Synthesis of Novel 3,7-Diazabicyclo[3.3.1]nonane Derivatives

<p>A series of 3-(3-ethoxypropyl)-7-heterocyclylalkyl-3,7-diazabicyclo[3.3.l]nonan-9-ones have been prepared by Mannich cyclocondensation of 1-(3-ethoxypropyl)-4-oxopiperidine with paraformaldehyde and primary amines followed by Wolff-Kischner reduction of the obtained bispidinones. The starting 1-(3-ethoxypropyl)-4-oxopiperidine was synthesized by Dickmann condensation of 3-ethoxypropylamine with ethylacrylate. The 3,7-diazabicyclo[3.3.1]nonanones were obtained in acceptable yields by condensation of 1-(3-ethoxypropyl)piperidin-4-one with primary amines: 1-(3-aminopropyl)imidazole or 1-(2-aminoethyl) piperazine and formaldehyde in the presence of acetic acid in methanol medium. Reduction of the obtained bispidinones with hydrazine hydrate was carried out in the presence of KOH in triethylene glycol at 160-170 °C for 5 hours. The syntheses were performed under the atmosphere of N₂. As the reaction products are viscous oils, the column chromatography (on III activity aluminum oxide, eluent – benzene: dioxane 5:1) was used for purification of novel bicyclic ketones and bicyclic nonanes. The completion of the reactions was monitored by TLC. Methods of ¹H and ¹³C NMR spectroscopy were used to determine the structures of the substances synthesized. The prior studies have demonstrated that variation on the substituents at nitrogen atoms in 3- and 7-positions of bispidine cycle could result in the increase of biological activity and effect on compound spectral characteristics. Spatial structures of bispidinones and related bispidines were determined on the basis of the data of the ¹³C and ¹H NMR spectra. A doublet of doublets of equatorial protons at C_2.4and C_6.8 with large geminal constants of 10.5-11 Hz and vicinal constants of 3.0-6.0 Hz in ¹H NMR spectrum revealed that those 3,7-diazabicyclo[3.3.1]nonane derivatives have a “chair-chair” conformation of both piperidine rings.</p>

The Garg Synthesis of (±)-Aspidophylline A

The pentacyclic Apocynaceae alkaloid aspidophylline A 3 reverses drug resistance in resistant KB cells. In developing a strategy for the assembly of 3, Neil K. Garg of UCLA envisioned (J. Am. Chem. Soc. 2011, 133, 8877) the intramolecular Pd-catalyzed cyclization of 1 to 2. The starting material for the cyclohexenone derivative 1 was the known tricyclic anhydride 7. This was readily available in gram quantities by oxidation of the commercial pyridone 4. The double decarboxylation to 8 was delicate but could be effected by iterative small-batch microwave heating. Protection of 8 followed by fragmentation and alkylation than delivered 1. The intramolecular Heck cyclization of 1 indeed proceeded smoothly, giving the bicyclic diene 2. Deprotection of the ketone revealed a doubly activated enone, which could be selectively reduced under modifi ed dissolving metal conditions to give the keto ester 12. Alkylation of the lithium enolate with allyl iodide then gave 13, predominantly as the diastereomer illustrated. Reduction followed by selective Johnson-Lemieux oxidative cleavage of the terminal alkene then completed the construction of the diol 14. The vision for the final assembly of the alkaloid was to effect interrupted Fischer indolization of an alkylated cyclohexanone such as 15. To this end, several bicyclic ketones were explored, but none was successful. Finally, attention was turned to the more rigid tricyclic lactone 15. Happily, exposure of 15 to phenylhydrazine in the presence of trifluoroacetic acid led to an intermediate that was not isolated, but directly combined with methanolic K2CO3 to open the lactone, allowing closure of the tetrahydrofuran ring, to give 16. Simple arene sulfonamides can be advantageous in synthesis, as they do not appear as rotameric mixtures in NMR, and are often crystalline. Nevertheless, they have not commonly been used because of the perceived difficulty of deprotection. Sonication of 16 with Mg powder in methanol containing solid NH4Cl led to smooth desulfonylation. Formylation then completed the synthesis of aspidophylline A 3.