Design of New, More Stable, Precursors to Organopalladium(II) Complexes and Methods for the Palladium-Mediated Late-Stage Diversification of Pharmaceuticals
Chapter 1. Pharmaceutical Diversification via Palladium Oxidative Addition Complexes Palladium-catalyzed cross-coupling reactions have transformed the exploration of chemical space in the search for materials, medicines, chemical probes, and other functional molecules. However, cross-coupling of...
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| Format: | Thesis |
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Massachusetts Institute of Technology
2022
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| Online Access: | https://hdl.handle.net/1721.1/139499 |
| _version_ | 1811093993856958464 |
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| author | King, Ryan P. |
| author2 | Buchwald, Stephen L. |
| author_facet | Buchwald, Stephen L. King, Ryan P. |
| author_sort | King, Ryan P. |
| collection | MIT |
| description | Chapter 1. Pharmaceutical Diversification via Palladium Oxidative Addition Complexes
Palladium-catalyzed cross-coupling reactions have transformed the exploration of chemical space in the search for materials, medicines, chemical probes, and other functional molecules. However, cross-coupling of densely functionalized substrates remains a major challenge. We devised an alternative approach using stoichiometric quantities of palladium oxidative addition complexes (OACs) derived from drugs or drug-like aryl halides as substrates. In most cases, cross-coupling reactions using OACs proceed under milder conditions and with higher success than the analogous catalytic reactions. OACs exhibit remarkable stability, maintaining their reactivity after months of benchtop storage under ambient conditions. We demonstrated the utility of OACs in a variety of experiments including automated nanomole-scale couplings between an OAC derived from rivaroxaban and hundreds of diverse nucleophiles, as well as the late-stage derivatization of the natural product k252a.
Chapter 2. A Ligand Exchange Process for the Diversification of Palladium Oxidative Addition Complexes
Palladium oxidative addition complexes (OACs) have recently emerged as powerful tools to enable challenging bond formations for the functionalization and diversification of pharmaceuticals and biomolecules. However, each OAC can only be formed with one particular ancillary ligand at a time. As no one ligand is optimal for every cross-coupling reaction and as the accessibility to pharmaceutically-derived OACs bearing different ligands is limited by arene availability, we herein disclose a ligand exchange protocol that allows for the preparation of a series of OACs bearing a diverse array of ancillary ligands ranging from phosphines to phosphites and bipyridyls from one common complex. The complexes generated were further applied to both stoichiometric and catalytic cross-coupling reactions.
Chapter 3. A Neophyl Palladacycle as an Air- and Thermally Stable Precursor to Oxidative Addition Complexes
The synthesis and utilization of isolated Palladium Oxidative Addition Complexes (OACs) has had a significant impact on Pd-catalyzed and Pd-mediated cross-coupling reactions. Despite their importance, widespread utility of OACs has been greatly limited by the instability of their Pd precursor complexes. Herein we report the use of Cámpora’s palladacycle as a new, more stable, precursor to Pd OACs. Using this palladacycle, a diverse series of biarylphosphine ligated OACs, including those with pharmaceutical-derived aryl halides and relevance to bioconjugation, were prepared. Additionally, Cámpora’s palladacycle was investigated as a thermally activated precatalyst for Pd-catalyzed C–N cross coupling reactions.
Chapter 4. Synthesis of (MeCN)2Pd(CF3)OTs, a General Precursor to Palladium(II)-Trifluoromethyl Complexes LPd(CF3)X
In palladium-catalyzed aryl–trifluoromethyl cross-coupling reactions, reductive elimination is often the rate-limiting step. Stoichiometric studies of reductive elimination have proved effective in evaluating the ability of various ligands to facilitate this challenging elementary step. However, the difficulty of synthesizing palladium trifluoromethyl complexes has hindered the use of this strategy. To address this deficiency, we herein report the synthesis of (MeCN)2Pd(CF3)OTs, an air- and moisture-stable solid that can be used as a common precursor to access various LPd(CF3)X complexes. From this complex we were able to prepare palladium trifluoromethyl complexes bearing many monophosphine, bisphosphine, and diamine ligands that are known to help facilitate Ar–CF3and vinyl–CF3 reductive elimination. Further, we found that the anionic ligand (X) could be readily changed by modifying the NaX or AgX salt used. |
| first_indexed | 2024-09-23T15:53:52Z |
| format | Thesis |
| id | mit-1721.1/139499 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T15:53:52Z |
