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. 2019 Mar 13;10(15):4339-4345.
doi: 10.1039/c8sc05612a. eCollection 2019 Apr 21.

A versatile catalyst system for enantioselective synthesis of 2-substituted 1,4-benzodioxanes

Eugene Chong  1 , Bo Qu  1 , Yongda Zhang  1 , Zachary P Cannone  1 , Joyce C Leung  1 , Sergei Tcyrulnikov  2 , Khoa D Nguyen  1 , Nizar Haddad  1 , Soumik Biswas  1 , Xiaowen Hou  1 , Katarzyna Kaczanowska  3 , Michał Chwalba  3 , Andrzej Tracz  3 , Stefan Czarnocki  3 , Jinhua J Song  1 , Marisa C Kozlowski  2 , Chris H Senanayake  1   4
Affiliations

A versatile catalyst system for enantioselective synthesis of 2-substituted 1,4-benzodioxanes

Eugene Chong et al. Chem Sci. .

Abstract

We report the synthesis of enantiomerically enriched 1,4-benzodioxanes containing alkyl, aryl, heteroaryl, and/or carbonyl substituents at the 2-position. The starting 1,4-benzodioxines were readily synthesized via ring closing metathesis using an efficient nitro-Grela catalyst at ppm levels. Excellent enantioselectivities of up to 99:1 er were obtained by using the versatile catalyst system [Ir(cod)Cl]2/BIDIME-dimer in the asymmetric hydrogenation of 2-substituted 1,4-benzodioxines. Furthermore, DFT calculations reveal that the selectivity of the process is controlled by the protonation step; and coordinating groups on the substrate may alter the interaction with the catalyst, resulting in a change in the facial selectivity.

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Figures

Fig. 1
Fig. 1. Examples of chiral 1,4-benzodioxane containing molecules.
Scheme 1
Scheme 1. Synthesis of 1,4-benzodioxines.
Scheme 2
Scheme 2. Asymmetric hydrogenation of 2-alkyl and 2-aryl-substituted 1,4-benzodioxinesa. aReaction conditions: 5 (0.2 mmol), [Ire(cod)Cl]2 (0.002 mmol), (R,R,R,R)-BIDIME-dimer L5 (0.006 mmol), THF (0.3 mL), MeOH (0.3 mL), AcOH (8 mmol, 40 equiv.), H2 (600 psi), 50 °C for 24 h. Isolated yield. Enantiomeric ratio was determined by chiral SFC or HPLC. b5f (5.0 mmol, 1.14 g), [Ir(cod)Cl]2 (0.005 mmol), L5 (0.015 mmol), THF (6 mL), MeOH (6 mL), AcOH (150 mmol, 30 equiv.), H2 (600 psi), 70 °C for 24 h. c25 °C.
Scheme 3
Scheme 3. Scope of Ir-catalyzed asymmetric hydrogenation of 2-heterocycle-substituted 1,4-benzodioxinesa. aUnless noted, standard reaction conditions: substrate 5 (0.2 mmol), [Ir(cod)Cl]2 (0.002 mmol), (R,R,R,R)-BIDIME-dimer L5 (0.006 mmol), THF (0.3 mL), MeOH (0.3 mL), AcOH (8 mmol), H2 (600 psi), 50 or 70 °C for 24 h. Isolated yield. Enantiomeric ratio was determined by chiral SFC or HPLC. b50 °C. c70 °C. d[Ir(cod)Cl]2 (2 mol%), BIDIME-dimer L5 (6 mol%).
Scheme 4
Scheme 4. Scope of Ir-catalyzed asymmetric hydrogenation of 1,4-benzodioxinesa. a Reaction conditions: 5 (0.2 moll), [Ir(cod)Cl]2 (0.002 mmol), (R,R,R,R)-BIDIME-dimer L5 (0.006 mmol), THF (0.3 mL), MeOH (0.3 mL), AcOH (8 mmol), H2 (600 psi), 50 °C for 24 h. Isolated yield. Enantiomeric ratio was determined by chiral SFC or HPLC.
Fig. 2
Fig. 2. Proposed hydrogenation mechanism. See ESI for the computational analysis of the active catalyst formation. Computational study performed for R = Me and R = CO2Me.
Fig. 3
Fig. 3. Possible solvation equilibrium and proposed protonation transition states for coordinating and non-coordinating substrates.
Fig. 4
Fig. 4. Energetics of the mode A protonation of the Me-substituted benzodioxine. Selectivity-determining conformations are shown. Free energy and enthalpy (in brackets) gaps are calculated using PBE-D2/6-311+G(d,p), Ir:LANL2DZ(f), IEFPCM-MeOH//PBE/6-31G(d), Ir:LANL2DZ. Values are in kcal mol–1. Ligand L3 was used for the calculation to minimize conformational isomers; the experimental value was taken from 6h.
Fig. 5
Fig. 5. Energetics of the mode B protonation of the CO2Me-substituted benzodioxine. Selectivity-determining conformations are shown. Free energy and enthalpy (in brackets) gaps are calculated using PBE-D2/6-311+G(d,p), Ir:LANL2DZ(f), IEFPCM-MeOH//PBE/6-31G(d), Ir:LANL2DZ. Values are in kcal mol–1. Ligand L3 was used for the calculation to minimize conformational isomers; the experimental value was taken from 6z.
Fig. 6
Fig. 6. Stereochemical models for mode A and mode B protonations. Substrate approaches for face A and face B attacks are shown in blue and red respectively.
Fig. 7
Fig. 7. Model of lowest energy mode B protonation for the 2-methoxycarbonyl-1,4-benzodioxine showing electronic stabilizing interactions (π–π and sp2CH–π interactions).
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