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. 2017 Apr 1;8(4):2904-2913.
doi: 10.1039/c7sc00009j. Epub 2017 Jan 30.

Racemic hemiacetals as oxygen-centered pronucleophiles triggering cascade 1,4-addition/Michael reaction through dynamic kinetic resolution under iminium catalysis. Development and mechanistic insights

Ane Orue  1 , Uxue Uria  1 , David Roca-López  2 , Ignacio Delso  3 , Efraím Reyes  1 , Luisa Carrillo  1 , Pedro Merino  2 , Jose L Vicario  1
Affiliations

Racemic hemiacetals as oxygen-centered pronucleophiles triggering cascade 1,4-addition/Michael reaction through dynamic kinetic resolution under iminium catalysis. Development and mechanistic insights

Ane Orue et al. Chem Sci. .

Abstract

2-Hydroxydihydropyran-5-ones behave as excellent polyfunctional reagents able to react with enals through oxa-Michael/Michael process cascade under the combination of iminium and enamine catalysis. These racemic hemiacetalic compounds are used as unconventional O-pronucleophiles in the initial oxa-Michael reaction, also leading to the formation of a single stereoisomer under a dynamic kinetic resolution (DKR) process. Importantly, by using β-aryl or β-alkyl substituted α,β-unsaturated substrates as initial Michael acceptors either kinetically or thermodynamically controlled diastereoisomers were formed with high stereoselection through the careful selection of the reaction conditions. Finally, a complete experimental and computational study confirmed the initially proposed DKR process during the catalytic oxa-Michael/Michael cascade reaction and also explained the kinetic/thermodynamic pathway operating in each case.

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Figures

Scheme 1
Scheme 1. Organocatalytic cascade processes initiated by conjugate addition of O-nucleophiles.
Scheme 2
Scheme 2. Enantioselective oxa-Michael/Michael cascade reaction between enals and hydroxypyranone 1.
Scheme 3
Scheme 3. Survey of transformations carried out on adducts 4, 5 and 6.
Fig. 1
Fig. 1. Linear correlation between %ee of catalyst 3a and product 6a.
Scheme 4
Scheme 4. Calculated catalytic cycle for the model reaction between 1 and 2a catalyzed by pyrrolidine (achiral model).
Fig. 2
Fig. 2. Energy diagram of the catalytic cycle illustrated in Scheme 4.
Fig. 3
Fig. 3. TS structures leading to compounds 4 and 5.
Scheme 5
Scheme 5. Possible intermediates involved in the kinetic resolution process.
Scheme 6
Scheme 6. Study of the resolution process.
Scheme 7
Scheme 7. Proposed catalytic cycles for DKR.
See this image and copyright information in PMC

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