Chirality and Biological Activity

Abstract

The relationship between chirality and biological activity has been of increasing importance to the pharmaceutical and biopharmaceutical areas as evidenced by a growing number of chiral drugs that have been developed within the last two decades. This chapter covers several areas of importance in the design and synthesis of novel small molecule chiral drugs for medicinal chemists. The focus of this chapter is to provide an overview of the impact of chirality in medicinal chemistry and pharmaceutical sciences, and this should not be considered an exhaustive review of the topic. Several examples reported in the recent literature have been used to highlight the impact of chirality on development of therapeutics for various molecular targets. Chirality, as used in this chapter, also includes examples of atropisomers. The effects of chirality on pharmacological activities, absorption, distribution, metabolism, and excretion and toxicity are exemplified. In addition to chirality at carbon, examples of chiral compounds involving chirality at noncarbon atoms are included. A section on chirality in drug design provides several examples from recent literature covering diverse target classes. Regulatory considerations that apply to chiral drugs are addressed briefly. Section 10 covers recent drug development and marketed single enantiomers. Multiple synthetic approaches to produce chiral compounds with high enantiomeric purity, including chromatographic separation and enantioselective syntheses, were covered adequately in the 6th edition, and thus these areas and general definitions of chirality are not repeated in this chapter.

Chiral Hypervalent, Pentacoordinated Phosphoranes

“…Number of Different Structures and Their Chirality PL5 1 achiral PL 1 4L 2 2 achiral PL 1 3L 2 2 3 achiral PL 1 3L 2 L 3 2 achiral and 2 pairs of enantiomers PL 1 2L 2 2L 3 2 achiral and 3 pairs of enantiomers PL 1 2L 2 L 3 L 4 1 achiral and 6 pairs of enantiomers PL 1 L 2 L 3 L 4 L 5 10 pairs of enantiomers It is evident from this table that phosphoranes containing at least three different ligands can be chiral and for structures PL 1 2L 2 2L 3 chirality may appear in the symmetric bicyclic spiro derivatives They constitute the family of hypervalent derivatives, showing "trigonal bipyramidal chirality" in which the central phosphorus atom has expanded its valence shell from 8 to 10 electrons (the concept was for the first time proposed by Musher in 1969) [13]. According to general systematic scheme proposed by Martin and coworkers [14,15] [N-P-L ( n A m B) coding system, in which N stands for the number of valence electrons associated formally with a central phosphorus atom and L shows the number of ligands (A and B stand for the bonding element)]-this group should be considered as the family of 10-P-5 derivatives.…”

“…Number of Different Structures and Their Chirality PL5 1 achiral PL 1 4L 2 2 achiral PL 1 3L 2 2 3 achiral PL 1 3L 2 L 3 2 achiral and 2 pairs of enantiomers PL 1 2L 2 2L 3 2 achiral and 3 pairs of enantiomers PL 1 2L 2 L 3 L 4 1 achiral and 6 pairs of enantiomers PL 1 L 2 L 3 L 4 L 5 10 pairs of enantiomers It is evident from this table that phosphoranes containing at least three different ligands can be chiral and for structures PL 1 2L 2 2L 3 chirality may appear in the symmetric bicyclic spiro derivatives The nature of bonding of hypervalent derivatives is presented in details in a few chapters of "The Chemistry of Hypervalent Compounds" [16,17] and more recently has again been studied using the topological analysis of the electron localization function (ELF)" [18]. Their structure and reactivity are dominated by the weak three-center-four-electron (3c-4e) bond.…”

“…Chlorine and bromine reacted with 181 to give the corresponding halospirophosphoranes 184a,b. In this context it is interesting to note that the corresponding fluorospirophosphorane 184c was obtained from the dichlorofluoro-perfluoropinacolophosphorane FCl 2 P(CH 2 Ph)[OC(CF 3 )C(CF 3 )O] 185 and dilithium perfluoropinacolate LiOC(CF 3 )C(CF 3 )OLi 186. In the presence of triethylamine the hydrophosphorane 181 reacted with benzyl bromide or acetyl chloride to form the phosphoranes 187 or 188.…”

“…The phenomenon of chirality plays a very important role in organic chemistry and biological processes [1][2][3][4][5]. Therefore an easy access to chiral compounds, especially optically active species, constitutes a vital challenge in modern synthetic organic chemistry.…”

“…They have the general formula P(L a ) 2 (L e ) 3 , where "a" means an axial position and "e" means an equatorial position ( Figure 1). They constitute the family of hypervalent derivatives, showing "trigonal bipyramidal chirality" in which the central phosphorus atom has expanded its valence shell from 8 to 10 electrons (the concept was for the first time proposed by Musher in 1969) [13].…”