Enantioselective synthesis

It helps if you review the concepts in Chapter 5: Stereochemistry of Bruice's Organic Chemistry before embarking on comprehending this summary

Most of the molecules on earth are chiral, such as amino acids and carbohydrates. Enantioselective synthesis is an important means by which enantiopure chiral molecules may be obtained for study and medicine. The study of enantioselective synthesis has evolved from issues of diastereoselectivity, through auxiliary-based methods for the synthesis of enantiomerically pure compounds (diastereoselectivity followed by separation and auxiliary cleavage), to asymmetric catalysis. In the latter technology, enantiomers are the products, and highly selective reactions allow preparation - in a single step - of chiral substances in high enantiomeric excess (ee) for many reaction types.

Enantioselective synthesis, also known as asymmetric synthesis, is organic synthesis that introduces one or more new and desired elements of chirality. This methodology is important in the field of pharmaceuticals because the different enantiomers or diastereomers of a molecule often have different biological activity. See examples from Chapter 5 of Bruice's Organic Chemistry.

Methodologies of Asymmetric Synthesis

Chiral pool synthesis

Chiral pool synthesis is the easiest approach: A chiral starting material is manipulated through successive reactions using achiral reagents that retain its chirality to obtain the desired target molecule. This is especially attractive for target molecules having the similar chirality to a relatively inexpensive naturally occurring building-block such as a sugar or amino acid. However, the number of possible reactions the molecule can undergo is restricted, and lengthy synthetic routes may be required. Also, this approach requires a stoichiometric amount of the enantiopure starting material, which may be rather expensive if not occurring in nature, whereas chiral catalysis requires only a catalytic amount of chiral material.

Enantioselective induction

What many strategies in chiral synthesis have in common is asymmetric induction. The aim is to make enantiomers into diastereomers, since diastereomers have different reactivity, but enantiomers do not. To make enantiomers into diastereomers, the reagents or the catalyst need to be incorporated with an enantiopure chiral center. The reaction will now proceed in different rate for different enantiomers, because the transition state of the reaction can exist in two diastereomers with respect to the enantiopure center, and these diastereomeric transition states have different stability, hence the reaction rates are different.

Enantioselective catalysis

This process can be described as using small amounts of chiral, enantiomerically pure catalysts to promote reactions and lead to the formation of large amounts of enantiomerically pure or enriched products. Three kinds of commonly used chiral catalysts are shown here:

1. metal ligand complexes derived from chiral ligands

2. chiral organocatalysts

3. biocatalysts.

The first methods were pioneered by Knowles and Noyori (Nobel Prize in Chemistry 2001). Knowles in 1968 replaced the achiral triphenylphosphine ligands in Wilkinson's catalyst by the chiral phosphine ligands P(Ph)(Me)(Propyl), thus creating the first asymmetric catalyst. This experimental catalyst was employed in an asymmetric hydrogenation with a modest 15% enantiomeric excess result. In the same year and independently, Noyori published his chiral ligand for a cyclopropanation reaction of styrene. The initial result for the enantiomeric excess for this first-generation ligand was only 6%.