The Role of Allylic Strain for Conformational Control in Medicinal Chemistry

Abstract

It is axiomatic in medicinal chemistry that optimization of the potency of a small molecule at a macromolecular target requires complementarity between the ligand and target. In order to minimize the conformational penalty on binding, both enthalpically and entropically, it is therefore preferred to have the ligand preorganized in the bound conformation. In this Perspective, we highlight the role of allylic strain in controlling conformational preferences. Allylic strain was originally described for carbon-based allylic systems, but the same principles apply to other types of structure with sp 2 or pseudo-sp 2 arrangements. These systems include benzylic (including heteroaryl methyl) positions, amides, N-aryl groups, aryl ethers, and nucleotides. We have derived torsion profiles from small molecule X-ray structures for these systems. Through multiple examples, we show how these effects have been applied in drug discovery and how they can be used prospectively to influence conformation in the design process.

Quantitative Colorimetric Sensing of Carbidopa in Anti-Parkinson Drugs Based on Selective Reaction with Indole-3-Carbaldehyde

“…The remarkable splitting and difference in elution time for these peaks is here attributed to azine stereoisomers generated by a different mechanism of synthesis with respect to previously reported I3A-hydrazine condensation [31]. These isomers are likely associated with different double-bond configurations of the azine region and/or with different conformations for the rotation around the single bond between the nitrogen atoms limited by steric hindrance, analogous to allylic strain [32], to which the indole rings derived from I3A molecules contribute, in large part. However, further characterization would be necessary for a full description.…”

Quantitative Colorimetric Sensing of Carbidopa in Anti-Parkinson Drugs Based on Selective Reaction with Indole-3-Carbaldehyde

“…The remarkable splitting and difference in elution time for these peaks is here attributed to azine stereoisomers generated by a different mechanism of synthesis with respect to previously reported I3A-hydrazine condensation [31]. These isomers are likely associated with different double-bond configurations of the azine region and/or with different conformations for the rotation around the single bond between the nitrogen atoms limited by steric hindrance, analogous to allylic strain [32], to which the indole rings derived from I3A molecules contribute, in large part. However, further characterization would be necessary for a full description.…”

Leveraging Kinase Drugs for Neurosciences: Discovery of Selective, CNS-Penetrant Reversible Bruton’s Tyrosine Kinase Inhibitors as Therapeutics for Neuroinflammation

“…Building on this knowledge, compounds 14 and 15 were synthesized to test the hypothesis that replacing the benzannulene motif with the simplified core would afford analogs with comparable biological profiles and improved ADME properties ( Table ). Despite 14 exhibiting a loss in WB cellular potency, which was attributed to a putative pseudo-A­(1,3) strain forcing the amide into a less favorable binding conformation, the des-methyl analog 15 surpassed all expectations with respect to overall drug-like properties. To our delight, removal of the methyl substituent afforded 15 , which decreased the lipophilicity and molecular weight ( c log P = 3.9; MW = 446) while demonstrating MDCK efflux, solubility, cytochromes P450 (CYP), and human Ether-à-go-go Related Gene (hERG) activities comparable to compound 13 .…”

Modified Julia Olefination Approach to Chiral α‐Fluorovinyl Amino Alcohols and Amino Acids, via Fluorovinyl Oxazolidine Precursors, Conformational and Crystallographic Analyses

“…[50] Due to the cis arrangement of bulky substituents at the double bond in (S,E)-2f, 1,3-allylic strain is expected to be much larger due to buttressing of the aromatic moiety and the allylic substituent in conformations II and III, compared to conformation I where the double bond is eclipsed with H B (Figure 5, upper panel). [50,58] In the present case, bisected conformation IV, with the fluorine atom eclipsed with methine H B proton, needs to be considered as well (Figure 5, upper panel). [50] In addition, conformations I-IV can adopt syn (s) or anti (a) envelope conformations of the oxazolidine ring.…”

“…Thus, conformations of II-IV can be ignored in the consideration of the equilibrium population. [50,58] In the 1 H - 19 F HOESY spectrum of (S,E)-2f (please see the Supporting Information), the most intense correlations are between the fluorine atom and the vinylic H A proton (expected), one of the diastereotopic CH 3 groups, and the oxazolidine CH 2 protons. Strong correlations between the fluorine atom and the oxazolidine CH 3 and CH 2 protons and the absence of significant correlation between the fluorine atom and the H B proton (which would be indicative of conformations II, III, and IV), support conformations of I as major in solution.…”

Quantitative Colorimetric Sensing of Carbidopa in Anti-Parkinson Drugs Based on Selective Reaction with Indole-3-Carbaldehyde

“…The remarkable splitting and difference in elution time for these peaks is here attributed to azine stereoisomers generated by a different mechanism of synthesis with respect to previously reported I3A-hydrazine condensation [31]. These isomers are likely associated with different double-bond configurations of the azine region and/or with different conformations for the rotation around the single bond between the nitrogen atoms limited by steric hindrance, analogous to allylic strain [32], to which the indole rings derived from I3A molecules contribute, in large part. However, further characterization would be necessary for a full description.…”

