{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/273347"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/273347","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Organic Synthesis: Taming Chemistry using Enabling Technologies","abstract":"This thesis describes the application of flow chemistry to discovery and development of medicinal compound synthesis and new chemical methodologies respectively. It is divided into three distinct sections. The first section addresses a brief introduction to flow chemistry, highlighting the advantages and challenges that have been faced in the past and present and also the outlook to the future. The second section reports the integration of machine-assisted methods with batch processes to produce two medicinal compounds, a precursor to the sacubitril and OZ439 respectively. In the respect to the precursor to sacubritil, a flow-batch integrated synthesis is developed to provide the desired product in 54% yield over 7 steps from commercially available 4-iodophenyl. In particular, a tube-in-tube gas flow reactor was employed in three gas-liquid reactions without the need for installing a costly highpressure autoclave. These gas-lquid reactions were an ethylene Heck coupling reaction, an anti-Markovnikov Wacker oxidation and a rhodium-catalysed stereoselective hydrogenation respectively. In addition, a diastereoselective Reformatsky-type carbethoxyallylation using zinc metal was also highlighted in this synthesis to install an important stereocentre. A new antimalarial agent, OZ439 containing a trioxolane unit as the main structural feature, has the unique property of providing a single-dose cure for malaria in humans and has recently completed phase IIb trials. A machine-enabled process for the preparation of OZ439 was developed in 33% overall yield over 5 steps without the need of column chromatography purification. This preparation features a selective continuous hydrogrenation, Griesbaum ozonlysis and a Zn-catalysed amide reduction in the present of triethoxylsilane. The third section contains the development of two new methodologies of diazo compounds with organoboron compounds. The first methodology involves an in situ generation of transient allylic boronic species by reacting TMSCHN2 and E-vinyl boronic acids in flow, followed by subsequent trapping with a range of aldehydes (15 examples, 55-97% yield) and on a large scale (10 mmol) to provide homoallylic alcohols with high diastereoselectivity (>20:1 dr confirmed by 1H NMR). This multicomponent metal-free reaction could also be applied under batch conditions (20 further examples, 60-82% yield). The second methodology involves the preparation of an organodimetallic compound, α-trimethylsilyl benzylboronic acid pinacol esters, by reacting TMSCHN2 and phenylboronic anhydrides (21 examples, 60-91% yield), and the development of their applications as bifunctional building blocks to complex structures.","abstract_html":"This thesis describes the application of flow chemistry to discovery and development of medicinal compound synthesis and new chemical methodologies respectively. It is divided into three distinct sections. The first section addresses a brief introduction to flow chemistry, highlighting the advantages and challenges that have been faced in the past and present and also the outlook to the future. The second section reports the integration of machine-assisted methods with batch processes to produce two medicinal compounds, a precursor to the sacubitril and OZ439 respectively. In the respect to the precursor to sacubritil, a flow-batch integrated synthesis is developed to provide the desired product in 54% yield over 7 steps from commercially available 4-iodophenyl. In particular, a tube-in-tube gas flow reactor was employed in three gas-liquid reactions without the need for installing a costly highpressure autoclave. These gas-lquid reactions were an ethylene Heck coupling reaction, an anti-Markovnikov Wacker oxidation and a rhodium-catalysed stereoselective hydrogenation respectively. In addition, a diastereoselective Reformatsky-type carbethoxyallylation using zinc metal was also highlighted in this synthesis to install an important stereocentre. A new antimalarial agent, OZ439 containing a trioxolane unit as the main structural feature, has the unique property of providing a single-dose cure for malaria in humans and has recently completed phase IIb trials. A machine-enabled process for the preparation of OZ439 was developed in 33% overall yield over 5 steps without the need of column chromatography purification. This preparation features a selective continuous hydrogrenation, Griesbaum ozonlysis and a Zn-catalysed amide reduction in the present of triethoxylsilane. The third section contains the development of two new methodologies of diazo compounds with organoboron compounds. The first methodology involves an in situ generation of transient allylic boronic species by reacting TMSCHN2 and E-vinyl boronic acids in flow, followed by subsequent trapping with a range of aldehydes (15 examples, 55-97% yield) and on a large scale (10 mmol) to provide homoallylic alcohols with high diastereoselectivity (>20:1 dr confirmed by 1H NMR). This multicomponent metal-free reaction could also be applied under batch conditions (20 further examples, 60-82% yield). The second methodology involves the preparation of an organodimetallic compound, α-trimethylsilyl benzylboronic acid pinacol esters, by reacting TMSCHN2 and phenylboronic anhydrides (21 examples, 60-91% yield), and the development of their applications as bifunctional building blocks to complex structures.","abstract_has_math":false,"creators":["Lau, Shing Hing"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Ley, Steven"],"committee_chairs":[],"committee_members":[],"year":2018,"date_issued":"2018-07-20","date_published":"2018-07-20","updated_at":"2026-07-22T22:24:24Z","subjects":["Synthetic Organic Chemistry","Flow Chemistry","API Syntheses","Chemistry"],"languages":["en"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/3f59d534-9a8e-4a4f-8c4e-e97144e07b35/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000169676576","0000000278160042"],"render_values":[{"text":"0000-0001-6967-6576","href":"https://orcid.org/0000-0001-6967-6576","code":true},{"text":"0000-0002-7816-0042","href":"https://orcid.org/0000-0002-7816-0042","code":true}]}]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.20374","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Ley, Steven"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["The Croucher Foundation"]},{"key":"dc:creator","label":"Author","values":["Lau, Shing Hing"]},{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000169676576","0000000278160042"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2018-07-20"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/273347"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Synthetic Organic Chemistry","Flow Chemistry","API Syntheses","Chemistry"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/3f59d534-9a8e-4a4f-8c4e-e97144e07b35/download","https://www.rioxx.net/licenses/all-rights-reserved/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["10.17863/CAM.20374"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/17cd4e9e-9408-49a4-a408-3d9b6792fe89/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["This thesis describes the application of flow chemistry to discovery and development of medicinal compound synthesis and new chemical methodologies respectively. 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In addition, a diastereoselective Reformatsky-type carbethoxyallylation using zinc metal was also highlighted in this synthesis to install an important stereocentre. A new antimalarial agent, OZ439 containing a trioxolane unit as the main structural feature, has the unique property of providing a single-dose cure for malaria in humans and has recently completed phase IIb trials. A machine-enabled process for the preparation of OZ439 was developed in 33% overall yield over 5 steps without the need of column chromatography purification. This preparation features a selective continuous hydrogrenation, Griesbaum ozonlysis and a Zn-catalysed amide reduction in the present of triethoxylsilane. The third section contains the development of two new methodologies of diazo compounds with organoboron compounds. 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The second methodology involves the preparation of an organodimetallic compound, α-trimethylsilyl benzylboronic acid pinacol esters, by reacting TMSCHN2 and phenylboronic anhydrides (21 examples, 60-91% yield), and the development of their applications as bifunctional building blocks to complex structures."]},{"key":"dc:format.checksum.md5","label":"Dc Format Checksum Md5","values":["234a3abe10c09ade1d747aebbd5c348c","87eda9de84448d1f82354d60eee3eb5f"]},{"key":"dc:title","label":"Title","values":["Organic Synthesis: Taming Chemistry using Enabling Technologies"]}]}],"canonical_facts":{"dc:contributor.advisor":["Ley, Steven"],"dc:contributor.sponsor":["The Croucher Foundation"],"dc:creator":["Lau, Shing Hing"],"dc:creator.authoridentifier":["0000000169676576","0000000278160042"],"dc:date.issued":["2018-07-20"],"dc:description.abstract":["This thesis describes the application of flow chemistry to discovery and development of medicinal compound synthesis and new chemical methodologies respectively. 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In addition, a diastereoselective Reformatsky-type carbethoxyallylation using zinc metal was also highlighted in this synthesis to install an important stereocentre. A new antimalarial agent, OZ439 containing a trioxolane unit as the main structural feature, has the unique property of providing a single-dose cure for malaria in humans and has recently completed phase IIb trials. A machine-enabled process for the preparation of OZ439 was developed in 33% overall yield over 5 steps without the need of column chromatography purification. This preparation features a selective continuous hydrogrenation, Griesbaum ozonlysis and a Zn-catalysed amide reduction in the present of triethoxylsilane. The third section contains the development of two new methodologies of diazo compounds with organoboron compounds. 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