The Synthesis and Absolute Configuration of Enantiomeric Pure (R)- and (S)-3-(piperidin-3-yl)-1H-Indole Derivatives
Marek Król1, Grzegorz Ślifirski1, Jerzy Kleps1
1Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097 Warsaw, Poland.
International Journal of Molecular Sciences
|January 8, 2023
Summary
This study synthesizes novel chiral 3-(piperidin-3-yl)-1H-indole derivatives using diastereomers. The molecular structures and absolute configurations were confirmed using X-ray crystallography and spectroscopic methods.
Area of Science:
- Organic Chemistry
- Stereochemistry
- Crystallography
Background:
- Chiral 3-(piperidin-3-yl)-1H-indole derivatives are important scaffolds in medicinal chemistry.
- Controlling stereochemistry during synthesis is crucial for developing enantiomerically pure compounds.
Purpose of the Study:
- To synthesize new chiral 3-(piperidin-3-yl)-1H-indole derivatives.
- To determine the molecular structure and absolute configuration of synthesized compounds.
- To investigate the crystallization behavior of racemic intermediates.
Main Methods:
- N-alkylation of racemic 3-(piperidin-3-yl)-1H-indoles with chiral sulfonyloxy derivatives.
- Single crystal X-ray crystallography for structural elucidation.
- Nuclear Magnetic Resonance (NMR) spectroscopy (1H, 13C), High-Performance Liquid Chromatography (HPLC), and High-Resolution Mass Spectrometry (HRMS) for characterization.
Main Results:
- Successful synthesis of chiral 3-(piperidin-3-yl)-1H-indole derivatives (R)-10a-c and (S)-11a-c.
- Determination of the absolute configuration for key enantiomeric pairs.
- Identification of different crystallization behaviors for racemic intermediates (true racemates vs. racemic conglomerate).
Conclusions:
- The synthetic strategy effectively produced chiral indole derivatives with confirmed stereochemistry.
- X-ray crystallography and spectroscopic analyses provided unambiguous structural assignments.
- Understanding the solid-state behavior of intermediates aids in optimizing synthetic routes.
Keywords:
HPLC separationX-ray crystallographychiral auxiliariesenantiomerspiperidin-3-yl-1H-indolesserotonin analogsMore Related Videos
Related Concept Videos
02:21Naming Enantiomers
20.7K
The naming of enantiomers employs the Cahn–Ingold–Prelog rules that involve assigning priorities to different substituent groups at a chiral center. Each enantiomer, being a distinct molecule, is assigned a unique name by the Cahn–Ingold–Prelog (CIP) rules, also called the R–S system. The prefix R- or S- attached to the chiral centers in an enantiomer is dependent on the spatial arrangement of the four substituents on the chiral center. The R–S system...
20.7K
02:30Chirality at Nitrogen, Phosphorus, and Sulfur
5.8K
Chirality is most prevalent in carbon-based tetrahedral compounds, but this important facet of molecular symmetry extends to sp3-hybridized nitrogen, phosphorus and sulfur centers, including trivalent molecules with lone pairs. Here, the lone pair behaves as a functional group in addition to the other three substituents to form an analogous tetrahedral center that can be chiral.
A consequence of chirality is the need for enantiomeric resolution. While this is theoretically possible for all...
A consequence of chirality is the need for enantiomeric resolution. While this is theoretically possible for all...
5.8K
02:33Stereoisomerism of Cyclic Compounds
9.1K
In this lesson, we delve into the role of ring conformation and its stability, which determines the spatial arrangement and, consequently, the molecular symmetry and stereoisomerism of cyclic compounds. 1,2-Dimethylcyclohexane is used as a case study to evaluate the possible number of stereoisomers. Here, given the multiple (n = 2) chiral centers, there are 2n = 4 possible configurations that lack a plane of symmetry, as the ring skeleton exists in a non-planar chair conformation. In addition,...
9.1K
02:05Prochirality
3.9K
The concept of prochirality leads to the nomenclature of the individual faces of a molecule and plays a crucial role in the enantioselective reaction. It is a concept where two or more achiral molecules react to produce chiral products. A typical process is the reaction of an achiral ketone to generate a chiral alcohol. Here, the achiral reactant reacts with an achiral reducing agent, sodium borohydride, to generate an equimolar mixture of the chiral enantiomers of the product. For example, an...
3.9K
02:32Stereoisomers
13.2K
On the basis of mirror symmetry, stereoisomers of an organic molecule can be further classified into diastereomers and enantiomers. Diastereomers are stereoisomers that are not mirror images of each other. Substituted alkenes, such as the cis and trans isomers of 2-butene, are diastereomers, as these molecules exhibit different spatial orientations of their constituent atoms, are not mirror images of each other, and do not interconvert. Here, the interconversion is suppressed due to...
13.2K
02:52Stereoisomerism
12.3K
Isomerism in Complexes
Isomers are different chemical species that have the same chemical formula.
Transition metal complexes often exist as geometric isomers, in which the same atoms are connected through the same types of bonds but with differences in their orientation in space. Coordination complexes with two different ligands in the cis and trans positions from a ligand of interest form isomers. For example, the octahedral [Co(NH3)4Cl2]+ ion has two isomers (Figure 1) In the cis...
Isomers are different chemical species that have the same chemical formula.
Transition metal complexes often exist as geometric isomers, in which the same atoms are connected through the same types of bonds but with differences in their orientation in space. Coordination complexes with two different ligands in the cis and trans positions from a ligand of interest form isomers. For example, the octahedral [Co(NH3)4Cl2]+ ion has two isomers (Figure 1) In the cis...
12.3K