Intermolecular [2π+2σ]-photocycloaddition enabled by triplet energy transfer

Kleinmans, Roman; Pinkert, Tobias; Dutta, Subhabrata; Paulisch, Tiffany O.; Keum, Hyeyun; Daniliuc, Constantin G.; Glorius, Frank

doi:10.1038/s41586-022-04636-x

Cited by 147 publications

(111 citation statements)

References 47 publications

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“…The resulting products provide a unique platform for chemical space exploration in pursuit of new, C sp 3 ‐rich drug candidates, especially given the functional group compatibility exhibited with respect to heterocycles and diverse synthetic handles. Work is ongoing to explore the mechanistic and synthetic features of cycloaddition to bicyclobutanes, and to apply these techniques toward complex molecule synthesis relevant to the discovery of active pharmaceutical ingredients containing bicyclic scaffolds [47–50] …”

Section: Discussionmentioning

confidence: 99%

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Beyond Bioisosteres: Divergent Synthesis of Azabicyclohexanes and Cyclobutenyl Amines from Bicyclobutanes**

et al. 2022

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The development of two divergent and complementary Lewis acid catalyzed additions of bicyclobutanes to imines is described. Microscale high‐throughput experimentation was integral to the discovery and optimization of both reactions. N‐arylimines undergo formal (3+2) cycloaddition with bicyclobutanes to yield azabicyclo[2.1.1]hexanes in a single step; in contrast, N‐alkylimines undergo an addition/elimination sequence to generate cyclobutenyl methanamine products with high diastereoselectivity. These new products contain a variety of synthetic handles for further elaboration, including many functional groups relevant to pharmaceutical synthesis. The divergent reactivity observed is attributed to differences in basicity and nucleophilicity of the nitrogen atom in a common carbocation intermediate, leading to either nucleophilic attack (N‐aryl) or E1 elimination (N‐alkyl).

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Section: Discussionmentioning

confidence: 99%

“…Work is ongoing to explore the mechanistic and synthetic features of cycloaddition to bicyclobutanes, and to apply these techniques toward complex molecule synthesis relevant to the discovery of active pharmaceutical ingredients containing bicyclic scaffolds. [47][48][49][50]…”

Section: Discussionmentioning

confidence: 99%

Beyond Bioisosteres: Divergent Synthesis of Azabicyclohexanes and Cyclobutenyl Amines from Bicyclobutanes**

et al. 2022

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“…Triplet energy transfer (EnT) photocatalysis promotes a broad range of valuable chemical transformations including cycloadditions, electrocyclic reactions, deracemizations, migrations, and rearrangements, many of which are not accessible from the ground state. [1][2][3][4][5][6][7][8] Photons offer a convenient and tuneable source of energy to selectively access reactive excited state intermediates under mild reaction conditions. Perhaps the most prominent class of photochemical reactions are [2+2]cycloadditions, which construct cyclobutanes, oxetanes and azetidines.…”

Section: Introductionmentioning

confidence: 99%

A Designed Photoenzyme Promotes Enantioselective [2+2]-Cycloadditions via Triplet Energy Transfer

Trimble

Crawshaw

Hardy

et al. 2022

Preprint

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The ability to programme new modes of catalysis into proteins would allow the development of enzyme families with functions beyond those found in nature. To this end, genetic code expansion methodology holds particular promise, as it allows the site-selective introduction of new functional elements into proteins as non-canonical amino acid side chains. Here, we exploit an expanded genetic code to develop a photoenzyme that operates via triplet energy transfer catalysis, a versatile mode of reactivity in organic synthesis that is currently not accessible to biocatalysis. Installation of a genetically encoded photosensitiser into the beta-propeller scaffold of DA_20_00 converts a de novo Diels-Alderase into a photoenzyme for [2+2]-cycloadditions (EnT1.0). Subsequent development and implementation of a platform for photoenzyme evolution afforded an efficient and enantioselective enzyme (EnT1.3, up to 99% e.e.) that can promote selective cycloadditions that have proven challenging to achieve with small molecule catalysts. EnT1.3 performs >300 turnovers and, in contrast to small molecule photocatalysts, can operate effectively under aerobic conditions. A 1.7 Å resolution X-ray crystal structure of an EnT1.3-product complex shows how multiple functional components work in synergy to promote efficient and selective photocatalysis. This study opens the door to a wealth of new excited-state chemistry in protein active sites and establishes the framework for developing a new generation of evolvable photocatalysts with efficiencies and specificities akin to natural enzymes.

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“…However, in stark contrast to the numerous sp 3 -rich bioisosteres for ortho-and para-substituted arenes (7)(8)(9)11), a geometrically-accurate bioisostere for meta-arenes is yet to be discovered. Recent reports on the use of (hetero)bicyclo[2.1.1]hexanes (12)(13)(14)(15)(16) and bridge-substituted BCPs (17)(18)(19) have contributed to this arena (Fig. 1B).…”

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confidence: 99%

Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane

Frank

Nugent

Shire

et al. 2022

Preprint

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Small-ring cage hydrocarbons are common bioisosteres for para-substituted benzene rings in drug design, exhibiting superior pharmacokinetic properties compared to the parent aromatics. In contrast, scaffolds mimicking meta-substituted arenes are lacking due to the challenge of synthesising saturated isosteres that accurately reproduce the substituent vectors of the corresponding arene. Here we report the use of [3.1.1]propellane as a convenient and scalable precursor to bicyclo[3.1.1]heptanes (BCHeps), hydrocarbons whose bridgehead substituents map precisely onto the geometry of meta-substituted benzenes. This precursor undergoes a range of radical-based transformations to generate medicinally-relevant carbon- and heteroatom-substituted BCHeps, including BCHep pharmaceutical analogues. Comparison of ADME properties of the latter reveals improved metabolic stability relative to their parent drugs, validating the potential of this meta-arene analogue as an sp3-rich motif in drug design.

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Intermolecular [2π+2σ]-photocycloaddition enabled by triplet energy transfer

Cited by 147 publications

References 47 publications

Beyond Bioisosteres: Divergent Synthesis of Azabicyclohexanes and Cyclobutenyl Amines from Bicyclobutanes**

Beyond Bioisosteres: Divergent Synthesis of Azabicyclohexanes and Cyclobutenyl Amines from Bicyclobutanes**

A Designed Photoenzyme Promotes Enantioselective [2+2]-Cycloadditions via Triplet Energy Transfer

Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane

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