O-(N-Succinimidyl)-1,1,3,3-tetramethyluronium Tetrafluoroborate (TSTU)

[105832-38-0]  · C9H16BF4N3O3  · (301.051)

(reagent for carboxamide formation from a carboxylic acid and a primary amine; peptide coupling reagent)

Physical Data: mp 198-201 °C.

Solubility: soluble in DMF, CH2Cl2, CHCl3, CH3CN (0.1 g mL-1), DMF/1,4-dioxane/water (2:2:1).

Form Supplied in: colorless powder. Commercially available from Advanced ChemTech (Louisville, KY, USA), Aldrich (Milwaukee, WI, USA), and Fluka Chemical (Milwaukee, WI, USA).

Handling, Storage, and Precautions: irritant (eye, skin, respiratory tract). Avoid breathing dust, vapor, moisture, or gas. Avoid contact with skin, eyes and clothing. Moisture-sensitive. For long-term storage, keep under nitrogen atmosphere and refrigerate.

Carboxamide Formation

O-(N-Succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU) reacts with carboxylic acids in the presence of ≥2 equiv base to give succinimidyl active esters,1,2 which are capable of reacting with primary amines to afford carboxamides (eq 1). The coupling reactions between carboxylic acids and primary amines with TSTU can also be performed in situ. The reaction proceeds rapidly and efficiently with only a slight excess of TSTU. The coupling reaction can be carried out even in the presence of water, such as in DMF/1,4-dioxane/water mixtures.3 This feature allows hydrophilic amines to be derivatized with hydrophobic carboxylic acids, as demonstrated in the coupling of bathophenanthroline-ruthenium(III) complexes and 5-amino-5-deoxy oligonucleotides.1

The amino group of an amino alcohol can be selectively acylated by using TSTU without O-protection (eq 2).

TSTU can be employed as a coupling reagent in peptide synthesis, like analogous reagents (see Related Reagents). An amino acid, of which the a-amino group is protected with a urethane-type protecting group, e.g. Boc, Cbz, or Fmoc, can be coupled without a significant level of enantiomerization or epimerization. The segment condensation with these reagents, however, causes significant levels of epimerization of the carboxy-terminal amino acid residue of the acyl component except the cases where the carboxy-terminal residue is Gly or Pro.

Peptides having a C-terminal N-methylamino acid residue are highly prone to epimerization in the segment condensation. Simultaneous use of N-hydroxysuccinimide and CuCl2 with TSTU eliminates the epimerization of the N-methylamino acid residue (eq 3), whereas analogous coupling reagents, (benzotriazol-1-yl)oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), give significant levels of epimerization, even in the presence of CuCl2.4

Related Reagents.

(Benzotriazol-1-yl)oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) [56602-33-6];5 (benzotriazol-1-yl)oxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) [128625-52-5];6 O-(N-benzotriazolyl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) [94790-37-1];7 O-(N-benzotriazolyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) [125700-67-6];2 2-(5-norbornene-2,3-dicarboxamido)-1,1,3,3-tetramethyluronium tetrafluoroborate (TNTU) [125700-73-4];2 (7-azabenzotriazol-1-yl)oxytris(pyrrolidino)phosphonium hexafluorophosphonate (PyAOP) [156311-83-0];8 O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) [148893-10-1].9

1. Bannwarth, W.; Schmidt, D.; Stallard, R. L.; Hornung, C.; Knorr, R.; Muller, F., Helv. Chim. Acta 1988, 71, 2085.
2. Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillssen, D., Tetrahedron Lett. 1989, 30, 1927.
3. Bannwarth, W.; Knorr, R., Tetrahedron Lett. 1991, 32, 1157.
4. Nishiyama, Y.; Ishizuka, S.; Mori, T.; Kurita, K., Chem. Pharm. Bull. 2000, 48, 442.
5. Castro, B..; Dormoy, J. R..; Evin, G..; Selve, C., Tetrahedron Lett. 1975, 1219.
6. Coste, J.; Le-Nguyen, D.; Castro, B., Tetrahedron Lett. 1990, 31, 205.
7. Dourtoglou, V.; Ziegler, J. C.; Gross, B., Tetrahedron Lett. 1978, 1269.
8. Albericio, F.; Cases, M.; Alsina, J.; Triolo, S. A.; Carpino, L. A.; Kates, S. A., Tetrahedron Lett. 1997, 38, 4853.
9. Carpino.; L. A., J. Am. Chem. Soc. 1993, 115, 4397.

Yasuhiro Nishiyama

University of Texas-Houston Medical School, Houston, TX, USA

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