TY - JOUR

T1 - Merging nucleophilic phosphine catalysis and photocatalysis for the rapid assembly of 2-oxabicyclo-[2.1.1]hexane scaffolds from feedstock allyl alcohols †

AU - Whalley, David M.

AU - Carlino, Luca

AU - Putra, Okky Dwichandra

AU - Anderson, Niall A.

AU - Coote, Susannah C.

AU - Lorthioir, Olivier

PY - 2024/12/14

Y1 - 2024/12/14

N2 - The previously unreported combination of nucleophilic phosphine catalysis and energy transfer catalysis allows for the rapid construction of structurally distinct 2-oxabicyclo[2.1.1]hexanes (2-oxa-BCH) from readily available building blocks with high atom economy. Previous multistep routes to these important phenyl ring bioisosteres have largely depended on the use of bespoke strain-release agents or on multiple post-functionalisation reactions to access structural diversity of the scaffold. In contrast, this cascade reaction allows the medicinal chemist to exploit the breadth of commercial allyl alcohols to synthesise systematically diverse 2-oxa-BCH architectures. Using a combination of polar and radical disconnections in the same reaction flask, every position of the scaffold can be substituted with useful functional handles such as protected amines, esters and alcohols, as well as arenes and alkyl groups. Cyclic allyl alcohols can even be employed to yield single diastereomers of sp3-rich bridged spirocyclic structures. Aromatic groups at the 1-position can be varied to incorporate a plethora of arenes including medicinally relevant heterocycles such as indole, pyrazole and pyridine.

AB - The previously unreported combination of nucleophilic phosphine catalysis and energy transfer catalysis allows for the rapid construction of structurally distinct 2-oxabicyclo[2.1.1]hexanes (2-oxa-BCH) from readily available building blocks with high atom economy. Previous multistep routes to these important phenyl ring bioisosteres have largely depended on the use of bespoke strain-release agents or on multiple post-functionalisation reactions to access structural diversity of the scaffold. In contrast, this cascade reaction allows the medicinal chemist to exploit the breadth of commercial allyl alcohols to synthesise systematically diverse 2-oxa-BCH architectures. Using a combination of polar and radical disconnections in the same reaction flask, every position of the scaffold can be substituted with useful functional handles such as protected amines, esters and alcohols, as well as arenes and alkyl groups. Cyclic allyl alcohols can even be employed to yield single diastereomers of sp3-rich bridged spirocyclic structures. Aromatic groups at the 1-position can be varied to incorporate a plethora of arenes including medicinally relevant heterocycles such as indole, pyrazole and pyridine.

U2 - 10.1039/d4sc06684g

DO - 10.1039/d4sc06684g

M3 - Journal article

C2 - 39568909

VL - 15

SP - 19564

EP - 19570

JO - Chemical Science

JF - Chemical Science

SN - 2041-6520

IS - 46

ER -