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The self-disproportionation of enantiomers (SDE) via column chromatography of β-amino-α,α-difluorophosphonic acid derivatives

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Abstract

This work presents the first study of the self-disproportionation of enantiomers via chromatography (SDEvC) of β-aminophosphonic acid esters, several of which have been synthesized for the first time. Three types of structures were examined, N-acetylated, dipeptide construction with N-Cbz glycine, and a free amine. In the latter case, this is the first time that SDEvC has been reported for free amine amino acids. In all the three types of structures, significant SDE magnitudes (Δee’s up to 55%) were exhibited underscoring the ubiquitous nature of the SDE phenomenon. Chemical models of homo- versus heterochiral intermolecular interactions are proposed to rationalize the SDE magnitude differences amongst these new β-aminophosphonic acid derivatives. In addition, the incorporation of additional, competing binding modes to a molecule, was found to lead to a reduction of the SDE magnitude by shifting the intermolecular binding away from the stereogenic center and/or by leading to a convoluted binding system that disrupts the structured and relatively stable assemblies that give rise to the SDE.

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References

  • Abás S, Arróniz C, Molins E, Escolano C (2018) Access to the enantiopure pyrrolobenzodiazepine (PBD) dilactam nucleus via self-disproportionation of enantiomers. Tetrahedron 74:867–871

    Article  CAS  Google Scholar 

  • Blackmond DG, Klussmann M (2007) Spoilt for choice: Assessing phase behavior models for the evolution of homochirality. Chem Commun (39):3990–3996

  • Han J, Nelson DJ, Sorochinsky AE, Soloshonok VA (2011) Self-disproportionation of enantiomers via sublimation; new and truly green dimension in optical purification. Curr Org Synth 8:310–317

    Article  CAS  Google Scholar 

  • Han J, Kitagawa O, Wzorek A, Klika KD, Soloshonok VA (2018a) The self-disproportionation of enantiomers (SDE): a menace or an opportunity? Chem Sci 9:1718–1739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han J, Soloshonok VA, Klika KD, Drabowicz J, Wzorek A (2018b) Chiral sulfoxides: Advances in asymmetric synthesis and problems with the accurate determination of the stereochemical outcome. Chem Soc Rev 47:1307–1350

    Article  CAS  PubMed  Google Scholar 

  • Han J, Wzorek A, Kwiatkowska M, Soloshonok VA, Klika KD (2019) The self-disproportionation of enantiomers (SDE) of amino acids and their derivatives. Amino Acids 51:865–889

    Article  CAS  PubMed  Google Scholar 

  • Hosaka T, Imai T, Wzorek A, Marcinkowska M, Kolbus A, Kitagawa O, Soloshonok VA, Klika KD (2019) The self-disproportionation of enantiomers (SDE) of α-amino acid derivatives: facets of steric and electronic properties. Amino Acids 51:283–294

    Article  CAS  PubMed  Google Scholar 

  • Kafarski P, Lejczak B (1991) Biological activity of aminophosphonic acids. Phosphorus Sulfur 63:193–215

    Article  CAS  Google Scholar 

  • Kafarski P, Lejczak B (2001) Aminophosphonic acids of potential medical importance. Curr Med Chem Anti-Cancer Agents 1:301–312

    Article  CAS  PubMed  Google Scholar 

  • Klika KD, Budovská M, Kutschy P (2010) NMR spectral enantioresolution of spirobrassinin and 1-methoxyspirobrassinin enantiomers using (S)-(−)-ethyl lactate and modeling of spirobrassinin self-association for rationalization of its self-induced diastereomeric anisochronism (SIDA) and enantiomer self-disproportionation on achiral-phase chromatography (ESDAC) phenomena. J Fluor Chem 131:467–476

    Article  CAS  Google Scholar 

  • Klussmann M, Iwamura H, Mathew SP, Wells DH Jr, Pandya U, Armstrong A, Blackmond DG (2006a) Thermodynamic control of asymmetric amplification in amino acid catalysis. Nature 441:621–623

