Chirality: a key parameter in chemical probes

Abstract

Many small molecule bioactive and marketed drugs are chiral. They are often synthesised from commercially available chiral building blocks. However, chirality is sometimes incorrectly assigned by manufacturers with consequences for the end user ranging from: experimental irreproducibility, wasted time on synthesising the wrong product and reanalysis, to the added cost of purchasing the precursor and resynthesis of the correct stereoisomer. Further on, this could lead to loss of reputation, loss of funding, to safety and ethical concerns due to potential in vivo administration of the wrong form of a drug. It is our firm belief that more stringent control of chirality be provided by the supplier and, if needed, requested by the end user, to minimise the potential issues mentioned above. Certification of chirality would bring much needed confidence in chemical structure assignment and could be provided by a variety of techniques, from polarimetry, chiral HPLC, using known chiral standards, vibrational circular dichroism, and x-ray crystallography. A few case studies of our brushes with wrong chirality assignment are shown as well as some examples of what we believe to be good practice.

Fig. 1. Examples of chiral drugs and their enantiomers.

Fig. 2. (A) Synthesis of (+)-JD1. (B) HPLC chromatograms of the initially procured commercial “(+)-JQ1” ((i) R_t = 10.9 and (ii) 12.9 min), (iii) authentic (+)-JQ1 from Bio-Techne (Tocris) (R_t = 10.9 min), and a co-injection of both samples (right). (C) (i) VCD of (+)-JQ1 vs. rac.JQ1 (ii) (+)-JQ1 experimental VCD and calculated.

Fig. 3. (A) Synthesis of 1(S),2(S)-N,N chiral ligand for catalysis and projection of the crystal structure of the chiral (S)-,(S)- (left) and (R)-,(R)- (right) organic ligands. (B) VCD spectra of (R)-,(R)- and (S)-,(S)- ligands.

Fig. 4. Selected examples of LCC stock compounds with known absolute configuration.

Fig. 5. Selected examples of novel building blocks requiring determination of absolute configuration. Bottom figure shows A22923 structural assignment by VCD.

Scheme 1. A 3-aminopyrazole yields a 3-aminopyrazole product, not the 4-regioisomer, as expected from the label.