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. 2020 Sep 7;11(45):12282-12288.
doi: 10.1039/d0sc03935g.

Merging C(sp3)-H activation with DNA-encoding

Zhoulong Fan  1 , Shuai Zhao  1 , Tao Liu  1 , Peng-Xiang Shen  1 , Zi-Ning Cui  1 , Zhe Zhuang  1 , Qian Shao  1 , Jason S Chen  2 , Anokha S Ratnayake  3 , Mark E Flanagan  3 , Dominik K Kölmel  3 , David W Piotrowski  3 , Paul Richardson  4 , Jin-Quan Yu  1
Affiliations

Merging C(sp3)-H activation with DNA-encoding

Zhoulong Fan et al. Chem Sci. .

Abstract

DNA-encoded library (DEL) technology has the potential to dramatically expedite hit identification in drug discovery owing to its ability to perform protein affinity selection with millions or billions of molecules in a few experiments. To expand the molecular diversity of DEL, it is critical to develop different types of DNA-encoded transformations that produce billions of molecules with distinct molecular scaffolds. Sequential functionalization of multiple C-H bonds provides a unique avenue for creating diversity and complexity from simple starting materials. However, the use of water as solvent, the presence of DNA, and the extremely low concentration of DNA-encoded coupling partners (0.001 M) have hampered the development of DNA-encoded C(sp3)-H activation reactions. Herein, we report the realization of palladium-catalyzed C(sp3)-H arylation of aliphatic carboxylic acids, amides and ketones with DNA-encoded aryl iodides in water. Notably, the present method enables the use of alternative sets of monofunctional building blocks, providing a linchpin to facilitate further setup for DELs. Furthermore, the C-H arylation chemistry enabled the on-DNA synthesis of structurally-diverse scaffolds containing enriched C(sp3) character, chiral centers, cyclopropane, cyclobutane, and heterocycles.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. Exploiting diversity of C–H activation in DELs.
Fig. 2
Fig. 2. Ligand-promoted on-DNA C–H arylation of free carboxylic acids. Unless otherwise noted, condition of entry 1 was used as the standard condition. For 2: corresponding A, 500 equiv. For 3–14, 18, 19, and 39–44: AgTFA, 300 equiv.; corresponding A, 300 equiv.; 36 h. For 15: Ag3PO4, 200 equiv.; corresponding A, 300 equiv.; 36 h. For 21: corresponding A, 300 equiv.; 36 h. For 16: AgOTf, 300 equiv.; corresponding A, 300 equiv.; 36 h. For 17: H2O/DMA (6/1).
Fig. 3
Fig. 3. On-DNA C–H arylation of amides. Unless otherwise noted, condition of entry 1 was used as the standard condition. Yields at room temperature are listed in parentheses. DMTMM, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride.
Fig. 4
Fig. 4. DNA-compatible C–H arylation of ketones. Unless otherwise noted, condition of entry 1 was used as the standard condition. For 89 and 90: Pd(OAc)2, 30 equiv.; L8, 30 equiv.; H2O/DMA (2/1).
Fig. 5
Fig. 5. The utility of multiple C–H activation in DEL synthesis. (A) Workflow for building DEL diversity through multiple C–H activation; (B) representative synthesis. Conditions: (a) A1 (1000 equiv.), Pd(OAc)2 (10 equiv.), L1 (20 equiv.), Ag2CO3 (300 equiv.), NaOAc (150 equiv.), H2O/DMA/HFIP (8/1/1), 80 °C, 16 h. (b) 4-Iodobenzylamine (300 equiv.), DMTMM (300 equiv.), phosphate buffer (pH 5.5), r.t. 16 h. (c) C10 (300 equiv.), Pd(OAc)2 (40 equiv.), L8 (40 equiv.), AgTFA (500 equiv.), NaOAc (150 equiv.), H2O/DMA (9/1), 80 °C, 20 h.
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