    Article  CAS  PubMed  Google Scholar 

  • Klussmann M, White AJP, Armstrong A, Blackmond DG (2006b) Rationalization and prediction of solution enantiomeric excess in ternary phase systems. Angew Chem Int Ed 45:7985–7989

    Article  Google Scholar 

  • Klussmann M, Mathew SP, Iwamura H, Wells DH Jr, Armstrong A, Blackmond DG (2006c) Kinetic rationalization of nonlinear effects in asymmetric catalysis based on phase behavior. Angew Chem Int Ed 45:7989–7992

    Article  CAS  Google Scholar 

  • Klussmann M, Izumi T, White AJP, Armstrong A, Blackmond DG (2007) Emergence of solution-phase homochirality via crystal engineering of amino acids. J Am Chem Soc 129:7657–7660

    Article  CAS  PubMed  Google Scholar 

  • Kudzin ZH, Kudzin MH, Drabowicz J, Stevens CV (2011) Aminophosphonic acids–phosphorus analogues of natural amino acids. Part 1: Syntheses of α-aminophosphonic acids. Curr Org Chem 15:2015–2071

    Article  CAS  Google Scholar 

  • Kukhar VP, Hudson HR (eds) (2000) Aminophosphonic and aminophosphinic acids: Chemistry and biological activity. Wiley, Chichester

    Google Scholar 

  • Kukhar VP, Soloshonok VA, Solodenko VA (1994) Asymmetric synthesis of phosphorus analogs of amino acids. Phosphorus Sulfur 92:239–264

    Article  CAS  Google Scholar 

  • Lejczak B, Kafarski P (2009) Biological activity of aminophosphonic acids and their short peptides. In: Bansal RK (ed) Phosphorous heterocycles I. Topics in Heterocyclic Chemistry, vol 20. Springer, Berlin, pp 31–63

    Chapter  Google Scholar 

  • Maeno M, Tokunaga E, Yamamoto T, Suzuki T, Ogino Y, Ito E, Shiro M, Asahi T, Shibata N (2015) Self-disproportionation of enantiomers of thalidomide and its fluorinated analogue via gravity-driven achiral chromatography: mechanistic rationale and implications. Chem Sci 6:1043–1048

    Article  CAS  PubMed  Google Scholar 

  • Martens J, Bhushan R (2014) Purification of Enantiomeric Mixtures in Enantioselective Synthesis: Overlooked Errors and Scientific Basis of Separation in Achiral Environment. Helv Chim Acta 97:161–187

    Article  CAS  Google Scholar 

  • Matsuoka M, Goto M, Wzorek A, Soloshonok VA, Kitagawa O (2017) Diastereoselective α-alkylation of metallo enamines generated from N-C axially chiral mebroqualone derivatives. Org Lett 19:2650–2653

    Article  CAS  PubMed  Google Scholar 

  • Mayani VJ, Abdi SHR, Kureshy RI, Khan NH, Agrawal S, Jasra RV (2009) Enantiomer self-disproportionation of chiral compounds on achiral ordered mesoporous silica M41S and regular silica gel as a stationary phase. Chirality 21:255–261

    Article  CAS  PubMed  Google Scholar 

  • Mucha A, Kafarski P, Berlicki Ł (2011) Remarkable potential of the α-aminophosphonate/phosphinate structural motif in medicinal chemistry. J Med Chem 54:5955–5980

    Article  CAS  PubMed  Google Scholar 

  • Nakamura T, Tateishi K, Tsukagoshi S, Hashimoto S, Watanabe S, Soloshonok VA, Aceña JL, Kitagawa O (2012) Self-disproportionation of enantiomers of non-racemic chiral amine derivatives through achiral chromatography. Tetrahedron 68:4013–4017

    Article  CAS  Google Scholar 

  • Nieminen V, Murzin DYu, Klika KD (2009) NMR and molecular modeling of the dimeric self-association of the enantiomers of 1,1′-bi-2-naphthol and 1-phenyl-2,2,2-trifluoroethanol in the solution state and their relevance to enantiomer self-disproportionation on achiral-phase chromatography (ESDAC). Org Biomol Chem 7:537–542

