1,3-dipolar cycloaddition reactions stereochemistry

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). 

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... 

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). 

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).)... 

The dipolar cycloaddition reaction is general, and a structurally diverse series of azanorbomene complexes (79-95) have been synthesized. The yields and exo endo ratios of these reactions are summarized in Table 4. The stereochemistry of the cycloadducts is assigned based primarily on H NMR (coupling constants, NOE) data. For 7-azanorbomene... 

Dipolar cycloaddition reactions proceed with preservation of dipolarophile stereochemistry,a result which is obviously of synthetic utility. The dipole and dipolarophile approach one another in parallel planes with the substituents attached to the dipolarophile oriented in either an endo or an exo relationship with respect to the dipole in the transition state. Depending upon which orientation is of lower energy, varying degrees of diastereoselectivity result vide it fra). The consequences of these generalizations are expressed repeatedly in the chemistry described below. 

The 1,3-dipolar cycloaddition reactions proceed via a concerted suprafacial pathway, which ensures the complete transfer of stereochemical information from the substrates to the cycloadducts. Thus, the stereochemistry of the alkene is retained in the product [40] (Scheme 10.15). With these reactions, up to four stereogenic centers can be formed in one step. Stereodifferentiating groups can be introduced either in the dipole or in the dipolarophile. 

The rearrangement of 5 to 6 competes successfully with the trapping of 5 with frans-stilbene which established the stereochemistry of 5. The stereochemistry of 2 and 3 has similarly been determined by 1,3-dipolar cycloaddition reactions. 

There are essentially two selectivity problems when dealing with 1.3-dipolar cycloaddition reactions to alkenes regioselectivity and stereoselectivity. The issue of regiocontrol has received extensive coverage116 and will not be further discussed here. This chapter will deal with the problem of stereochemistry of the cycloaddition which can be addressed at three different levels. 

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. 

Also, Gong and co-workers reported a Brpnsted add catalyzed three-component asymmetric 1,3-dipolar cycloaddition reactions between aldehydes 213, amino esters 214, and dipolarphiles 215 by catalyst 216, providing pyrrolidines 217 in high yields with excellent enantioselectivity. Scheme 3.69 [86], The methodology introduced a concept that stereochemistry can be controlled by use of a chiral Br0nsted acid (BH), e.g., phosphoric acid. The chiral BH provided sufficient acidity... 

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. 

Nitrile ylides derived from the photolysis of 1-azirines have also been found to undergo a novel intramolecular 1,1-cycloaddition reaction (75JA3862). Irradiation of (65) gave a 1 1 mixture of azabicyclohexenes (67) and (68). On further irradiation (67) was quantitatively isomerized to (68). Photolysis of (65) in the presence of excess dimethyl acetylenedicar-boxylate resulted in the 1,3-dipolar trapping of the normal nitrile ylide. Under these conditions, the formation of azabicyclohexenes (67) and (68) was entirely suppressed. The photoreaction of the closely related methyl-substituted azirine (65b) gave azabicyclohexene (68b) as the primary photoproduct. The formation of the thermodynamically less favored endo isomer, i.e. (68b), corresponds to a complete inversion of stereochemistry about the TT-system in the cycloaddition process. 

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... 

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. 

At about the same time, Wenkert and c-workers (75) reported a similar smdy into the intramolecular 1,3-dipolar cycloaddition of 2-alkenoyl-aziridine derived azomethine ylides. Thermolysis of 231 at moderate temperature (85 °C) produced 232 as a single isomer in 58% yield. Similarly, 233 furnished 234 in 67% yield. In each case, the same stereoisomers were produced regardless of the initial stereochemistry of the initial aziridine precursors. However, the reaction proved to be sensitive to both the substituents of the aziridine and tether length, as aziridines 235 and 236 furnished no cycloadducts, even at 200 °C (Scheme 3.79). 

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. 

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