Direct catalytic asymmetric synthesis of α-chiral bicyclo[1.1.1]pentanes
Bicyclo[1.1.1]pentanes (BCPs) are important motifs in contemporary drug design as linear spacer units that improve pharmacokinetic profiles. The synthesis of BCPs featuring adjacent stereocenters is highly challenging, but desirable due to the fundamental importance of 3D chemical space in medicinal...
| Main Authors: | , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2021
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| _version_ | 1797096445294149632 |
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| author | Wong, MLJ Sterling, AJ Mousseau, JJ Duarte Gonzalez, FJ Anderson, EA |
| author_facet | Wong, MLJ Sterling, AJ Mousseau, JJ Duarte Gonzalez, FJ Anderson, EA |
| author_sort | Wong, MLJ |
| collection | OXFORD |
| description | Bicyclo[1.1.1]pentanes (BCPs) are important motifs in contemporary drug design as linear spacer units that improve pharmacokinetic profiles. The synthesis of BCPs featuring adjacent stereocenters is highly challenging, but desirable due to the fundamental importance of 3D chemical space in medicinal chemistry. Current methods to access these high-value chiral molecules typically involve transformations of pre-formed BCPs, and can display limitations in substrate scope. Here we describe an approach to synthesize α-chiral BCPs involving the direct, asymmetric addition of simple aldehydes to [1.1.1]propellane, the predominant BCP precursor. This is achieved by combining a photocatalyst and an organocatalyst to generate a chiral α-iminyl radical cation intermediate, which installs a stereocenter simultaneously with ring-opening of [1.1.1]propellane. The reaction proceeds under mild conditions, displays broad scope, and provides an array of α-chiral BCPs in high yield and enantioselectivity. We also present a theoretical model for stereoinduction in this mode of photoredox organocatalysis. |
| first_indexed | 2024-03-07T04:41:58Z |
| format | Journal article |
| id | oxford-uuid:d1f3178c-42d3-457b-97cf-1d1d87e48774 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:41:58Z |
| publishDate | 2021 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:d1f3178c-42d3-457b-97cf-1d1d87e487742022-03-27T08:00:30ZDirect catalytic asymmetric synthesis of α-chiral bicyclo[1.1.1]pentanesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:d1f3178c-42d3-457b-97cf-1d1d87e48774EnglishSymplectic ElementsSpringer Nature2021Wong, MLJSterling, AJMousseau, JJDuarte Gonzalez, FJAnderson, EABicyclo[1.1.1]pentanes (BCPs) are important motifs in contemporary drug design as linear spacer units that improve pharmacokinetic profiles. The synthesis of BCPs featuring adjacent stereocenters is highly challenging, but desirable due to the fundamental importance of 3D chemical space in medicinal chemistry. Current methods to access these high-value chiral molecules typically involve transformations of pre-formed BCPs, and can display limitations in substrate scope. Here we describe an approach to synthesize α-chiral BCPs involving the direct, asymmetric addition of simple aldehydes to [1.1.1]propellane, the predominant BCP precursor. This is achieved by combining a photocatalyst and an organocatalyst to generate a chiral α-iminyl radical cation intermediate, which installs a stereocenter simultaneously with ring-opening of [1.1.1]propellane. The reaction proceeds under mild conditions, displays broad scope, and provides an array of α-chiral BCPs in high yield and enantioselectivity. We also present a theoretical model for stereoinduction in this mode of photoredox organocatalysis. |
| spellingShingle | Wong, MLJ Sterling, AJ Mousseau, JJ Duarte Gonzalez, FJ Anderson, EA Direct catalytic asymmetric synthesis of α-chiral bicyclo[1.1.1]pentanes |
| title | Direct catalytic asymmetric synthesis of α-chiral bicyclo[1.1.1]pentanes |
| title_full | Direct catalytic asymmetric synthesis of α-chiral bicyclo[1.1.1]pentanes |
| title_fullStr | Direct catalytic asymmetric synthesis of α-chiral bicyclo[1.1.1]pentanes |
| title_full_unstemmed | Direct catalytic asymmetric synthesis of α-chiral bicyclo[1.1.1]pentanes |
| title_short | Direct catalytic asymmetric synthesis of α-chiral bicyclo[1.1.1]pentanes |
| title_sort | direct catalytic asymmetric synthesis of α chiral bicyclo 1 1 1 pentanes |
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