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. 2020 May 22;11(1):2559.
doi: 10.1038/s41467-020-16486-0.

Activation of allylic esters in an intramolecular vinylogous kinetic resolution reaction with synergistic magnesium catalysts

Dan Li  1 , Yuling Yang  1 , Minmin Zhang  1 , Linqing Wang  1 , Yingfan Xu  1 , Dongxu Yang  2 , Rui Wang  3
Affiliations

Activation of allylic esters in an intramolecular vinylogous kinetic resolution reaction with synergistic magnesium catalysts

Dan Li et al. Nat Commun. .

Abstract

Kinetic resolution (KR) of racemic starting materials is a powerful and practical alternative to prepare valuable enantiomerically enriched compounds. A magnesium-catalyzed kinetic resolution based on a designed intramolecular vinylogous Michael reaction is disclosed. Here we show a synergistic catalytic strategy based on the development of chiral ligands. Substrates containing linear allylic ester structures are designed and synthesized to construct key [6.6.5]-tricyclic chiral skeletons via this kinetic resolution process. Detailed mechanistic studies reveal a rational mechanism for the current intramolecular vinylogous KR reaction. The desired direct intramolecular asymmetric vinylogous Michael reaction of linear allylic esters is realized in high efficiency and enantioselectivity with the synergistic catalytic system.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Reaction design and related compounds containing the key [6.6.5]-tricyclic skeletons.
a Synergistic catalytic strategy for the direct intramolecular asymmetric vinylogous Michael reaction. b Related natural products and pharmaceutically active compounds containing the tricyclic skeletons.
Fig. 2
Fig. 2. Selection and development of bifunctional chiral ligands and related synthetic methods.
a Bifunctional chiral ligands screened in the optimization process. b Synthetic method of chiral ligand L10 and related X-ray analysis.
Fig. 3
Fig. 3. Substrate scope of the KR reaction.
See Supplementary Information for the detail experiment processes. All yields shown were based on isolated products. er values were determined by chiral HPLC analysis. s = ln[(1 − C)(1 − ee)]/ln[(1 − C)(1 + ee)], where ee = ee1a*/100, ee1a* = (R1a* – S1a*)/(R1a* + S1a*)*100, C is monitored by HPLC analysis and calculated according to C = ee1a*/(ee1a* + ee2a).
Fig. 4
Fig. 4. Further extensions of the substrate scope of the KR reaction.
All yields shown were based on isolated products. er values were determined by chiral HPLC analysis.
Fig. 5
Fig. 5. Site-selective results of the substrate 1t in the KR reaction.
Isolated yields are reported.
Fig. 6
Fig. 6. Gram scale trial and related transformation of 1a*.
a Gram scale experiments of the KR process. b Transformations of the isolated chiral allylic ester 1a*.
Fig. 7
Fig. 7. Transformations of resolution products.
Conditions: a with CuI (2.5 mol%), Pd(PPh3)4 (2.5 mol%), Et3N (2.0 equiv) in DMF at room temperature. b with PPh3 (20 mol%), Pd(OAc)2 (10 mol%), Et3N (2.0 equiv) in THF/CH3CN at room temperature. c with PPh3 (6 mol%), PdCl2(PPh3)2 (3 mol%), K2CO3 (1.5 equiv) in Dioxane at 80 °C. d with Pd(PPh3)4 (5 mol%), K2CO3 (2.0 equiv) in H2O/ Dioxane reflux for 24 h.
Fig. 8
Fig. 8. Mechanistic studies for the synergistic catalyst in the KR reaction.
a Control experiments of the KR reaction under different catalytic conditions. b Nonlinear effects studies of the KR reaction. c ESI experiments of the initial reaction complexes to investigate the activation mode.
Fig. 9
Fig. 9. Proposed mechanism.
Possible reaction mechanism for the synergistic magnesium catalyst promoted KR reaction.
See this image and copyright information in PMC

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