Privileged scaffolds for library design and drug discovery

Abstract

This review explores the concept of using privileged scaffolds to identify biologically active compounds through building chemical libraries. We hope to accomplish three main objectives: to provide one of the most comprehensive listings of privileged scaffolds; to reveal through four selected examples the present state of the art in privileged scaffold library synthesis (in hopes of inspiring new and even more creative approaches); and also to offer some thoughts on how new privileged scaffolds might be identified and exploited.

Figure 1

A potential privileged scaffold found in natural products?

Scheme 1

Synthesis of 1,4-benzodiazepine library Reagents and conditions: (a) 20% piperidine in DMF; (b) N-Fmoc-amino acid fluoride in CH₂Cl₂; (c) 5% acetic acid in DMF; (d) lithiated 5-phenylmethyl-2-oxazolidinone in DMA/THF, 1:10 (v/v); alkylating agent in DMF; (e) TFA/H₂O/Me₂S, 95:5:10 (v/v).

Scheme 2

Solid phase synthesis of 2,6,9-substituted purine library Reagents and conditions: (a) p-methoxybenzylamine, NaBH(OAc)₃, AcOH (2%), DMF, 25 °C; (b) SEM-Cl (1.2 eq), DIEA, DMF, 0→25 °C; (c) DIEA, n-BuOH-DMSO (1:1), 7; (d) TBAF (0.25 M), THF, 60 °C; (e) i-PrOH (0.5 M), DIAD (0.5 M), Ph₃P (1.0 M), THF/CH₂Cl₂ (1/1); (f) 3-amino-1-propanol, DIEA, N-methylpyrrolidinone, 110 °C; (g) TFA-H₂O (95:5), 25 °C.

Scheme 3

Two alternative solution phase routes for purine library synthesis Reagents and conditions: (a) R¹OH (2 equiv), DEAD (1.1 equiv), Ph₃P (2 equiv), THF, -10→25 °C; (b) (CF₃)₂O, CH₂Cl₂, 0→25 °C; (c) R²OH (2 equiv), DEAD (1 equiv), Ph₃P (2 equiv), THF, 0→25 °C; K₂CO₃, MeOH; (d) R3R4NH (4 equiv), DIEA, n-BuOH, 110 °C; AcOH/H₂O/THF (3/1/1); (e) R1OH (1.2 equiv), DEAD (1.3 equiv), Ph₃P (1.3 equiv), THF, -10→25 °C; (f) R²R³NH (1 equiv), DIEA, n-BuOH, 140 °C; (g) R⁴NH₂ (1.5 equiv), DIEA, n-BuOH, 150–170 °C.

Scheme 4

Synthesis of amide and amine-based 2-arylindole libraries. Reagents and conditions: (a) DIC, THF/CH₂Cl₂ followed by resin and 4-DMAP; (b) archive, mix and split resin; (c) aryl hydrazine, ZnCl₂, AcOH; (d) pentafluorobenzyl alcohol, Ph₃P, DIAD, THF; (e) R₂R₃NH; (f) polystyryl isothiocyanate resin; (g) BMS, dioxane, 50 °C; (h) HCl/MeOH, 50 °C then azeotrope.

Scheme 5

Initial aldehyde scaffold for 3,3-dimethylbenzopyran library synthesis; schemes illustrates key branching point where organometallic addition, reductive amination and Knoevangel condensation can then occur.