Dipolarophiles stereoselectivity

H(65)1889, 2005EJO3553>. Starting dihydro[l,2,4]triazolo[3, 4-4]benzo[l,2,4]triazines 482 readily react with aromatic aldehydes to yield iminium salts 483. These salts treated with a base (e.g., triethylamine) are deprotonated to reactive 1,3-dipolar azomethine imines 484. In contrast to related five-membered heterocycles, these compounds are relatively unstable on storage in the solid form and particularly in solution. Fortunately, this obstacle can be easily circumvented by their in situ preparation and subsequent 1,3-dipolar cycloaddition. These compounds can participate in 1,3-dipolar cycloadditions with both symmetric and nonsymmetric dipolarophiles to give the expected 1,3-cycloadducts in stereoselective manner. Selected examples are given in Scheme 82. 

The three-component reaction between isatin 432a, a-aminoacids 433 (proline and thioproline) and dipolarophiles in methanol/water medium was carried out by heating at 90 °C to afford the pyrrolidine-2-spiro-3 -(2-oxindoles) 51. The first step of the reaction is the formation of oxazlidinones 448. Loss of carbon dioxide from oxazolidinone proceeds via a stereospecific 1,3-cycloreversion to produce the formation of oxazolidinones almost exclusively with /razw-stereoselectivity. This /f-azomethine ylide undergo 1,3-dipolar cycloaddition with dipolarophiles to yield the pyrrohdinc-2-r/ V -3-(2-oxindolcs) 51. (Scheme 101) <2004EJ0413>. 

In the reaction of fused aziridines with alkene dipolarophiles, the opportunity for stereoselectivity as well as facial selectivity arises since exo- or entfo-isomers can be formed (Scheme 10). In practice, maleic anhydride 6, A-methyl maleimide and JV-phenyl maleimide each reacted exo-stereoselectively with TV-benzyl aziridine 69 to form adducts of type 71 (Scheme 10b), the stereochemistries of which were confirmed by NOE measurement between Hb and He. Similar reaction of the Y-phenyl aziridine 67 with N-Ph maleimide gave a 1 1 mixture of endo-adduct 72 and exo-adduct 73 (Scheme 10c). Adducts 68, 71-73 all exhibited a low-field methano-bridge proton (Ha) in the range 5 3.06-3.60 confirming the syn-facial stereochemistry of the two bridges. 

Transition state energies have been determined by computation (PM3 and AMI) for the reaction of norbomadiene 74a (X=CH2) and 7-isopropylidenenorbomadiene 74b (X is C=CMe2) with the 1,3 dipoles 23 formed from ring-opening of the A -phenyl and A -benzyl derivatives of aziridine 22 (see, Table 1). These data demonstrate the preference for formation of exo,exo-isomers 75 with norbomadiene in the A -benzyl series, however the energy difference between the transition states for the A -phenyl series is much closer and accords with the drop in stereoselectivity. Introduction of the isopropylidene substituent into the 7-position of the dipolarophile favours formation of the bent-frame isomers 76, especially in the A -phenyl series. These predictions accord well with the stereoselectivities observed experimentally. 

The stereoselectivity established for the trident series, was tested using the C-bridged bis-aziridine 58 which produced the ONCNO-[5]polynorbomane 115 by reaction with the O-bridged dipolarophile 36 (two equivalents) in 70% yield (Scheme 19). However, as noted above, replacing the central C-bridge with the A-Z bridge caused loss in stereoselectivity. Accordingly the type B approach was preferred. 

These isomers resulted from the non-stereoselectivity of the initial coupling process typical of the aza-ACE reactions of the 7-isopropylidene-bridged dipolarophile 38, while molecular weight measurements and the presence of an isopropenyl group in the H NMR of each product supported C,A-methano-bridge formation. Such products were considered to arise via the bond reorganisation depicted by the arrows in adduct 156 in which one of the isopropylidene rc-bonds acted as the nucleophile to attack the methylene carbon of the adjacent A-methoxymethyl group. 

