Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles
August 22nd, 2018
Bicyclic aziridinium ions such as 1-azoniabicyclo[4.1.0]heptane tosylate were generated from 2-[4-tolenesulfonyloxybutyl]aziridine, which was utilized for the preparation of substituted piperidines and azepanes via regio- and stereospecific ring-expansion with various nucleophiles. This highly efficient protocol allowed us to prepare diverse azaheterocycles including natural products such as fagomine, febrifugine analogue and balanol.
This method can help to answer key questions in the field of bicyclic aziridinium ion chemistry for the synthesis of various various azaheterocycles including bipyridine and azepine ring systems. The main advantage of this technique is that the synthesis of kai-dal bipyridines and azepine core present in various natural products is achieved in a straight-forward manner. First, add 100 milligrams of the alcohol, 140 microliters of triethylamine, and a magnetic stir bar into an oven dried 25 milliliter two-neck round bottom flask under nitrogen atmosphere.
Using an airtight syringe, add 5 milliliters of anhydrous dichloromethane to the reaction flask. Cool the reaction mixture to 0 degrees Celsius using an ice water bath and stir the mixture for 5 minutes. Next, add 164 milligrams of p-toluenesulfonic anhydride to the reaction mixture and stir for another 45 minutes.
After stirring for 45 minutes, warm the reaction mixture to room temperature and stir for 30 minutes. Monitor the reaction progress by thin layer chromatography using hexanes and ethyl acetate as the eluant. After the complete consumption of the starting alcohol, quench the reaction mixture with 5 milliliters of water.
Then extract the heterogeneous mixture three times with 15 milliliters of dichloromethane. Dry the combined organic layer over anhydrous sodium sulfate for 10 minutes. After filtration, concentrate the filtrate in vacuo using a rotary evaporator.
Purify the crude product by flash-column chromatography using a gradient of hexanes and ethyl acetate to afford the tosylate in 96%yield as a viscous liquid. Now, transfer 5 milligrams of the tosylate in an NMR tube and add 300 microliters of deuterated acetonitrile. Set aside this solution at room temperature for 24 hours to attain complete conversion to the azoniabicyclo.
Monitor the conversion by NMR at different time points. Add 160 milligrams of the previously prepared tosylate and a magnetic stir bar into an oven-dried 25 milliliter round-bottom flask. Using an airtight syringe, add 4 milliliters of anhydrous acetonitrile to the reaction flask.
Add three equivalents of a suitable nucleophile to the reaction mixture and stir for 8 to 15 hours. Once the reaction is complete, quench the mixture with 5 milliliters of water. Then extract three times with 15 milliliters of dichloromethane.
Dry the combined organic layer over anhydrous sodium sulfate. After filtration, concentrate the filtrate in vacuo using a rotary evaporator. Purify the crude product by column chromatography using a gradient of hexanes and ethyl acetate to afford the pure ring expanded products.
Transfer 100 milligrams of the aziridinyl tosylate and a magnetic stir bar into an oven dried 25 milliliter round-bottom flask fitted with a reflux condenser. Using a syringe, add 4 milliliters of 1, 4-dioxane to the reaction flask. Add 0.4 milliliters of 2 molar sodium hydroxide solution to the reaction mixture and heat to reflux for 2 hours.
Once the reaction is complete, quench the mixture with 4 milliliters of water. Then extract the reaction mixture four times with 15 milliliters of dichloromethane. Dry the combined organic layer over anhydrous sodium sulfate.
After filtration, concentrate the filtrate in vacuo using a rotary evaporator. Purify the crude product by column chromatography using a gradient of hexanes and ethyl acetate to afford the pure hydroxy-azepane in a 97%yield. Transfer 220 milligrams of the aziridinyl alcohol, 180 microliters of triethylamine, and a magnetic stir bar into an oven-dried 25 milliliter two-neck round-bottom flask under nitrogen atmosphere.
Using an airtight syringe, add 4 milliliters of anhydrous dichloromethane to the reaction flask. Cool the reaction mixture to 0 degrees Celsius, and stir for 5 minutes. Following this, add 200 milligrams of p-toluenesulfonic anhydride to the reaction mixture, and stir for another 45 minutes.
