Endo and exo selectivity

Clearly, an important feature will be the selectivity of these reactions. In this respect, the control of endo- and exo-selectivity using different Lewis acids, the induced diastereoselectivity with chiral heterobutadienes as well as chiral heterodienophiles and finally the use of chiral Lewis acids for the enantioselec-tive synthesis will be discussed. In recent time some attention has been paid to hetero Diels-Alder reactions in aqueous solutions and in the presence of inor-... 

Maleimides and maleic anhydride have been most frequently employed as cyclic cis-olefin dipolarophiles in the stereochemical investigation of 1,3-dipolar cycloadditions, especially on the endo and exo selection of the reaction. They are one of the most reactive dipolarophiles toward many kinds of azomethine ylide 1,3-dipoles. Because of their structural simplicity, the only stereochemical variation possible in cycloadditions is an endo and exo selection. If a strong attractive interaction exists between the extended conjugation of these dipolarophiles and azomethine ylides, an endo-selective cycloaddition results. 

This adduct 23 contains three of the four stereocentres and we should look a little more carefully at the reaction that has just occurred. The two molecules 22 and 17 could have approached each other in two ways which correspond to endo and exo selectivity. In the endo case, on the left, giving 23, the anti relationship between the methyl group and the formyl group stems from the trans geometry of crotonaldehyde and is stereospecific. The syn relationship between the formyl group and the carbamate comes from the endo selectivity in the transition state and is stereoselective. Had the two components of the cycloaddition chosen to come together in the alternative exo way (on the right) then there would have been an anti relationship here and 24 would have been formed. 

As a preliminary conclusion of these studies involving chiral Cu(II) complexes, the endo- and exo-selectivity can be controlled to some extend by the nature of the chiral metal complexes and by the substrates employed in the reaction. The cycloadducts were obtained with good to moderate diastereo-and enantioselectivities, but the presence of imdesirable mixtures of endo-.exo cycloadducts at the end of the reaction are imavoidable. 

Another form of selectivity can arise when substitirted dienes and dienophiles are employed in the Diels-Alder reaction. Two different cycloadducts denoted as endo and exo can then be formed (Figure 1.2). 

Under the usual conditions their ratio is kinetically controlled. Alder and Stein already discerned that there usually exists a preference for formation of the endo isomer (formulated as a tendency of maximum accumulation of unsaturation, the Alder-Stein rule). Indeed, there are only very few examples of Diels-Alder reactions where the exo isomer is the major product. The interactions underlying this behaviour have been subject of intensive research. Since the reactions leadirig to endo and exo product share the same initial state, the differences between the respective transition-state energies fully account for the observed selectivity. These differences are typically in the range of 10-15 kJ per mole. ... 

In the 1,3-dipolar cycloaddition reactions of especially allyl anion type 1,3-dipoles with alkenes the formation of diastereomers has to be considered. In reactions of nitrones with a terminal alkene the nitrone can approach the alkene in an endo or an exo fashion giving rise to two different diastereomers. The nomenclature endo and exo is well known from the Diels-Alder reaction [3]. The endo isomer arises from the reaction in which the nitrogen atom of the dipole points in the same direction as the substituent of the alkene as outlined in Scheme 6.7. However, compared with the Diels-Alder reaction in which the endo transition state is stabilized by secondary 7t-orbital interactions, the actual interaction of the N-nitrone p -orbital with a vicinal p -orbital on the alkene, and thus the stabilization, is small [25]. The endojexo selectivity in the 1,3-dipolar cycloaddition reaction is therefore primarily controlled by the structure of the substrates or by a catalyst. 

It has been more difficult to obtain the exo isomer in the above described reaction. Application of the TiCl2-TADDOLate complex induced fair exo selectivity and up to 60% ee. This was improved by the application of succinimide as an auxiliary for the alkene. This approach has been the only entry to a highly exo selective reaction and up to 72% ee of the exo isomer was obtained. In the Pd(BF4)2-BI-NAP-catalyzed reaction which gave mixtures of the endo and exo isomers, high ee of up to 93% was in a single case obtained for the minor exo isomer. In one case it was also observed that a Zn(OTf)2-BOX complex induced some exo selectivity and up to 82% ee of the exo isomer. 

