Chemistry:HBTU

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HBTU (Hexafluorophosphate Benzotriazole Tetramethyl Uronium) is a coupling reagent used in solid phase peptide synthesis. It was introduced in 1978 and shows resistance against racemization.[1][2] It is used because of its mild activating properties.[3]

HBTU is prepared by reaction of hydroxybenzotriazole with TCFH under basic conditions[4] and was assigned to a uronium type structure, presumably by analogy with the corresponding phosphonium salts, which bear a positive carbon atom instead of the phosphonium residue. Later, it was shown by X-ray analysis that salts crystallize as guanidinium rather than the corresponding uronium salts.[5][6]

Mechanism

File:Mechanism tiff.tif HBTU activates carboxylic acids by forming a stabilized HOBt (Hydroxybenzotriazole) leaving group. The activated intermediate species attacked by the amine during aminolysis is the HOBt ester.

To create the HOBt ester, the carboxyl group of the acid attacks the imide carbonyl carbon of HBTU. Subsequently, the displaced anionic benzotriazole N-oxide attacks of the acid carbonyl, giving the tetramethyl urea byproduct and the activated ester. Aminolysis displaces the benzotriazole N-oxide to form the desired amide.[7]

Safety

In vivo dermal sensitization studies according to OECD 429[8] confirmed HBTU is a moderate skin sensitizer, showing a response at 0.9 wt% in the Local Lymph Node Assay (LLNA) placing it in Globally Harmonized System of Classification and Labelling of Chemicals (GHS) Dermal Sensitization Category 1A.[9] Thermal hazard analysis by differential scanning calorimetry (DSC) shows HBTU is potentially explosive.[10]

See also

References

  1. ↑ Dourtoglou, Vassilis. (April 1978). "L'hexafluorophosphate de O-benzotriazolyl-N,N-tetramethyluronium: Un reactif de couplage peptidique nouveau et efficace". Tetrahedron Letters 19 (15): 1269–1272. doi:10.1016/0040-4039(78)80103-8. 
  2. ↑ Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. (1989). "New coupling reagents in peptide chemistry". Tetrahedron Letters 30 (15): 1927–1930. doi:10.1016/S0040-4039(00)99616-3. 
  3. ↑ Solange, A. (1992). "HBTU: a mild activating agent of muramic acid". Bioorganic & Medicinal Chemistry Letters 2 (6): 571–574. doi:10.1016/S0960-894X(01)81199-9. 
  4. ↑ , Louis A."New reagents for peptide couplings" patent WO1994007910A1, issued 1994-04-14
  5. ↑ Carpino, L.; Imazumi, H.; El-Faham, A.; Ferrer, F.; Zhang, C.; Lee, Y.; Foxman, B.; Henklein, P. et al. (2002). "The uronium/guanidinium peptide coupling reagents: Finally the true uronium salts". Angewandte Chemie International Edition 41 (3): 441–445. doi:10.1002/1521-3773(20020201)41:3<441::AID-ANIE441>3.0.CO;2-N. PMID 12491372. 
  6. ↑ Abdelmoty, I.; Albericio, F.; Carpino, L.; Foxman, B.; Kates, S. (1994). "Structural studies of reagents for peptide bond formation: Crystal and molecular structures of HBTU and HATU". Letters in Peptide Science 1 (2): 57–67. doi:10.1007/BF00126274. 
  7. ↑ Bradley, Mark; Valeur, Eric (2009-01-26). "Amide bond formation: beyond the myth of coupling reagents" (in en). Chemical Society Reviews 38 (2): 606–631. doi:10.1039/B701677H. ISSN 1460-4744. PMID 19169468. 
  8. ↑ OECD (2010) (in en). Test No. 429: Skin Sensitisation: Local Lymph Node Assay. Paris: Organisation for Economic Co-operation and Development. https://www.oecd-ilibrary.org/environment/test-no-429-skin-sensitisation_9789264071100-en. 
  9. ↑ Graham, Jessica C.; Trejo-Martin, Alejandra; Chilton, Martyn L.; Kostal, Jakub; Bercu, Joel; Beutner, Gregory L.; Bruen, Uma S.; Dolan, David G. et al. (2022-06-20). "An Evaluation of the Occupational Health Hazards of Peptide Couplers" (in en). Chemical Research in Toxicology 35 (6): 1011–1022. doi:10.1021/acs.chemrestox.2c00031. ISSN 0893-228X. PMID 35532537. 
  10. ↑ Sperry, Jeffrey B.; Minteer, Christopher J.; Tao, JingYa; Johnson, Rebecca; Duzguner, Remzi; Hawksworth, Michael; Oke, Samantha; Richardson, Paul F. et al. (2018-09-21). "Thermal Stability Assessment of Peptide Coupling Reagents Commonly Used in Pharmaceutical Manufacturing" (in en). Organic Process Research & Development 22 (9): 1262–1275. doi:10.1021/acs.oprd.8b00193. ISSN 1083-6160. https://pubs.acs.org/doi/10.1021/acs.oprd.8b00193. 



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