One-pot Microwave-assisted Conversion of Anomeric Nitrate-esters to Trichloroacetimidates

Podsumowanie

A 2-azido-1-nitrate-ester can be converted to the corresponding 2-azido-1-trichloroacetimidate in a one-pot procedure. The goal of the manuscript is to demonstrate utility of the microwave reactor in carbohydrate synthesis.

Streszczenie

The goal of the following procedure is to provide a demonstration of the one-pot conversion of a 2-azido-1-nitrate-ester to a trichloroacetimidate glycosyl donor. Following azido-nitration of a glycal, the product 2-azido-1-nitrate ester can be hydrolyzed under microwave-assisted irradiation. This transformation is usually achieved using strongly nucleophilic reagents and extended reaction times. Microwave irradiation induces hydrolysis, in the absence of reagents, with short reaction times. Following denitration, the intermediate anomeric alcohol is converted, in the same pot, to the corresponding 2-azido-1-trichloroacetimidate.

Wprowadzenie

Due to their ubiquity in molecular biology, carbohydrates have been longstanding targets for chemical synthesis.^1,2,3 At the core of any successful synthetic campaign is the correct deployment of glycosylation reactions to build the oligosaccharide chain.^{4,5,6,7,8,9,10,11,12} Not surprisingly, there are a large number of methods to install glycosidic bonds.^13,14 The Koenigs-Knorr method is one of the earliest known procedures and involves coupling a glycosyl chloride or bromide with an alcoholic component, usually under heavy metal (mercury or silver) activation.¹⁵ Related glycosyl fluorides were first introduced as donors in 1981 by the Mukaiyama group and have found widespread application due to their increased thermal and chemical stability.¹⁶ On the opposite end of the reactivity spectrum are glycosyl iodides, which are far more reactive than the other halides. Increased reactivity is accompanied by increased stereocontrol, particularly when forming α-linked oligosaccharides.¹⁷ In addition to "haloglycosides", thioglycosides have found wide utility, in part, due to their ease of formation, stability to a multitude of reaction conditions, and activation with electrophilic reagents.¹⁸

The methods described above focus on converting an anomeric alcohol to a "non-oxygen" containing, latent leaving group that is activated and ultimately displaced by an alcohol from an acceptor molecule. Anomeric oxygen activation as described by the Schmidt school, focuses on converting the C1 oxygen itself, to a leaving group.¹⁹ This method is the most powerful and widely used in chemical glycosylation reactions. Trichloroacetimidate donors are readily prepared from a reducing sugar and trichloroacetonitrile in the presence of a base such as potassium carbonate (K2CO3) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). These species are then activated using Lewis acids.²⁰

Recently, we have reported that 2-azido-1-trichloroacetimidate donors can be directly prepared from glycals. The process involves a two reaction, one-pot procedure from 2-azido-1-nitrate esters.²¹ This detailed protocol is intended to assist practitioners in successfully completing the transformation in high yield. Of particular interest is the first step of the sequence, which focuses on thermal denitration under microwave- assisted heating. We also hope to provide a visual tutorial on employing microwave reactors in organic synthesis.

Protokół

1. Representative Microwave-Assisted Denitration

1. Place the azido nitrate ester (1.0 equiv., 0.2 mmol) in an 8 mL microwave reaction vial. The scale of the reaction can be increased to several mmol without any adverse effect on reaction progress.
2. Dissolve the azido-nitrate ester in 20% aq. acetone (0.1 M, 2.0 mL). Add pyridine (5.0 equiv., 0.08 mL, 1.0 mmol) to the reaction vessel. Cap the microwave irradiation vial and place the reaction vessel in a microwave reactor cavity.
3. Irradiate the solution at 120 °C for 15 min with stirring and with a fixed hold time. The hold time represents how long the irradiation will occur at the designated temperature and resultant pressure. Heat all reactions to the reported temperature over a 2-minute ramping period. Monitor the temperature by a builtin IR sensor.
4. After 15 min, analyze the reaction mixture using thin layer chromatography (TLC) to confirm consumption of the starting material. Use 1:1 ethyl acetate/hexanes as the eluent.
   1. Visualize the TLC plate using ceric ammonium molybate stain. The R_f of the reactant and product will vary, but the reducing alcohol is generally 0.05 to 0.1 lower R_f than the reactant.

2. Formation of the trichloroacetimidate

1. Following complete consumption of the starting material, evaporate the solvent to a reduced volume using an airline. Then, dilute with (dichloromethane) CH₂Cl₂ (1.0 mL) and use a syringe to remove the water layer. Once the water layer is removed, cool the reaction mixture to 0 °C using an ice-water bath.
2. Next, add DBU (10 eq, 0.3 mL, 1.9 mmol) and 2,2,2-trichloroacetonitrile (50 eq, 1.0 mL, 10 mmol) to the reaction vessel. Both reagents are added in excess and a minimum of 1 equivalent of base and 1 equivalent of 2,2,2-trichloroacetonitrile are needed.
3. Allow the reaction mixture to stir while warming to ambient temperature. Monitor the reaction by TLC to confirm consumption of the starting material.
   1. Use 1:1 ethyl acetate/hexanes as the eluent. Visualize the TLC plate using ceric ammonium molybate stain. The R_f of the reactant and product will vary.
4. After complete consumption of starting material, transfer the reaction mixture to a recovery flask and concentrate the mixture in vacuo at 30 °C. Evaporation of solvent will provide a crude pale yellow to brown oil.
5. Purify the crude product by silica gel column chromatography with a 1.5 cm chromatography column and 1:4 ethyl acetate/hexanes as eluent. The physical form of the imidate will vary from molecule to molecule.

Figure 1. Representative examples of the one-pot conversion of 2-azido-1-nitrate esters to 2-azido-1-trichloroimidates. Please click here to view a larger version of this figure.

Wyniki

The technology described herein was demonstrated on a pool of three 2-azido-1-nitrate esters. In each case the first step of the reaction was complete within 20 minutes.

Figure 2. Representative example of hydrolysis (1 ->2), and one-pot conversion of 2-azido-1-nitrate ester of

Dyskusje

The protocol described in this tutorial provides a method to convert nitrate esters to useful, reactive functionality. In a broader sense, employing a microwave reactor to complete specific maneuvers over the course of a carbohydrate synthesis has the potential to make difficult transformations facile and routine. Our goal in this tutorial is to demonstrate how to handle carbohydrates in the context of microwave irradiation.

In the case of the parent reaction, previous efforts to achieve denit...

Materiały

Name	Company	Catalog Number	Comments
230 400 mesh silica gel	SiliCycle Inc	R10030B
TLC plates	SiliCycle Inc	TLG-R10014B-527
Ceric ammonium molybdate	Sigma-Aldrich	A1343
Solvent Still	Mbraun	MB-SPS-800
Infared spectrometer	Thermo	Thermo Electron IR100
Nuclear Magnetic Resonance	Bruker		400, 600 MHz
LC/MS	Thermo/Dionex		Single quad, ESI
HRMS	Agilent	Synapt G2 S HDMS
Microwave reactor	Anton Parr	Anton Parr G10 Monowave 200
DBU	Sigma-Aldrich	139009
CCl3CN	Sigma-Aldrich	T53805
Pyridine	Sigma-Aldrich	270970
Acetone	Fisher Scientific	A18-20	Tech. grade
Phase separator	Biotage	120-1901-A
Rotary evaporator	Buchi	R-100