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New methodologies in asymmetric allylic substitution and organocascade reactions

New methodologies in asymmetric allylic substitution and organocascade reactions
New methodologies in asymmetric allylic substitution and organocascade reactions
Asymmetric organocatalysis and organometallic catalysis are rapidly developing. The first catalytic process can be traced back in the XIX century. Since then, research in the field of catalysis grew, especially in the last decades exponentially. Four projects involving organocatalysis are described in this thesis: “Highly enantioselective addition of anthrones to MBH-carbonates”, “Synergistic catalysis: Highly diastereoselective benzoxazole addition to Morita-Baylis-Hillman carbonates”, “Three-component diastereoselective cascade synthesis of thiohydantoins” and “Highly diastereoselective synthesis of spiropyrazolones”.

A) Asymmetric allylic substitution
Since Tsuji and Trost reported their first examples of allylic substitution catalysed by palladium salts in 1963, many examples of allylic substitution were published involving other types of transition metals. Later, in 2002, Kim et al. reported the first allylic substitution using a metal-free approach.
Morita-Baylis-Hillman carbonates are important scaffolds in the synthesis of more complex molecules due to the presence of numerous functional groups.
In this thesis two examples of asymmetric allylic substitution involving Morita-Baylis-Hillman (MBH) carbonates are described.

Highly enantioselective addition of anthrones to Morita-Baylis-Hillman carbonates
Anthrone derivatives are present in various natural sources and are known for their medicinal effects. We were interested in the enantioselective addition of anthrone to MBH-carbonates. The products were synthesised in very good yields and enantioselectivity by using a (DHQD)2AQN as catalyst. Moreover, a kinetic resolution was perfomed in order to better understand the mechanistic process.

Synergistic catalysis: Highly diastereoselective benzoxazole addition to Morita-Baylis-Hillman carbonates

Catalysis is one of the most efficient strategies for identifying new chemical reactions. Usually, a catalytic pathway relies on the interaction of a single catalyst with a single reagent in order to lower the energetic barrier. In some cases, the mono-catalytic concept is not enough and other strategies are used, in particular, synergistic catalysis. This consists in the activation of the electrophile and the nucleophile by two different catalysts for reaction to occur. Based on this idea, we studied the addition of benzoxazoles to Morita-Bayllis-Hillman carbonates by the use of two different catalysts (Metal Lewis acid and Organic Lewis base). Both catalysts work in a concerted way giving the final compound in high yield and diastereoselectivity.

B) Organocascade reactions

Synthesis of complex organic molecules is a challenge for every chemist. The aim is achieveing the final product in as few steps as possible using safer, cleaner and environmentally friendly techniques. One-pot reactions emerged as a powerful tool in creating several bonds in one step. Based on this idea, we studied two reactions:

Three-component diastereoselective cascade synthesis of thiohydantoins

Thiohydantoins have interesting medicinal applications such as antibacterial, antiviral, antimutagenic, etc. Synthesising these scaffolds in one step via three-component one-pot reaction was our main focus. We developed a three-component cascade reaction for the synthesis of thiohydantoins. The reaction between ?-amino esters, nitrostyrenes and aromatic isothiocyanates is efficiently promoted by organic bases to afford highly substituted thiohydantoins in moderate to good yields and diastereoselectivities.

Highly diastereoselective synthesis of spiropyrazolones

Spiro compounds are present in various natural products and are powerful active agents. We have developed a methodology for the synthesis of spiropyrazolone bearing fourchiral centres. The reaction was catalysed by a secondary amine in
a Michael-aldol cascade fashion affording the product in very good yields and diastereoselectivity.
Ceban, Victor
2e53f2b7-42ff-4c26-96e9-ef75891af166
Ceban, Victor
2e53f2b7-42ff-4c26-96e9-ef75891af166
Rios Torres, Ramon
609bedf2-e886-4d62-a676-a32b6f8c1441

Ceban, Victor (2015) New methodologies in asymmetric allylic substitution and organocascade reactions. University of Southampton, Faculty of Natural and Environmental Sciences, Doctoral Thesis, 227pp.

