Controlling Site Selectivity in the Phosphorylation of Amphiphilic Diols: Aminopyridine Organocatalysts vs. Stoichiometric Amine Bases
Shai Ben Sasson, Noa Naama, Mikhail Kozlov, Ibrahim Amer, Moshe Portnoy
Organics · pp. 25–25 · Published 11 Jun 2026
10.3390/org7020025Abstract
Our recent studies demonstrated that dialkylaminopyridine organocatalysts featuring an extensive secondary sphere preferentially phosphorylate the alcohol at the apolar domain of a model amphiphilic diol. In the present study, this site-selective behavior was corroborated across a broader range of amphiphilic diols. Furthermore, we found that the site selectivity can be inverted by applying certain saturated aliphatic amine bases in stoichiometric amounts. Screening identified cis-2,6-dimethylpiperidine as the most selective promoter, consistently inducing phosphorylation at the polar domain across all tested diols. Remarkably, despite being a secondary amine, this base did not produce any detectable phosphoramidate byproduct.
References (51)
- 1 Westheimer, 1987, Why Nature chose phosphates [DOI]
- 2 Bowler, 2010, Why did Nature select phosphate for its dominant roles in biology? [DOI]
- 3 Marks, F. (1996). Protein Phosphorylation, Wiley-VCH. [DOI]
- 4 Hunter, 2012, Why nature chose phosphate to modify proteins [DOI]
- 5 Derouiche, 2012, Protein phosphorylation from the perspective of systems biology [DOI]
- 6 Brognard, 2011, Protein kinase signaling networks in cancer [DOI]
- 7 Berridge, 1984, Inositol triphosphate, a novel 2nd messenger in cellular signal transduction [DOI]
- 8 Berridge, 1989, Inositol phosphates and cell signaling [DOI]
- 9 Potter, 1995, Chemistry of inositol lipid-mediated cellular signaling [DOI]
- 10 Balla, 2013, Phosphoinositides: Tiny lipids with giant impact on cell regulation [DOI]
- 11 Dowhan, 1997, Molecular basis for membrane phospholipid diversity: Why are there so many lipids? [DOI]
- 12 Hunter, 1995, Protein-kinases and phosphatases—The yin and yang of protein-phosphorylation and signaling [DOI]
- 13 Crans, 1985, Glycerol kinase: Synthesis of dihydroxyacetone phosphate, sn-glycerol-3-phosphate, and chiral analogs [DOI]
- 14 Chenault, 1998, Kinetic chiral resolutions of 1,2-diols and desymmetrization of glycerol catalyzed by glycerol kinase [DOI]
- 15 Wohlgemuth, 2017, Biocatalytic phosphorylations of metabolites: Past, present, and future [DOI]
- 16 Gauss, 2018, Phosphorylation catalyzed by dihydroxyacetone kinase [DOI]
- 17 Wohlgemuth, 2021, Key advances in biocatalytic phosphorylations in the last two decades: Biocatalytic syntheses in vitro and biotransformations in vivo (in humans) [DOI]
- 18 Matsumi, 2014, Biocatalytic asymmetric phosphorylation of mevalonate [DOI]
- 19 Hardt, 2017, Biocatalytic asymmetric phosphorylation catalyzed by recombinant glycerate-2-kinase [DOI]
- 20 Domon, 2020, Catalytic chemoselective O-phosphorylation of alcohols [DOI]
- 21 Ociepa, 2021, Mild and chemoselective phosphorylation of alcohols using a Psi-reagent [DOI]
- 22 Huang, 2021, A P(V) platform for oligonucleotide synthesis [DOI]
- 23 Eason, 2023, Catalyst identification for chemoselective phosphorylation of phenols and aliphatic alcohols [DOI]
- 24 Rygus, 2023, Direct nucleophilic and electrophilic activation of alcohols using a unified boron-based organocatalyst scaffold [DOI]
