Selectivity in the Diels Alder Reaction

The Diels-Alder reaction is one of the powerful reactions referred to by Corey in his LHASA program for synthesis (sec. 10.4.B). One of the powerful features of the Diels-Alder reaction is the stereochemical selectivity inherent to the cycloaddition and many examples exist in the total synthesis of natural products.  

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The cationic aqua complexes prepared from traws-chelating tridentate ligand, R,R-DBFOX/Ph, and various transition metal(II) perchlorates induce absolute enantio-selectivity in the Diels-Alder reactions of cyclopentadiene with 3-alkenoyl-2-oxazoli-dinone dienophiles. Unlike other bisoxazoline type complex catalysts [38, 43-54], the J ,J -DBFOX/Ph complex of Ni(C104)2-6H20, which has an octahedral structure with three aqua ligands, is isolable and can be stored in air for months without loss of catalytic activity. Iron(II), cobalt(II), copper(II), and zinc(II) complexes are similarly active. 

Coxon J. M., McDonald D. Q., Steel P. J. Diastereofacial Selectivity in the Diels-Alder Reaction Adv. Detailed React. Mech. 1994 3 131-166... 

Abstract Diels-Alder reaction is one of the most fundamental and important reactions for organic synthesis. In this chapter we review the smdies of the rr-facial selectivity in the Diels-Alder reactions of the dienes having unsymmetrical rr-plane. The theories proposed as the origin of the selectivity are discussed. 

Inagaki, Fujimoto and Fukui demonstrated that ir-facial selectivity in the Diels-Alder reaction of 5-acetoxy- and 5-chloro-l,3-cyclopentadienes, 1 and 2, can be explained in terms of deformation of a frontier molecular orbital FMO [2], The orbital mixing rule was proposed to predict the nonequivalent orbital deformation due to asymmetric perturbation of the substituent orbital (Chapter Orbital Mixing Rules by Inagaki in this volume). 

Table 6 Activation energies and Jt-facial selectivity in the Diels-Alder reactions of 5-X-cyclopentadienes with ethylene...

TT-Facial selectivity in the Diels-Alder reactions of thiophen 1-oxides has recently attracted keen attention (Scheme 49). Fallis and coworkers reported in situ generated 2,5-dimethylthiophene 1-oxide 98 reacted with various electron-deficient dienophiles exclusively at the syn face with respect to sulfoxide oxygen [57],... 

SCHEME 5. High cxo-selectivities in the Diels-Alder reaction of -substituted dienophiles with cyclopentadiene... 

A significantly lower selectivity in the Diels-Alder reaction was obtained with the use of the alkyl ester corresponding to 4 or when no catalyst was used. Give reasons for this finding. 

Breslow and co-workers have performed some of the most outstanding work in this field and their results initiated a flurry of research. They found that the rates of reaction and selectivity in the Diels-Alder reactions are improved in an aqueous system (Figure 3.6). Additionally, the presence of salts or 3-cyclo-dextrins can enhance the hydrophobic effect, which causes organic molecules to cluster together in aqueous solution, and further accelerate the Diels-Alder reaction. It should also be noted that related photochemical [2 + 2] additions can be performed using water, and in some cases these show similar rate enhancements due to hydrophobic effects. 

Although exo-endo selectivity in the Diels-Alder reaction of olefinic dienophiles has been extensively studied both experimentally and theoretically [31], exo-endo selectivity of the transition structure in the reaction of acetylenic dienophiles has not previously been investigated, because the adducts produced via exo- or endo-transi-tion-state assembly are identical diastereomerically. We used ab initio molecular orbital calculations at the RHF/6-31G level [32] to identify the transition struetures of simple processes of this type, i.e. acid-free and BFs-promoted reactions of cyclopenta-diene and propynal (Fig. 9). As expected, our calculations showed that the exo transition structures are more stable than the endo structures by 0.8 kcal mol" for the former reaction and by 2.0 and 2.4 kcal moF for anti and syn pairs, respectively, for the latter. These calculations strongly suggest the predominance of an exo transition structure and its enhancement by coordination of the Lewis acid. 

It was first found that a chiral Yb catalyst, prepared in situ from Yb(OTf)3, (R)-(+)-l,T-bi-2-naphthol [(l )-BINOL], and a tertiary amine, in dichloromethane, was quite effective in enantioselective Diels-Alder reactions [36]. Some additives were also found to be effective not only in stabilizing the catalyst but also in controlling enantiofacial selectivity in the Diels-Alder reaction. When 3-acetyl-l,3-oxazolidin-2-one was combined with the chiral catalyst as an additive, the (2S,3R) form of the endo adduct was obtained in 93 % ee. When, on the other hand, 3-phenylacetylacetone was mixed with the catalyst as an additive, the (2R,3S) form of the endo adduct was obtained in 81 % ee [37]. 

