated in detail in Reference 157. Several reviews appeared, which are devoted to problems of regio- and stereoselectivity of cycloaddition reactions of nitrile oxides with alkenes. Two of them deal with both inter- and intramolecular reactions (158, 159). Important information on regio-and stereochemistry of intermolecular 1,3-dipolar cycloaddition of nitrile oxides to alkenes was summarized in Reference 160. 

The 1,3-dipolar cycloaddition reactions of the chiral 3-benzoyl-4-methylene-2-phenyloxazolidin-5-one 118 and nitrile oxides RCNO (R = Ph, Me) had the expected stereochemistry, addition of the 1,3-dipole having occurred from the less hindered n-face of the exocyclic methylene of 118 (282). 

The relative stereochemistry of tricycle-fused isoxazolines resulting from 1,3-dipolar cycloaddition of cyclo-1,3-diene-tethered nitrile oxides is cis-cis, whereas from cyclohepta-l,3,5-triene-tethered nitrile oxides the cis-trans isomer predominates (412). 

A total synthesis of (+ )-vinblastine widely used in cancer chemotherapy, has been reported. It includes the synthesis of (-)-vindoline. 1,3-Dipolar cycloaddition of a nitrile oxide has played an important role in the preparation of the indoloazacycloundecane moiety, whose coupling with (-)-vindoline occurs with the desired stereochemistry, leading to an intermediate readily transformed to the target (+ )-vinblastine (492). 

Main Aspects of Chemistry and Stereochemistry of Cyclic Nitroso Acetals Chemistry of cyclic nitroso acetals or nitrosals (the term was introduced by Prof. Seebach) has attracted interest only after the discovery of the 1,3-dipolar cycloaddition reaction of nitronates with olefins in 1962 by the research group of Prof. Tartakovsky. (Principal data on nitroso acetals up to 1990 were summarized in the review by Rudchenko (395).)... 

Derivative 165 was treated with tosyl azide at room temperature for 48 h to give 167. Formation of this product was rationalized by a 1,3-dipolar cycloaddition with participation of the C=C bond in the pyrimidine ring in 165 to form a cycloadduct 166 at first, which underwent a [l,2]-methyl shift and a nitrogen elimination to yield 167. Stmcture elucidation of this product revealed the relative rzr-stereochemistry of the phenyl and methyl substituents. 

A full account of the preparation and 1,3-dipolar cycloadditions of the meso-ionic l,3-thiazol-4-ones (114) has now been published. A detailed chemical and spectroscopic study of the stereochemistry of the 1 1 adducts of the l,3-thiazol-4-ones (114) with olefinic 1,3-dipolarophiles has been reported. ... 

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