Propylphosphonic Anhydride (T3P®)-Mediated One-Pot Rearrangement of Carboxylic Acids to Carbamates

Augustine, John Kallikat; Bombrun, Agnès; Mandal, Ashis Baran; Alagarsamy, Padma; Atta, Rajendra Nath; Selvam, Panneer

doi:10.1055/s-0030-1259964

Cited by 27 publications

(9 citation statements)

References 2 publications

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“…We hypothesized that intramolecular reaction of the intermediate isocyanate with the diazepine was leading to complications and examined alternative conditions involving the use of TMSN 3 under mild conditions. 37,38 Under these conditions JQ1-carbamoyl azide 17 was isolated, which could then be easily deprotected within minutes by employing KO t -Bu in aq. t- BuOH.…”

Section: Resultsmentioning

confidence: 99%

Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable PhotoPROTACs

et al. 2019

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Off-tissue effects are persistent issues of modern inhibition-based therapies. By merging the strategies of photopharmacology and small-molecule degraders, we introduce a novel concept for persistent spatiotemporal control of induced protein degradation that potentially prevents off-tissue toxicity. Building on the successful principle of bifunctional all-small-molecule Proteolysis Targeting Chimeras (PROTACs), we designed photoswitchable PROTACs (photoPROTACs) by including ortho-F4-azobenzene linkers between both warhead ligands. This highly bistable yet photoswitchable structural component leads to reversible control over the topological distance between both ligands. The azo-cis-isomer is observed to be inactive because the distance defined by the linker is prohibitively short to permit complex formation between the protein binding partners. By contrast, the azo-trans-isomer is active since it can engage both protein partners to form the necessary and productive ternary complex. Importantly, due to the bistable nature of the ortho-F4-azobenzene moiety employed, the photostationary state of the photoPROTAC is persistent, with no need for continuous irradiation. This technique offers reversible on/off switching of protein degradation that is compatible with an intracellular environment and, therefore, could be useful in experimental exploration of biological signaling pathways—such as those crucial for oncogenic signal transduction. Additionally, this strategy may be suitable for therapeutic intervention to address a variety of diseases. By enabling reversible activation and deactivation of protein degradation, photoPROTACs offer advantages over conventional photocaging strategies that irreversibly release active agents.

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Section: Resultsmentioning

confidence: 99%

Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable PhotoPROTACs

et al. 2019

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“…We hypothesized that intramolecular reaction of the intermediate isocyanate with the diazepine was leading to complications and examined alternative conditions involving the use of TMSN3 under mild conditions. 36,37 Under these conditions JQ1-carbamoyl azide 17 was isolated, which could then be easily deprotected within minutes by employing KOt-Bu in aq. t-BuOH.…”

Section: Results Synthetic Efforts Commenced With the Generation Of mentioning

confidence: 99%

Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable photoPROTACs

Pfaff¹,

Samarasinghe²,

Crews³

et al. 2019

Preprint

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Off-target effects are persistent issues of modern inhibition-based therapies. By merging the strategies of photopharmacology and small molecule degraders, we introduce a novel concept for persistent spatiotemporal control of induced protein degradation that potentially prevents off-target toxicity. Building on the successful principle of bifunctional all-small molecule Proteolysis Targeting Chimeras (PROTACs), we designed photoswitchable PROTACs (photoPROTACs) by including ortho-F4-azobenzene linkers between both warhead ligands. This highly bistable yet photoswitchable structural component leads to reversible control over the topological distance between both ligands. The azo-cis-isomer is observed to be inactive because the distance defined by the linker is prohibitively short to permit complex formation between the protein binding partners. By contrast, the azo-trans-isomer is active because it can engage both protein partners to form the necessary and productive ternary complex. Importantly, due to the bistable nature of the ortho-F4-azobenzene moiety employed, the photostationary state of the photoPROTAC is persistent, with no need for continuous irradiation. This technique offers reversible on/off switching of protein degradation that is compatible with an intracellular environment and, therefore, could be vastly useful in experimental probing of biological signaling pathways – especially those crucial for oncogenic signal transduction. Additionally, this strategy may be suitable for therapeutic implementation in a wide variety of disease phenotypes. By enabling reversible activation and deactivation of protein degradation, photoPROTACs offer advantages over conventional photocaging strategies that irreversibly release active agents.

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“…A new protocol for the Curtius rearrangement was reported by Augustine and co-workers describing the conversion of carboxylic acids to carbamates in the presence of propylphosphonic acid anhydride (T3P®) and azidotrimethylsilane in a single step. 63 A one-pot domino reaction for the conversion of acrylic acid derivatives to novel photochromic oxazines was developed by Zhao and Carreira. 64 Recently, Ley and co-workers developed a modular mesofluidic flow reactor for performing Curtius rearrangement as a continuous flow process.…”

Section: General Procedures For the Curtius Rearrangementmentioning

confidence: 99%

The Curtius rearrangement: mechanistic insight and recent applications in natural product syntheses

2018

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The Curtius rearrangement is a versatile reaction in which a carboxylic acid can be converted to an isocyanate through an acyl azide intermediate under mild conditions. The resulting stable isocyanate can then be readily transformed into a variety of amines and amine derivatives including urethanes and ureas. There have been wide-ranging applications of the Curtius rearrangement in the synthesis of natural products and their derivatives. Also, this reaction has been extensively utilized in the synthesis and application of a variety of biomolecules. In this review, we present mechanistic studies, chemical methodologies and reagents for the synthesis of isocyanates from carboxylic acids, the conversion of isocyanates to amines and amine derivatives, and their applications in the synthesis of bioactive natural products and their congeners.

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Propylphosphonic Anhydride (T3P®)-Mediated One-Pot Rearrangement of Carboxylic Acids to Carbamates

Cited by 27 publications

References 2 publications

Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable PhotoPROTACs

Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable PhotoPROTACs

Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable photoPROTACs

The Curtius rearrangement: mechanistic insight and recent applications in natural product syntheses

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