Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-021-21936-4
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Funding
- EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine [EP/L015838/1]
- AstraZeneca
- Diamond Light Source
- Defence Science and Technology Laboratory
- Evotec
- GlaxoSmithKline
- Janssen
- Novartis
- Pfizer
- Syngenta
- Takeda
- UCB
- Vertex
- EPSRC [EP/S013172/1, EP/P020267/1]
- EPSRC Centre for Doctoral Training for Theory and Modelling in Chemical Sciences [EP/L015722/1]
- University of Edinburgh
- EPSRC [EP/P020267/1] Funding Source: UKRI
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Bicyclo[1.1.1]pentanes (BCPs) are essential in contemporary drug design, yet methods to access BCPs with adjacent stereocenters are limited. This study presents a photo- and organocatalyzed asymmetric addition of simple aldehydes to [1.1.1]propellane to generate enantioenriched alpha-chiral BCPs.
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 alpha -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 alpha -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 alpha -chiral BCPs in high yield and enantioselectivity. We also present a theoretical model for stereoinduction in this mode of photoredox organocatalysis. Bicyclo[1.1.1]pentanes (BCPs) are important motifs in contemporary drug design, however, approaches to BCPs featuring adjacent stereocenters are rather limited. Here, the authors report a photo- and organocatalyzed asymmetric addition of simple aldehydes to [1.1.1]propellane to generate enantioenriched alpha -chiral BCPs.
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