Ni(C104)2 6H2O showed a litde better enantioselectivity than the anhydrous complex. Although the uncatalyzed reaction was highly exo selective (cis/trans=i 97), the catalyzed reactions were very poor in diastereoselectivity, a mixture of endo and exo cycloadducts being formed. We expected that this poor diastereoselectivity would not be a serious problem since the same enantioface should be involved at the 2-position of the diastereomeric cycloadducts (Scheme 7.27). The best enantioselectivity (cis > 99% ee, trans 94% ee) was observed when the reaction was catalyzed by l ,J -DBFOX/Ph-Ni(SbF6)2 (50 mol%). With the decreased amount of catalyst (10 mol%) still a satisfactory level of enantioselectivity was observed for the cis cycloadduct (94% ee). 

Binaphthol-derived titanium complexes [64], prepared from chiral ligands 65 (Figure 3.13), also performed very well in the cycloadditions of conjugated aldehydes with cyclic and acyclic dienes. Judging from the absolute configurations of endo and exo adducts, this catalyst should cover the re-face of carbonyl on its u tz-coordination to s-trans a,/l-unsaturated aldehydes, and hence dienes should approach selectively from the si-face. 

The chiral catalyst 142 achieves selectivities through a double effect of intramolecular hydrogen binding interaction and attractive tt-tt donor-acceptor interactions in the transition state by a hydroxy aromatic group [88]. The exceptional results of some Diels-Alder reactions of cyclopentadiene with substituted acroleins catalyzed by (R)-142 are reported in Table 4.21. High enantio- and exo selectivity were always obtained. The coordination of a proton to the 2-hydroxyphenyl group with an oxygen of the adjacent B-0 bond in the nonhelical transition state should play an important role both in the exo-endo approach and in the si-re face differentiation of dienophile. 

Concerted cycloaddition reactions provide the most powerful way to stereospecific creations of new chiral centers in organic molecules. In a manner similar to the Diels-Alder reaction, a pair of diastereoisomers, the endo and exo isomers, can be formed (Eq. 8.45). The endo selectivity in the Diels-Alder arises from secondary 7I-orbital interactions, but this interaction is small in 1,3-dipolar cycloaddition. If alkenes, or 1,3-dipoles, contain a chiral center(s), the approach toward one of the faces of the alkene or the 1,3-dipole can be discriminated. Such selectivity is defined as diastereomeric excess (de). 

Deshayes described the cydoaddition of 1-amino-1,3-butadienes 63 with ethyl acrylate (34) under the action of microwave irradiation in a monomode reactor with temperature control [59]. Irradiation for 30 min at 70 °C in the absence of solvent afforded a 60 40 ratio of an inseparable mixture of the endo and exo isomers in 90% yield. Classical heating under the same conditions did not affect the selectivity but the yield was lower (Scheme 9.17). 

Figure 8. Structures of a, a-dimethylcyclobutylmethyl cation, and endo- and exo- a-methylcyclobutylmethyl cations, with selected bond distances (A at B3LYP/6-311+G ).

Allenic esters react with cydopentadiene to give the two [4+2]-cycloadducts endo-and exo-102 in high yields (Table 12.5) [28, 91]. The use of a Lewis acid lowers the reaction temperature and improves the yield and endo selectivity. 

Okamura and coworkers151 studied the base catalyzed Diels-Alder reactions between 3-hydroxy-2-pyrone (224) and chiral l,3-oxazolidin-2-one based acrylate derivatives. Catalysis of the reaction between 224 and 225 by triethylamine gave fair to good de values, somewhat dependent on the solvent system used (equation 63, Table 7). Addition of 5% of water to the solvent isopropanol, for example, increased the de of the endo adduct 226 substantially. When the amount of water was increased, however, the triethylamine catalyzed reaction became less endo and diastereofacially selective, a small amount of exo 227 being obtained. Replacing triethylamine by the chiral base cinchonidine also improved the de, but now independently of the solvent system used. 

Taguchi and coworkers175 studied the Lewis acid catalyzed asymmetric Diels-Alder reactions of chiral 2-fluoroacrylic acid derivatives with isoprene and cyclopentadiene. When a chiral l,3-oxazolidin-2-one and diethylaluminum chloride were used as the chiral auxiliary and the Lewis acid catalyst, respectively, a de of 90% was observed for the reaction with isoprene. The reaction with cyclopentadiene afforded a 1 1 mixture of endo and exo isomers with de values of 95% and 96%, respectively. The endo/exo selectivity was improved by using 8-phenylmenthol as the chiral auxiliary. Thus, the reaction... 