Cycloaddition with nitrile oxides occur with compounds of practically any type with a C=C bond alkenes and cycloalkenes, their functional derivatives, dienes and trienes with isolated, conjugated or cumulated double bonds, some aromatic compounds, unsaturated and aromatic heterocycles, and fullerenes. The content of this subsection is classified according to the mentioned types of dipolarophiles. Problems of relative reactivities of dienophiles and dipoles, regio- and stereoselectivity of nitrile oxide cycloadditions were considered in detail by Jaeger and... 

The cycloaddition of 3,5-dichloro-2,4,6-trimethylbenzonitrile oxide to tricar-bonylchromium complexed styrenes proceeds with high stereoselectivity (Scheme 1.17), thus offering a new synthetic route to optically active 3,5-di-substituted 4,5-dihydroisoxazoles (213). The preferred formation of cycloadducts 44 rather than 45 shows that nitrile oxide attacks the it face opposite to Cr(CO)3 and the reactive rotamer of the dipolarophile is transoid (213). 

Heterocycles Both non-aromatic unsaturated heterocycles and heteroaromatic compounds are able to play the role of ethene dipolarophiles in reactions with nitrile oxides. 1,3-Dipolar cycloadditions of various unsaturated oxygen heterocycles are well documented. Thus, 2-furonitrile oxide and its 5-substituted derivatives give isoxazoline adducts, for example, 90, with 2,3- and 2,5-dihydro-furan, 2,3-dihydropyran, l,3-dioxep-5-ene, its 2-methyl- and 2-phenyl-substituted derivatives, 5,6-bis(methoxycarbonyl)-7-oxabicyclo[2.2.1]hept-2-ene, and 1,4-epoxy-l,4-dihydronaphthalene. Regio- and endo-exo stereoselectivities have also been determined (259). 

Dipolarophiles D1 and D2. In the study of steric and electronic factors on regioselectivity and stereoselectivity of 1,3-cycloaddition of nitrones to olefins, 1-decene (734) and styrene derivatives (735) have been used. By comparative analyses of the kinetic and thermodynamic parameters in the 1,3-cycloadditions... 

Nitrones derived from cyclic acetals of D-erythrose (479) and (689) and of D-threose (480) and (690), reacted with N -phenylmaleimide D15a to afford the corresponding diastereomeric isoxazolidines (691-706) (Scheme 2.295). The stereoselectivity is dependent on the substituents in the nitrone. In the case of nitrones (479) and (689) the cycloaddition is exo-selective. It was observed that microwave irradiation decreased the reaction times of the cycloadditions dramatically. For example, for nitrone (689) and dipolarophile D15a the reaction time decreased from 11 h to 8 min and for nitrone (690) and D15a it decreased from 3 h to 10 min. Moreover, microwave irradiation reversed the ratio of erythro-frans/erythro-r/.v adducts from 63 37 to 39 55, see compound (689). Cycloadditions of the chiral maleimides D15b and D15c are less stereoselective (817). 

Regio- and stereoselectivity of the process depend on the nature of its participants and are determined by the character of the approach of the dipolarophile to the dipole. (In Scheme 3.127, this is demonstrated for the reaction of mono-substituted nitronates with monosubstituted olefins.)... 

The general method, that has been widely used for the synthesis of perhydropyrrolo[1,2-6]isoxazoles, is based on a cycloaddition reaction of cyclic nitrones with dipolarophiles. The nitrone is easily available by oxidation of the corresponding hydroxylamine with mercuric chloride. The cycloaddition of nitrone to dipolarophiles is highly regioselective and stereoselective and have been often applied in the total synthesis of natural products <20010L1367, 2004BML3967, 2005JOC3157>. As one representative example of dipolar cycloaddition, reaction... 

Two questions are of immediate interest for predicting the structure of 1,3-dipolar cycloaddition products (1) What is the regioselectivity and (2) what is the stereoselectivity Many specific examples demonstrate that 1,3-dipolar cycloaddition is a stereospecific syn addition with respect to the dipolarophile. This is what would be expected for a concerted process. 

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