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. 2022 Jun 20;61(25):e202200266.
doi: 10.1002/anie.202200266. Epub 2022 Apr 27.

Hydrogen Atom Transfer Driven Enantioselective Minisci Reaction of Alcohols

Avene C Colgan  1 , Rupert S J Proctor  1 , David C Gibson  1 , Padon Chuentragool  1 , Antti S K Lahdenperä  1 , Kristaps Ermanis  1   2 , Robert J Phipps  1
Affiliations

Hydrogen Atom Transfer Driven Enantioselective Minisci Reaction of Alcohols

Avene C Colgan et al. Angew Chem Int Ed Engl. .

Abstract

Catalytic enantioselective Minisci reactions have recently been developed but all instances so far utilize α-amino radical coupling partners. We report a substantial evolution of the enantioselective Minisci reaction that enables α-hydroxy radicals to be used, providing valuable enantioenriched secondary alcohol products. This is achieved through the direct oxidative coupling of two C-H bonds on simple alcohol and pyridine partners through a hydrogen atom transfer (HAT)-driven approach: a challenging process to achieve due to the numerous side reactions that can occur. Our approach is highly regioselective as well as highly enantioselective. Dicumyl peroxide, upon irradiation with 390 nm light, serves as both HAT reagent and oxidant whilst selectivity is controlled by use of a chiral phosphoric acid catalyst. Computational and experimental evidence provide mechanistic insight as to the origin of selectivity, revealing a stereodetermining deprotonation step distinct from the analogous reaction of amide-containing substrates.

Keywords: Asymmetric Catalysis; Chiral Phosphoric Acids; Heterocycles; Minisci Reaction; Organocatalysis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Previous work and the present study.
Scheme 1
Scheme 1
Mechanistic probe experiments.
Figure 2
Figure 2
Computational modelling results of the CPA‐catalyzed reaction steps, using a model phosphoric acid. Relative free energies shown in kcal mol−1, calculated at B2PLYPD3/def2‐TZVP[32]/SMD(ethylacetate)//M06‐2X/6‐31G**/SMD(ethylacetate).
Figure 3
Figure 3
A) Previous results from the amide Minisci computational study. B) Summary of different deprotonation modes explored for the alcohol Minsici reaction, using chiral DIP catalyst. C) Comparison of alcohol vs amide deprotonation modes and stereochemical outcome. Relative free energies shown in kcal mol−1, calculated at M06‐2X/def2‐TZVP/SMD(ethylacetate)//B3LYP/6‐31G**.
Figure 4
Figure 4
Lowest energy deprotonation TSs for the experimentally major and minor products. * Relative free energies shown calculated at M06‐2X/def2‐TZVP/SMD(ethylacetate)//B3LYP/6‐31G**/SMD(ethylacetate). ** Relative free energies shown calculated at M06‐2X/def2‐TZVP/SMD(ethylacetate)//M06‐2X/6‐31G**/SMD(ethylacetate).
Figure 5
Figure 5
NCI plots of the lowest energy deprotonation TSs for the experimentally major (a) and minor (b) products. Calculated at M06‐2X/def2‐TZVP/SMD(ethylacetate)//M06‐2X/6‐31G**/SMD(ethylacetate).
See this image and copyright information in PMC

References

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