150255-96-2Relevant articles and documents
Novel, Self-Assembling Dimeric Inhibitors of Human β Tryptase
Giardina, Sarah F.,Werner, Douglas S.,Pingle, Maneesh,Feinberg, Philip B.,Foreman, Kenneth W.,Bergstrom, Donald E.,Arnold, Lee D.,Barany, Francis
, p. 3004 - 3027 (2020/04/17)
β-Tryptase, a homotetrameric serine protease, has four identical active sites facing a central pore, presenting an optimized setting for the rational design of bivalent inhibitors that bridge two adjacent sites. Using diol, hydroxymethyl phenols or benzoyl methyl hydroxamates, and boronic acid chemistries to reversibly join two [3-(1-acylpiperidin-4-yl)phenyl]methanamine core ligands, we have successfully produced a series of self-assembling heterodimeric inhibitors. These heterodimeric tryptase inhibitors demonstrate superior activity compared to monomeric modes of inhibition. X-ray crystallography validated the dimeric mechanism of inhibition, and compounds demonstrated high selectivity against related proteases, good target engagement, and tryptase inhibition in HMC1 xenograft models. Screening 3872 possible combinations from 44 boronic acid and 88 diol derivatives revealed several combinations that produced nanomolar inhibition, and seven unique pairs produced greater than 100-fold improvement in potency over monomeric inhibition. These heterodimeric tryptase inhibitors demonstrate the power of target-driven combinatorial chemistry to deliver bivalent drugs in a small molecule form.
Bedford-type palladacycle-catalyzed miyaura borylation of aryl halides with tetrahydroxydiboron in water
Zernickel, Anna,Du, Weiyuan,Ghorpade, Seema A.,Sawant, Dinesh N.,Makki, Arwa A.,Sekar, Nagaiyan,Eppinger, J?rg
, p. 1842 - 1851 (2018/02/23)
A mild aqueous protocol for palladium catalyzed Miyaura borylation of aryl iodides, aryl bromides and aryl chlorides with tetrahydroxydiboron (BBA) as a borylating agent is developed. The developed methodology requires low catalyst loading of Bedford-type palladacycle catalyst (0.05 mol %) and works best under mild reaction conditions at 40 °C in short time of 6 h in water. In addition, our studies show that for Miyaura borylation using BBA in aqueous condition, maintaining a neutral reaction pH is very important for reproducibility and higher yields of corresponding borylated products. Moreover, our protocol is applicable for a broad range of aryl halides, corresponding borylated products are obtained in excellent yields up to 93% with 29 examples demonstrating its broad utility and functional group tolerance.
Nickel-catalyzed borylation of halides and pseudohalides with tetrahydroxydiboron [B2(OH)4]
Molander, Gary A.,Cavalcanti, Livia N.,Garcia-Garcia, Carolina
, p. 6427 - 6439 (2013/07/26)
Arylboronic acids are gaining increased importance as reagents and target structures in a variety of useful applications. Recently, the palladium-catalyzed synthesis of arylboronic acids employing the atom-economical tetrahydroxydiboron (BBA) reagent has been reported. The high cost associated with palladium, combined with several limitations of both palladium- and copper-catalyzed processes, prompted us to develop an alternative method. Thus, the nickel-catalyzed borylation of aryl and heteroaryl halides and pseudohalides using tetrahydroxydiboron (BBA) has been formulated. The reaction proved to be widely functional group tolerant and applicable to a number of heterocyclic systems. To the best of our knowledge, the examples presented here represent the only effective Ni-catalyzed Miyaura borylations conducted at room temperature.
COFERONS AND METHODS OF MAKING AND USING THEM
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Page/Page column 207, (2012/12/13)
The present invention is directed to a monomer useful in preparing therapeutic compounds. The monomer includes one or more pharmacophores which potentially binds to a target molecule with a dissociation constant of less than 300 μM and a linker element connected to the pharmacophore. The linker element has a molecular weight less than 500 daltons, is connected, directly or indirectly through a connector, to the pharmacophore.
Scope of the palladium-catalyzed aryl borylation utilizing bis-boronic acid
Molander, Gary A.,Trice, Sarah L. J.,Kennedy, Steven M.,Dreher, Spencer D.,Tudge, Matthew T.
supporting information; experimental part, p. 11667 - 11673 (2012/09/05)
The Suzuki-Miyaura reaction has become one of the more useful tools for synthetic organic chemists. Until recently, there did not exist a direct way to make the most important component in the coupling reaction, namely the boronic acid. Current methods to make boronic acids often employ harsh or wasteful reagents to prepare boronic acid derivatives and require additional steps to afford the desired boronic acid. The scope of the previously reported palladium-catalyzed, direct boronic acid synthesis is unveiled, which includes a wide array of synthetically useful aryl electrophiles. It makes use of the newly available second generation Buchwald XPhos preformed palladium catalyst and bis-boronic acid. For ease of isolation and to preserve the often sensitive C-B bond, all boronic acids were readily converted to their more stable trifluoroborate counterparts.
