Subscribe to RSS
DOI: 10.1055/s-0035-1561387
Intramolecular Catalysis of Hydrazone Formation of Aryl-Aldehydes via ortho-Phosphate Proton Exchange
Publication History
Received: 27 September 2015
Accepted after revision: 19 January 2016
Publication Date:
17 February 2016 (online)
![](https://www.thieme-connect.de/media/synlett/201609/lookinside/thumbnails/st-2015-b0769-l_10-1055_s-0035-1561387-1.jpg)
Abstract
Bioorthogonal site-specific chemical reaction to label biomolecules in vitro and in living cells is one of the most powerful and convenient tools in chemical biology. Reactive pairs frequently used for chemical conjugation are aldehydes/ketones with hydrazines/hydrazides/hydroxylamines. Although the reaction is generally specific for the two components, even in a cellular environment, the reaction is very slow under physiological conditions. Addition of a phosphate group at the ortho position of an aromatic aldehyde increases the reaction rate by an order of magnitude and enhances the aqueous solubility of the reagent and the product. We have synthesized phosphate-substituted aldehyde synthetic models to study kinetics of their reactions with hydrazines and hydrazides that contain a fluorophore. This rapid bioorthogonal reaction should therefore be potentially a very useful reaction for routine site-specific chemical ligations to study and image complex cellular processes in biological systems.
Supporting Information
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0035-1561387.
- Supporting Information
-
References and Notes
- 1 Chattopadhaya S, Abu Bakar FB, Yao SQ. Curr. Med. Chem. 2009; 16: 4527
- 2 King M, Wagner A. Bioconjugate Chem. 2014; 25: 825
- 3 Jencks WP. J. Am. Chem. Soc. 1959; 81: 475
- 4a Jencks WP. Catalysis in Chemistry and Enzymology (McGraw-Hill Series in Advanced Chemistry). McGraw-Hill; New York: 1969: 644
- 4b Schmidt P, Zhou L, Tishinov K, Zimmermann K, Gillingham D. Angew Chem. Int. Ed. 2014; 53: 10928
- 4c Schmidt P, Stress C, Gillingham D. Chem. Sci. 2015; 6: 329
- 4d Bandyopadhyay A, Gao J. Chem. Eur. J. 2015; 21: 14748
- 4e Cal PM. S. D, Vicente JB, Pires E, Coelho AV, Veiros LF, Cordeiro C, Gois PM. P. J. Am. Chem. Soc. 2012; 134: 10299
- 5 Dirksen A, Dawson PE. Bioconjugate Chem. 2008; 19: 2543
- 6 Wendeler M, Grinberg L, Wang X, Dawson PE, Baca M. Bioconjugate Chem. 2014; 25: 93
- 7 Kool ET, Crisalli P, Chan KM. Org. Lett. 2014; 16: 1454
- 8 Wang X, Canary JW. Bioconjugate Chem. 2012; 23: 2329
- 9 Crisalli P, Kool ET. Org. Lett. 2013; 15: 1646
- 10a Dilek Ö, Bane SL. Tetrahedon Lett. 2008; 49: 1413
- 10b Banerjee A, Panosian TD, Mukherjee K, Ravindra R, Gal S, Sackett DL, Bane S. ACS Chem. Biol. 2010; 5: 777
- 11 Synthesis of Compound 5 Coumarin hydrazine2 (100 mg, 0.44 mmol) was added to dibenzyl-SA-P (0.162 g, 0.44 mmol) in MeOH. The reaction was stirred at r.t. for 2 h. Completion of the reaction was monitored by TLC. The precipitate was filtered and washed with excess MeOH and dried. Yellow product was obtained (130 mg, yield 55%). 1H NMR (DMSO-d 6): δ = 2.36 (s, 3 H), 5.17 (s, 2 H), 7.26 (s, 2 H), 5.20 (s, 2 H), 6.07 (s, 1 H), 6.99–7.05 (m, 2 H), 7.25–7.39 (m, 14 H), 7.62 (d, 1 H), 8.23 (s, 1 H), 11.09 (s, 1 H) ppm. 13C NMR (DMSO-d 6): δ = 18.0, 69.6, 97.9, 109.3, 109.5, 111.8, 120.6, 125.6, 125.9, 126.5, 126.6, 127.9, 128.5, 128.6, 129.7, 133.7, 135.5, 135.6, 147.7, 147.8, 148.3, 158.4, 155.1, 160.4 ppm. Synthesis of Compound 6 (Deprotection) Compound 5 was added to TFA–CH2Cl2 (1:1) and stirred at r.t. for overnight. Solvent was removed to yield actual product (60 mg, yield 100%). 1H NMR (DMSO-d 6): δ = 2.35 (s, 3 H), 6.05 (s, 1 H), 6.95–7.06 (m, 2 H), 7.14–7.39 (m, 3 H), 7.60 (d, 1 H), 8.01 (d, 1 H), 8.26 (s, 1 H), 11.09 (s, 1 H) ppm. 13C NMR (DMSO-d 6): δ = 18.0, 97.8, 109.3, 111.6, 120.9, 124.4, 125.4, 126.5, 126.7, 129.6, 135.1, 148.6, 149.4, 149.5, 153.6, 155.2, 160.5 ppm. ESI-MS [M+]: 373.08; found: 374.
- 12 Bender ML, Lawlor JM. J. Am. Chem. Soc. 1963; 85: 3010
- 13 Silverberg JL, Dillon LJ, Vemishetti P. Tetrahedron Lett. 1996; 27: 771