The presentation focuses on atropisomerism, a type of stereoisomerism arising from restricted rotation around a bond axis due to steric hindrance or electronic factors, with applications in pharmaceutical compounds like KRAS inhibitors for lung cancer treatment. It covers the definition, energy of activation, nomenclature for assigning configurations, and catalyst-controlled stereoselective synthesis, emphasizing the time-dependent chirality and its potential impact if not properly managed. The content includes references to key studies and highlights ongoing challenges in achieving high enantiomeric excess in atropisomer-selective oxidative coupling reactions.

1. 1
Atropisomerism in
Drug Discovery
Vinayak V Khairnar

2. Outline
2
✓Introduction
✓Scope
✓Methods

3. 3
Chirality: Two Forms
Atropisomerism

4. 4
Sotorasib (AMG510)
Pharmaceutical Importance
Mastigophorene A Knipholone (-)-N- Acetylallocolchinol
KRAS Inhibitor Presently in
Clinical trials For treatment of
Lung cancer

5. 5
Definition of Atropisomerism
A stereoisomer where the element of chirality is not
located on a atom but instead on a molecular plane or axis.
The isomerism is directly derived from
“the potential energy barrier between 2
adjacent minima of the molecular entity
as a function of the torsional angle.”
The arbitrary definition is:
an atropisomerism exists when the
half-life of the inter conversion is
greater than 1000 sec. (r.t.)
Eliel, E,; etal. Stereochemistry ofOrganic Cmpds.
Oki, M. Top. Stereochemistry. 1984, 14, 1-81.

6. 6
In Dynamic NMR studies of biphenyl systems (1) a direct
correlation between rotational energies around the central axis
and the Van der Waals radii of the substituents is seen.
1
These observations have led to the accepted hypothesis that the governing force behind
atropisomer’s chirality lies primarily in steric manifestations
Energy of Activation in Atropisomerism

7. 7
Assigning Configuration
The two main accepted nomenclature for assigning atropisomers
Cahn Ingold Prelog
Helical Nomenclature
Example

8. 8
Know More….
❑An often overlooked source of chirality
❑ It is time-dependent chirality.
❑Results from slow rotation along a bond axis due to steric hindrance
and/or electronic factors.
If undetected or not managed properly,has the potential to lead to serious consequences.

9. Unattended Chirality
9
▪ R-thalidomide is the bioactive form of the molecule.
▪ The individual enantiomers can racemize to each other due to the acidic hydrogen at
the chiral centre the phthalimide substituent.
▪ The racemization process can occur in vivo

10. 10
QM Energy profiles
❑ Energy barriers to axial rotation were calculated using quantum mechanics, from which predicted high barriers
could be experimentally validated.
❑ A calculated rotational energy barrier of 20 kcalmol1 was established as a suitable threshold to distinguish
between atropisomers and non-atropisomers with a prediction accuracy of 86%.
❑ This methodology was applied to subsets of drug databases in the course of which atropisomeric drugs were
identified.

11. Synthetic Strategies
Intramolecular Coupling
11
ChiralAuxiliary (Bridges):
InherentChirality (Natural Bridge):
Steganone
Antimitotic and
Antitubulin activity
Intramolecular Coupling have less success rate
TM

12. 12
Intermolecular Coupling
Synthetic Strategies
Meyers,A. J. Am.Chem Soc. 1985, 107, 682.
Hayashi, T. Tett. Lett., 1993, 34, 107.
Hayashi, T. J. Am.Chem. Soc., 1988, 110, 8153.
Buchwald, S. J. Am.Chem. 2000, 122, 12051.
ChiralAuxiliary
Asymmetric Ni-Pd Coupling
Asymmetric Oxidative Coupling
Kumada Approach Suzuki Approach

13. 13
Catalyst-Controlled Stereoselective Synthesis of Atropisomers
Atroposelective O-Alkylation
❑ Enantioselectivity controlled by the ion-pairing catalyst 5.
❑ Binaphthols (4), which grant access to catalysts whose steric and electronic properties differ
from typical BINOL derivatives.
❑ Excellent yields and with retention of optical purity.
Dynamic kinetic
resolution
Chiral cinchona-derived
ammonium salt

14. 14
Selective Synthesis of Aryl cyclohexenonesvia SuzukiCoupling
❑ The transfer of the stereo chemical information was achieved by the bidentate ferrocenyl
aminophosphine ligand (9).
❑ The obtained axially chiral enones are configurationally stable precursors of the 2,2′-biphenol
scaffolds
❑ Other biaryl and nonbiaryl structures,(carbazoles, quinones or haloarenes) are accessible
without diminishing the enantiomeric excess of the starting enone (8).
▪ Carbazole
▪ Quinones
▪ Haloarene
Access to Biaryls
Catalyst-Controlled Stereoselective Synthesis of Atropisomers

15. 15
Atroposelective Benzidine Rearrangement
Atroposelective BenzidineRearrangement
BINAM scaffold
Rearrangement
❑ Obtained C2-symmetricBINAM derivatives with excellent Selectivity and a catalytic amount of chiral
phosphoric acids.
❑ Use of axially chiral phosphoric acids also proved to be a particularly effective catalyst for the conversion
of quinones and imino quinones to form atropisomeric diols.
chiral phosphoric acids

16. 16

17. CONCLUSION
17
❑ Atropisomerism selective oxidative coupling reactions are still in their infancy.
❑ Even the best examples provide only moderate enantiomeric excess and generally are
substrate dependant.
❑ Atropisomer selective coupling (metal based) will be an avenue of focused research quite
possibly in the near future.
Decisionscan be made during early discovery stages such as “hit-to-lead”and “lead
optimization,”to foresee and validatethe presence of atropisomers and to exercise
optionsof removing, further stabilizing,or rendering the chiralaxis of interest more freely
rotatablevia SAR design, thereby decreasing this potentialliabilitywithin a compound
series.

18. 18