Glycal inspired synthesis of antimalarial thiochromans, biologically relevant pyranotetrahydroquinolines and chromenoquinolines
- Authors: Moshapo, Paseka Thendo
- Date: 2016
- Subjects: Substitution reactions , Organic compounds - Synthesis , Heterocyclic compounds - Therapeutic use , Heterocyclic chemistry
- Language: English
- Type: Doctoral (Thesis)
- Identifier: http://hdl.handle.net/10210/233947 , uj:23897
- Description: Ph.D. (Chemistry) , Abstract: The work presented in this thesis describes the transformation of readily available glycals into a series of novel S- and N-heterocycles, namely, thiochromans, pyranotetrahydroquinolines and chromenoquinolines. The thiochroman derivatives have been synthesised by an efficient and versatile substitution of the side-chain iodo substituent in 2-deoxy-2-C- iodomethyl glucosides by thiophenolate ions, and subsequent intramolecular Friedel-Crafts alkylation to generate a series of molecular analogues bearing electron donating aryl substituents. These were further oxidised to their sulfoxide and sulfone derivatives providing a diverse library that exhibited antimalarial activities at low IC50 micromolar concentrations. Structure activity relationship studies and further chemical manipulations of these compounds revealed that the oxidation state, aryl lipophilic substituents as well as the presence of benzyl ethers on the sugar moiety are some of the factors found to be crucial for the antimalarial properties of these compounds. The methodology developed for the synthesis of thiochromans was then successfully extended to the diastereoselective synthesis of novel pyranotetrahydroquinolines. However, the initial trial reactions proceeded with some unexpected rearrangements to yield α,β-unsaturated carbaldehydes and glycals via interesting reaction mechanisms that are also discussed. Reaction optimisation studies and substrate manipulation then successfully afforded a series of tetrahydroquinoline derivatives containing both electron donating and electron withdrawing substituents and these have been fully characterised. This thesis also describes the novel synthesis of fused 5-membered ring pyranotetrahydroquinolines through a scandium triflate [Sc(OTf)3] catalysed multicomponent reaction consisting of a glycal, aniline and salicylaldehyde variants. The formation of 4C1 and B1,4 product mixtures was proposed based on the 1-D and 2-D NMR studies of the formed reaction products. The reaction is also proposed to proceed via a domino Ferrier rearrangement and intramolecular cyclisation mechanism to afford the observed...
- Full Text:
- Authors: Moshapo, Paseka Thendo
- Date: 2016
- Subjects: Substitution reactions , Organic compounds - Synthesis , Heterocyclic compounds - Therapeutic use , Heterocyclic chemistry
- Language: English
- Type: Doctoral (Thesis)
- Identifier: http://hdl.handle.net/10210/233947 , uj:23897
- Description: Ph.D. (Chemistry) , Abstract: The work presented in this thesis describes the transformation of readily available glycals into a series of novel S- and N-heterocycles, namely, thiochromans, pyranotetrahydroquinolines and chromenoquinolines. The thiochroman derivatives have been synthesised by an efficient and versatile substitution of the side-chain iodo substituent in 2-deoxy-2-C- iodomethyl glucosides by thiophenolate ions, and subsequent intramolecular Friedel-Crafts alkylation to generate a series of molecular analogues bearing electron donating aryl substituents. These were further oxidised to their sulfoxide and sulfone derivatives providing a diverse library that exhibited antimalarial activities at low IC50 micromolar concentrations. Structure activity relationship studies and further chemical manipulations of these compounds revealed that the oxidation state, aryl lipophilic substituents as well as the presence of benzyl ethers on the sugar moiety are some of the factors found to be crucial for the antimalarial properties of these compounds. The methodology developed for the synthesis of thiochromans was then successfully extended to the diastereoselective synthesis of novel pyranotetrahydroquinolines. However, the initial trial reactions proceeded with some unexpected rearrangements to yield α,β-unsaturated carbaldehydes and glycals via interesting reaction mechanisms that are also discussed. Reaction optimisation studies and substrate manipulation then successfully afforded a series of tetrahydroquinoline derivatives containing both electron donating and electron withdrawing substituents and these have been fully characterised. This thesis also describes the novel synthesis of fused 5-membered ring pyranotetrahydroquinolines through a scandium triflate [Sc(OTf)3] catalysed multicomponent reaction consisting of a glycal, aniline and salicylaldehyde variants. The formation of 4C1 and B1,4 product mixtures was proposed based on the 1-D and 2-D NMR studies of the formed reaction products. The reaction is also proposed to proceed via a domino Ferrier rearrangement and intramolecular cyclisation mechanism to afford the observed...
- Full Text:
Synthesis of sulfoxide and sulfone mycothiol bioisosteres and novel carbohydrate-based thiochromans
- Authors: Moshapo, Paseka Thendo
- Date: 2013-12-09
- Subjects: Biosynthesis , Enzymes - Synthesis , Thiols - Synthesis , Heterocyclic compounds - Synthesis
- Type: Thesis
- Identifier: uj:7861 , http://hdl.handle.net/10210/8754
- Description: M.Sc. (Chemistry) , Inhibition of mycothiol biosynthesis pathway has attracted attention from chemists and biochemists who aim to develop novel anti-TB drugs. A possible route to inhibit the production of mycothiol in cells may be via the inhibition of enzymes involved in the biosynthetic pathways. Molecular analogues that mimic mycothiol and containing tetrahedral-forming functional groups have been reported to show activity against mycothiol biosynthesis by inhibiting the enzymes in the mycothiol biosynthetic pathway...
- Full Text:
- Authors: Moshapo, Paseka Thendo
- Date: 2013-12-09
- Subjects: Biosynthesis , Enzymes - Synthesis , Thiols - Synthesis , Heterocyclic compounds - Synthesis
- Type: Thesis
- Identifier: uj:7861 , http://hdl.handle.net/10210/8754
- Description: M.Sc. (Chemistry) , Inhibition of mycothiol biosynthesis pathway has attracted attention from chemists and biochemists who aim to develop novel anti-TB drugs. A possible route to inhibit the production of mycothiol in cells may be via the inhibition of enzymes involved in the biosynthetic pathways. Molecular analogues that mimic mycothiol and containing tetrahedral-forming functional groups have been reported to show activity against mycothiol biosynthesis by inhibiting the enzymes in the mycothiol biosynthetic pathway...
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