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. 2020 Nov 9;59(46):20455-20458.
doi: 10.1002/anie.202008952. Epub 2020 Sep 2.

Synthesis of Acyclic Aliphatic Amides with Contiguous Stereogenic Centers via Palladium-Catalyzed Enantio-, Chemo- and Diastereoselective Methylene C(sp3)-H arylation

Ye-Qiang Han  1 , Xu Yang  2 , Ke-Xin Kong  1 , Yao-Ting Deng  1 , Le-Song Wu  1 , Yi Ding  1 , Bing-Feng Shi  1
Affiliations

Synthesis of Acyclic Aliphatic Amides with Contiguous Stereogenic Centers via Palladium-Catalyzed Enantio-, Chemo- and Diastereoselective Methylene C(sp3)-H arylation

Ye-Qiang Han et al. Angew Chem Int Ed Engl. .

Abstract

The enantioselective desymmetrizing C-H activation of α-gem-dialkyl acyclic amides remains challenging because the availability of four chemically identical unbiased methylene C(sp3)-H bonds and increased rotational freedoms of the acyclic systems add tremendous difficulties for chemo- and stereocontrol. We have developed a method for the synthesis of acyclic aliphatic amides with α,β-contiguous stereogenic centers via PdII-catalyzed asymmetric arylation of unbiased methylene C(sp3)-H, in good yields and with high levels of enantio-, chemo- and diastereoselectivity (up to >99 % ee and >20:1 d.r.). Successive application of this method enables the sequential arylation of the gem-dialkyl groups with two different aryl iodides, giving a range of β-Ar1-β'-Ar2-aliphatic acyclic amides containing three contiguous stereogenic centers with excellent diastereoselectivity.

Keywords: chemoselectivity; contiguous stereogenic centers; diastereoselectivity; enantioselectivity; palladium.

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