Recent Advances in Divergent Synthetic Strategies for Indole-Based Natural Product Libraries

Abstract

Considering the potential bioactivities of natural product and natural product-like compounds with highly complex and diverse structures, the screening of collections and small-molecule libraries for high-throughput screening (HTS) and high-content screening (HCS) has emerged as a powerful tool in the development of novel therapeutic agents. Herein, we review the recent advances in divergent synthetic approaches such as complexity-to-diversity (Ctd) and biomimetic strategies for the generation of structurally complex and diverse indole-based natural product and natural product-like small-molecule libraries.

Complexity‐to‐Diversity and Pseudo‐Natural Product Strategies as Powerful Platforms for Deciphering Next‐Generation Therapeutics

“…[84][85][86] Huigens et al employed different ring distortion pathways using this NP, which led to the generation of a pilot collection of stereochemically and skeletally diverse scaffolds (Scheme 2). [37,87] In the presence of methyl propionate, the tertiary amine moiety of vincamine (8) induced ring cleavage affording compound 9 (Scheme 2). Another chemoselective ring cleavage was employed on compound 8 generating compound 10.…”

“…It focuses on utilizing simple starting materials to construct a collection of small molecules possessing NP-like core structures, employing step-economic synthetic transformations (Figure 2). [3,[34][35][36][37][38][39][40][41] Over the past two decades, DOS contributed to important discoveries in the DD field, such contributions included the introduction of privileged scaffolds or "chemical navigators" by Evans et al which widened the scope of DOS (Figure 3). [42][43][44][45] Moreover, to engage DOS libraries with biologically relevant chemical space, Waldmann et.…”

“…It focuses on utilizing simple starting materials to construct a collection of small molecules possessing NP‐like core structures, employing step‐economic synthetic transformations (Figure 2). [3,34–41] …”

Ruthenium-Catalyzed Oxidative Synthesis of N-(2-triazine)indoles by C-H Activation

“…Indoles are one of the most important nitrogen heterocycles in medicinal chemistry, natural products, and organic synthesis [1][2][3][4][5][6][7]. Additionally, indoles are termed privileged motifs because of their excellent biological activities and applications in drug discovery.…”

“…(2,3-bis(4-chlorophenyl)-1H-indol-1-yl)-N,N-dimethyl-1,3,5-triazin-2-amine (3o) White solid, yield 154.2 mg (67%), m.p: 173.9-174.5• C; 1 H NMR (400 MHz, CDCl 3 ) δ 8.58 (s, 1H, CH), 8.57 (d, J = 7.8 Hz, 1H, Ar-H), 7.59 (dd, J = 7.8, 0.7 Hz, 1H, Ar-H), 7.40 (t, J = 7.8 Hz, 1H, Ar-H), 7.34-7.29 (m, 3H, Ar-H), 7.26 (d, J = 8.5 Hz, 2H, Ar-H), 7.23-7.18 (m, 2H, Ar-H), 7.14 (d, J = 8.5 Hz, 2H, Ar-H), 3.16 (s, 3H, N-CH 3 ), 2.55 (s, 3H, N-CH 3 ); 13 C NMR (100 MHz, CDCl 3 ) δ 165.9, 163.6, 162.7, 136.9, 134.7, 133.1, 132.7, 132.4, 131.9, 131.5, 131.4, 129.3, 128.6, 128.2, 124.7, 123.0, 121.5, 119.4, 115.3, 36.5, 35.6; HRMS (ESI) [M + H] + , calcd for C 25 H 20 N 5 Cl 2 : 460.1096, found: 460.1104.4-(2,3-bis(4-fluorophenyl)-1H-indol-1-yl)-N,N-dimethyl-1,3,5-triazin-2-amine (3p) White solid, yield 149.6 mg (70%), m.p: 175.8-176.5 • C; 1 H NMR (400 MHz, CDCl 3 ) δ 8.60-8.53 (m, 2H, Ar-H, CH), 7.58 (d, J = 7.7 Hz, 1H, Ar-H), 7.45-7.35 (m, 1H, Ar-H), 7.32-7.29 (m, 1H, Ar-H), 7.26-7.20 (m, 2H, Ar-H), 7.20-7.15 (m, 2H, Ar-H), 7.07-7.01 (m, 2H, Ar-H), 7.00-6.94 (m, 2H, Ar-H) 3.16 (s, 3H, N-CH 3 ), 2.57 (s, 3H, N-CH 3 ); 13 C NMR (100 MHz, CDCl 3 ) δ 166.0, 163.8, 162.8, 161.9 (d, J = 246.9 Hz, C-F); 161.7 (d, J = 246.0 Hz, C-F); 136.7, 134.9, 131.8, 131.7, 130.0 (d, J = 3.5 Hz, C-F), 129.6, 129.5 (d, J = 3.3 Hz, C-F), 124.5, 122.9, 121.4, 119.4, 115.3 (d, J = 21.4 Hz, C-F), 115.2, 114.9 (d, J = 21.6 Hz, C-F), 36.5, 35.7; HRMS (ESI) [M + H] + , calcd for C 25 H 20 N 5 F 2 : 428.1687, found: 428.1694. 4-(2,3-di(thiophen-2-yl)-1H-indol-1-yl)-N,N-dimethyl-1,3,5-triazin-2-amine (3q) White solid, yield 90.6 mg (45%), m.p: 186.1-186.9 • C; 1 H NMR (400 MHz, CDCl 3 ) δ 8.59 (s, 1H, CH), 8.51 (d, J = 8.4 Hz, 1H, Ar-H), 7.85 (d, J = 7.8 Hz, 1H, Ar-H), 7.44-7.37 (m, 2H, Ar-H), 7.36-7.33 (m, 1H, thiazole-H), 7.31 (dd, J = 5.1, 1.0 Hz, 1H, thiazole-H), 7.13 (dd, J = 3.6, 1.0 Hz, 1H, thiazole-H), 7.10-7.07 (m, 1H, thiazole-H), 7.06 (dd, J = 3.6, 1.3 Hz, 1H, thiazole-H), 7.03 (dd, J = 5.1, 3.5 Hz, 1H, thiazole-H), 3.18 (s, 3H, N-CH 3 ), 2.72 (s, 3H, N-CH 3 ); 13 C NMR (100 MHz, CDCl 3 ) δ 166.2, 164.3, 162.7, 136.7, 134.7, 134.4, 129.5, 129.0, 128.8, 127.1, 126.8, 126.7, 125.4, 124.9, 122.9, 120.0, 117.5, 115.0, 36.5, 35.9.…”