Then warm the reaction mixture to room temperature, and stir for 30 minutes. Monitor the reaction progress by thin layer chromatography using hexanes and ethyl acetate as the eluant. After the complete consumption of the alcohol, quench the reaction mixture with 5 milliliters of water.
Then extract three times with 15 milliliters of dichloromethane. Dry the combined organic layer over anhydrous sodium sulfate. After filtration, concentrate the filtrate in vacuo using a rotary evaporator.
Now, transfer the crude tosylate and a magnetic stir bar into an oven-dried 25 milliliter round-bottom flask. Using an airtight syringe, add 4 milliliters of anhydrous acetonitrile to the reaction flask. Next, add 125 milligrams of sodium acetate to the reaction mixture and stir for 12 hours.
Once the reaction is complete, quench the mixture with 5 milliliters of water. Then extract three times with 15 milliliters of dichloromethane. Dry the combined organic layer over anhydrous sodium sulfate.
After filtration, concentrate the filtrate in vacuo using a rotary evaporator. Finally, purify the crude product by column chromatography using a gradient of hexanes and ethyl acetate to afford the pure substituted properidine in 83%yield. The proton NMR spectrum of tosylate-2 at different time intervals shows the conversion to azoniabicyclo.
A quartet at 4.07 PPM in the NMR spectrum of ring expanded product 5a corresponds to the CH proton of phenylethyl group. A similar quartet at 3.81 PPM was observed for ring expanded product 6a. The aziridine ring expansion of cyanide, thiocyanide, and acetate nucleophiles afforded properidine rings, while azide, hydroxide, and amine nucleophiles yielded azepane rings.
Synthesis of natural azasugar d-fagomine and its three epimer was achieved by ring expansion of aziridinyl-alcohol-7, followed by removal of the protecting groups to afford the product in 94%yield. Benzyl protected alcohol-10 was treated with p-toluenesulfonic anhydride and triethylamine followed by nucleophilic ring opening resulting in the ring-expanded cyanomethyl-properidine-11 in 90%yield as a single isomer. The ring expansion of alcohol-13 followed by reaction with sodium azide yielded hydroxy-azapane-14 which was used for the azepane core of Balanol by one-pot benzyl deprotection and azide reduction under catalytic hydrogenation.
Once mastered, this technique for aziridine ring expansion can be done in six to eight hours if it is performed properly. While attempting this procedure, it is important to remember to use para-toluenesulfonic anhydride, because it is more sensitive to moisture. Following this procedure, other methods like use of para-toluenesulfonic chloride instead of para-toluenesulfonic anhydride can be used in order to explore the eco-friendly nature of the pro-gen protocol.
After its development, this technique paved the way for the researchers in the field of synthetic organic chemistry to explore the environment of aziridinium ion in azaheterocycles and natural product synthesis. After watching this video, you should have a good understanding of how to use bicyclic aziridinium ion chemistry for the synthesis of biologically-relevant molecules having an azaheterocycles including a variety of natural products. Don't forget that working with toxic reagents such as sodium cyanide used in the synthesis as a nucleophile can be extremely hazardous, and extreme safety precautions should always be taken while performing this procedure.
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Overview
This study presents a method for generating bicyclic aziridinium ions, which are utilized in synthesizing various azaheterocycles. The protocol demonstrates regio- and stereospecific ring-expansion, leading to the efficient preparation of substituted piperidines and azepanes.
Key Study Components
Area of Science
- Chemistry
- Organic Synthesis
- Natural Products
Background
- Bicyclic aziridinium ions are important intermediates in organic synthesis.
- They can be used to create complex molecular structures.
- Understanding their chemistry can lead to advancements in synthesizing natural products.
- This study focuses on a specific method for their generation and application.
Purpose of Study
- To develop an efficient protocol for synthesizing bicyclic aziridinium ions.
- To explore the regio- and stereospecific ring-expansion of these ions.
- To prepare diverse azaheterocycles, including natural product analogues.
Methods Used
- Generation of bicyclic aziridinium ions from aziridine derivatives.
- Utilization of various nucleophiles for ring-expansion reactions.
- Preparation of substituted piperidines and azepanes.
- Application of the method to synthesize natural product analogues.
