Diastereo-selectivity of diels-alder cycloaddtions of erythrose benzylidene-acetal 1,3-Butadienes with maleimides

Maleimides were combined with D-erythrose benzylidene-acetal 1,3-butadienes 1 and 2 to study the facial selectivity of the Diels-Alder cycloadditions. The selectivity was found to be from moderate to good. The reaction diastereotopicity can be reversed with the temperature. Simultaneous coordination of diene 1, having a free hydroxyl group, and maleimide 3 to a chiral bimetallic Lewis acid catalyst (LACASA-DA reaction) occurs with complete diastereo-control to give a single adduct, using an extra chiral inductor either Ror SBINOL. Small chiral synthons are being more and more appealing to synthetic chemists to build up target molecules possessing multi-stereogenic centres. We have been looking at the usefulness of D-erythrose 1,3-butadienes, like 1 and 2, 1 as chiral counterparts in diastereoselective Diels-Alder (DA) cycloadditions. In the past it was found a high diastereotopicity associated to Diels-Alder of these dienes to 2-methoxycarbonyl-pbenzoquinones. 1 In a previous study in our laboratory a complete chiral induction was also found in [4π+2π] cycloadditions of some D-erythrose benzylidene-acetal 1,3-butadienes, having an ether protection at C-5, with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD). 2 NH-Maleimide (3) and N-phenylmaleimide (4) were now combined with D-erythrose dienes 1 and 2. The facial selectivity of the DA are moderate to good in thermal reactions, and interestingly the topicity was reversed when the cycloadditions were run at 5 oC. Self-assembly of the components of the DA in a Lewis acid template turned the selectivity complete in two cases. D-Erythrose benzylidene-acetal 1,3-butadienes possessing the alcohol function protected (like 2) reacted before with PTAD to give a single product, the endo, S configuration adduct at the new stereogenic centre. 2 The reaction turned out to be less selective when the diene bears an unprotected hydroxyl group at C-5, 1. Reacting now diene 2 with N-phenylmaleimide in dichloromethane (the solvent used in reactions with PTAD) the selectivity was reduced from complete to a 2:1 ratio of endo-diastereomers; the major being the S isomer, 5, and the minor its diastereomer R, 6. The selectivity dropped to zero when diene 1 reacted with Nphenylmaleimide (4). The best selectivity with maleimides occurs when at least one of the reagents has the possibility of acting as a proton donor in a hydrogen bond: combination of diene 2 to NH-maleimide (3) affords a 3 (S) : 1 (R) ratio of isomers; combination of diene 1 with NH-maleimide (3) also yields the same ratio of isomers. Scheme 1 recorded the four possible combinations of the reagents. The reactions conditions and the yields of products are collected in table 1. Scheme 1 – Four possible combinations of dienes 1/2 to maleimides 3/4 giving compounds 5 and 6 Considering the unexpected behavior of maleimides in relation to PTAD, figure 1 shows a possible explanation for the fact. The reagents superimposition in pictures A, B and C show the dienophiles approaches to the re face of the diene, leading to the R configuration products. In case A the proximity in space between the two electronegative atoms of the diene and dienophile may result in repulsion between reagents and turn the approach unlikely. Picture B does not evidence repulsion due to the own nature of maleimides, which may result in a likely approach in case B, that did not occur in case A. Even so, as picture C shows, attack on the si face would result in a less bulky interaction between reagents, which may explain the S configuration compounds as the major isomers in most reactions. Figure 1Different interaction at the rear double bond in maleimides and PTAD with the erythrose dienes (A/B and C) O O Ph