Cz-symmetric ligand 224 was also utilised in the process and gave the much more modest yield of 57% but in a similar enantiomeric excess of 3% in favour of the (S}-enantiomer. It is possible that in the case o f ligand 240a, only the P-aminoalcohol linkage aggregates around the nickel centre (figure 5.1), whereas the whole o f ligand 224 aggregates around the nickel so that the stereogenic centres of the diaminocyclohexane are closer to the nickel centre. This is a possible reason for the slightly higher enantiomeric excess. Nevertheless, it is clear the chiral centres o f the diamine are insufficient to induce sufficient chirality on the process. a) H N OH 2 4 0 a b) OH OH 224
ax
Figure 5.1a) The P-aminoalcohol unit of 240a binds, but the chiral centres of the diamine are remote, b) With ligand 224 despite the proximity of these stereogenic centres, they fail to promote any enantioselectivity.
Chapter 5 Enantioseïective 1,4-conjugate additions 131
The lower yields associated with ligand 224 might be due to the more sterically hindered environment. The benzyl groups are sufficiently large to make substrate approach to the metallic centre that little bit more difficult than the relatively constraint-free environment of figure 5.1a.
It was hoped that by reducing the size of the 7V-alkyl group and the introduction o f chiral groups on the p-aminoalcohol would improve both the yields and enantioselectivities. Ligands 322 and 324 were the first ligands to be tested that fulfilled both those criteria. The Æ-methyl groups were small enough not to inhibit substrate approach and the additional chiral centres were hoped to improve the enantioselectivity of the process as they did in the case o f the addition of diethylzinc to benzaldehyde (see chapter 4).
OH H
N H
322 324
Both these ligands successfully catalysed the reaction. Ligand 322 gave (i?)-103b in a 72% yield and a 37% enantiomeric excess. This seemed to confirm that the use o f smaller A^-alkyl groups led to higher yields. Furthermore, it was clear the introduction of these extra stereogenic centres was the main factor in giving better enantioselectivities. Ligand 324 gave a similarly improved yield of
6 8%, but this time (5)-103b was produced in a 10% enantiomeric excess. This
seemed to imply two things. Firstly, the main factor in determining the enantioselectivity o f the reaction was the absolute configuration o f the new chiral centres. A reversal in this absolute configuration gives rise to a reversal in the enantioselectivity. Secondly, the new chiral centre does not wholly determine this
Chapter 5 Enantioseïective 1,4-conjugate additions 132
selectivity. The fact that the enantiomeric excess does not go from 37% (.R)-103b to 37% (5 )1 03 b upon reversal o f the absolute configuration o f the new centre suggests that the new chiral centre is in the first instance working with the stereogenic centre of the diaminocyclohexane {i.e. matched) and in the second instance it is working against it {mismatched).
A further set o f ligands was synthesised in which the extra stereogenic centres were isopropyl groups rather than phenyl groups. All three diastereomers were synthesised 323, 325 and 326 (in the case of the previous set, synthetic problems prevented the preparation o f the ‘pseudo-me^o’ isomer).
OH H N H OH 323 325 326
Ligand 323 gave (^)-103b in a chemical yield of 63% and a 13% enantiomeric excess, whereas with ligand 325, (5)-103b was produced in a 70% yield but only an 8% enantiomeric excess. In contrast, the curious non-Ci-
symmetric ligand 326 gave a fairly high chemical yield o f 103b (61%), but no enantiomeric excess at all.
Again, despite the fairly low enantioselectivities (although fairly consistent yields), there is a similar pattern to the previous set of ligands - there is a matching and mismatching effect. Furthermore, the matching effects occur in both ligands where the extra stereogenic centre is pointing in the same direction as the chiral proton of the diaminocyclohexane.
The enantioselectivity of the process can be explained by the models shown in figure 5.2, 5.3 and 5.4. With ligands 322 and 323 (figure 5.2), the extra chiral centre is at a fairly perpendicular angle. The chiral proton of the
Chapter 5 Enantioseïective 1,4-conjugate additions 133
diaminocyclohexane depicted points up as does the methyl group on the opposite nitrogen atom. This has the effect o f producing a channel which is fairly restrictive of any movement o f the substrate once it has ‘docked’. The closer side o f the chalcone molecule shown (the re-face) is blocked by the extra chiral centre and so forces alkyl delivery to occur from the opposite ^/-face.
Me
103b
Figure 5.2 ; A channel is formed owing to the positioning of the chiral methylene units in diaminocyclohexane, the iV-methyl group and the new stereogenic centre.
However, with ligands 324 and 325, the chiral group on the p- aminoalcohol is not only on the opposite side, but is also at a slight angle {i.e. not so perpendicular). This leads to the formation of a slanted wall rather than a channel which, although still sufficiently restrictive enough to favour one enantiomer, allows the substrate to move much more freely giving lower enantioselectivities (figure 5.3). The chalcone molecule would also reside in the position (shown) where there is minimum steric hindrance, and so the alkyl group is delivered to the re-face.
° ‘ VZn
103b
Figure 5.3 : Altering the absolute configuration of the chiral group on the P-aminoalcohol destroys the channel and instead forms a wall into which the chalcone attempts to settle almost parallel.
Chapter 5 Enantioseïective 1,4-conjugate additions 134
Lastly, in the non-Ci-symmetric ligand 326, the two non-equivalent stereogenic centres are both pointing in the same direction, thereby virtually blocking off one face of the molecule. The accessible face of the molecule has a very poor chiral environment as there are no guiding factors for the alkyl group consistent the 0% enantiomeric excess obtained using this ligand (figure 5.4).
Me
. . O -
Zn
(±)-103b
Figure 5.4 : With the non-Cz-symmetric ligand, one face is virtually blocked, forcing the chalcone to approach from the side, leading to virtually no asymmetric induction.
5.2.3 O ther ligands used for the asymm etric Michael addition
The enhancement of the sigma interaction between the carbonyl group of the chalcone and the nickel centre was also attempted by substituting //-Me with A^-nitrobenzyl. The electron-withdrawing properties of the latter group would make the nickel atom slightly more electropositive, thereby enhancing the interaction of the 6' carbonyl and the metal. Unfortunately, this compound could
not be successfully synthesised (see page 106, scheme 3.23). However, ligand 256 was, and it closely resembled a ligand used by Asami and co-workers^^° 348 (Scheme 5.4) in that it contained a secondary aromatic amine vicinal to a tertiary aliphatic amine. Asami obtained (5)-103b in a 36% e.e. and an 8 8% yield
Unfortunately, however, no product was obtained using ligand 256. This was probably due to side reactions of diethylzinc with the nitro group.
Chapter 5 Enantioseïective 1,4-conjugate additions 135
e.NH
256
HN
348 1 0 2a 103b
Scheme 3.23 : Reagents : i) NiClz 3 mol%, 348 30 mol%, -30 °C.
5.3 Conclusions
Again it has been shown that it is the p-aminoalcohols which have the most potential as catalysts in the asymmetric Michael addition. As with the addition of diethylzinc to benzaldehyde, it has been shown that the stereogenic centres within the Ci-symmetric ligands can help or hinder each other - thus confirming the phenomenon of the matching and mismatching o f chiral centres within a ligand. However, the modest enantioselectivities obtained with these Ci-
symmetric catalysts suggest that they are not really ideal as catalytic systems, although further work would introduce many varying groups on the stereogenic centre alpha to the alcohol in order to really understand the scope of these catalysts.