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Synthesis of Acyclic Aliphatic Amides with Contiguous Stereogenic Centers via Palladium‐Catalyzed Enantio‐, Chemo‐ and Diastereoselective Methylene C(sp 3 )−H arylation
Author(s) -
Han YeQiang,
Yang Xu,
Kong KeXin,
Deng YaoTing,
Wu LeSong,
Ding Yi,
Shi BingFeng
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202008952
Subject(s) - stereocenter , methylene , chemistry , enantioselective synthesis , stereochemistry , palladium , catalysis , aryl , combinatorial chemistry , medicinal chemistry , organic chemistry , alkyl
The enantioselective desymmetrizing C−H activation of α‐ gem ‐dialkyl acyclic amides remains challenging because the availability of four chemically identical unbiased methylene C(sp 3 )−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 Pd II ‐catalyzed asymmetric arylation of unbiased methylene C(sp 3 )−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‐Ar 1 ‐β′‐Ar 2 ‐aliphatic acyclic amides containing three contiguous stereogenic centers with excellent diastereoselectivity.