Application of Trimethylsilylethoxycarbonyl (Teoc) Protecting Group

Structural formula:

The introduction mechanism of trimethylsilylethoxycarbonyl (Teoc):

The introduction of Teoc protecting group takes Teoc-Osu as an example, the mechanism is as follows:

The removal mechanism of trimethylsilylethoxycarbonyl (Teoc):

Application of Trimethylsilylethoxycarbonyl (Teoc):

In recent years, the use of silicon-based reagents for protecting active functional groups has been developing rapidly, and trimethylsilylethoxycarbonyl (Teoc) is the most used as a protecting agent for amino groups in organic synthesis and biochemistry. Trimethylsilylethoxycarbonyl (Teoc) is different from Cbz, Boc, Fmoc and Alloc. It is very stable to acids, most alkalis, and noble metal catalysis. In its presence, Cbz, Boc, Fmoc and Alloc, etc. It can be selectively deprotected, and its removal is usually carried out in fluoride anion, such as TBAF, TEAF and HF. Alternatively, TFA can also selectively deprotect the trimethylsilylethoxycarbonyl group.

Application 1: Protection of conventional amino groups

The Teoc protecting group usually uses Teoc-Cl, Teoc-NT, Teoc-OSu or Teoc-OBt to react with amino compounds in the presence of a base. The base can be an organic base pyridine or triethylamine, or an inorganic base sodium bicarbonate , so that Teoc-protected amino derivatives can be obtained.

Mamoru explained in the study of carbamate-protected amino groups that the reaction stability of the Teoc protecting group is high, the protecting reagent is not easy to absorb moisture and can even be exposed to the reaction, and the nitrotriazole produced by using Teoc-NT can also be recycled, and in most In some cases, the use of high-purity Teoc reagent can obtain amino derivatives with higher purity without tedious column chromatography purification.

Example 1: Teoc-OBt/triethylamine system, yield 92%

Example 2: Teoc-Cl/sodium bicarbonate system, yield 87%

Example 3: Teoc-Osu/triethylamine system, yield 95%

Example 4: Teoc-NT/triethylamine system, yield 98%

Application 2: Amino protection of nucleoside derivatives

Since the introduction of the Teoc protecting group is relatively clean and easy to handle, it is also often used in nucleotide protection. For example, cytidine derivatives can introduce Teoc groups without a base, as shown in the figure below:

Similarly, the 6-NH2 of adenosine derivative 14A is also very successful in selectively introducing Teoc groups under neutral conditions, but the reaction of the amino group of guanosine derivatives is difficult to carry out without a base, and triethylamine is needed. As the base, Teoc-Cl as the introduction agent, as shown in the figure below:

Although the Teoc group has been widely used in nucleoside derivatives, the introduction of the Teoc group to the 2-NH2 of 2,2'-deoxyguanosine derivatives has not been successful from the reports so far.

Application 3: Amino protection of amino acid derivatives

Due to the diversity of amino acid derivatives, the protection of their amino groups is also more important. There are a variety of protecting groups to be selected according to different needs, and the Teoc protecting group is also commonly selected.

Richard's experimental table on Teoc protection of amino acid derivatives:

L-serine uses triethylamine as the base and Teoc-Cl as the introduction agent, as shown in the figure below:

Teoc protection of L-glutamic acid, as follows:

It can be seen from the above reports that the Teoc protecting group has strong applicability in amino acid protection.

Experimental operation:

Protection on instance 1:

The starting material (3.0 g, 12.4 mmol, 1.0) was added to dichloromethane (50 mL), followed by triethylamine (3.25 g, 32.2 mmol, 2.6), and then Teoc-OBt (3.52 g, 13.63 mmol, 1.1), control the temperature at 20-25°C until the raw materials are completely consumed. Add 20mL of saturated potassium hydrogensulfate solution to the reaction, separate the organic phase and wash it with 20mL of saturated brine, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate to obtain 4.4g of the product with a yield of 92%.

Example 2 deprotection:

The raw material (5.5g, 18.68mmol, 1.0) was added to tetrahydrofuran (70mL), and tetrabutylammonium fluoride (7.33g, 28.02mmol, 1.5) was added in batches, and reacted at room temperature until the raw material was completely consumed. The reaction solution was concentrated to remove tetrahydrofuran, and the crude product obtained 2.38 g of the product by column chromatography, with a yield of 85%.

references:

[1]Boger, Dale L; Kim, Seng Heon et al., J. Am. Chem. Soc., 2001, 123(9), 1862-1871;

[2]Shute, Richard; Rich, Daniel H; Synthesis, 1987, 4, 346-349

[3] Mamoru Shimizu; Mikiko Sodeoka., ORGANIC LETTERS., 2007 , Vol. 9, No. 25, 5231-5234

[4]Seng Heon et al., J. Am. Chem. Soc., 2000, 122(30), 7416-7417

[5]Gugiu, Bogdan G; Salomon, Robert G; Org. Lett., 2003, 5(16), 2797-2800

[6]Tius, Marcus A; Thurkauf, Andrew; Tetrahedron Lett., 1986, 27(38), 4541-4544