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Synthesis of a Linear Symmetrically Fused Tröger's Base Analogue

Alcantara Martinez, Fabio LU (2025) KEMP30 20251
Department of Chemistry
Abstract
Julius Tröger first synthesised ‘C17H18N2’ as an unknown product from the condensation of anilines with formaldehyde. From that point on, the history of Tröger’s base (TB) has widely evolved as new applications for its characteristic rigid, chiral framework easy to functionalise. It is in the field of supramolecular chemistry that TB has gathered the most attention these last years. This work is framed inside the more ambitious project of developing a heptakis-TB structure aimed at drug delivery through bilayer membranes.
The synthesis begins from a commercially available aniline, leading to a TB analogue through condensations and functionalisation of the TB analogue. During this synthesis, chiral centers are introduced to obtain... (More)
Julius Tröger first synthesised ‘C17H18N2’ as an unknown product from the condensation of anilines with formaldehyde. From that point on, the history of Tröger’s base (TB) has widely evolved as new applications for its characteristic rigid, chiral framework easy to functionalise. It is in the field of supramolecular chemistry that TB has gathered the most attention these last years. This work is framed inside the more ambitious project of developing a heptakis-TB structure aimed at drug delivery through bilayer membranes.
The synthesis begins from a commercially available aniline, leading to a TB analogue through condensations and functionalisation of the TB analogue. During this synthesis, chiral centers are introduced to obtain enantiomerically pure intermediates. However, the separation of diastereomers 22a and 22b ends up being a bottleneck due to the troublesome purification conditions and the low yields resulting from it. In order to surmount this obstacle, two strategies are explored: late-stage separation and the synthesis of a simpler linear tris-TB analogue.
For the late-stage separation, intermediates 24 and 24’ are synthesised, but none of them offered improved purification towards to the original step. However, a new synthetic route has been developed to produce 37, a linear tris-TB, through condensation of the mono-protected 2,8-diamino-TB 36. Despite preliminary LC-MS data seems to confirm the presence of 37, further purification and configurational isomers separation methods must be developed.
Overall, this project showcases the synthetic complexity of TB analogues and the need to optimize methodologies for diastereomer handling. Albeit the heptakis-TB analogue remains a future goal, having successfully formed a simpler tris-TB creates new opportunities for the future of modular and functional TB systems. (Less)
Popular Abstract
Tröger’s base (TB) is a molecule discovered by Julius Tröger in the late 1800s. It is its three-dimensional structure that provides this molecule with very interesting properties and uses. Tröger’s base has a rigid V-shape that allows for a perfect building block in structures with a particular geometry. Nowadays, TB is especially useful in various fields of chemistry and biochemistry such as drug delivery, molecular recognition and DNA binding.
This work is aimed at synthesising a new version of Tröger’s base combining three of the units, resulting in a linear and symmetric TB analogue. The goal of the project in which this work is part of, is to build a larger circular structure with seven of the TB units which when achieved, it will... (More)
Tröger’s base (TB) is a molecule discovered by Julius Tröger in the late 1800s. It is its three-dimensional structure that provides this molecule with very interesting properties and uses. Tröger’s base has a rigid V-shape that allows for a perfect building block in structures with a particular geometry. Nowadays, TB is especially useful in various fields of chemistry and biochemistry such as drug delivery, molecular recognition and DNA binding.
This work is aimed at synthesising a new version of Tröger’s base combining three of the units, resulting in a linear and symmetric TB analogue. The goal of the project in which this work is part of, is to build a larger circular structure with seven of the TB units which when achieved, it will allow for safe transport of drugs through cell membranes.
To get to the new version of a TB, a new synthetic path was developed and tested starting from a commercially available chemical. In the process, it was tried to separate different complementary molecules (isomers) in order to try and improve other synthetic paths. However, that proved to be a major challenge and required more advanced purification techniques.
Eventually, a simpler three-unit Tröger’s base was created. Unfortunately, a pure molecule was not achieved, and the full potential of this new TB was not tested due to time constraints. Nonetheless, the obtention of said molecule has been proved and therefore laid important groundwork for future research.
In conclusion, this work has contributed and lead one step closer to the final objective of the project, which was designing an artificial tunnel for drugs to go through cell membranes. (Less)
Please use this url to cite or link to this publication:
author
Alcantara Martinez, Fabio LU
supervisor
organization
course
KEMP30 20251
year
type
L3 - Miscellaneous, Projetcs etc.
subject
keywords
Organic Chemistry, Supramolecular Chemistry, Tröger’s base, Diastereomers, Tris-Tröger’s Base
language
English
id
9201031
date added to LUP
2025-06-23 11:29:07
date last changed
2025-06-23 11:29:07
@misc{9201031,
  abstract     = {{Julius Tröger first synthesised ‘C17H18N2’ as an unknown product from the condensation of anilines with formaldehyde. From that point on, the history of Tröger’s base (TB) has widely evolved as new applications for its characteristic rigid, chiral framework easy to functionalise. It is in the field of supramolecular chemistry that TB has gathered the most attention these last years. This work is framed inside the more ambitious project of developing a heptakis-TB structure aimed at drug delivery through bilayer membranes.
The synthesis begins from a commercially available aniline, leading to a TB analogue through condensations and functionalisation of the TB analogue. During this synthesis, chiral centers are introduced to obtain enantiomerically pure intermediates. However, the separation of diastereomers 22a and 22b ends up being a bottleneck due to the troublesome purification conditions and the low yields resulting from it. In order to surmount this obstacle, two strategies are explored: late-stage separation and the synthesis of a simpler linear tris-TB analogue.
For the late-stage separation, intermediates 24 and 24’ are synthesised, but none of them offered improved purification towards to the original step. However, a new synthetic route has been developed to produce 37, a linear tris-TB, through condensation of the mono-protected 2,8-diamino-TB 36. Despite preliminary LC-MS data seems to confirm the presence of 37, further purification and configurational isomers separation methods must be developed.
Overall, this project showcases the synthetic complexity of TB analogues and the need to optimize methodologies for diastereomer handling. Albeit the heptakis-TB analogue remains a future goal, having successfully formed a simpler tris-TB creates new opportunities for the future of modular and functional TB systems.}},
  author       = {{Alcantara Martinez, Fabio}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{Synthesis of a Linear Symmetrically Fused Tröger's Base Analogue}},
  year         = {{2025}},
}