Cholic acid, molecular model

FIGURE 7.12 Cholic acid. Its 11 chirality centers are those carbons at which stereochemistry is indicated in the structural drawing at the left. The molecular model at the right more clearly shows the overall shape of the molecule. 

Figure 26.13 Expression for three-axial chirality of cholic acid molecule, (a) A molecular structure of cholic acid, (b) a space-filling model of cholic acid with the three-axial chirality expression, as in the case of (c) a vertebrate amimal.

Molecular modelling has also played an important role in the design of novel reagents. Skidmore showed recently that cholic acid 26 provides an excellent chiral template for stannane-based reagents. Indeed, computational data recommended 27 and 28 as the reagents of choice for enantioselective reduction these stannanes were subsequently prepared from cholic acid and lithocholic acid (Scheme 6). ... 

With this information in hand, it seemed reasonable to attempt to use force field methods to model the transition states of more complex, chiral systems. To that end, transition state.s for the delivery of hydrogen atom from stannanes 69 71 derived from cholic acid to the 2.2,.3-trimethy 1-3-pentyl radical 72 (which was chosen as the prototypical prochiral alkyl radical) were modeled in a similar manner to that published for intramolecular free-radical addition reactions (Beckwith-Schicsscr model) and that for intramolecular homolytic substitution at selenium [32]. The array of reacting centers in each transition state 73 75 was fixed at the geometry of the transition state determined by ah initio (MP2/DZP) molecular orbital calculations for the attack of methyl radical at trimethyltin hydride (viz. rsn-n = 1 Si A rc-H = i -69 A 6 sn-H-C = 180°) [33]. The remainder of each structure 73-75 was optimized using molecular mechanics (MM2) in the usual way. In all, three transition state conformations were considered for each mode of attack (re or ) in structures 73-75 (Scheme 14). In general, the force field method described overestimates experimentally determined enantioseleclivities (Scheme 15), and the development of a flexible model is now being considered [33]. 

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