| publishDate | 2022 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/1394992022-01-15T03:07:00Z Design of New, More Stable, Precursors to Organopalladium(II) Complexes and Methods for the Palladium-Mediated Late-Stage Diversification of Pharmaceuticals King, Ryan P. Buchwald, Stephen L. Massachusetts Institute of Technology. Department of Chemistry Chapter 1. Pharmaceutical Diversification via Palladium Oxidative Addition Complexes Palladium-catalyzed cross-coupling reactions have transformed the exploration of chemical space in the search for materials, medicines, chemical probes, and other functional molecules. However, cross-coupling of densely functionalized substrates remains a major challenge. We devised an alternative approach using stoichiometric quantities of palladium oxidative addition complexes (OACs) derived from drugs or drug-like aryl halides as substrates. In most cases, cross-coupling reactions using OACs proceed under milder conditions and with higher success than the analogous catalytic reactions. OACs exhibit remarkable stability, maintaining their reactivity after months of benchtop storage under ambient conditions. We demonstrated the utility of OACs in a variety of experiments including automated nanomole-scale couplings between an OAC derived from rivaroxaban and hundreds of diverse nucleophiles, as well as the late-stage derivatization of the natural product k252a. Chapter 2. A Ligand Exchange Process for the Diversification of Palladium Oxidative Addition Complexes Palladium oxidative addition complexes (OACs) have recently emerged as powerful tools to enable challenging bond formations for the functionalization and diversification of pharmaceuticals and biomolecules. However, each OAC can only be formed with one particular ancillary ligand at a time. As no one ligand is optimal for every cross-coupling reaction and as the accessibility to pharmaceutically-derived OACs bearing different ligands is limited by arene availability, we herein disclose a ligand exchange protocol that allows for the preparation of a series of OACs bearing a diverse array of ancillary ligands ranging from phosphines to phosphites and bipyridyls from one common complex. The complexes generated were further applied to both stoichiometric and catalytic cross-coupling reactions. Chapter 3. A Neophyl Palladacycle as an Air- and Thermally Stable Precursor to Oxidative Addition Complexes The synthesis and utilization of isolated Palladium Oxidative Addition Complexes (OACs) has had a significant impact on Pd-catalyzed and Pd-mediated cross-coupling reactions. Despite their importance, widespread utility of OACs has been greatly limited by the instability of their Pd precursor complexes. Herein we report the use of Cámpora’s palladacycle as a new, more stable, precursor to Pd OACs. Using this palladacycle, a diverse series of biarylphosphine ligated OACs, including those with pharmaceutical-derived aryl halides and relevance to bioconjugation, were prepared. Additionally, Cámpora’s palladacycle was investigated as a thermally activated precatalyst for Pd-catalyzed C–N cross coupling reactions. Chapter 4. Synthesis of (MeCN)2Pd(CF3)OTs, a General Precursor to Palladium(II)-Trifluoromethyl Complexes LPd(CF3)X In palladium-catalyzed aryl–trifluoromethyl cross-coupling reactions, reductive elimination is often the rate-limiting step. Stoichiometric studies of reductive elimination have proved effective in evaluating the ability of various ligands to facilitate this challenging elementary step. However, the difficulty of synthesizing palladium trifluoromethyl complexes has hindered the use of this strategy. To address this deficiency, we herein report the synthesis of (MeCN)2Pd(CF3)OTs, an air- and moisture-stable solid that can be used as a common precursor to access various LPd(CF3)X complexes. From this complex we were able to prepare palladium trifluoromethyl complexes bearing many monophosphine, bisphosphine, and diamine ligands that are known to help facilitate Ar–CF3and vinyl–CF3 reductive elimination. Further, we found that the anionic ligand (X) could be readily changed by modifying the NaX or AgX salt used. Ph.D. 2022-01-14T15:15:42Z 2022-01-14T15:15:42Z 2021-06 2021-06-16T17:17:43.366Z Thesis https://hdl.handle.net/1721.1/139499 0000-0002-0798-313X In Copyright - Educational Use Permitted Copyright MIT http://rightsstatements.org/page/InC-EDU/1.0/ application/pdf Massachusetts Institute of Technology |
| spellingShingle | King, Ryan P. Design of New, More Stable, Precursors to Organopalladium(II) Complexes and Methods for the Palladium-Mediated Late-Stage Diversification of Pharmaceuticals |
| title | Design of New, More Stable, Precursors to Organopalladium(II) Complexes and Methods for the Palladium-Mediated Late-Stage Diversification of Pharmaceuticals |
| title_full | Design of New, More Stable, Precursors to Organopalladium(II) Complexes and Methods for the Palladium-Mediated Late-Stage Diversification of Pharmaceuticals |
| title_fullStr | Design of New, More Stable, Precursors to Organopalladium(II) Complexes and Methods for the Palladium-Mediated Late-Stage Diversification of Pharmaceuticals |
| title_full_unstemmed | Design of New, More Stable, Precursors to Organopalladium(II) Complexes and Methods for the Palladium-Mediated Late-Stage Diversification of Pharmaceuticals |
| title_short | Design of New, More Stable, Precursors to Organopalladium(II) Complexes and Methods for the Palladium-Mediated Late-Stage Diversification of Pharmaceuticals |
| title_sort | design of new more stable precursors to organopalladium ii complexes and methods for the palladium mediated late stage diversification of pharmaceuticals |
| url | https://hdl.handle.net/1721.1/139499 |
| work_keys_str_mv | AT kingryanp designofnewmorestableprecursorstoorganopalladiumiicomplexesandmethodsforthepalladiummediatedlatestagediversificationofpharmaceuticals |