Main Results
- Successful generation of bicyclic aziridinium ions.
- Efficient synthesis of substituted piperidines and azepanes.
- Preparation of diverse azaheterocycles, including natural product analogues.
- Demonstration of regio- and stereospecificity in reactions.
Conclusions
- The developed method is a valuable tool for organic synthesis.
- It allows for the straightforward synthesis of complex azaheterocycles.
- This approach can facilitate further research in natural product synthesis.
Frequently Asked Questions
Executive Industry Relevance
This method enables efficient synthesis of piperidine and azepane scaffolds, which are prevalent in bioactive natural products and pharmaceuticals. By providing regio- and stereospecific ring expansion via bicyclic aziridinium ions, it supports target validation and lead identification in early discovery. The approach enhances predictive confidence in synthesizing complex azaheterocycles relevant to drug discovery pipelines.
Strategic Applications in Biopharma R&D
Early Discovery & Target Validation
- Scientific Value: Enables interrogation of therapeutic hypotheses through precise construction of nitrogen-containing heterocycles.
- Operational Value: Provides a reliable method for generating piperidine and azepane cores found in bioactive compounds.
- Strategic Value: Supports de-risking of synthetic routes to natural product analogues like fagomine and balanol.
Screening & Assay Development
- Scientific Value: Produces diverse, substituted azaheterocycles for screening libraries with defined stereochemistry.
- Operational Value: Delivers high-yield, purified products amenable to downstream biochemical assays.
- Strategic Value: Enables scalable preparation of scaffold-diverse compounds for hit-to-lead optimization.
Translational & Preclinical Research
- Scientific Value: Facilitates synthesis of natural product analogues with relevance to preclinical disease models.
- Operational Value: Ensures reproducibility and purity required for pharmacological profiling.
- Strategic Value: Supports translational continuity from hit identification to lead optimization.
Pipeline & Workflow Integration
The method fits within early discovery workflows, enabling rapid access to piperidine and azepane scaffolds prior to lead identification and preclinical evaluation.
- Discovery Biology: Supports hypothesis-driven synthesis of bioactive heterocycles for target engagement studies.
- Screening: Generates quantifiable, pure compounds for assay-ready library expansion.
- Analytics: Provides structurally defined outputs for SAR analysis and structure-activity relationship mapping.
- Translational Research: Connects to preclinical validation through synthesis of analogues like fagomine and balanol.
- Enterprise Reuse: Offers a reusable platform for generating diverse nitrogen heterocycles across multiple projects.
Operational & Enterprise Impact
- Scientific Value: Enhances predictive confidence in constructing complex azaheterocycles with regio- and stereocontrol.
- Operational Value: Delivers high-yield, scalable synthesis with minimal purification steps.
- Strategic Value: Improves capital efficiency by reducing steps to access key pharmacophores.
- Portfolio Impact: Enables risk-adjusted prioritization of synthetic routes to natural product-derived leads.
Implementation Considerations
- Requires expertise in organic synthesis and handling of moisture-sensitive reagents like p-toluenesulfonic anhydride.
- Needs standard laboratory instrumentation including rotary evaporator, NMR, and column chromatography systems.
- Demands strict anhydrous conditions and inert atmosphere for reproducible aziridinium ion formation.
- Involves hazardous nucleophiles such as sodium cyanide, necessitating specialized safety protocols.
- Adaptability across substrates may require optimization of nucleophile choice and reaction time.
Biopharma FAQs
Chapters in this video
0:04
Title
0:35
Synthesis of (6R)-1-[(R)-1-Phenylethyl)-1-Azoniabicyclo[4.1.0]Heptane Tosylate
2:49
General Procedure for the Expansion of 1-Azoniabicyclo[4.1.0]Heptane Tosylate
3:53
Synthesis of (S)-1-[(R)-1-Phenylethyl]azepan-3-ol
5:14
Synthesis of [(2R,3R,4R)-3,4-Bis(Benzyloxy)-1-(S)-1-Phenylethyl)Piperidin-2-Yl]Methyl Acetate
8:03
Results: Synthesis and Characterization of Bicyclic Aziridinium Ions and its Ring Expansion to Azaheterocycles
9:53
Conclusion
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