Cycloaddition reactions diastereofacial selectivity

Another route to the 1,2,4-triazine ring is the cycloaddition of 2-azabutadienes (411) with azo compounds (412) leading to l,2,3,6-tetrahydro-l,2,4-triazines (413) (Equation (48)) <86CC1179, 87HCA1255, 90TL397, 9iJOC4459>. In a few Cases of these reactions diastereofacial selectivity has been observed. 

The diastereofacial selectivity of this asymmetric [3C+2S] process is explained following a model similar to that described in Sect. 2.6.4.4 for the reaction of chiral alkenylcarbene complexes and 1,3-dienes. Thus, the proposed mechanism that explains the stereochemistry observed assumes a [4+2] cycloaddition reaction between the chromadiene system and the C=N double bond of the imine. The necessary s-cis conformation of the complex makes the imine... 

Highly uMtr-diastereofacial selective cycloaddition of isoprene (2) with 4-isopropyl-2-cyclohexenone allowed a short regiocontrolled and stereocon-trolled synthesis [13] of jS-cadinene and (y2-cadinene, Scheme 3.3). High anti-diastereofacial selectivity also occurs in the Diels-Alder reaction of optically active cyclohexenones 6-9 (Figure 3.2), readily available from the chiral pool, with open chain dienes [14-16]. Their cycloadducts are valuable intermediates in the synthesis of optically active sesquiterpenes in view of the easy conversion of the gem-dimethylcyclopropane and gem-dimethylcyclobutane in a variety of substituents. 

It has been shown that the sulfinyl group present as chiral auxiliary either in dienophiles or in dienes is very useful for controlling the enantio- and diastereofacial selectivity in the asymmetric Diels-Alder reaction [43]. A wide variety of enantiomerically pure cyclohexadienedicarboxylates has been produced by cycloaddition of the sulfinylmaleate 39 with several dienes under catalyzed... 

Silica gel [11] or alumina [11a, 12] alone, or silica and alumina together modified by Lewis-acid treatment [13] and zeolites [14], have been widely used as catalysts in Diels-Alder reactions, and these solids have also been tested as catalysts in asymmetric Diels-Alder reactions [12,13b,14]. Activated silica gel and alumina at 140 °C were used [15] to catalyze the asymmetric cycloaddition of (-)-menthyl-N-acetyl-a, S-dehydroalaninate (3) (R = NHCOMe) with cyclopentadiene in the key step for synthesizing optically active cycloaliphatic a-amino acids. When the reactions were carried out in the absence of solvent, a higher conversion was obtained. Some results are reported in Table 4.5 and compared with those obtained by using silica and alumina modified by treatment with Lewis acids. Silica gel gives a reasonable percentage of conversion after 24 h with complete diastereofacial selectivity in exo addition. 

Regio- and diastereoselectivity in 1,3-dipolar cycloadditions of nitrile oxides to 4-substituted cyclopent-2-enones was studied (238, 239). The reactions are always regioselective, while the diastereofacial selectivity depends on the nature of the substituents. Thus, 4-hydroxy-4-methylcyclopent-2-enone (75) gives preferably adducts 76a, the 76a 76b ratio warying from 65 35 to 85 15 (Scheme 1.22). 

Cyclic imidate esters, 2-ethoxypyrrolin-5-one and 2-ethoxy-1II -indol-3-one, undergo 1,3-dipolar cycloaddition reactions with nitrile oxides, the reaction site being at the pyrroline C=N bond (317). Rigid and sterically congested pyrroline spiro compounds 148 demonstrate complete diastereofacial selection in site and regiospecific cycloaddition reactions with nitrile oxides to give products 149 (318). 

For the first time, DFT theory has been applied to a study of diastereofacial selectivity in 1,3-dipolar cycloadditions of nitrones to di-3,4-dimethylcyclobutene. ° The stereochemical outcome of the INAC reactions of nitrones (49) and (52) derived from 3-(9-allyl-D-hexoses is dependent only on the relative configuration at C(2,3), and thus 3-(9-allyl-D-glucose (48) and -o-altrose (threo configuration) afford oxepanes (50) selectively whereas 3-O-allyl-D-allose (51) and -D-mannose (erythro configuration) give tetrahydrofurans (53) and (54) selectively (Scheme 18). frani-2-Methylene-... 