    Article  CAS  PubMed  Google Scholar 

  • Ogawa S, Nishimine T, Tokunaga E, Nakamura S, Shibata N (2010) Self-disproportionation of enantiomers of heterocyclic compounds having a tertiary trifluoromethyl alcohol center on chromatography with a non-chiral system. J Fluor Chem 131:521–524

    Article  CAS  Google Scholar 

  • Orsini F, Sello G, Sisti M (2010) Aminophosphonic acids and derivatives. Synthesis and biological applications. Curr Med Chem 17:264–289

    Article  CAS  PubMed  Google Scholar 

  • Ouryupin AB, Kadyko MI, Petrovskii PV, Fedin EI, OkruszekA Kinas R, Stec WJ (1995) Enantiomeric 2-anilino-2-oxo-1,3,2-oxazaphosphorinanes: Synthesis and NMR-investigation of their non-racemic mixtures. Tetrahedron Asymmetry 6:1813

    Article  CAS  Google Scholar 

  • Reyes-Rangel G, Vargas-Caporali J, Juaristi E (2017) Asymmetric Michael addition reaction organocatalyzed by stereoisomeric pyrrolidine sulfinamides under neat conditions. A brief study of self-disproportionation of enantiomers. Tetrahedron 73:4707–4718

    Article  CAS  Google Scholar 

  • Röschenthaler G-V, Kukhar VP, Kulik IB, Sorochinsky AE, Soloshonok VA (2011) Convenient synthesis of fluoroalkyl α- and β-aminophosphonates. J Fluorine Chem 132:834–837

    Article  CAS  Google Scholar 

  • Röschenthaler G-V, Kukhar VP, Kulik IB, Belik MY, Sorochinsky AE, Rusanov EB, Soloshonok VA (2012) Asymmetric synthesis of phosphonotrifluoroalanine and its derivatives using N-tert-butanesulfinyl imine derived from fluoral. Tetrahedron Lett 53:539–542

    Article  CAS  Google Scholar 

  • Soloshonok VA (2006) Remarkable amplification of the self-disproportionation of enantiomers on achiral-phase chromatography columns. Angew Chem Int Ed 45:766–769

    Article  CAS  Google Scholar 

  • Soloshonok VA, Berbasov DO (2006a) Self-disproportionation of enantiomers on achiral phase chromatography. One more example of fluorine’s magic powers. Chim Oggi Chem Today 24:44–47

    Google Scholar 

  • Soloshonok VA, Berbasov DO (2006b) Self-disproportionation of enantiomers of (R)-ethyl 3-(3,5-dinitrobenzamido)-4,4,4-trifluorobutanoate on achiral silica gel stationary phase. J Fluor Chem 127:597–603

    Article  CAS  Google Scholar 

  • Soloshonok VA, Klika KD (2014) Terminology related to the phenomenon ‘self-disproportionation of enantiomers’ (SDE). Helv Chem Acta 97:1583–1589

    Article  CAS  Google Scholar 

  • Soloshonok VA, Cai C, Hruby VJ, Van Meervelt L (1999) Asymmetric synthesis of novel highly sterically constrained (2S,3S)-3-methyl-3-trifluoro-methyl- and (2S,3S,4R)-3-trifluoromethyl-4-methylpyroglutamic acids. Tetrahedron 55:12045–12058

    Article  CAS  Google Scholar 

  • Soloshonok VA, Roussel Ch, Kitagawa O, Sorochinsky AE (2012) Self-disproportionation of enantiomers via achiral chromatography: a warning and an extra dimension in optical purifications. Chem Soc Rev 41:4180–4188

    Article  CAS  PubMed  Google Scholar 

  • Sorochinsky AE, Katagiri T, Ono T, Wzorek A, Aceña JL, Soloshonok VA (2013a) Optical purifications via self-disproportionation of enantiomers by achiral chromatography: Case study of a series of α-CF3-containing secondary alcohols. Chirality 25:365–368

