6301-54-8Relevant articles and documents
Conformational Studies by Dynamic Nuclear Magnetic Resonance. 59. Stereodynamics of Conformational Enantiomers in the Atropisomers of Hindered Naphthylcarbinols
Casarini, Daniele,Lunazzi, Lodovico,Mazzanti, Andrea
, p. 3315 - 3323 (1997)
Naphthyldialkylmethanols ArRR'COH (Ar = 1-naphthyl or 1-naphthyl-2-methyl) exist as a pair of atropisomers created by the restricted rotation about the Ar-COH bond.They can be detected by low-temperature NMR spectroscopy but can also be separated as stable compounds at room temperature if both the alkyl substituents are bulky tert-butyl groups (one such example is provided by compound 1, R = R' = But with Ar = 1-naphthyl).The free energies of activation (ΔG%) for the interconversion of these atropisomers were found to vary between 7.6 kcal mol-1 (as in 7, R = R' = Me, Ar = 1-naphthyl-2-methyl) and 32.9 kcal mol-1 (as in 1).The syn-periplanar (sp) or anti-periplanar (ap) structires were assigned either by means of difference NOE experiments or by taking advantage of the H-8 chemical shifts which are vastly different in the two atropisomers.Depending on the substituents the more stable species at the equilibrium can be either the sp or the ap atropisomer.When R = R' = Pri and R = R' = Et (respectively 2 and 3 if Ar = 1-naphthyl), the sp atropisomers adopt an asymmetric conformation, thus creating a pair of conformational enantiomers which interchange by rotating the isopropyl or the ethyl groups about the appropriate sp3-sp3 bonds, with ΔG% values of 7.2 and 6.1 kcal mol-1, respectively.On the contrary the corresponding 3-ap and 2-ap atropisomers adopt a symmetric (meso) conformation, as predicted by molecular mechanics calculations.In the case of R=Pri, R'=Et, and Ar=1-naphthyl (10-sp atropisomer), two asymmetric conformers were found to be appreciably populated (ratio 9:1 at -135 deg C).
Preparation of Quaternary Centers via Nickel-Catalyzed Suzuki-Miyaura Cross-Coupling of Tertiary Sulfones
Ariki, Zachary T.,Maekawa, Yuuki,Nambo, Masakazu,Crudden, Cathleen M.
supporting information, p. 78 - 81 (2018/01/17)
We describe the development of a nickel-catalyzed Suzuki-Miyaura cross-coupling of tertiary benzylic and allylic sulfones with arylboroxines. A variety of tertiary sulfones, which can easily be prepared via a deprotonation-alkylation route, were reacted to afford symmetric and unsymmetric quaternary products in good yields. We highlight the use of either BrettPhos or Doyle's phosphines as effective ligands for these challenging desulfonative coupling reactions. The utility of this methodology was demonstrated in the concise synthesis of a vitamin D receptor modulator analogue.
Discovery of flexible naphthyltriazolylmethane-based thioacetic acids as highly active uric acid transporter 1 (URAT1) inhibitors for the treatment of hyperuricemia of gout
Zhang, Xiansheng,Wu, Jingwei,Liu, Wei,Liu, Yuqiang,Xie, Yafei,Shang, Qian,Zhou, Zhixing,Xu, Weiren,Tang, Lida,Wang, Jianwu,Zhao, Guilong
, p. 260 - 281 (2017/05/31)
Background: Gout is the most common inflammatory arthritis, which, if left untreated or inadequately treated, will lead to joint destruction, bone erosion and disability due to the crystal deposition. Uric acid transporter 1 (URAT1) was the promising therapeutic target for urate-lowering therapy. Objective: The goal of this work is to understand the structure-activity relationship (SAR) of a potent lesinurad-based hit, sodium 2-((5-bromo-4-((4-cyclopropyl-naphth-1-yl)methyl)-4H-1,2,4-triazol-3-yl)thio)acetate (1c), and based on that discover a more potent URAT1 inhibitor. Methods: The SAR of 1c was systematically explored and the in vitro URAT1 inhibitory activity of synthesized compounds 1a-1t was determined by the inhibition of URAT1-mediated [8-14C]uric acid uptake by human embryonic kidney 293 (HEK293) cells stably expressing human URAT1. Results: Twenty compounds 1a-1t were synthesized. SAR analysis was performed. Two highly active URAT1 inhibitors, sodium 2-((5-bromo-4-((4-n-propylnaphth-1-yl)methyl)-4H-1,2,4-triazol-3-yl)thio)acetate (1j) and sodium 2-((5-bromo-4-((4-bromonaphth-1-yl)methyl)-4H-1,2,4-triazol-3-yl)thio)acetate (1m), were identified, which were 78- and 76-fold more active than parent lesinurad in in vitro URAT1 inhibitory assay, respectively (IC50 values for 1j and 1m were 0.092 μM and 0.094 μM, respectively, against human URAT1 vs 7.18 μM for lesinurad). Conclusion: Two highly active URAT1 inhibitors were discovered. The SAR exploration also identified more flexible naphthyltriazolylmethane as a novel molecular skeleton that will be valuable for the design of URAT1 inhibitors, as indicated by the observation that many of the synthesized naphthyltriazolylmethane-bearing derivatives (1b-1d, 1g, 1j and 1m) showed significantly improved UART1 inhibitory activity (sub-micromolar IC50 values) as compared with lesinurad which has the rigid naphthyltriazole skeleton.
