Direct catalytic asymmetric synthesis of α-chiral bicyclo[1.1.1]pentanes

Abstract

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.

Use of Strain-Release for the Diastereoselective Construction of Quaternary Carbon Centers

“…Since Baran’s fundamental work on C–N bond formation by a strain-release approach, chemists’ interest in utilizing the unique properties of these molecules has been renewed. , In 2019, the group of Aggarwal expanded the toolbox of BCB chemistry by carbopalladation of the central C–C σ-bond of BCB boronate complexes triggered by a 1,2-metalate rearrangement (Figure a). Subsequent cross-coupling gave access to valuable difunctionalized cyclobutyl boronates .…”

Light‐Mediated Aminocatalysis: The Dual‐Catalytic Ability Enabling New Enantioselective Route

“…The combined action of photo‐ and organocatalyst along with the HAT catalysis worked here to facilitate the generation of chiral α‐iminyl radical cation intermediate, which reacted with [1.1.1]propellane 44 to deliver a diverse range of α‐chiral bicyclo[1.1.1]pentanes 45 . Aldehyde substrates 44 containing alkyl, aryl, and heterocyclic ones were screened to show the versatility of this developed protocol (Scheme 12a) [21] …”

“…Asymmetric synthesis of α-chiral bicyclo [1.1.1]pentanes under photoredox/amine dual catalysis. [21] Scheme 13. Photoredox/amine catalyzed synthesis C2-Quaternary Indolin-3ones.…”

Asymmetric Photocatalysis Enabled by Chiral Organocatalysts

“…In 2021, the Anderson group developed a chiral amine/photocatalytic synthesis of α‐chiral bicyclo[1.1.1]pentanes (BCPs) (Scheme 15). [100] Aldehydes bearing alkyl chains, alkenes, alkynes, (thio)ethers, esters, halides, amines, and (hetero)aromatic groups coupled with [1.1.1]propellane to form the corresponding α‐chiral bicyclo[1.1.1]pentanes that were reduced to the desired alcohols in 25–99 % yields and 64–98 % ee. The α‐functionalized aldehydes could also be converted to carboxylic acids, amines, secondary alcohols, and alkynes with complete stereo retention.…”

“… Synthesis of chiral bicyclo[1.1.1]pentanes by use of a chiral amine under visible light conditions [100] …”