Restriction of conformational flexibility

In chiral ligand 24, the two cyclopentane rings restrict the conformational flexibility of the nine-membered ring, and the four stereogenic centers in the backbone dictate the orientation of the four R-phenyl groups. Scheme 6 15 shows the application of Rh-24 in the asymmetric hydrogenation of dehy-droacylamino acids. 

The research on viloxazine implies that different conformations of /3-blockers are responsible for their poor target selectivity. Restriction of the flexibility by a standard method, tying the molecule with a ring, boosts selectivity for one of the targets. 

The four-membered analogues, phosphetanes, are also attractive for application as chiral ligands in asymmetric catalytic systems, especially because phosphetanes have a rigid structure, restrict the conformational flexibility, and can enhance the efficiency of the chiral transfer in the catalytic process. Hence, many efforts in the development of catalytic chemistry using chiral phosphetane have been performed <1998CCR755>. 

Conformational restriction of biologically flexible molecules is a successful strategy in drug development. Application of this concept to ceramide, the membrane anchor of sphingolipids, led to the unexpected inhibition of glycosyltransferases involved in the combinatorial biosynthesis of gangliosides. This discovery offers a new approach to cell surface engineering. 

Enantioselective protonation of prochiral silyl enol ethers is a very simple and attractive means of preparing optically active carbonyl compounds [135]. It is, however, difficult to achieve high enantioselectivity by use of simple chiral Brpnsted acids because of conformational flexibility in the neighborhood of the proton. It is expected that coordination of a Lewis acid to a Brpnsted acid would restrict the direction of the proton and increase its acidity. In 1994, the author and Yamamoto et al. found that the Lewis acid assisted chiral r0nsted acid (LBA) is a highly effective chiral proton donor for enantioselective protonation [136]. 

In cyclic compounds, there are much greater restrictions on conformational flexibility. In six-membered rings, the antiperiplanar requirement for E2 elimination is satisfied when both the leaving group and the adjacent H atom are axial. Compounds in which such a conformation is readily achievable undergo E2 elimination much more readily than those in which it is not. For example, in menthyl chloride, the C-Cl bond is not antiperiplanar to any adjacent C-H bond in the lowest energy conformation, and E2 elimination is therefore much slower than it is in the diastereomer neomenthyl chloride, in which the C-Cl bond is antiperiplanar to two C-H bonds in the lowest energy conformation. Moreover, two C-H bonds are antiperiplanar to the C-Cl bond in the reactive conformation of neomenthyl chloride, so two products are obtained upon E2 elimination, whereas only one C-H bond is antiperiplanar to the C-Cl bond in the reactive conformation of menthyl chloride, so only one product is obtained. 

An acidic functionality is available even vdth the introduction of a ring system. It is likely that this ring system effectively restricts the conformational flexibility of the chiral backbone. 

During their studies on the aerobic oxidation of Jt-allylchloro (NHC)nick-el(II) complexes, Sigman and co-workers demonstrated that conformational restriction around NHC metal bonds was relevant to catalysis and should be considered in terms of catalyst design and for rationalization of observed reactivity patterns. In particular, it appeared that a monodentate ligand with a lesser volume within the square plane was more likely to promote p-hydride elimination. The issue of conformational flexibility versus rigidity was then expected to directly impact the catalytic behaviour of NHC-Ni complexes. 

---