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" with electron-donating substituent at nitrogen is quite stable and inert to the nucleophiles, unless it is activated as an aziridinium ion as I_a (Figure 1a)^5,6,7. The ring opening of a non-activated aziridine depends on various factors such as the substituents at C2 and C3 carbon of aziridine, the electrophile to activate the aziridine ring and the incoming nucleophile. The isolation and characterization of an aziridinium ion is not possible due to its high reactivity towards ring-opening reaction by nucleophiles, but its formation and characteristics were observed spectroscopically with a non-nucleophilic counter anion^5,8,9,10. The regio- and stereoselective ring-opening reaction of aziridinium ion by a suitable nucleophile yields nitrogen-containing acyclic valuable molecules (P_i and P_ii)^5,6,7,8,9,10.

Similarly, a bicyclic aziridinium ion (I_b) is possibly generated via the removal of the leaving group by the nucleophilic attack of ring nitrogen of aziridine in intramolecular fashion (Figure 1b). Then, this intermediate undergoes ring-expansion with the incoming nucleophile via the release of ring strain. The formation and stability of bicyclic aziridinium ion are dependent on many factors such as the substituents, the size of the ring, and solvent medium⁹. The regio- and stereoselectivity of the aziridine ring-expansion is a pivotal aspect of its synthetic utility, which depends on the nature of the substituents in the starting substrate and the characteristics of applied nucleophile.

In our early study, we succeeded to prepare 1-azoniabicyclo [3.1.0]hexane tosylate I_b (n = 1) whose subsequent ring-expansion resulted in the formation of a pyrrolidine and a piperidine (P_iii and P_iv, n = 1, Figure 1)⁸. As a part of our continuing study on the bicyclic aziridinium ion chemistry, we describes herein the formation of 1-azoniabicyclo [4.1.0]heptane tosylate I_b (n = 2) as a representative example. This was prepared from 2-(4-toluensulfonyloxybutyl)aziridine and its ring-expansion was trigged by a nucleophile to afford valuable piperidine and azepane (P_i and P_ii, n = 2, Figure 1) with diverse substituents around the ring¹¹. The ring-expansion of enantiopure aziridine 4-[(R)-1-(R)-1-phenylethyl)aziridin-2-yl]butan-1-ol (1) resulted in the asymmetric synthesis of substituted azaheterocycles which are applicable to build biologically active molecules with piperidine and azepane skeleton. This synthetic protocol has been applied for various compounds ranging from simple 2-cyanomethylpiperidine 5f, 2-acetyloxymethylpiperidine 5h and 3-hydroxyazepane 6j to more complex molecules including natural products such as fagomine (9), febrifugine analogue (12) and balanol (15) in optically pure forms¹¹.

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 flask using airtight syringe.
   3. Cool the reaction mixture at 0 °C using ice bath and stir the mixture for 5 min.
   4. Add p-toluenesulfonic anhydride (164 mg, 0.50 mmol, 1.10 equiv) to the reaction mixture and stir for another 45 min.
   5. Warm the reaction mixture to room temperature (RT) and stir for 30 min.
   6. Monitor the reaction using a thin layer chromatography (TLC) by using hexanes:ethyl acetate (EtOAc) (1:1 v/v, retention factor R_f = 0.55) as an eluent.
   7. After the complete consumption of starting alcohol 1, quench the reaction mixture with water (5 mL). Extract the heterogeneous mixture with CH₂Cl₂ (3 x 15 mL), dry the combined organic layer over anhydrous sodium sulphate (Na₂SO₄) for 10 min and concentrate in vacuo using a rotary evaporator.
   8. Purify the crude product with flash column chromatography eluting with hexanes:EtOAc (2:1 to 1:2 v/v) to afford 165 mg (0.44 mmol, 96% yield) of 4-(R)-[1-(R)-1-phenylethyl)aziridin-2-yl]butyl 4-methylbenzenesulfonate (R_f = 0.55, hexanes:EtOAc (1:1 v/v)) as a viscous liquid.
2. Synthesis of (6R)-1-[(R)-1-phenylethyl)-1-azoniabicyclo[4.1.0]heptane tosylate (4)
   1. Transfer 5 mg of freshly prepared 2 in a NMR tube and add acetonitrile-d₃ (CD₃CN, 300 µL).
   2. Keep the above solution at RT for 24 h to attain the complete conversion to (6R)-1-[(R)-1-phenylethyl)-1-azoniabicyclo[4.1.0]heptane tosylate 4.
   3. Monitor the conversion of 2 to 4 by nuclear magnetic resonance (NMR) spectrum in CD₃CN at different time points (10 min, 1, 5, 7 and 24 h).

2. General Procedure for the Expansion of 1-Azoniabicyclo[4.1.0]Heptane Tosylate

1. Use steps 1.1.1 to 1.1.7 for the preparation of corresponding tosylate 2.
2. Add the above crude tosylate, and a magnetic stir-bar into an oven-dried 25 mL round-bottom flask.
3. Add anhydrous CH₃CN (4.0 mL) to the reaction flask using airtight syringe.
4. Add the corresponding nucleophile (1.37 mmol, 3.0 equiv) to the reaction mixture and stir for 8-15 h.
5. Quench the reaction mixture with water (5 mL), extract with CH₂Cl₂ (3 x 15 mL), dry the combined organic layer over anhydrous Na₂SO₄ and concentrate in vacuo using a rotary evaporator.
6. Purify the crude product with column chromatography by using hexanes:EtOAc (19:1 to 7:3 v/v) to afford pure ring expanded products.
   NOTE: All compounds were synthesized using above procedure except 6j (entry j, Table 1).
   Caution: Dried CH₃CN is prepared by distilling it from calcium hydride (CaH₂) under N₂ atmosphere. Sodium cyanide is toxic among the most poisonous substances known and it is used under chemical fume hood with proper safety protection. Quenching of NaCN was performed with potassium permanganate (KMnO₄) solution.