The formation of spirocyclopropanes from the reaction of diazodiphenylmethane and ( )-8-phenylmenthyl esters of acrylic acid and methyl fumarate occurred with a modest level of diastereofacial selectivity (136). In contrast, diastereoselectivities of 90 10 were achieved in the cycloadditions of diazo(trimethylsilyl)methane with acrylamides 65 derived from camphor sultam as the chiral auxiliary (137) (Scheme 8.16). Interestingly, the initial cycloadducts 66 afforded the nonconjugated A -pyrazolines 67 on protodesilylation the latter were converted into optically active azaproline derivatives 68. In a related manner, acrylamide 69 was converted into A -pyrazolines 70a,b (138). The major diastereoisomer 70a was used to synthesize indolizidine 71. The key step in this synthesis involves the hydrogenolytic cleavage of the pyrazoline ring. 

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. 

Mukai et al. (36,37) applied the chiral tricarbonyl(r -arene)chromium(0)-derived nitrone 24b in 1,3-dipolar cycloadditions with various alkenes, such as styrene 25 (Scheme 12.11). The analogous nonmetallic nitrone 24a was used in a reference reaction with 25, giving the isoxazohdine 26a with an endo/exo ratio of 82 18. By the apphcation of nitrone 24b in the 1,3-dipolar cycloaddition with 25, the endo/exo-selectivity changed significantly to give exo-26b as the only observable product. The tricarbonylchromium moiety effectively shielded one face of the nitrone, leading to high diastereofacial selectivity. The product exo- 26b was obtained with 96-98% de. 

Padwa and Prein (105,106) applied chiral, but racemic, isomiinchnone dipoles in diastereoselective 1,3-dipolar cycloadditions. The carbonyl ylide related isomiinch-none derivative rac-70 was obtained from the rhodium-catalyzed cyclization of diazo-derivative rac-69 (Scheme 12.24) (105). The reactions of the in situ formed dipole with a series of alkenes was described and in particular the reaction with maleic acid derivatives 71a-c gave rise to reaction with high selectivities. The tetracyclic products 72a-c were all obtained in good yield with high endo/ exo and diastereofacial selectivities. In another paper by the same authors, the reactions of racemic isomilnchnones having an exo-cyclic chirality was described (106). 

Saito et al. (32,121) developed a variety of tartaric acid derivatives, including Ci-symmetric chiral alkenes such as 76. The 1,3-dipolar cycloaddition between 76 and 77 gave primarily endo-1%. (Scheme 12.26) The diastereofacial selectivity of the reaction is excellent, as endo-1% is obtained with >98% de. Other cyclic and acyclic nitrones have been employed in reactions with 76, and in all cases, moderate to excellent endo/exo-selectivities and excellent diastereofacial selectiv-ities were obtained (32,121). Three other research groups have applied various y-hydroxylated ot,p-unsaturated carbonyl compounds in related reactions with nitrones (122-124). However, the selectivities were somewhat lower than those obtained by Saito and et al. (32,121). 

Another type of chiral alkene applied in 1,3-dipolar cycloadditions are vinyl groups attached to chiral phosphine oxides or sulfoxides. Brandi et al. (150,151) used chiral vinyl phosphine oxide derivatives as alkenes in 1,3-dipolar cycloadditions with chiral nitrones. This group also studied reactions of achiral nitrones with chiral vinyl phosphine oxide derivatives. Using this type of substrate, fair endo/exo-selectivities were obtained. In reactions involving optically pure vinyl phosphine oxides, diastereofacial selectivities of up to 42% de were obtained. Chiral vinyl... 

Alkenyl nitrones, having the alkene connected to the nitrone nitrogen atom, have been used in another approach to intramolecular reactions (231-235). Holmes and co-workers have this method for the synthesis of the alkaloid (—)-indolizidine 209B 137 (210,231). The alkenyl nitrone 134, was obtained from the chiral hydroxylamine 133 and an aldehyde. In the intramolecular 1,3-dipolar cycloaddition, 135 was formed as the only isomer (Scheme 12.45). The diastereofacial selectivity was controlled by the favored conformation of the cyclohexane-like transition state in which the pentyl group was in a pseudoequatorial position, as indicated by 134. Further transformation of 135 led to the desired product 137. 

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