Towards the optimal screening collection: a synthesis strategy

Abstract

The development of effective small-molecule probes and drugs entails at least three stages: 1) a discovery phase, often requiring the synthesis and screening of candidate compounds, 2) an optimization phase, requiring the synthesis and analysis of structural variants, 3) and a manufacturing phase, requiring the efficient, large-scale synthesis of the optimized probe or drug. Specialized project groups tend to undertake the individual activities without prior coordination; for example, contracted (outsourced) chemists may perform the first activity while in-house medicinal and process chemists perform the second and third development stages, respectively. The coordinated planning of these activities in advance of the first small-molecule screen tends not to be undertaken, and each project group can encounter a bottleneck that could, in principle, have been avoided with advance planning. Therefore, a challenge for synthetic chemistry is to develop a new kind of chemistry that yields a screening collection comprising small molecules that increase the probability of success in all three phases. Although this transformative chemistry remains elusive, progress is being made. Herein, we review a newly emerging strategy in diversity-oriented small-molecule synthesis that may have the potential to achieve these challenging goals.

Figure 1

Stereochemical diversity using the build/couple/pair strategy: the complete matrix of stereoisomeric products results from mixing and matching all stereoisomeric building blocks. The couple and pair steps may increase stereochemical diversity if new stereocenters are created, ideally with the ability to achieve all possible stereochemical outcomes selectively.

Figure 2

Skeletal diversity using the build/couple/pair strategy: in the pair phase, chemoselective and intramolecular joining of strategically positioned polar (blue), and non-polar (black) functional groups affords diverse skeletons.

Figure 3

Positioning of paired functional groups in the couple phase and performing Rh-catalyzed cycloadditions in the pair phase results in diverse skeletons containing indolizidines. The notation A → B is short for: carbonyl ylide on site A reacts with dipolarophile on site B.

Figure 4

Solid-phase, catalytic enantioselective Suga-Ibata reactions and diastereoselective enolate alkylations in the couple phase (coupling functional groups: oxazole/aldehyde; enolate/benzyl bromide) were followed by Staudinger-type reductive cyclizations in the pair phase (pairing functional groups: azide/methyl ester).

Figure 5

Solid-phase peptide deprotections and amide bond formations in the couple phase (coupling functional groups: amine/activated carboxylic acid) were followed by aldehyde-amide condensation and subsequent addition of a nucleophile to an iminium intermediate in the pair phase (pairing functional groups: N-acyliminium ion/heteroaromatic ring, aromatic ring, amine, carbamyl, amide, alcohol, thiol).

Figure 6

Fukuyama-Mitsunobu reactions in the couple phase (coupling functional groups: alcohol/N-brosyl or N-nosyl) were followed by Ru-catalyzed ring-closing metathesis reactions in the pair phase (pairing functional groups: alkene/alkene; alkene/alkyne). Diels-Alder cycloadditions were demonstrated as methods to enable subsequent optimization of additional skeletal diversification (pairing functional groups: diene/triazolinedione).

Figure 7

Enantioselective Michael additions in the couple phase (coupling functional groups: malonate/nitroalkene) were followed by nitro reduction/lactamizations (nitro/ester), Diels-Alder cycloadditions (diene/triazolinedione), and 1,3-dipolar cycloadditions (nitro/alkene, nitro/alkyne) in the pair phase.

Fugure 8

Three skeletons formed via metal-mediated functional group-pairing reactions of an enyne substrate.

Figure 9

Multicomponent aldehyde/amide/dienophile reactions used in the couple phase and metal-mediated cyclizations used in the pair phase.

Figure 10

Four skeletons formed via metal-mediated functional group-pairing reactions of alkynyl allenes.

Figure 11

Petasis 3-component reactions in the couple phase (coupling functional groups: α-hydroxy aldehyde, amine, vinylboronic acid) were followed by reagent-controlled reactions leading to multiple skeletons in the pair phase (polar pairing functional groups: hydroxyl, amino, ester; non-polar pairing functional groups: alkene, alkyne, cyclopropane).

Figure 12

Small molecules originating from different sources, including from synthetic pathways using the Build/Couple/Pair strategy described in this review, are being annotated by their performance in large numbers of common small-molecule screens. Chemical research is entering an important new phase where intuition and bias concerning the specialness of different types of compounds can, in the near future, be replaced by quantitative analyses.

Sidebar. Differences between nucleic acid-based and small molecule-based modulation of protein function, emphasizing the reasons small molecules are being used with increased frequency.