    Article  CAS  PubMed  Google Scholar 

  • Sorochinsky AE, Aceña JL, Soloshonok VA (2013b) Self-disproportionation of enantiomers of chiral, non-racemic fluoroorganic compounds: role of fluorine as enabling element. Synthesis 45:141–152

    CAS  Google Scholar 

  • Storch G, Haas M, Trapp O (2017) Attracting enantiomers: chiral analytes that are simultaneously shift reagents allow rapid screening of enantiomeric ratios by NMR spectroscopy. Chem Eur J 23:5414–5418

    Article  CAS  PubMed  Google Scholar 

  • Suzuki Y, Han J, Kitagawa O, Aceña JL, Klika KD, Soloshonok VA (2015) A comprehensive examination of the self-disproportionation of enantiomers (SDE) of chiral amides via achiral, laboratory-routine, gravity-driven column chromatography. RSC Adv 5:2988–2993

    Article  CAS  Google Scholar 

  • Szakács Z, Sánta Z, Lomoschitz A, Szántay C Jr (2018) Self-induced recognition of enantiomers (SIRE) and its application in chiral NMR analysis. Trends Anal Chem 109:180–197

    Article  CAS  Google Scholar 

  • Takahashi M, Tanabe H, Nakamura T, Kuribara D, Yamazaki T, Kitagawa O (2010) Atropisomeric lactam chemistry: catalytic enantioselective synthesis, application to asymmetric enolate chemistry and synthesis of key intermediates for NET inhibitors. Tetrahedron 66:288–296

    Article  CAS  Google Scholar 

  • Terada S, Hirai M, Honzawa A, Kitagawa O, Kamizela A, Wzorek A, Soloshonok VA (2017) Possible case of halogen bond-driven self-disproportionation of enantiomers (SDE) via achiral chromatography. Chem Eur J 23:14631–14638

    Article  CAS  PubMed  Google Scholar 

  • Turcheniuk KV, Poliashko KO, Kukhar VP, Rozhenko AB, Soloshonok VA, Sorochinsky AE (2012) Efficient asymmetric synthesis of trifluoromethylated β-aminophosphonates and their incorporation into dipeptides. Chem Commun 48:11519–11521

    Article  CAS  Google Scholar 

  • Turcheniuk KV, Kukhar VP, Röschenthaler G-V, Aceña JL, Soloshonok VA, Sorochinsky AE (2013) Recent advances in the synthesis of fluorinated aminophosphonates and aminophosphonic acids. RCS Adv 3:6693–6716

    CAS  Google Scholar 

  • Virieux D, Volle J-N, Pirat J-L (2012) Acyclic to cyclic aminophosphonic and phosphinic acids. ARKIVOC iv:264–277

    Google Scholar 

  • Wang J, Sánchez-Roselló M, Aceña JL, del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H (2014) Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001–2011). Chem Rev 114:2432–2506

    Article  CAS  Google Scholar 

  • Wzorek A, Klika KD, Drabowicz J, Sato A, Aceña JL, Soloshonok VA (2014) The self-disproportionation of the enantiomers (SDE) of methyl n-pentyl sulfoxide via achiral, gravity-driven column chromatography: a case study. Org Biomol Chem 12:4738–4746

    Article  CAS  PubMed  Google Scholar 

  • Wzorek A, Sato A, Drabowicz J, Soloshonok VA, Klika KD (2015) Enantiomeric enrichments via the self-disproportionation of enantiomers (SDE) by achiral, gravity-driven column chromatography: a case study using N-(1-phenylethyl)acetamide for optimizing the enantiomerically pure yield and magnitude of the SDE. Helv Chem Acta 98:1147–1159

    Article  CAS  Google Scholar 

  • Wzorek A, Sato A, Drabowicz J, Soloshonok VA, Klika KD (2016a) Remarkable magnitude of the self-disproportionation of enantiomers (SDE) via achiral chromatography: Application to the practical-scale enantiopurification of β-amino acid esters. Amino Acids 48:605–613

