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Total synthesis of natural product-Like 3D molecular scaffolds for drug discovery.

Total synthesis of natural product-Like 3D molecular scaffolds for drug discovery.
Total synthesis of natural product-Like 3D molecular scaffolds for drug discovery.
The design and total synthesis of a 3D collection compounds containing the spirocyclic piperidine privileged building block, taking into consideration drug-like descriptors (parameters) such as physicochemical and pharmacokinetic properties and based on the natural product molecular core framework of furofuranones, have been achieved via two distinct stereoselective cyclopropanation reactions, for drug discovery. Key reactions included an enantioselective cyclopropanation through a Mn(III)/Cu(II) promoted oxidative cyclisation and a diastereoselective cyclopropanation via the chiral dirhodium(II) catalyst dirhodium tetrakis (S)-N-1,8-naphthanoyl tert-leucinate, Rh2[(S)-NTTL]4. The enantiomerically enriched key intermediate, which have been synthesised implementing an efficient parallel enzymatic kinetic resolution accomplishing excellent enantioselectivity (>99%), was further derivatised with fragments or building blocks of pharmaceutical interest to achieve the synthesis of 7 final drug-like compounds, 3 precursors for further derivatisation, for screening purposes. Additionally, towards the total synthesis of a respective furolactam key intermediate an unusual Mitsunobu reaction has been achieved between a sec-allylic alcohol and the weakly acidic coupling partner para-bromo aniline.
University of Southampton
Peroulias, Angelos Dimitrios
9a978d7e-02fa-4580-95f6-d0efd4c5a02a
Peroulias, Angelos Dimitrios
9a978d7e-02fa-4580-95f6-d0efd4c5a02a
Brown, Richard
21ce697a-7c3a-480e-919f-429a3d8550f5
Harrowven, David
bddcfab6-dbde-49df-aec2-42abbcf5d10b

Peroulias, Angelos Dimitrios (2023) Total synthesis of natural product-Like 3D molecular scaffolds for drug discovery. University of Southampton, Doctoral Thesis, 206pp.

Record type: Thesis (Doctoral)

Abstract

The design and total synthesis of a 3D collection compounds containing the spirocyclic piperidine privileged building block, taking into consideration drug-like descriptors (parameters) such as physicochemical and pharmacokinetic properties and based on the natural product molecular core framework of furofuranones, have been achieved via two distinct stereoselective cyclopropanation reactions, for drug discovery. Key reactions included an enantioselective cyclopropanation through a Mn(III)/Cu(II) promoted oxidative cyclisation and a diastereoselective cyclopropanation via the chiral dirhodium(II) catalyst dirhodium tetrakis (S)-N-1,8-naphthanoyl tert-leucinate, Rh2[(S)-NTTL]4. The enantiomerically enriched key intermediate, which have been synthesised implementing an efficient parallel enzymatic kinetic resolution accomplishing excellent enantioselectivity (>99%), was further derivatised with fragments or building blocks of pharmaceutical interest to achieve the synthesis of 7 final drug-like compounds, 3 precursors for further derivatisation, for screening purposes. Additionally, towards the total synthesis of a respective furolactam key intermediate an unusual Mitsunobu reaction has been achieved between a sec-allylic alcohol and the weakly acidic coupling partner para-bromo aniline.

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Published date: 15 June 2023

Identifiers

Local EPrints ID: 478503
URI: http://eprints.soton.ac.uk/id/eprint/478503
PURE UUID: 6f2e060b-883e-4a3b-a8e2-732a5e92ef80
ORCID for Richard Brown: ORCID iD orcid.org/0000-0003-0156-7087
ORCID for David Harrowven: ORCID iD orcid.org/0000-0001-6730-3573

Catalogue record

Date deposited: 04 Jul 2023 17:40
Last modified: 01 Sep 2024 04:01

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Contributors

Author: Angelos Dimitrios Peroulias
Thesis advisor: Richard Brown ORCID iD
Thesis advisor: David Harrowven ORCID iD

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