- 25 Yoshida, 2024, Organocatalyzed amine-free O-phosphorylation of alcohols with 4-methylpyridine N-oxide [DOI]
- 26 Lv, 2025, SnCl2-catalyzed phosphorylation of alcohols and selective phosphorylation/phosphinoylation of carbohydrates [DOI]
- 27 Han, 2013, Asymmetric catalysis at a distance: Catalytic, site-selective phosphorylation of teicoplanin [DOI]
- 28 Coppola, 2014, Selective phosphorylation of diols with a Lewis acid catalyst [DOI]
- 29 Konowalchuk, 2025, Selective monophosphorylation of cyclic diols and polyols via hemiboronic acid catalysis [DOI]
- 30 Murray, 2014, Highly efficient and selective phosphorylation of amino acid derivatives and polyols catalysed by 2-aryl-4-(dimethylamino)pyridine-N-oxides—Towards kinase-like reactivity [DOI]
- 31 Sculimbrene, 2001, Discovery of a catalytic asymmetric phosphorylation through selection of a minimal kinase mimic: A concise total synthesis of D-myo-inositol-1-phosphate [DOI]
- 32 Sculimbrene, 2002, Enantiodivergence in small-molecule catalysis of asymmetric phosphorylation: Concise total syntheses of the enantiomeric D-myo-inositol-1-phosphate and D-myo-inositol-3-phosphate [DOI]
- 33 Liu, 2012, First catalytic enantioselective synthesis of P-stereogenic phosphoramides via kinetic resolution promoted by a chiral bicyclic imidazole nucleophilic catalyst [DOI]
- 34 Ouellette, 2021, Desymmetrization of diols by phosphorylation with a titanium-BINOLate catalyst [DOI]
- 35 DiRocco, 2017, A multifunctional catalyst that stereoselectively assembles prodrugs [DOI]
- 36 Wang, 2020, Catalytic asymmetric synthesis of the anti-COVID-19 drug Remdesivir [DOI]
- 37 Gannedi, 2021, Practical Remdesivir synthesis through one-pot organocatalyzed asymmetric (s)-p-phosphoramidation [DOI]
- 38 Fallek, 2022, Improving site selectivity in phosphorylation of amphiphilic diols through catalyst design [DOI]
- 39 Fleischer, O., Targel, T., Saady, F., and Portnoy, M. (2023). Similarities and differences between site-selective acylation and phosphorylation of amphiphilic diols, promoted by nucleophilic organocatalysts decorated with outer-sphere appendages. Catalysts, 13. [DOI]
- 40 Saady, 2024, Tuning the Structure of 4-Aminopyridine Catalysts for Improved Activity and Selectivity in Functionalization of Alcohols [DOI]
- 41 Ashush, 2020, Base- and catalyst-induced orthogonal site selectivities in acylation of amphiphilic diols [DOI]
- 42 Fallek, 2020, Phosphorylation organocatalysts highly active by design [DOI]
- 43 Fallek, 2021, Goldilocks effect of base strength on site selectivity in acylation of amphiphilic diols [DOI]
- 44 Castells, 1983, The formoin reaction [DOI]
- 45 Ammer, 2010, Nucleophilic reactivities of tertiary alkylamines [DOI]
- 46 Leffek, 1989, Basicity of substituted 2-phenyl-1,1,3,3-tetramethylguanidines and other bases in acetonitrile solvent [DOI]
- 47 Baidya, 2007, DABCO and DMAP—Why are they different in organocatalysis [DOI]
- 48 Baidya, 2008, Nucleophilicities and carbon basicities of DBU and DBN
- 49 Maji, 2012, Guanidines: Highly nucleophilic organocatalysts [DOI]
- 50 Jones, 2016, DBN hexafluorophosphate salts as convenient sulfonylating and phosphonylating agents [DOI]
- 51 Kanzian, T., Nigst, T., Maier, A., Pichl, S., and Mayr, H. (2009). Nucleophilic reactivities of primary and secondary amines in acetonitrile. Eur. J. Org. Chem., 6379. [DOI]
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