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.

Keywords: biomimetic synthesis; complexity-to-diversity (Ctd) strategy; diversity-oriented synthesis; indole; natural products; small-molecule library.

Figure 1

Natural products as starting points in the complexity-to-diversity (Ctd) strategy along with representative compounds generated via ring-distortion reactions.

Scheme 1

Ring distortion of yohimbine (8) for rapid access to complex and diverse indole-based natural product-like small molecules and identification of new anti-plasmodial agent compound 20.

Scheme 2

Ring distortion of vincamine (21) for rapid access to complex and diverse indole-based natural product-like small molecules and identification of a new HCRTR2 antagonist compound, 33. m-CPBA, meta-chloroperbenzoic acid; 2-I-BnOH, 2-iodobenzyl alcohol.

Scheme 3

Ctd strategy based on nature-inspired indole monoterpenoids (36 and 37). Pd/C, palladium on carbon.

Scheme 4

(a) Biosynthetic transformation of strictosidine (47), branching point of the biogenesis, and subsequent formation of monoterpenoid indole alkaloids. (b) Divergent synthetic pathways for the construction of an 847-member skeletally complex natural product-like compound library using a new biomimetic branching point, indoloquinolizidines (55).

Scheme 5

(a) Biosynthetic transformation of preakuammicine (60) via the postulated branching point, i.e., intermediate 61 to monoterpenoid indole alkaloids. (b) Biomimetic route for the preparation of monoterpenoid indole-type alkaloids via the transformation of dehydrosecodine derivatives (76–78), which act as biomimetic branching points. dppf, 1,1′-bis(diphenylphosphino)ferrocene; bpy, 2,2′-bipyridine; Teoc, 2-(trimethylsilyl)-ethoxycarbonyl.

Scheme 6

Divergent synthetic pathways to generate seven natural product and natural product-like monoterpene indole alkaloids using a new biomimetic branching point, intermediate 90. DBU, 1,8-diazabicyclo 5.4.0 undec-7-ene; DIBAL-H, diisobutylaluminium hydride; MsCl, methanesulfonyl chloride.

Scheme 7

Biomimetic routes for the preparation of various iboga and “post-iboga” alkaloids from (+)-catharanthine (63) as the biomimetic branching point. ZrCp₂HCl, bis(cyclopentadienyl)zirconium chloride hydride; DMDO, dimethyldioxirane.