Assembly of four diverse heterocyclic libraries enabled by Prins cyclization, Au-catalyzed enyne cycloisomerization, and automated amide synthesis

Abstract

We describe a unified synthetic strategy for efficient assembly of four new heterocyclic libraries. The synthesis began by creating a range of structurally diverse pyrrolidinones or piperidinones. Such compounds were obtained in a simple one-flask operation starting with readily available amines, ketoesters, and unsaturated anhydrides. The use of tetrahydropyran-containing ketoesters, which were rapidly assembled by our Prins cyclization protocol, enabled efficient fusion of pyran and piperidinone cores. A newly developed Au(I)-catalyzed cycloisomerization of alkyne-containing enamides further expanded heterocyclic diversity by providing rapid entry into a wide range of bicyclic and tricyclic dienamides. The final stage of the process entailed diversification of each of the initially produced carboxylic acids using a fully automated platform for amide synthesis, which delivered 1872 compounds in high diastereomeric and chemical purity.

Figure 1

General Synthetic Strategy to Skeletally Diverse Heterocyclic Libraries. The assembly process is divided into two stages. First, a number of skeletally diverse lactams 7–10 are produced starting with readily available primary amines 1, ketoesters 2 and unsaturated anhydrides 4 or 5. Second, each of the lactams 7–10 is coupled to amines 11 in a fully automated fashion to deliver the resulting amide-containing heterocyclic libraries 12–15.

Figure 2

Development of an automation platform for solution-phase amide synthesis and liquid–liquid extraction. (A) Synthetic scheme used for the development of automated amide synthesis and extractive purification. Carboxylic acids 7 were manually prepared from primary amines 1, ketoesters 2, and anhydride 4 as previously described.¹² Automated amide synthesis entailed activation of each carboxylic acid 7 with 1,1′-carbonyldiimidazole (CDI, 16), followed by treatment of the resulting acyl imidazole 17 with 3 equivalents of amines 11 for 48 h at 20 °C and washing the resulting chloroform solution with 1.2 M aqueous solution of HCl. (B) Structures and isolated yields of four representative amides, which were prepared by the above protocol following solvent evaporation. The purity of each compound was established by LCMS analysis and confirmed by ¹H NMR spectroscopy.

Figure 3

Synthesis of a 216-membered library of bicyclic pyrrolidinones. (A) Two-stage assembly process entailed preparation of nine carboxylic acids 7 starting with 3 amines 1 and 3 ketoesters 2, followed by automated amide-bond synthesis using a set of 24 amines 11. (B) Structures of 3 amines 1. (C) Structures of 3 ketoesters 2. (D) Structures of 24 amines 11.

Figure 4

Proposed explanation of the diastereoselective formation of 2-pyrrolidinones 7 and 2-piperidinones 8. In both cases, the tandem reaction sequence entails a conjugate addition of the enamine to unsaturated anhydride followed by a ring-opening and a proton transfer. Initial approach of each anhydride facilitates subsequent lactam formation by placing the reactive imine and carbonyl moieties in close spatial proximity, as shown in intermediates B and F.

Figure 5

Synthesis of a 768-membered library of bicyclic piperidinones. (A) Two-stage assembly process entailed preparation of 32 carboxylic acids 8 starting with 8 amines 1 and 4 ketoesters 2, followed by automated amide-bond synthesis using a set of 24 amines 11. (B) Structures of 8 amines 1. (C) Structures of 4 ketoesters 2. (D) Structures of 24 amines 11.

Figure 6

Synthesis of a 768-membered library of 2-piperidinones fused to dihydropyrans. (A) Assembly process entailed preparation of 32 carboxylic acids 26 starting with 8 amines 1 and 4 ketoesters 2, followed by automated amide-bond synthesis using a set of 24 amines 11. (B) Structures of 8 amines 1. (C) Structures of 4 ketoesters 2. (D) Structures of 24 amines 11.

Figure 7

Synthesis of a 120-Membered Library of Tetrahydro-oxo-indolizines and Hexahydro-oxo-quinolizines. (A) Structures of five enamides employed for the Au-catalyzed cycloisomerization, followed by alkene hydrogenation. (B) Structures of tetrahydro-oxo-indolizines 37, 38 and 39 and hexahydro-oxo-quinolizines 40 and 41. (C) Structures of 24 amines 11 used for automated amide syntheis. (D) Final amide-containing library incorporating five skeletally diverse lactams.