Leveraging Kinase Drugs for Neurosciences: Discovery of Selective, CNS-Penetrant Reversible Bruton’s Tyrosine Kinase Inhibitors as Therapeutics for Neuroinflammation

“…Building on this knowledge, compounds 14 and 15 were synthesized to test the hypothesis that replacing the benzannulene motif with the simplified core would afford analogs with comparable biological profiles and improved ADME properties ( Table ). Despite 14 exhibiting a loss in WB cellular potency, which was attributed to a putative pseudo-A­(1,3) strain forcing the amide into a less favorable binding conformation, the des-methyl analog 15 surpassed all expectations with respect to overall drug-like properties. To our delight, removal of the methyl substituent afforded 15 , which decreased the lipophilicity and molecular weight ( c log P = 3.9; MW = 446) while demonstrating MDCK efflux, solubility, cytochromes P450 (CYP), and human Ether-à-go-go Related Gene (hERG) activities comparable to compound 13 .…”

Modified Julia Olefination Approach to Chiral α‐Fluorovinyl Amino Alcohols and Amino Acids, via Fluorovinyl Oxazolidine Precursors, Conformational and Crystallographic Analyses

“…[50] Due to the cis arrangement of bulky substituents at the double bond in (S,E)-2f, 1,3-allylic strain is expected to be much larger due to buttressing of the aromatic moiety and the allylic substituent in conformations II and III, compared to conformation I where the double bond is eclipsed with H B (Figure 5, upper panel). [50,58] In the present case, bisected conformation IV, with the fluorine atom eclipsed with methine H B proton, needs to be considered as well (Figure 5, upper panel). [50] In addition, conformations I-IV can adopt syn (s) or anti (a) envelope conformations of the oxazolidine ring.…”

“…Thus, conformations of II-IV can be ignored in the consideration of the equilibrium population. [50,58] In the 1 H - 19 F HOESY spectrum of (S,E)-2f (please see the Supporting Information), the most intense correlations are between the fluorine atom and the vinylic H A proton (expected), one of the diastereotopic CH 3 groups, and the oxazolidine CH 2 protons. Strong correlations between the fluorine atom and the oxazolidine CH 3 and CH 2 protons and the absence of significant correlation between the fluorine atom and the H B proton (which would be indicative of conformations II, III, and IV), support conformations of I as major in solution.…”

Quantitative Colorimetric Sensing of Carbidopa in Anti-Parkinson Drugs Based on Selective Reaction with Indole-3-Carbaldehyde

“…The remarkable splitting and difference in elution time for these peaks is here attributed to azine stereoisomers generated by a different mechanism of synthesis with respect to previously reported I3A-hydrazine condensation [31]. These isomers are likely associated with different double-bond configurations of the azine region and/or with different conformations for the rotation around the single bond between the nitrogen atoms limited by steric hindrance, analogous to allylic strain [32], to which the indole rings derived from I3A molecules contribute, in large part. However, further characterization would be necessary for a full description.…”

Leveraging Kinase Drugs for Neurosciences: Discovery of Selective, CNS-Penetrant Reversible Bruton’s Tyrosine Kinase Inhibitors as Therapeutics for Neuroinflammation

“…Building on this knowledge, compounds 14 and 15 were synthesized to test the hypothesis that replacing the benzannulene motif with the simplified core would afford analogs with comparable biological profiles and improved ADME properties ( Table ). Despite 14 exhibiting a loss in WB cellular potency, which was attributed to a putative pseudo-A­(1,3) strain forcing the amide into a less favorable binding conformation, the des-methyl analog 15 surpassed all expectations with respect to overall drug-like properties. To our delight, removal of the methyl substituent afforded 15 , which decreased the lipophilicity and molecular weight ( c log P = 3.9; MW = 446) while demonstrating MDCK efflux, solubility, cytochromes P450 (CYP), and human Ether-à-go-go Related Gene (hERG) activities comparable to compound 13 .…”

Modified Julia Olefination Approach to Chiral α‐Fluorovinyl Amino Alcohols and Amino Acids, via Fluorovinyl Oxazolidine Precursors, Conformational and Crystallographic Analyses

“…[50] Due to the cis arrangement of bulky substituents at the double bond in (S,E)-2f, 1,3-allylic strain is expected to be much larger due to buttressing of the aromatic moiety and the allylic substituent in conformations II and III, compared to conformation I where the double bond is eclipsed with H B (Figure 5, upper panel). [50,58] In the present case, bisected conformation IV, with the fluorine atom eclipsed with methine H B proton, needs to be considered as well (Figure 5, upper panel). [50] In addition, conformations I-IV can adopt syn (s) or anti (a) envelope conformations of the oxazolidine ring.…”

“…Thus, conformations of II-IV can be ignored in the consideration of the equilibrium population. [50,58] In the 1 H - 19 F HOESY spectrum of (S,E)-2f (please see the Supporting Information), the most intense correlations are between the fluorine atom and the vinylic H A proton (expected), one of the diastereotopic CH 3 groups, and the oxazolidine CH 2 protons. Strong correlations between the fluorine atom and the oxazolidine CH 3 and CH 2 protons and the absence of significant correlation between the fluorine atom and the H B proton (which would be indicative of conformations II, III, and IV), support conformations of I as major in solution.…”