Diastereoselective Intermolecular Diels-Alder Reactions

Subsequently to the intermolecular Diels-Alder reaction, a new diene is produced which can then be utilized in a second cycloaddition process. The feasibility of the second Diels-Alder process was demonstrated by the thermal cycloaddition of 44 with a variety of dienophiles to afford the cycloadducts 47 in high yields, albeit with moderate diastereoselectivity (Scheme 8.8). Additional investigations will be necessary to delineate further the scope and limitations of this rapid increase in molecular complexity. 

Trisubstituted 2-azetidinones have been prepared by diastereoselective and jr-facially selective Lewis acid-catalyzed intermolecular Diels-Alder reactions of 3-butadienylazetidin-... 

Intramolecular Diels-Alder (IMDA) reactions of 1,6,8-nonatrienes and 1,7,9-decatrienes have been used frequently for the construction of chiral ring systems of complex natural products (18-20), Although saccharide derivatives have been employed many times in intermolecular Diels-Alder reactions (21-28) their IMDA reaction appears not to have been studied so far. The diastereoselectivity of IMDA reactions can be influenced, among other factors, by the size of substituents, and by the chirality of carbons of the connecting chain. Our aim was to study the possibilities of the application of single monosaccharides as tether chains in IMDA reactions. The influence of the presence of three or four chiral... 

Mainly because of the strong relativistic effect, exaltation of the % and a Lewis acidities of gold cations has been largely used over the past decade [31,32]. To begin with, a diastereoselective Au(in)-catalyzed 5-pjt -cycloisomerization of alkenynols 61 to enol ether 62 followed by an intermolecular Diels-Alder reaction was reported by Barluenga et al. for the preparation of the desired spiro adduct 63 (Scheme 9.17) [33]. The total diastereoselectivity observed could be explained by an endo-approach... 

The chiral copper reagent 24 is an effective catalyst not only for intermolecular, hut also for intramolecular Diels-Alder reactions, as shown in the following schemes (Scheme 1.41, 1,42, 1.43). Synthetically useful octalin and decalin skeletons were synthesized in high enantio- and diastereoselectivity. The synthetic utility of this intramolecular Diels-Alder reaction has been demonstrated hy a short total synthesis of isopulo upone [23, 33d]. 

Intermolecular befera-Diels-Alder reactions of enamino ketones with highly substituted vinyl ethers. Effect of high pressure on the kinetics and diastereoselectivity [77]... 

A one-pot, four-component process involving the in situ formation of an azadiene followed by an intermolecular or intramolecular Diels-Alder reaction for the synthesis of highly functionalized piperidone scaffolds has been reported [81]. The compounds were obtained in good yields and diastereoselectivities (Figure 5). 

At Tokyo College of Pharmacy [284], esters of 2-(trifluoromethyl)propenoic acid were used to synthesise 16,16,16-trifluororetinal (Eq. 101). Intermolecular Lewis acid-catalysed Diels-Alder reaction with a pantolactone chiral auxiliary allowed the diastereoselective construction of the core cyclohexenone portion with the quaternary centre set in the desired absolute configuration. 

An effect of high pressure on the diastereoselectivity is also observed for intramolecular hetero Diels-Alder reactions as found for the cycloaddition of the benzylidene-isoxazolone 8-23 to afford the cis-annulated 8-24 as the major product together with the frans-diastereomer 8-25 (Fig. 8-8) [549], However, the difference in activation volume with AAV =1.6 0.2 cm3 mol"1 is rather small. The activation volume with AV = 19.6 0.5 cm3 mol-1 at 343 K lies significantly below the usual values found for intermolecular cycloadditions of 1-oxa-1,3-butadienes, indicating that this reaction may be on the border line to a two-step reaction but see also below. 

Tietze, L. F., Geissler, H., Fennen, J., Brumby, T., Brand, S., Schulz, G. Intra- and intermolecular hetero-Diels-Alder reactions. 45. Simple and induced diastereoselectivity in intramolecular hetero-Diels-Alder reactions of 1-oxa-1,3-butadienes. Experimental data and calculations. 

Pressure effects on the diastereoselectivity can also be observed for intramolecular cycloadditions such as the hetero-Diels-Alder reaction of 90, even though the AAV are smaller compared to intermolecular reactions (Scheme 8.23). The kinetics were again measured by on-line FT-IR spectroscopy and the stereoselectivity by HPLC. At atmospheric pressure in toluene under reflux the reaction of 90 led to a 5.2 1 ratio of the diastereomeric cycloadducts 91 and 92 in 93 % yield. Increasing pressure favors the formation of the cis-adduct 91, which is probably formed via an endo-E-syn transition structure. Interestingly, in the ground state of 90 the Z-configuration is more stable and it is therefore assumed that isomerization of the Z- to the B-double bond occurs prior to the cycloaddition [51]. From the slope of the plot of ln(91/92) versus pressure, AAV is calculated to be -(1.6 + 0.2) cm mol with the individual values for AV = -(19.4 + 0.2) and AV = —(17.9 0.6) cm mol at 343 K. Although the AV values are relatively low in comparison with data reported for other intramolecular Diels-Alder reactions e.g. 

The diastereoselectivity inherent to the Diels-Alder reaction can be seen in most of the examples in preceding reactions. The reaction is not, however, enantioselective since there is no facial control for intermolecular reactions (some facial control is available for intramolecular reactions). The ortho rule, the endo rule (secondary orbital interactions), and steric interactions provide some orientational control but facial control is also required for enantioselectivity. When ethyl acrylate reacts with 2-methyl-1,3-pentadiene, it can approach from the bottom as in 247A or from the top as in 247B. Clearly, the two products (248A and 248B) are mirror images and enantiomers. This lack of facial selectivity leads to racemic mixtures in all Diels-Alder cyclizations discussed to this point. 

A strategy developed by Tietze and coworkers early in his independent career involved the application of intramolecular or intermolecular inverse electron demand hetero-Diels-Alder reactions to iridoid total synthesis. The intermolecular [4+ 2]-cycloaddition of ethyl vinyl ether and unsaturated aldehyde 31 provided acetal 32, which underwent double bond isomerization to afford 33 (Scheme 1) An intramolecular variant of this reaction is discussed in detail later (Scheme 10). More recently, Jacobsen and Chavez extended this work with the enantio- and diastereoselective synthesis of a range of iridoid natural products. Utilizing tridentate Cr(III) catalyst 34, acetal 35 was prepared in 98% ee with good diastereoselectivity (Scheme 1)P... 

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