Cyclic isomers--Azabicyclic molecular building blocks to aid drug design

Product Manager：Nick Wilde

Recently, Ukrainian scientists reported a breakthrough research result in the journal Angewandte Chemie International Edition.They synthesized a new ring isomer, 3-azabicyclo[3.1.1]heptanes(aza-BCHP for short), by the reduction of spiroepoxetane, and Aladdin Scientific is available as a related product.

3-Azabicyclo[3.1.1]heptane can be used to displace the pyridine ring, and visual comparison of BCHP with 3,5-disubstituted pyridines requires attention to differences in spatial structure and variations in π-π interactions. Specific chemical design and drug synthesis schemes need to take these factors into account.

1. BCHP can be viewed as a saturated analog of pyridine

In the field of drug discovery, 3-azabicyclo[3.1.1]heptane (BCHP) has received much attention as a saturated isostane skeleton with potential for modeling bioactive compounds with meta-substituted benzene fragments. It has similar angles and distances to pyridine and has similar physicochemical properties. Due to these properties, researchers have become interested in introducing amino atoms into bicyclo[3.1.1]heptanes, as such a molecular system could theoretically be viewed as a saturated analog of pyridine (Scheme 1).

Scheme 1.Bicyclo[3.1.1]heptanes as bioisosteres of benzenes. This work:3-azabicyclo[3.1.1]heptanes.

2.During the synthesis of spirocyclic amines 2, the unexpected by-product 3a was generated.Subsequently, large-scale reaction optimization studies could be carried out to explore further chemical synthesis strategies.

Spirocycles are now widely used in chemistry, and the reduction of nitrile 1 with LiAlH4 in tetrahydrofuran at room temperature afforded spirocylic amines 2 (Scheme 2). At the same time, the reduction of oxetane 3 unexpectedly yielded the by-product 3 a. This opens a new door for the efficient synthesis of aza-BCHP.

Scheme 2.Unexpected formation of product 3a.

The research team obtained the target 3-azabicyclo[3.1.1]heptane compounds by reducing the spirocyclic derivatives of oxypropanecarbonitrile via a conformational rearrangement reaction. This synthetic route is versatile, with all types of substituents applicable and yields up to the gram scale. This strategy afforded 40 g of 3a-HCl product in a single run. The structure was confirmed by X-ray analysis. The structure was confirmed by X-ray analysis.

Scheme 3.Scalable synthesis of compound 3a⋅HCl

In addition, the reduction and recirculation steps using two complementary approaches can be well tolerated with various substituents on aromatic nuclei (Scheme 4).

Scheme 4. Reaction conditions: [LiAlH4]: nitrile (1 equiv), LiAlH4 (1 equiv), THF, 12 h,rt.[NaBH4/CoCl2]:nitrile (1 equiv), NaBH4 (10 equiv), CoCl2⋅6 H2O (0.1 equiv), MeOH, 20 h, reflux. aProducts were isolated as hydrochloride salts: (i) amine, 4 N HCl in dioxane, 30 min, rt; (ii) evaporation. bX-ray crystal structure of compound 3 a⋅HCl. Hydrogen and chlorine atoms are omitted for clarity. cN-Boc protection was additionally performed. dReaction conditions: (i) nitrile (1 equiv),NaBH4 (3 equiv), MeOH, 12 h, reflux; (ii) Boc2O (1 equiv), 12 h, rt.

3. Substitution of the pyridine ring in the structure of lupatadine by aza-BCHP greatly improves its physicochemical properties

Scientists introduced BCHP, a new ring core, into the structure of the antihistamine drug repagliflozin, successfully replacing the original pyridine ring. The results showed that the water solubility of the new compound was increased by more than 10-fold, and the metabolic half-life was prolonged by 10-fold in a human model. This proves that the new saturated ring isomer can indeed significantly improve the pharmacokinetic properties of the drug without affecting the activity.

Scheme 5. Synthesis of compound 52-saturated analog of Rupatadine.

3-Azabicyclo[3.1.1]heptane, as an emerging medicinal chemical structure, has significant potential in the field of drug research and development. It is foreseeable that a variety of new isomeric ring systems will rise rapidly, providing more choices for the development of old drugs for new uses and the development of innovative drugs. Let's wait and see how ring isomers will continue to fuel new breakthroughs in drug design!

Reference

1. Dmitry Dibchak, Mariya Snisarenko, etal. General Synthesis of 3-Azabicyclo[3.1.1]heptanes and Evaluation of Their Properties as Saturated Isosteres. Angew. Chem. Int. Ed. 2023, e202304246 (1 of 8) .  https://doi.org/10.1002/anie.202304246

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