Taguchi and colleagues189 studied the reactions of axially chiral maleimide and anilide derivatives 298 and 300 with cyclopentadiene (equation 83). The reaction of 298 with cyclopentadiene, catalyzed by diethylaluminum chloride, proceeded quantitatively with almost complete endo and diastereofacial selectivities to give 299 and 301, respectively. The reaction of 300 with cyclopentadiene was catalyzed by iodine and proceeded via a cationic iodocyclization intermediate. The reaction afforded a mixture of endo and exo isomers in a ratio of endo/exo = 97/3, the endo isomer being obtained with 97% de. 

Although the exact reaction mechanisms and origin of endo versus exo selectivity remain to be clarified, these reactions should find wide use in the... 

The potential activation of different Lewis acid catalysts and their load effect when used in combination with this solvent were explored, in order to determine the improvement of rates and selectivity to the endo and exo isomers. The list of Lewis acid catalysts included Li(OTf), Li(NTf2), Znl2, AICI3, BF3, HOTf, HNTf2, Ce(0Tf)4 5H20, Y(OTf)3, Sc(OTf)3, Sc(NTf2) and a blank without any Lewis acid. The reaction conditions were as follows 2.2 mmol of cyclopentadiene + 2.0 mmol of dienophile + 0.2 mol% of catalyst in 2 mL [hmim][BF4]. When no catalyst was added, the two ketones (R =Me-C=0 R2 = R3 = H and Ri=Et-C=0 R2 = R3 = H) showed modest activity ( 50% in 1 h) with endojexo selectivity = 85/15. Whereas acrolein showed modest activity (59% conversion in 2 h), methacrolein and crotonaldehyde were inert without a Lewis acid catalyst. Acrylonitrile and methyl acrylate underwent low conversions in 1 h (16-17%) whereas, N-phenylmaleimide, maleic anhydride and 2-methyl-1,4-benzoquinone showed complete reaction in 5 min with high endo isomer yields. 

Grigg and co-workers (310) recently examined the 1,3-APT reaction of various aldoximes (270) (R or R = H) with divinyl ketone (Scheme 1.56). While ketoximes 270 (R = R) form a mixture of adducts, 271 and 272 via nitrone 273, the aldoximes selectively afford 272 (as a mixture of endo and exo diastereoisomers). Under the thermal reaction conditions, the oxime starting materials can undergo ( /Z) isomerization, while the nitrone intermediate was expected to be unaffected and the isolated cycloadducts showed no interconversion via cycloreversion. Thus, the increasing selectivity for endo-212 [via ( )-273, R = H] over exo-212 [via (Z)-273, R = H] with the increasing size of the aldoxime substituent was attributed primarily to the inhibition of oxime isomerization by steric clash between R or R and the oxime OH. In contrast, Lewis acid catalysis, in particular by hafnium (iv) chloride, of the cycloaddition of various aldoximes with this dipolarophile gave exo-271 exclusively (216). 

The stereoselectivity of monosubstituted dipolarophiles has also been studied with cyclic nitronates (Table 2.30) (84). In most cases, an exo selectivity was observed. The ratio between the endo and exo adducts can be correlated to the size of the substituents on the dipolarophile. Because of the endo preference observed with acrolein, it is believed that there is a slight electronic preference for the endo orientation in the transition state, in the absence of steric hindrance. In line with these results is the observation that, for 49, maleic anhydride reacts with complete exo selectivity, in contrast the cycloaddition with 47 (69). 

Consider, for example, endolexo selectivity in the Diels-Alder cycloaddition of cyclopentadiene and 2-butanone. In cyclopentadiene as a solvent, the observed endolexo product ratio is 80 20 (endo preferred), corresponding to a transition state energy difference on the order of 0.5 kcal/mol. With water as the solvent, this ratio increases to 95 5, corresponding to an energy difference on the order of 2 kcal/ mol. Hartree-Fock 6-3IG caleulations on the respective endo and exo transition states are largely in accord. Uncorrected for solvent, they show a very slight (0.3 kcal/mol) preference for endo in accord with the data in (non-polar) cyclopentadiene. This preference increases to 1.5 kcal/mol when the solvent is added (according to the Cramer/... 

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