Stereoselectivity biological targets

Toward a biological target, the potency of two enantiomers can sometimes differ considerably, sometimes be very similar (Table 26.1). Often the activity is concentrated in only one enantiomer. When such a high stereoselectivity arises, it is admitted that the mechanism of action at the molecular level involves a highly specific interaction between the ligand, a chiral molecnle and the recognition site, a chiral environment. It is to be expected that the most active isomer, in... 

There have been several recent solid-phase and solution-phase libraries reported that contain the spiroketal moiety (Figure 7.5). These libraries introduce additional structural complexity and new interaction modes of carbohydrate-like molecules with biological targets. Ley and cowoikers reported the solid-supported synthesis of spiroketals. Using stereoselective aldol reactions of boron enolates, the Waldmann and Paterson groups reported the solid-phase synthesis of 6,6-spiioketals. The 1,7-dioxaspiro [5.5]undecane spiroketal served as the core template for Porco s three-point diversity library to explore protein-protein interactions. ... 

Chirality of NDEs is crucial because of the three-dimensional nature of biological target molecules and 68% of the top 200 marketed drugs are optically pure. Consequently, the stereoselective approach to drug molecules will remain important for many years to come. 

Biological target Menthol is a natural terpenoid with agonist activity at the thermoreceptive, non-selective cation channel, transient receptor potential mela-statin type 8 (TRPM8). Present on nerve fibres and skin cells, these channels are activated by a fall in temperature and mediate analgesia. Menthol is also an agonist at GABAa receptors, for which (+)-menthol reveals stereoselectivity. 

A hydrogen bond, involving an acidic hydrogen atom borne by a fluorine-substituted or halogen-substituted carbon, seems to contribute to the activity and selectivity of volatile fluorinated anesthetics (Table 3.2). These molecules, although nonfunctional, can bind stereoselectively with protein targets of the central nervous system. Different biological behaviors have been reported for both enantiomers of isoflurane (cf. Chapter 8). ... 

On account of their very important biological activity, /9-lactams are important synthetic targets [4-9]. Fused polycyclic -lactam subunits appear in many natural products such as penicillins [4-6] and trinems/tribac-tams [10-13]. Fu et al. reported that such frameworks can be prepared with high levels of enantioselectivity via the intramolecular Kinugasa reaction [ 14, 15] of alkyne-nitrone in the presence of a planar chiral Cu/phosphaferrocene-oxazoline catalyst [16]. For instance, compound 1 was transformed into tricyclic /9-lactam 3 in good stereoselectivity and yielded (88% ee and 74% yield) using 5 mol % of CuBr and 5.5 mol % of complex 2 (Scheme 1). 

The biological activity of the diterpenoids of the aphidicolin-stemodin series makes these compounds attractive targets. The total synthesis of stemodin (96) has been described.172 The key spiro-centre at C-9 was constructed by the internal aldol condensation of the keto-aldehyde (97) to afford (98). Several stereoselective syntheses of aphidicolin have been reported with different solutions to the problem... 

---