Record type: Thesis (Doctoral)

Abstract

Asymmetric organocatalysis and organometallic catalysis are rapidly developing. The first catalytic process can be traced back in the XIX century. Since then, research in the field of catalysis grew, especially in the last decades exponentially. Four projects involving organocatalysis are described in this thesis: “Highly enantioselective addition of anthrones to MBH-carbonates”, “Synergistic catalysis: Highly diastereoselective benzoxazole addition to Morita-Baylis-Hillman carbonates”, “Three-component diastereoselective cascade synthesis of thiohydantoins” and “Highly diastereoselective synthesis of spiropyrazolones”.

A) Asymmetric allylic substitution
Since Tsuji and Trost reported their first examples of allylic substitution catalysed by palladium salts in 1963, many examples of allylic substitution were published involving other types of transition metals. Later, in 2002, Kim et al. reported the first allylic substitution using a metal-free approach.
Morita-Baylis-Hillman carbonates are important scaffolds in the synthesis of more complex molecules due to the presence of numerous functional groups.
In this thesis two examples of asymmetric allylic substitution involving Morita-Baylis-Hillman (MBH) carbonates are described.

Highly enantioselective addition of anthrones to Morita-Baylis-Hillman carbonates
Anthrone derivatives are present in various natural sources and are known for their medicinal effects. We were interested in the enantioselective addition of anthrone to MBH-carbonates. The products were synthesised in very good yields and enantioselectivity by using a (DHQD)2AQN as catalyst. Moreover, a kinetic resolution was perfomed in order to better understand the mechanistic process.

Synergistic catalysis: Highly diastereoselective benzoxazole addition to Morita-Baylis-Hillman carbonates

Catalysis is one of the most efficient strategies for identifying new chemical reactions. Usually, a catalytic pathway relies on the interaction of a single catalyst with a single reagent in order to lower the energetic barrier. In some cases, the mono-catalytic concept is not enough and other strategies are used, in particular, synergistic catalysis. This consists in the activation of the electrophile and the nucleophile by two different catalysts for reaction to occur. Based on this idea, we studied the addition of benzoxazoles to Morita-Bayllis-Hillman carbonates by the use of two different catalysts (Metal Lewis acid and Organic Lewis base). Both catalysts work in a concerted way giving the final compound in high yield and diastereoselectivity.

B) Organocascade reactions

Synthesis of complex organic molecules is a challenge for every chemist. The aim is achieveing the final product in as few steps as possible using safer, cleaner and environmentally friendly techniques. One-pot reactions emerged as a powerful tool in creating several bonds in one step. Based on this idea, we studied two reactions:

Three-component diastereoselective cascade synthesis of thiohydantoins

Thiohydantoins have interesting medicinal applications such as antibacterial, antiviral, antimutagenic, etc. Synthesising these scaffolds in one step via three-component one-pot reaction was our main focus. We developed a three-component cascade reaction for the synthesis of thiohydantoins. The reaction between ?-amino esters, nitrostyrenes and aromatic isothiocyanates is efficiently promoted by organic bases to afford highly substituted thiohydantoins in moderate to good yields and diastereoselectivities.

Highly diastereoselective synthesis of spiropyrazolones

Spiro compounds are present in various natural products and are powerful active agents. We have developed a methodology for the synthesis of spiropyrazolone bearing fourchiral centres. The reaction was catalysed by a secondary amine in
a Michael-aldol cascade fashion affording the product in very good yields and diastereoselectivity.

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Published date: 30 October 2015
Organisations: University of Southampton, Chemistry

Identifiers

Local EPrints ID: 397983
URI: http://eprints.soton.ac.uk/id/eprint/397983
PURE UUID: 381525db-4bf7-4fcc-bff2-6381bfe46142
ORCID for Ramon Rios Torres: ORCID iD orcid.org/0000-0002-3843-8521

Catalogue record

Date deposited: 15 Jul 2016 11:00
Last modified: 23 Jun 2019 04:01

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