Synthesis of Chiral Building Blocks for Use in Drug Discovery

Abstract

In the past decade there has been a significant growth in the sales of pharmaceutical drugs worldwide, but more importantly there has been a dramatic growth in the sales of single enantiomer drugs. The pharmaceutical industry has a rising demand for chiral intermediates and research reagents because of the continuing imperative to improve drug efficacy. This in turn impacts on researchers involved in preclinical discovery work. Besides traditional chiral pool and resolution of racemates as sources of chiral building blocks, many new synthetic methods including a great variety of catalytic reactions have been developed which facilitate the production of complex chiral drug candidates for clinical trials. The most ambitious technique is to synthesise homochiral compounds from non-chiral starting materials using chiral metal catalysts and related chemistry. Examples of the synthesis of chiral building blocks from achiral materials utilizing asymmetric hydrogenation and asymmetric epoxidation are presented.

Half-sandwich Ru(η6-C6H6) complexes with chiral aroylthioureas for enhanced asymmetric transfer hydrogenation of ketones – experimental and theoretical studies

“…48 Pharmaceuticals which require chiral alcohols for their synthesis are antihypertensive, antiarrhythmic, anticholesterol and antiviral drugs, calcium and potassium channel blocking drugs and β 3 -receptor agonists. The need for optically active drugs has been increased in recent years and, therefore, chiral alcohols are in demand.…”

Application of chiral technology in a pharmaceutical company. Enantiomeric separation and spectroscopic studies of key asymmetric intermediates using a combination of techniques. Phenylglycidols

“…A lead series may involve a key chiral intermediate, which may be prepared through chiral starting materials, asymmetric synthesis, asymmetric enzymatic transformation, chiral salt resolution, or preparative enantiomeric separation. [1][2][3][4][5][6][7][8][9][10][11] Critical to understanding fully the structure-activity relationships (SAR) [12][13][14] and structure-property relationships (SPR) [15][16][17][18][19] often based on ''pharmaceutical profiling'' 20 is knowing the absolute stereochemistry of each analog prepared or separated, and being able to track the absolute stereochemistry to the final product with the desired biological activity profile (eutomer) and desirable drug-like properties, instead of the undesired profile (distomer). 21,22 Idealized steps in drug discovery can be summarized as follows:…”

Synthesis and in vitro biological evaluation of novel diaminothiophene scaffolds as antitumor and anti-influenza virus agents. Part 2

“…5 Likewise, this approach represents a rapid way to prepare drug candidates in medicinal chemistry. 6 On the other hand, it is worth designing effective small molecules with low IC 50 values at this rst step of investigations. BBs containing various pharmacophore ring systems, linkers or fragments, 7 play a key role for HTS-based drug discovery.…”