Palladium-catalyzed borylation of aryl and heteroaryl halides utilizing tetrakis(dimethylamino)diboron: One step greener
Molander, Gary A.,Trice, Sarah L. J.,Kennedy, Steven M.
supporting information, p. 4814 - 4817,4 (2012/12/12)
The palladium-catalyzed borylation of aryl and heteroaryl halides with a novel borylating agent, tetrakis(dimethylamino)diboron [(Me2N) 2B-B(NMe2)2], is reported. The method is complementary to the previously reported method utilizing bis-boronic acid (BBA) in that certain substrates perform better under one set of optimized reaction conditions than the other. Because tetrakis(dimethylamino)diboron is the synthetic precursor to both BBA and bis(pinacolato)diboron (B 2Pin2), the new method represents a more atom-economical and efficient approach to current borylation methods.
A practical and cost-efficient, one-pot conversion of aldehydes into nitriles mediated by 'activated DMSO'
Augustine, John Kallikat,Bombrun, Agnes,Atta, Rajendra Nath
, p. 2223 - 2227 (2011/10/31)
Participation of activated DMSO in the one-pot transformation of aldehydes to nitriles has been described by reacting aldehydes with NHHHCl in DMSO in the absence of any added base or catalyst. The method is applicable to access a wide range of aromatic, heterocyclic, and aliphatic nitriles, in which only water is a byproduct. A straightforward and practical procedure is demonstrated on a multigram scale. Georg Thieme Verlag Stuttgart - New York.
Lithium aminoborohydrides 17. Palladium catalyzed borylation of aryl iodides, bromides, and triflates with diisopropylaminoborane prepared from lithium diisopropylaminoborohydride
Haddenham, Dustin,Bailey, Christopher L.,Vu, Chau,Nepomuceno, Gabby,Eagon, Scott,Pasumansky, Lubov,Singaram, Bakthan
experimental part, p. 576 - 583 (2011/03/18)
The Alcaraz-Vaultier borylation of aryl halides and triflates is reported utilizing diisopropylaminoborane (BH2N(iPr)2) prepared from the corresponding lithium aminoborohydride (LAB reagent). BH 2N(iPr)2, prepared by reacting lithium diisopropylaminoborohydride with trimethylsilyl chloride, provided the most consistent isolated yields from this reaction. Catalytic amounts of palladium dichloride produced the highest yields from aryl iodides, while catalytic tris(dibenzylideneacetone)dipalladium(chloroform) provided the best yields for aryl bromides and triflates. This route to boronic acids is mild enough to tolerate various functionalities and for the first time employs aryl triflates as substrates for the Alcaraz-Vaultier borylation. In addition, it was found that both boronic acid and ester compounds could be isolated from the reaction mixture utilizing simple work-up procedures. Treatment of the reaction intermediate with an acid/base work-up provided the corresponding boronic acid, while treating the same intermediate with a diol, such as neopentyl glycol, afforded the corresponding boronic ester.
Substituent effects on aryltrifluoroborate solvolysis in water: Implications for Suzuki-Miyaura coupling and the design of stable 18F-labeled aryltrifluoroborates for use in PET imaging
Ting, Richard,Harwig, Curtis W.,Lo, Justin,Li, Ying,Adam, Michael J.,Ruth, Thomas J.,Petrin, David M.
, p. 4662 - 4670 (2008/09/20)
(Chemical Equation Presented) Whereas electron withdrawing substituents retard the rate of aryltrifluoroborate solvolysis, electron-donating groups enhance it. Herein is presented a Hammett analysis of the solvolytic lability of aryltrifluoroborates where log(Ksolv) values correlate to a values with a ρ value of approximately -1. This work provides a predictable rubric for tuning the reactivity of boron for several uses including 18F-labeled PET reagents and has mechanistic implications for ArBF3-enhanced ligandless metal-mediated cross coupling reactions with aryltrifluoroborates.
Noncryogenic I/Br-Mg exchange of aromatic halides bearing sensitive functional groups using i-PrMgCl-Bis[2-(N,N-dimethylamino)ethyl] ether complexes
Wang, Xiao-Jun,Sun, Xiufeng,Zhang, Li,Xu, Yibo,Krishnamurthy, Dhileepkumar,Senanayake, Chris H.
, p. 305 - 307 (2007/10/03)
Iodo- and bromoaromatics bearing sensitive carboxylic ester and cyano groups underwent a selective halide-magnesium exchange with isopropylmagnesium chloride at ambient temperature in the presence of bis[2-(N,N-dimethylamino) ethyl] ether to afford the corresponding Grignard reagents. The newly formed reactive Grignard reagents were allowed to react with electrophiles such as trimethylborate to afford arylboronic acids in good to excellent yields.
