Making Analogues of Tröger's Base – Fused oligomers, endo/exo isomers and twisted amides

Abstract

The centenarian Tröger’s base (TB) was envisaged as scaffold for the construction of tubular-shaped cleft molecules due to its the remarkable structural properties. This endeavor started with the synthesis of the three possible diastereomers of a linear symmetrically fused tris-TB analogue, the anti-anti, the syn-syn, and the syn-anti. All three diastereomers showed unprecedented stability to acid isomerization. The desymmetrization protocol presented, established the foundations for the synthesis of higher generations of fused analogues of TB.

Following this, new methodologies for the functionalization of both the aromatic and the methanodiazocine ring of TB were introduced. The development of a palladium-catalyzed amination conditions converted 2,8-dihalo analogues of TB to their corresponding mono- and diamino analogues. Regarding the diazocine ring, the benzylic methylenes of TB were oxidized to give the first example of a twisted bis-amide. Its unconventional amide reactivity allowed the development of the first rational synthesis of 6,12-endo,endo-substituted analogues of TB. Alternatively, endo and exo functionalization of the benzylic methylenes was also achieved via metalation followed by electrophilic quenching.

All the knowledge acquired was ultimately used in the synthesis of the first fused heptakis-TB analogue. The functionalization at the benzylic positions of TB with (R)-menthyl ester groups allowed the diastereomeric resolution of the TB analogue. Each diastereomer was used to independently build two differently substituted fused heptakis-TB analogue. Our developed synthetic strategy, involving the sequential condensation, hydrolysis, desymmetrization, and condensation, together with a remarkable solubility in organic solvents observed for the heptakis-TB’s, sets the stage to build even higher generations of fused oligo-TB.

Abstract (Swedish)

Popular Abstract in English

The ability to make aromatic cleft compounds is of importance in the field of molecular recognition where many interactions of the guest with the receptor are based on interactions involving aromatic receptor moieties leading to π-π and cation-π interactions, as well as hydrophobic interactions commonly seen. One attractive framework for aromatic cleft compounds is Tröger's base (TB) and its analogues. The centenarian Tröger’s base is a chiral molecule with two stereogenic centers at the nitrogen atoms possessing a rigid structure with the plane of two aromatic rings approximately perpendicular.

In this thesis the synthetic chemistry of the TB system has been developed in the quest to make extended aromatic receptors for the use in molecular recognition with the ultimate long-term goal of making molecular tubes for the transport of acetylcholine in the interior of such a tube. Thus, the synthetic issues solved during the work described herein set the stage for the successful construction of higher generations of fused TB resulting in extended aromatic clefts: (a) Control of the regiochemistry by introducing substituents in the appropriate positions in the starting aniline. (b) The introduction of amino groups in the mono-TB building block, necessary for the further synthesis of higher generations of fused TB analogues. (c) A desymmetrization protocol for the controlled formation of higher generations of fused TB-analogues (d) The development of rational protocols for the synthesis of mono- and di- endo and exo substituted isomers of TB resulting in the attachment of soluble side chains in the TB system, and also allowing for the resolution of TB enantiomers.

All over, this has resulted in the synthesis of a fully soluble fused tris-TB analogue and for the first time a heptakis-TB analogue. In this process the first twisted bis-amide has been synthesized and the kinetics for its acid-catalyzed hydrolysis has been investigated. Moreover, its unconventional amide reactivity allowed the synthesis of endo,endo-bis-TB crown ether.

• author: Artacho Ruiz, Josep
• supervisor: Kenneth Wärnmark
• opponent: Lacour, Jérôme, Département de chimie organique, Université de Genève, Genève, Schweiz.
• organization: Centre for Analysis and Synthesis
• publishing date: 2011
• type: Thesis
• publication status: published
• subject: Organic Chemistry
• defense location: Kemicentrum, sal K:B
• defense date: 2011-10-06 09:30:00
• language: English
• LU publication?: yes
• additional info: The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Organic chemistry (S/LTH) (011001240)
• id: 4b0cc7a0-c1e0-4225-a218-e36a1b47d5a5 (old id 2155887)
• date added to LUP: 2016-04-04 11:02:41
• date last changed: 2018-11-21 21:02:18