3. Synthesis of (S)-1-[(R)-1-Phenylethyl]azepan-3-ol (6j)

1. Transfer 4-(R)-[1-(R)-1-Phenylethyl)aziridin-2-yl]butyl 4-methylbenzenesulfonate (100 mg, 0.27 mmol, 1.0 equiv), and a magnetic stir-bar into an oven-dried 25 mL round-bottom flask fitted with reflux condenser.
2. Add 1,4-dioxane (4 mL) to the reaction flask using syringe.
3. Add 0.4 mL of 2.0 M sodium hydroxide solution (NaOH, 0.80 mmol, 3.0 equiv) to the reaction mixture and heat to reflux for 2.0 h.
4. Quench the reaction mixture with water (4 mL), extract with CH₂Cl₂ (4 x 15 mL), dry the combined organic layer over anhydrous Na₂SO₄ and concentrate in vacuo using a rotary evaporator.
5. Purify the crude product with column chromatography eluting with hexanes:EtOAc (2:1 to 1:1 (v/v)) (R_f = 0.60, hexanes:EtOAc (1:1 (v/v)) to afford 46 mg of (S)-1-[(R)-1-Phenylethyl]azepan-3-ol (0.21 mmol, 79% yield).

4. Synthesis of [(2R,3R,4R)-3,4-Bis(Benzyloxy)-1-(S)-1-Phenylethyl)Piperidin-2-Yl]Methyl Acetate (8):

1. Transfer (3R,4R)-3,4-bis(benzyloxy)-4-[(R)-1-(S)-1-phenylethyl)aziridin-2-yl]butan-1-ol ( 7) (220 mg, 0.51 mmol, 1.0 equiv), 180 µL of Et₃N (1.27 mmol, 2.5 equiv), and a magnetic stir-bar into an oven-dried 25 mL two-neck round-bottom flask under N₂ atmosphere.
2. Add anhydrous CH₂Cl₂ (4 mL) to the reaction flask using airtight syringe.
3. Cool the reaction mixture at 0 °C and stir for 5 min.
4. Add p-toluenesulfonic anhydride (200 mg, 0.61 mmol, 1.20 equiv) to the reaction mixture and stir for another 45 min.
5. Warm the reaction mixture to RT and stir for 30 min.
6. Monitor the progress of reaction by TLC using hexanes:EtOAc (7:3 v/v, R_f = 0.60) as an eluent.
7. After the complete consumption of alcohol 7, quench the reaction mixture with water (5 mL), extract with CH₂Cl₂ (3 x 15 mL), dry the combined organic layer over anhydrous Na₂SO₄ and concentrate in vacuo using a rotary evaporator.
8. Transfer the above crude tosylate, and a magnetic stir-bar into an oven-dried 25 mL round-bottom flask.
9. Add anhydrous CH₃CN (4 mL) to the reaction flask using airtight syringe.
10. Add 125 mg of sodium acetate (NaOAc, 1.53 mmol, 3.0 equiv) to the reaction mixture and stir for 12 h.
11. Quench the reaction mixture with water (5 mL), extract with CH₂Cl₂ (3 x 15 mL), dry the combined organic layer over anhydrous Na₂SO₄ and concentrate in vacuo using a rotary evaporator.
12. Purify the crude product with column chromatography by using hexanes: EtOAc (9:1 to 4:1 v/v) to afford pure compound 8 (200 mg, 83% yield).

5. Synthesis of (3R,4R)-3-Azido-1-[(R)-1-Phenylethyl]azepan-4-Ol (14):

1. Transfer (R)-1-[(S)-1-(R)-1-phenylethyl)aziridin-2-yl]butane-1,4-diol (13) (235 mg, 1.0 mmol, 1.0 equiv), 0.35 mL of Et₃N (2.50 mmol, 2.5 equiv), and a magnetic stir-bar into an oven-dried 25 mL two-neck round-bottom flask under nitrogen atmosphere.
2. Add anhydrous CH₂Cl₂ (8 mL, 0.12 M) to the reaction flask using airtight syringe.
3. Cool the reaction mixture at 0 °C and stir for 5 min.
4. Add p-toluenesulfonic anhydride (359 mg, 1.10 mmol, 1.10 equiv) to the reaction mixture and stir for another 45 min.
5. Monitor the progress of reaction by TLC using hexanes: EtOAc (1:1 v/v, R_f = 0.40) as an eluent.
6. After the complete consumption of starting alcohol 13, quench the reaction mixture with water (10 mL), extract with CH₂Cl₂ (3 x 15 mL), dry the combined organic layer over anhydrous Na₂SO₄ and concentrate in vacuo using a rotary evaporator.
7. Add the above crude tosylate, and a magnetic stir-bar into an oven-dried 25 mL round-bottom flask.
8. Add anhydrous CH₃CN (8 mL, 0.12 M) to the reaction flask using airtight syringe.
9. Add 214 mg of NaOAc (3.30 mmol, 3.30 equiv) to the reaction mixture and stir for 12 h.
10. Quench the reaction mixture with water (10 mL), extract with CH₂Cl₂ (15 mL x 3 times), dry the combined organic layer over anhydrous Na₂SO₄ and concentrate in vacuo using a rotary evaporator.
11. Purify the crude product with column chromatography by using hexanes: EtOAc (9:1 to 4:1 v/v) to afford pure compound 14 (133 mg, 51% yield).

6. Characterization of All Products

1. Characterize all the new compounds by ¹H, ¹³C NMR spectroscopy and high-resolution mass spectrometry (HRMS).

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