- Ligand-enabled β-C-H arylation of α-amino acids using a simple and practical auxiliary
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Pd-catalyzed β-C-H functionalizations of carboxylic acid derivatives using an auxiliary as a directing group have been extensively explored in the past decade. In comparison to the most widely used auxiliaries in asymmetric synthesis, the simplicity and practicality of the auxiliaries developed for C-H activation remains to be improved. We previously developed a simple N-methoxyamide auxiliary to direct β-C-H activation, albeit this system was not compatible with carboxylic acids containing α-hydrogen atoms. Herein we report the development of a pyridine-type ligand that overcomes this limitation of the N-methoxyamide auxiliary, leading to a significant improvement of β-arylation of carboxylic acid derivatives, especially α-amino acids. The arylation using this practical auxiliary is applied to the gram-scale syntheses of unnatural amino acids, bioactive molecules, and chiral bis(oxazoline) ligands.
- Chen, Gang,Shigenari, Toshihiko,Jain, Pankaj,Zhang, Zhipeng,Jin, Zhong,He, Jian,Li, Suhua,Mapelli, Claudio,Miller, Michael M.,Poss, Michael A.,Scola, Paul M.,Yeung, Kap-Sun,Yu, Jin-Quan
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supporting information
p. 3338 - 3351
(2015/03/30)
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- LIGAND-CONTROLLED C(SP3)-H ARYLATION AND OLEFINATION IN SYNTHESIS OF UNNATURAL CHIRAL ALPHA AMINO ACIDS
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The use of ligands to tune the reactivity and selectivity of transition metal-catalysts for C(-sp3)-H bond functionalization is a central challenge in synthetic organic chemistry. Herein, we report a rare example of catalyst-controlled C(sp3)-H arylation using pyridine and quinoline derivatives: the former promotes exclusive monoarylation, whereas the latter activates the catalyst further to achieve diarylation. Successive application of these ligands enables the sequential diarylation of a methyl group in an alanine derivative with two different aryl iodides, affording a wide range of β-Ar-p-Ar ' -cc-amino acids with excellent levels of diastereoselectivity (d.r. > 20:1). Both configurations of the β-chiral center can be accessed by choosing the order in which the aryl groups are installed. The use of a quinoline derivative as a ligand also enables C(sp3)-H olefination of a protected alanine.
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Page/Page column 263
(2015/10/05)
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