Late-Stage Saturation of Drug Molecules

Abstract

The available methods of chemical synthesis have arguably contributed to the prevalence of aromatic rings, such as benzene, toluene, xylene, or pyridine, in modern pharmaceuticals. Many such sp²-carbon-rich fragments are now easy to synthesize using high-quality cross-coupling reactions that click together an ever-expanding menu of commercially available building blocks, but the products are flat and lipophilic, decreasing their odds of becoming marketed drugs. Converting flat aromatic molecules into saturated analogues with a higher fraction of sp³ carbons could improve their medicinal properties and facilitate the invention of safe, efficacious, metabolically stable, and soluble medicines. In this study, we show that aromatic and heteroaromatic drugs can be readily saturated under exceptionally mild rhodium-catalyzed hydrogenation, acid-mediated reduction, or photocatalyzed-hydrogenation conditions, converting sp² carbon atoms into sp³ carbon atoms and leading to saturated molecules with improved medicinal properties. These methods are productive in diverse pockets of chemical space, producing complex saturated pharmaceuticals bearing a variety of functional groups and three-dimensional architectures. The rhodium-catalyzed method tolerates traces of dimethyl sulfoxide (DMSO) or water, meaning that pharmaceutical compound collections, which are typically stored in wet DMSO, can finally be reformatted for use as substrates for chemical synthesis. This latter application is demonstrated through the late-stage saturation (LSS) of 768 complex and densely functionalized small-molecule drugs.

Figure 1

Late-stage saturation can improve drug properties. (A) The well-established late-stage functionalization (LSF) approach facilitates chemical space exploration around drug leads, but the overall drug properties of LSF analogues are often decreased due to the large increase in molecular weight (mol wt). Late-stage saturation (LSS) can markedly change physicochemical properties, most notably the fraction of sp³ atoms (Fsp³), while maintaining overall drug-likeness since only 6 hydrogen atoms are installed (Δmol weight = 6.04 g/mol); (B) examples of aromatic-saturated matched pairs of molecules with dramatically modified drug properties.

Figure 2

Data-guided validation of the LSS concept. (A) Cheminformatic workflow for analyzing the ChEMBL database. (B) The resulted 9704 compound pairs show that aromatic-saturated matched pairs exist, but those available were generally accessed by total synthesis. (C) Kernel density of the fraction of sp³ atoms showing the change in this property upon performing a virtual LSS (green) of the aromatic drugs (gray) in the ChEMBL database. For details of cheminformatic analysis, see Supporting Information, Section 5.

Figure 3

Late-stage saturation scope of benzene-containing drugs under rhodium catalysis conditions. (A) Aromatic drugs transformed to saturated drugs by LSS: production of saturated drugs with distinct medicinal properties. (B) Scope of drugs containing a single arene. (C) Scope of drugs containing multiple arenes. Note: the catalyst [Rh(COD)OH]₂ is bench-stable for at least half a year and the reaction was conducted without the need of an autoclave or glovebox (for experimental details, see the Supporting Information). * Isolated yields shown in square brackets were obtained using ethylene glycol as solvent.

Figure 4

(A) LSS of indole-containing drugs under H₂SO₄-mediated reduction conditions. (B) LSS of quinoline-containing drugs under sequential photocatalysis and hydrogenation conditions. (C) Step-economic synthesis of lead compounds empowered by the LSS concept (for experimental details, see the Supporting Information).

Figure 5

Late-stage saturation (LSS) of drug libraries via ultrahigh-throughput experimentation. (A) A library of 768 pharmaceutically relevant complex molecules stored in wet DMSO were subjected to LSS using [Rh(COD)OH]₂, B₂(OH)₄ in ethylene glycol. (B) A sensitivity screen shows the protocol is tolerant of various changes to reaction conditions. (C) Selections of miniaturized reactions were confirmed on an ∼50 mg scale in ethanol to obtain isolated yields (for experimental details, see the Supporting Information). * Isolated yields shown in square brackets were obtained using ethylene glycol as solvent. ^†One isomer was isolated from the diastereoisomers mixture.

Figure 6

(A) Predicted properties for Prilocaine, Cinacalcet, and their LSS analogues 15 and 39. (B) Microsomal stability data obtained for 24 LSS reaction mixtures show the change in microsomal stability following saturation of various drugs.