More on selectivity in the Diels-Alder reaction and more comparison with Birch reduction. 

We have recently argued [39] that facial selectivity in the Diels-Alder reactions of 5-substituted cyclopenta-1,3-dienes is a reflection of hyperconjugative effects a frontier orbital analysis is shown in Fig. 6-10 [40], The molecule adopts a conformation where the better electron-donating group (C-Me rather than C-X) hinders approach of the dienophile from that face. Overlap of the C-C (T-bond (a better donor than C-X) increases the energy of the diene HOMO. Furthermore overlap of the C-C (T -orbital with the diene LUMO yP reduces the energy of the... 

This phenomenon is well known in most cycloadditions, i.e., additions in which two components are combined which have two enantiofaces each. Thus altogether four combinations are possible leading to two enantiomeric pairs of exo-endo-diastereomers (Scheme 31) [Diels-Alder addition, reaction (94)]. In the arbitrary combination shown is in the endo- and R in the exo-position. Rndo-selectivity in the Diels-Alder reaction (and other cycloadditions) means that the substituent with the higher potential for 7t-7t-interactions with the diene... 

Moreover, after screening several additives other than 29, it was found that some additives were effective not only in stabilizing the catalyst but also in controlling the enantiofacial selectivities in the Diels-Alder reaction. Selected examples are shown in Table 25. When 3-acetyl-l,3-oxazolidin-2-one (30) was combined with the original catalyst system (to form catalyst A), the endo adduct was... 

Moreover, after screening several additives other than 31, it was found that some additives were effective not only in stabilizing the catalyst but also in controlling the enantiofacial selectivities in the Diels-Alder reaction. Selected examples are shown in table 29. When 3-acetyl-l,3-oxazolidin-2-one (32) was combined with the original catalyst system (to form catalyst A), the endo adduct was obtained in 93% ee and the absolute configuration of the product was 2S, 3R. On the other hand, when acetyl acetone derivatives were mixed with the catalyst, reverse enantiofacial selectivities were observed. The endo adduct with an absolute configuration of 2R, 3S was obtained in 81% ee when 3-phenylacetylacetone (PAA) was used as an additive (catalyst B). In these cases, the chiral source was the same (Tf)-binaphthol. Therefore, the enantioselectivities were controlled by the achiral ligands, 3-acetyl-l,3-oxazolidin-2-one and PAA (Kobayashi and Ishitani 1994). 

It was also suggested that aggregation of the catalysts influenced the selectivities in the Diels-Alder reactions the reaction of 3-(2-butenoyl)-l,3-oxazolidin-2-one with cyclopentadiene using (7 )-binaphthol in lower enantiomeric excesses was examined (Oguni et al. 1988, Kitamura et al. 1989, Puchot et al. 1986). The results are shown in fig. 1. Very interestingly, a positive nonlinear effect was observed in the chiral Sc catalyst. 

Table 11.13. Selectivity in the Diels-Alder Reaction of Cyclopentadiene and Menthyl Acrylate...

A variety of other auxiliaries have been developed that gave excellent asymmetric induction in the Diels-Alder reaction. Helmchen and Schmierer also developed an auxiliary based on camphor that is quite useful.234 In addition, Helmchen prepared the lactone auxiliary 281 and the imide auxiliary 283 and showed they give opposite enantioface selectivity in the Diels-Alder reaction.235 in the presence of a Lewis acid such as TiCU, differences in coordination site led to a different chiral face in the transition state of the... 

In addition, theoretical frameworks for Diels-Alder reactions of dienes, such as cm, had been adumbrated by Houk [30] and Hehre [31]. Therefore, it was an opportune time for experimental clarification of 7c-facial selectivity in the Diels-Alder reaction of homochiral dienes containing an allylic chiral center. 

The effects of diene structure on endo selectivity in the Diels-Alder reaction have been examined. In the case of spiro[2,4]hepta-1,3-diene, interactions of the dienophile with the methylene groups of the cyclopropane have a major controlling influence on the stereoselectivity. ... 

The isopropylidenated enonates 9—12 have less conformational freedom than the tetraacetates 5—8 and were thus expected to show higher diastereofacial selectivities in the Diels—Alder reaction. This was borne out in the experimental data. The D-lvxo enonate 11 in particular gave a readily separable mixture after reaction with cyclopentadiene under thermal conditions, and afforded a 55% isolated yield of the crystalline si-exo product, mp 88—89 , along with 30% of the si-endo product. The structures of these products were confirmed as before by degradative sequences. The diastereofacial selectivity was >9 1 in favor of si-face attack ... 

Zinc chloride is often a preferred catalyst since it is less sensitive to water, even though its activity does not compare to that of AICI3 (37). Its mild acidity results in improved control of selectivities in the Diels-Alder reaction. It is also used in haloalkylation of aromatics and the Fischer indol synthesis. 

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