Reactions of 2‐Aryl‐1,3‐Dithianes and [1.1.1]Propellane

Trongsiriwat, Nisalak; Pu, Youge; Nieves‐Quinones, Yexenia; Shelp, Russell A.; Kozlowski, Marisa C.; Walsh, Patrick J.

doi:10.1002/ange.201905531

Cited by 16 publications

(10 citation statements)

References 51 publications

(20 reference statements)

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“…Aldehydes bearing aryl (16-18, 72-99%, 90-96% ee), alkenyl (19, 70%, 90% ee), and alkynyl (20, 50%, 90% ee) moieties also afforded the corresponding BCP products in good yields and high selectivities. Substrates featuring various heteroatom functionalities, including thioethers, carbamates, halides, esters, and ethers were successful in the reaction, again delivering BCP products with high efficiency and enantioselectivity (11,(21)(22)(23)(24)(25)(26), 83-99%, 86-97% ee). Particularly notable is the formation of enantioenriched BCP piperidine 25, a class of heterocyclic product that is of importance in pharmaceutical research.…”

Section: Resultsmentioning

confidence: 99%

“…Compounds containing this rigid three-dimensional motif, which often exhibit improved pharmacochemical profiles compared to their parent functionalities 10 , are most commonly accessed by ring-opening reactions of the inter-bridgehead bond of [1.1.1]propellane (1, tricyclo[1.1.1.0 1,3 ]pentane) [11][12][13][14] . Despite many recent advances in the preparation of BCPs [15][16][17][18][19][20][21][22][23][24][25][26][27][28] , the asymmetric synthesis of αchiral variants (which would serve as surrogates for benzylic, propargylic, or neopentylic stereocenters) is highly challenging; current approaches entail lengthy synthetic routes involving chemical resolution processes 29 or the use of stoichiometric chiral auxiliaries/reagents (Fig. 1b) 17,18,30,31 .…”

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confidence: 99%

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

Wong¹,

Sterling²,

Mousseau

et al. 2021

Nat Commun

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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.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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

Wong¹,

Sterling²,

Mousseau

et al. 2021

Nat Commun

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“…A primary alkyl Bpin (R 2 = H, R 3 = H) underwent smooth cyclization to the C1, C3 disubstituted BCP Bpin 16. Starting from secondary alkyl Bpins, a variety of C1, C2 and C3 trisubstituted BCPs, including C2-alkyl (17)(18)(19)(20)(21)(22)14) and C2-aryl substituted (23) BCP Bpins were prepared. Lastly, subjecting tertiary alkyl Bpin starting materials to cyclization condensations afforded BCPs with di-substituted C2 side chains (24,25).…”

Section: Figure 2 Cyclization Optimization To Access Bcpsmentioning

confidence: 99%

Synthesis of Multi-Substituted Bicycloalkyl Boronates: An Intramolecular Coupling Approach to Alkyl Bioisosteres

Yang¹,

Tsien²,

Hughes³

et al. 2021

Preprint

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Bicyclic hydrocarbons, bicyclo[1.1.1]pentanes (BCPs) in particular, play an emerging role as saturated bioisosteres in pharmaceutical, agrochemical, and material chemistry. Taking advantage of strain release strategies, prior synthetic studies have featured the synthesis of bridgehead-substituted (C1, C3) BCPs from [1.1.1]propellane. This work describes a novel approach to accessing multi-substituted BCPs via a new type of intramolecular cyclization. In addition to the C1, C3-disubstituted BCPs, this method also enables the construction of yet underexplored tri-substituted (C1, C2 and C3) BCPs from readily accessible cyclobutanones. The broad generality of this cyclization is examined through synthesis of a variety of caged bicyclic molecules, ranging from [1.1.1] to [3.2.1] scaffolds. The modularity afforded by the pendant bridgehead Bpin resulted from the cyclization is demonstrated via several downstream functionalizations, highlighting the ability of this approach for programmed and divergent synthesis of multi-substituted bicyclic hydrocarbons.

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“…BCPs are also useful motifs for organic materials, including rod-like one-dimensional polymers, 11 supramolecular spacer units, 12 liquid crystals 13 and FRET sensors. 14 Such applications have stimulated the development of a number of methods to access BCPs in a single step from 1, via radical [15][16][17][18][19][20] and anionic [21][22][23][24][25] intermediates (Figure 1b). Limitations nonetheless remain, in particular due to the surprisingly harsh reaction conditions often required for these processes, which can restrict functional group tolerance.…”

Section: Introductionmentioning

confidence: 99%

Rationalizing the diverse reactivity of [1.1.1]propellane through sigma-pi-delocalization

Sterling¹,

Dürr²,

Smith³

et al. 2020

Preprint

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[1.1.1]Propellane has gained increased attention due to its utility as a precursor to bicyclo[1.1.1]pentanes (BCPs) – motifs of high value in pharmaceutical and materials research – by addition of nucleophiles, radicals and electrophiles across its inter-bridgehead C–C bond. However, the origin of this broad reactivity profile is not well-understood. Here, we present a comprehensive computational study that attributes the omniphilicity of [1.1.1]propellane to a moldable, delocalized electron density, characterized by the mixing of the inter-bridgehead C–C bonding and antibonding orbitals. Reactions with anions and radicals are facilitated by stabilization of the adducts through sigma-pi-delocalization of electron density over the cage, while reactions with cations involve charge transfer that relieves Pauli repulsion inside the cage. These results provide a unified framework to rationalize propellane reactivity, opening up opportunities for the exploration of new chemistry of [1.1.1]propellane and related strained systems.

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Reactions of 2‐Aryl‐1,3‐Dithianes and [1.1.1]Propellane

Abstract: Scheme 1. Previous synthesis of BCP ketones, examples of bioactive diaryl ketones, general reactivity of dithianes, and synthesis of BCP dithianes.

Cited by 16 publications

References 51 publications

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

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

Synthesis of Multi-Substituted Bicycloalkyl Boronates: An Intramolecular Coupling Approach to Alkyl Bioisosteres

Rationalizing the diverse reactivity of [1.1.1]propellane through sigma-pi-delocalization

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