Diels-Alder reaction exo selectivity

However, exo-selective Diels-Alder reactions are found when a,/J-unsatu-rated exocyclic carbene complexes are used as dienophiles. The fixed s-cis conformation of the vinylcarbene moiety of the complex seems to be responsible for the exo selectivity observed in this reaction. Moreover, the reaction of optically active carbene complexes with 2-morpholino- 1,3-butadienes allows the asymmetric synthesis of spiro compounds [99] (Scheme 53). 

H. Oikawa, K. Katayama, Y. Suzuki, and A. Ichihara, Enzymic activity catalyzing exo-selective Diels-Alder reaction in solanapyrone biosynthesis, J. Chem. Soc., Chem. Commun. 1995, 1321-1322. 

SCHEME 10.39 An example of an exo-selective Diels-Alder reaction directed by a sugar derivative and chromium complexation. 

Weyershausen, B, Nieger, M, Doetz, K H, Stereospecific exo-selective Diels-Alder reactions with carbohydrate-functionalized a-exo-methylene-2-oxacyclopentylidene chromium complexes, J. Org. Chem., 64, 4206-4210, 1999. 

Chiral imidazolidinone carbene complexes undergo exo selective Diels-Alder reactions Powers TS, Jiang W,Su J,Wulff WD (1997) J Am Chem Soc 119 6438... 

Both 9-epiamino derivatives of 9-deoxyquinine and 9-deoxyquinidine promote exo-selective Diels-Alder reaction of 3-hydroxy-2-pyrones with enones. Actually, great latitude exists for tuning the reaction by partial structural changes of the catalysts. ... 

SC(0)C(PR3)S)] (R=NMe2) , and substitution reactions of [Fe2(CO)j p-SC(CF3)C(CF3))]. An interesting paper details the exo-selective Diels-Alder reactions of a,P-unsaturated acyl complexes [Fe2(CX))6 p-SPr") p-(MeCH=CH)C=0)] with dienes, addition of iodine or cerium... 

Scheme 3.76 Exo-selective Diels-Alder reaction with the Nazarov reagent.

Scheme 38.6 Chiral diamine salt catalyzed exo-selective Diels-Alder reactions.

Pandey, B. and Dalvi, P.V., Photoinduced exo-selective Diels-Alder reactions, Angew. Chem. Int. Ed. Engl, 32, 1612, 1993. 

Ionic liquids are excellent solvents for the Diels-Alder reaction providing significant increases in rate and selectivity. Diels-Alder reactions conducted in chloroa-luminate ionic liquids show considerable promise. For example, the endo.exo ratio for the reaction between cyclopentadiene and methyl acrylate (Scheme 7.5) could be varied by changing the composition of the ionic liquid (see Chapter 4) [11]. Although a high yield was obtained, in order to extract the products it was necessary to quench the ionic liquid in water. This is a considerable disadvantage and for this reason neutral ionic liquids have been the focus of subsequent attention. 

Interestingly, treatment of the allylic carbonate 23, which had proven problematic in the previous study, under analogous reaction conditions with the copper enolate derived from 24 furnished the a,/9-disubstituted ketone. Subsequent ring-closing metathesis furnished the 1,2-cyclohexenes 25a/25b in 75% overall yield favoring the trans-dia-stereomer 25a (2° 1°=30 1, ds=10 l) [14]. Overall, this reaction provides an alternative approach to an exo-selective Diels-Alder cycloaddition, and indicates that a-substituted enolates are even more tolerant nucleophiles than the unsubstituted derivatives. 

Cycloadditions. Oppolzer first used this chiral acrylate derivative as an auxiliary in the Diels-Alder reaction with cyclopen-tadiene. Promotion by Lewis acids such as TiCU SnCU, and Et2AlCl provides the adduct in greater than 90% de (eq 1). Lithium perchlorate-promoted [4 + 2] reaction between 1 and 1-acetoxybutadiene was similarly effective." More recently, an exo-selective Diels-Alder addition of 1 with 2-acylamino dienes provided a single diastereomer in 80% yield. Cyclopentane formation is possible through exposure of 1 to methylenecyclo-propane and Ni(0) (eq 2). An example of a higher-order cycloaddition with 1 gave only low diastereoselection (78 22) for the endo product. 

One of the most important application of MAD is e%o-selective Diels-Alder reaction of methacrolein with cyclopentadiene (Scheme 6.124) [148]. It is known that, in the presence of Me3Al, this reaction proceeds with moderate exo selectivity (endolexo = 1 15). On the other hand, the use of MAD instead of Me3Al resulted in improvement of exo selectivity as high as 48 1. ATPH is also a nice catalyst for e%o-selective Diels-Alder reaction of a-methyl-a,p-unsaturated ketones with cyclopentadiene. 

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 summary, it seems that for most Diels-Alder reactions secondary orbital interactions afford a satisfactory rationalisation of the endo-exo selectivity. However, since the endo-exo ratio is determined by small differences in transition state energies, the influence of other interactions, most often steric in origin and different for each particular reaction, is likely to be felt. The compact character of the Diels-Alder activated complex (the activation volume of the retro Diels-Alder reaction is negative) will attenuate these eflfects. The ideas of Sustmann" and Mattay ° provide an attractive alternative explanation, but, at the moment, lack the proper experimental foundation. 

In 1961 Berson et al. were the first to study systematically the effect of the solvent on the endo-exo selectivity of the Diels-Alder reaction . They interpreted the solvent dependence of the endo-exo ratio by consideririg the different polarities of the individual activated complexes involved. The endo activated complex is of higher polarity than the exo activated complex, because in the former the dipole moments of diene and dienophile are aligned, whereas in the latter they are pointing in... 

The regioselectivity benefits from the increased polarisation of the alkene moiety, reflected in the increased difference in the orbital coefficients on carbon 1 and 2. The increase in endo-exo selectivity is a result of an increased secondary orbital interaction that can be attributed to the increased orbital coefficient on the carbonyl carbon ". Also increased dipolar interactions, as a result of an increased polarisation, will contribute. Interestingly, Yamamoto has demonstrated that by usirg a very bulky catalyst the endo-pathway can be blocked and an excess of exo product can be obtained The increased di as tereo facial selectivity has been attributed to a more compact transition state for the catalysed reaction as a result of more efficient primary and secondary orbital interactions as well as conformational changes in the complexed dienophile" . Calculations show that, with the polarisation of the dienophile, the extent of asynchronicity in the activated complex increases . Some authors even report a zwitteriorric character of the activated complex of the Lewis-acid catalysed reaction " . Currently, Lewis-acid catalysis of Diels-Alder reactions is everyday practice in synthetic organic chemistry. 

Three years after the Breslow report on the large effects of water on the rate of the Diels-Alder reaction, he also demonstrated tliat the endo-exo selectivity of this reaction benefits markedly from employing aqueous media . Based on the influence of salting-in and saltirg-out agents, Breslow pinpoints hydrophobic effects as the most important contributor to the enhanced endo-exo... 

Studies on solvent effects on the endo-exo selectivity of Diels-Alder reactions have revealed the importance of hydrogen bonding interactions besides the already mentioned solvophobic interactions and polarity effects. Further evidence of the significance of the former interactions comes from computer simulations" and the analogy with Lewis-acid catalysis which is known to enhance dramatically the endo-exo selectivity (Section 1.2.4). 

Table 2,8, Solvent effect on the endo-exo selectivity (% endo -% exo) of the nncatalysed and Cu" -ion catalysed Diels-Alder reaction between 2,4c and 2,5 at 25°C.

---