Cycloaddition Strategies for the Synthesis of Diverse Heterocyclic Spirocycles for Fragment-Based Drug Discovery

Abstract

In recent years the pharmaceutical industry has benefited from the advances made in fragment-based drug discovery (FBDD) with more than 30 fragment-derived drugs currently marketed or progressing through clinical trials. The success of fragment-based drug discovery is entirely dependent upon the composition of the fragment screening libraries used. Heterocycles are prevalent within marketed drugs due to the role they play in providing binding interactions; consequently, heterocyclic fragments are important components of FBDD libraries. Current screening libraries are dominated by flat, sp²-rich compounds, primarily owing to their synthetic tractability, despite the superior physicochemical properties displayed by more three-dimensional scaffolds. Herein, we report step-efficient routes to a number of biologically relevant, fragment-like heterocyclic spirocycles. The use of both electron-deficient and electron-rich 2-atom donors was explored in complexity-generating [3+2]-cycloadditions to furnish products in 3 steps from commercially available starting materials. The resulting compounds were primed for further fragment elaboration through the inclusion of synthetic handles from the outset of the syntheses.

Keywords: Cycloaddition; Diversity‐oriented synthesis; Fragment‐based drug discovery; Heterocycles; Spirocycles.

Figure 1

Examples of spirocycle‐containing marketed drugs.30, 31

Figure 2

Recent advances in the synthesis of heterocyclic spirocycles (a) Wang and Bode generated unactivated imines and utilised metal hydride hydrogen atom transfer chemistry with manganese to generate a C‐centered radical, which underwent addition to the unactivated imine to generate the spirocycle with an N‐centered radical from which the unprotected‐N was unveiled by a second hydrogen atom transfer: 19 spirocycles with R = alkyl or aryl; X = NCbz, S or CH₂; n = 5 or 6;46 (b) Griggs et al. formed highly substituted 2‐spiropiperidines in a one‐pot reaction from N‐Boc imines via the addition of Chan's diene under Maitland–Japp conditions followed by in‐situ Boc‐deprotection and a sodium bicarbonate catalysed cyclisation onto a cyclic ketone: 10 spirocycles with R = alkyl or aryl; X = NCbz, O, S or CH₂; n = 4, 5 or 6;47 (c) Brady and Carreira used the addition of trifluoroborates to oxetanyl N,O‐acetals to generate products with oxetane and alkyne functionalities from which spiro heterocycles can be generated by orthogonal activation, such as intramolecular opening of the oxetane by the alcohol followed by catalytic intramolecular alkyne hydroalkoxylation to close the spirocyclic ring: 5 spirocycles with R = alkyl, aryl or TMS.42

Figure 3

The use of both acyclic (a) and exo‐cyclic (b) starting materials allowed the efficient synthesis of heterocyclic spirocyclic compounds. Based on the cyclisation approach taken, different functional handles in the final compounds [for example, ester (blue and pink), carbonyl (yellow and green), and aromatic (pink and green) moieties] were available for further modifications.

Scheme 1

Formation of key dipole (a) and acyclic (b) starting materials: (i) 11 (1.0 equiv.), NH₂OH (2.0 equiv.), EtOH, r.t., 10 min; then NCS (1.1 equiv.), DMF, r.t., 0.5 h, 99 %; (ii) 12 (1.0 equiv.), NEt₃ (1.0 equiv.), DCE, 0 °C, 3 min, used immediately; (iii) 14 (1.0 equiv.), Boc₂O (0.95 equiv.), K₂CO₃ (1.5 equiv.), EtOAc, H₂O, r.t., 12 h, 93 %; (iv) 15 (1.0 equiv.), MsCl (1.25 equiv.), NEt₃ (3.0 equiv.), DCM, –15 °C ‐ r.t., 2 h, 94 %.

Scheme 2

Synthesis of isoxazole‐based spirocycle 3, via [3+2]‐cycloaddition with nitrile‐oxide dipole generated in situ, followed by carbamate formation: (i) 1 (1.0 equiv.), 12 (6.0 equiv.) NEt₃ (6.8 equiv.), DCM, r.t., 1 h, 58 %; (ii) 2 (1.0 equiv.), NaBH₄ (1.0 equiv.), CH₃OH/THF (1:8), 0 °C ‐ r.t., 12 h, 55 %; (iii) 2′ (1.0 equiv.), KOtBu (2.0 equiv.), THF, 0 °C, 1 h, 56 %.

Scheme 3

Exploring other alkene cycloadditions: (i) 5b (1.0 equiv.), BnN₃ (10.0 equiv.), 100 °C, 48 h, 34 %; (ii) 5a (1.0 equiv.), NH₂NH₂ ·H₂O (1.2 equiv.), EtOH, 70 °C, 24 h, 68 %.

Scheme 4

Exploring imine cyclisations: (i) 4a (1.0 equiv.), p‐anisidine (1.0 equiv.), toluene, reflux, 20 h; (ii) 6 (1.0 equiv.), acetoxyacetyl chloride (2.4 equiv.), NEt₃ (3.0 equiv.), DCM, –78 °C – r.t., 20 h, 55 % over two steps.