Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles

Summary

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.

Abstract

Bicyclic aziridinium ions were generated by the removal of an appropriate leaving group through internal nucleophilic attack by nitrogen atom in the aziridine ring. The utility of bicyclic aziridinium ions, specifically 1-azoniabicyclo[3.1.0]hexane and 1-azoniabicyclo[4.1.0]heptane tosylate highlighted in the aziridine ring openings by the nucleophile with the release of the ring strain to yield the corresponding ring-expanded azaheterocycles such as pyrrolidine, piperidine and azepane with diverse substituents on the ring in regio- and stereospecific manner. Herein, we report a simple and convenient method for the preparation of the stable 1-azabicyclo[4.1.0]heptane tosylate followed by selective ring opening via a nucleophilic attack either at the bridge or at the bridgehead carbon to yield piperidine and azepane rings, respectively. This synthetic strategy allowed us to prepare biologically active natural products containing piperidine and azepane motif including sedamine, allosedamine, fagomine and balanol in highly efficient manner.

Introduction

Among three membered cyclic compounds, aziridine has similar ring strain energy as cyclopropane and oxirane to afford various nitrogen-containing cyclic and acyclic compounds via ring opening^1,2,3. However, the characteristics and reactivity of aziridine depend on the substituent of ring nitrogen. Aziridine with an electron-withdrawing group at the ring nitrogen⁴, is called "activated aziridine", which is activated to react with the incoming nucleophile without any additional activating reagent. On the other hand, "non-activated aziridine&#....

Protocol

1. Synthesis of (6R)-1-[(R)-1-Phenylethyl)-1-Azoniabicyclo[4.1.0]Heptane Tosylate (4)

1. Synthesis of 4-(R)-[1-(R)-1-phenylethyl)aziridin-2-yl]butyl 4-methylbenzenesulfonate (2)
   1. Add 100 mg of 4-[(R)-1-(R)-1-phenylethyl)aziridin-2-yl]butan-1-ol (1)¹² (0.46 mmol, 1.0 equiv), 140 µL of triethylamine (Et₃N, 1.0 mmol, 2.2 equiv), and a magnetic stir-bar into an oven-dried 25 mL two-neck round-bottom flask under nitrogen (N₂) atmosphere.
   2. Add anhydrous dichloromethane (CH₂Cl₂, 5 mL) to the reaction flas....

Results

The reaction of 4-[(R)-1-(R)-1-phenylethyl)aziridin-2-yl]butan-1-ol (1)¹² with p-toluenesulfonic anhydride and triethylamine in CH₂Cl₂ at room temperature for 1.0 h yielded the corresponding 2-(4-tosyloxybutyl)aziridine 2 in 96% yield¹¹. ¹H NMR (400 MHz) spectrum of compound 2 in CD₃CN at different time intervals shows th.......

Discussion

Piperidine and azepane are two most abundant azaheterocycles in many life-saving drugs and antibiotics including various biologically active natural products¹⁶. In order to access both enantiopure piperidine (5) and azepane (6) with diverse substituents, we develped an efficient synthetic method through the formation of 1-azoniabicyclo[4.1.0]heptane tosylate from entiopure 2-(4-hydroxybutyl)aziridne followed by regiospecific nucleophilic attack either at the bridg.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Thin Layer Chromatography (TLC)	Merck	100390
UV light	Sigma-Aldrich	Z169625-1EA
Bruker AVANCE III HD (400 MHz) spectrometer	Bruker	NA
JASCO P-2000	JASCO	P-2000	For optical rotation
High resolution mass spectra/ MALDI-TOF/TOF Mass Spectrometry	AB SCIEX	4800 Plus	High resolution mass spectra
(2R)-1-[(1R)-1-Phenylethyl]-2-aziridinecarboxylic acid (–)-menthol ester, 98%	Sigma-Aldrich	57,054-0
(2S)-1-[(1R)-1-Phenylethyl]-2-aziridinecarboxylic acid (–)-menthol ester	Sigma-Aldrich	57,051-6
Triethylethylamine	DAEJUNG	8556-4400-1L	CAS No: 121-44-8
Dichloromethane	SAMCHUN	M0822-18L	CAS No: 75-09-2
p-Toluenesulfonic anhydride	Sigma-Aldrich	259764-25G	CAS No: 4124-41-8
n-Hexane	SAMCHUN	H0114-18L	CAS No: 110-54-3
Ethyl acetate	SAMCHUN	E0191-18L	CAS No: 141-78-6
Sodium sulfate	SAMCHUN	S1011-1kg	CAS No: 7757-82-6
Acetonitrile-d3	Cambridge Isotope Laboratories, Inc	15G-744-25g	CAS No: 2206-26-0
Acetonitrile	SAMCHUN	A0127-18L	CAS No: 75-05-8
1,4-Dioxane	SAMCHUN	D0654-1kg	CAS No: 123-91-1
Sodium hydroxide	DUKSAN	A31226-1kg	CAS No: 1310-73-2
Sodium acetate	Alfa Aesar	11554-250g	CAS No: 127-09-3
Lithium aluminum hydride	TCI	L0203-100g	CAS No: 16853-85-3
Tetrahydrofuran	SAMCHUN	T0148-18L	CAS No: 109-99-9
Sodium azide	D.S.P	703301-500g	CAS No: 26628-22-8
Cesium fluoride	aldrich	18951-0250-25g	CAS No: 13400-13-0
Tetrabutylammonium bromide	aldrich	426288-25g	CAS No: 1643-19-2
Sodium iodide	aldrich	383112-100g	CAS No: 7681-82-5
Sodium cyanide	Acros Organics	424301000-100g	CAS No: 143-33-9
Sodium thiocyanate	aldrich	467871-250g	CAS No: 540-72-7
Sodium methoxide	aldrich	156256-1L	CAS No: 124-41-4
Benzylamine	Alfa Aesar	A10997-1000g	CAS No: 100-46-9
Phenol	TCI	P1610-500g	CAS No: 108-95-2
Sodium benzoate	Alfa Aesar	A15946-250g	CAS No: 532-32-1
Chloroform-d	Cambridge Isotope Laboratories, Inc	DLM-7TB-100S/16H-239, 100g	CAS No: 865-49-6
Dimethyl sulfoxide-d6	Cambridge Isotope Laboratories, Inc	DLM-10-25, 25g	CAS No: 2206-27-1
Methanol	SAMCHUN	M0585-18L	CAS No: 67-56-1
Ninhydrin	Alfa Aesar	A10409-250g	CAS No: 485-47-2
Phosphomolybdic acid hydrate	TCI	P1910-100g	CAS No: 51429-74-4
p-Anisaldehyde	aldrich	A88107-5g	CAS No: 123-11-5