Bidentate Directing Groups: An Efficient Tool in C–H Bond Functionalization Chemistry for the Expedient Construction of C–C Bonds

Rej, Supriya; Ano, Yusuke; Chatani, Naoto

doi:10.1021/acs.chemrev.9b00495

Cited by 747 publications

(322 citation statements)

References 663 publications

Supporting

Mentioning

318

Contrasting

Unclassified

Order By: Relevance

“…Transition metal-catalyzed C-H functionalization can promote the reaction of unactivated C(sp 3 )-H bonds with the aid of a directing group [21][22][23][24][25][26] . Here, C-H functionalization enabled installation of the appropriate aryl group on the pre-existing piperidine ring 27 , providing an attractive and short route to vary this functionality with inherent control of enantiomeric excess.…”

Section: Resultsmentioning

confidence: 99%

Chemical and structural investigation of the paroxetine-human serotonin transporter complex

Coleman

Navratna

Antermite

et al. 2020

eLife

View full text Add to dashboard Cite

Antidepressants target the serotonin transporter (SERT) by inhibiting serotonin reuptake. Structural and biochemical studies aiming to understand binding of small-molecules to conformationally dynamic transporters like SERT often require thermostabilizing mutations and antibodies to stabilize a specific conformation, leading to questions about relationships of these structures to the bonafide conformation and inhibitor binding poses of wild-type transporter. To address these concerns, we determined the structures of ∆N72/∆C13 and ts2-inactive SERT bound to paroxetine analogues using single-particle cryo-EM and x-ray crystallography, respectively. We synthesized enantiopure analogues of paroxetine containing either bromine or iodine instead of fluorine. We exploited the anomalous scattering of bromine and iodine to define the pose of these inhibitors and investigated inhibitor binding to Asn177 mutants of ts2-active SERT. These studies provide mutually consistent insights into how paroxetine and its analogues bind to the central substrate-binding site of SERT, stabilize the outward-open conformation, and inhibit serotonin transport.

show abstract

Section: Resultsmentioning

confidence: 99%

Chemical and structural investigation of the paroxetine-human serotonin transporter complex

Coleman

Navratna

Antermite

et al. 2020

eLife

View full text Add to dashboard Cite

show abstract

Section: Resultsmentioning

confidence: 99%

Chemical and structural investigation of the paroxetine-human serotonin transporter complex

Coleman

Navratna

Antermite

et al. 2020

Preprint

View full text Add to dashboard Cite

Antidepressants target the serotonin transporter (SERT) by inhibiting serotonin reuptake.Structural and biochemical studies aiming to understand the binding of small-molecules to conformationally dynamic transporters like SERT often require thermostabilizing mutations and antibodies to stabilize a specific conformation. Such modifications to SERT have led to questions about the relationships of these structures to the bona fide conformation and inhibitor binding poses of the wild-type transporter. To address these concerns, we characterized wildtype SERT with truncated N-and C-termini and thermostabilized variants of SERT bound with paroxetine using x-ray crystallography, single particle cryo-EM and biochemical techniques.Moreover, using a C-H functionalization approach to synthesize enantiopure analogues, we replaced the halide of the fluorophenyl group in paroxetine with either bromine or iodine. We then exploited the anomalous scattering of Br and I to define the pose of the respective paroxetine analog. These structures provide mutually consistent insights into how paroxetine and its analogs bind to the central substrate-binding site of SERT, stabilize the outward-open conformation, and inhibit serotonin transport.

show abstract

“…As a generic prototype of (di)nitrogen-directing moieties, we have selected 6-phenyl-2,2′-bipyridine (HPhbpy), rendering the protocol suitable for a wide range of bidentate and tridentate ligands. Bidentate directional group assisted C-H activations have recently gained high interest in organometallic catalysis [36,37,[42][43][44][45]. In a thorough and comprehensive scan of the reaction conditions (solvent; counter ion; temperature; external base(s); Schemes 2 and 3) we identified the combination of high-boiling nonpolar solvents and acetate/carbonate as a homogeneous/heterogeneous base couple to enable rather rapid and very efficient nickelation.…”

Section: Introductionmentioning

confidence: 99%

Direct Base-Assisted C‒H Cyclonickelation of 6-Phenyl-2,2′-bipyridine

et al. 2020

View full text Add to dashboard Cite

The organonickel complexes [Ni(Phbpy)X] (X = Br, OAc, CN) were obtained for the first time in a direct base-assisted arene C(sp2)–H cyclometalation reaction from the rather unreactive precursor materials NiX2 and HPhbpy (6-phenyl-2,2′-bipyridine) or from the versatile precursor [Ni(HPhbpy)Br2]2. Different from previously necessary C‒Br oxidative addition at Ni(0), an extended scan of reaction conditions allowed quantitative access to the title compound from Ni(II) on synthetically useful timescales through base-assisted C‒H activation in nonpolar media at elevated temperature. Optimisation of the reaction conditions (various bases, solvents, methods) identified 1:2 mixtures of acetate and carbonate as unrivalled synergetic base pairs in the optimum protocol that holds promise as a readily usable and easily tuneable access to a wide range of direct nickelation products. While for the base-assisted C‒H metalation of the noble metals Ru, Ir, Rh, or Pd, this acetate/carbonate method has been established for a few years, our study represents the leap into the world of the base metals of the 3d series.

show abstract

Bidentate Directing Groups: An Efficient Tool in C–H Bond Functionalization Chemistry for the Expedient Construction of C–C Bonds

Cited by 747 publications

References 663 publications

Chemical and structural investigation of the paroxetine-human serotonin transporter complex

Chemical and structural investigation of the paroxetine-human serotonin transporter complex

Chemical and structural investigation of the paroxetine-human serotonin transporter complex

Direct Base-Assisted C‒H Cyclonickelation of 6-Phenyl-2,2′-bipyridine

Contact Info

Product

Resources

About