    Article  CAS  PubMed  Google Scholar 

  • Wzorek A, Sato A, Drabowicz J, Soloshonok VA (2016b) Self-disproportionation of enantiomers (SDE) of chiral nonracemic amides via achiral chromatography. Isr J Chem 56:977–989

    Article  CAS  Google Scholar 

  • Wzorek A, Sato A, Drabowicz J, Soloshonok VA (2016c) Self-disproportionation of enantiomers via achiral gravity-driven column chromatography: A case study of N-acyl-α-phenylethylamines. J Chromatogr A 1467:270–278

    Article  CAS  PubMed  Google Scholar 

  • Wzorek A, Kamizela A, Sato A, Soloshonok VA (2017) Self-disproportionation of enantiomers (SDE) via achiral gravity-driven column chromatography of N-fluoroacyl-1-phenylethylamines. J Fluorine Chem 196:37–43

    Article  CAS  Google Scholar 

  • Xie C, Zhang L, Mei H, Pajkert R, Ponomarenko M, Pan Y, Röschenthaler G-V, Soloshonok VA, Han J (2016) New chiral reagent for installation of pharmacophoric (S)- or (R)-2-(alkoxyphosphono)-1-amino-2,2-difluoroethyl groups. Chem Eur J 22:7036–7040

    Article  CAS  PubMed  Google Scholar 

  • Yasumoto M, Ueki H, Ono T, Katagiri T, Soloshonok VA (2010) Self-disproportionation of enantiomers of isopropyl 3,3,3-(trifluoro) lactate. J Fluorine Chem 131:535–539

    Article  CAS  Google Scholar 

  • Zhou Y, Wang J, Gu Z, Wang S, Zhu W, Aceña JL, Soloshonok VA, Izawa K, Liu H (2016) Next generation of fluorine-containing pharmaceuticals, compounds currently in phase II–III clinical trials of major pharmaceutical companies: New structural trends and therapeutic areas. Chem Rev 116:422–518

    Article  CAS  PubMed  Google Scholar 

  • Zhu W, Wang J, Wang S, Gu Z, Aceña JL, Izawa K, Liu H, Soloshonok VA (2014) Recent advances in the trifluoromethylation methodology and new CF3-containing drugs. J Fluorine Chem 167:37–54

    Article  CAS  Google Scholar 

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Acknowledgements

The authors are grateful for financial support from the German Research Foundation (DFG, Grant RO 362/75-1) and IKERBASQUE, Basque Foundation for Science.

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Authors and Affiliations

  1. Institute of Chemistry, Jan Kochanowski University in Kielce, Świętokrzyska 15G, 25-406, Kielce, Poland

    Magdalena Kwiatkowska, Magdalena Marcinkowska & Alicja Wzorek

  2. Department of Life Sciences and Chemistry, Jacobs University Bremen gGmbH, 28759, Bremen, Germany

    Romana Pajkert & Gerd-Volker Röschenthaler

  3. Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing, 210037, Jiangsu, China

    Jianlin Han

  4. Molecular Structure Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Karel D. Klika

  5. Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizábal 3, 20018, San Sebastián, Spain

    Vadim A. Soloshonok

  6. IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, Plaza Bizkaia, 48013, Bilbao, Spain

    Vadim A. Soloshonok

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  1. Magdalena Kwiatkowska
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  2. Magdalena Marcinkowska
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  3. Alicja Wzorek
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  4. Romana Pajkert
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  5. Jianlin Han
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  6. Karel D. Klika
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  7. Vadim A. Soloshonok
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  8. Gerd-Volker Röschenthaler
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Correspondence to Alicja Wzorek, Jianlin Han, Vadim A. Soloshonok or Gerd-Volker Röschenthaler.

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Kwiatkowska, M., Marcinkowska, M., Wzorek, A. et al. The self-disproportionation of enantiomers (SDE) via column chromatography of β-amino-α,α-difluorophosphonic acid derivatives. Amino Acids 51, 1377–1385 (2019). https://doi.org/10.1007/s00726-019-02774-7

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