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. 2015 Mar 11;137(9):3338-51.
doi: 10.1021/ja512690x. Epub 2015 Mar 3.

Ligand-enabled β-C-H arylation of α-amino acids using a simple and practical auxiliary

Gang Chen  1 , Toshihiko Shigenari, Pankaj Jain, Zhipeng Zhang, Zhong Jin, Jian He, Suhua Li, Claudio Mapelli, Michael M Miller, Michael A Poss, Paul M Scola, Kap-Sun Yeung, Jin-Quan Yu
Affiliations

Ligand-enabled β-C-H arylation of α-amino acids using a simple and practical auxiliary

Gang Chen et al. J Am Chem Soc. .

Abstract

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.

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Figures

Figure 1
Figure 1
Advantages and disadvantages of different directing groups developed in our laboratory
Figure 2
Figure 2
Synthetic applications
Scheme 1
Scheme 1
Preliminary Discovery for Ligand-Promoted C–H Arylation
Scheme 2
Scheme 2
Removal of the Directing Group
Scheme 3
Scheme 3
Removal of the Directing Group
Scheme 4
Scheme 4
Gram-Scale Synthesis of Unnatural Amino Acids 7–9
Scheme 5
Scheme 5
Gram-Scale Synthesis of Unnatural amino Amino Acids 10–13
Scheme 6
Scheme 6
Application to Synthesis of a Variety of Biologically Active Compounds
Scheme 7
Scheme 7
Synthesis of PyBOX and BOX Ligands
See this image and copyright information in PMC

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