Leninsky Prospect, 47, Moscow
Phone: +7 499 137-29-44
Fax: +7 499 135-53-28

I. N. Nazarov Laboratory of Fine Organic Synthesis (N11)

Head: Prof. Sergei G. Zlotin (e-mail: zlotinioc.ac.ruб tel. +7(499) 135-63-45)

The laboratory was established in 1938 and headed by Full Member of the Academy I.N. Nazarov (1938-1957), Prof. V.F. Kucherov (1958-1980), and Prof. E.P. Serebryakov, Assoc. Memb. Acad. Sc. (1980-2000).

  1. Main directions of research:
  • Development of novel efficient and sustainable hybrid organocatalysts for asymmetric synthesis of chiral bioactive compounds;
  • Environment friendly synthesis of practically important organic compounds in fluid media (sub- or supercritical carbon dioxide, fluorinated hydrocarbons)

 

  1. Recent results:
  • A new area of asymmetric organocatalysis has been elaborated, which is based on the use of chiral amine/ionic liquid hybrid catalysts [“Ionic Liquid Organocatalysts”, in Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and Applications, ed. P.I. Dalco, Wiley-VCH, 2013, v. 2, p. 617-650; Russ. Chem. Bull., Int. Ed., 2012, 61, 1313; Russ. Chem. Rev., 2009, 78, 737; 2011, 80, 1067; 2015, 84, 1077]. Novel a-aminoacid, a-aminoamide and other chiral amine derivatives non-covalently supported on organic polyelectrolyte (poly(diallyldialkylammonium) hexafluorophosphate or sulfated polystyrene) or tagged to a cation fragment (imidazolium, triazolium, pyridinium) by the covalent bond have been synthesized. Most of the prepared compounds melt below 150oC and can be considered as task-specific chiral ionic liquids (Scheme 1).

 

 

  • Anti- and syn-aldol reactions, in particular in aqueous medium, asymmetric Michael reactions involving iminium ion formation step and Michael-initiated domino reactions have been successfully accomplished in the presence of the prepared IL-modified catalysts (5-15 мол. %) to afford corresponding chiral products with extremely high diastereo- (dr up to 99:1) and enantioselectivity (up to 99% ee). Furthermore, a poorly soluble in organic solvents and (in some cases) in water IL-supported catalysts can be easily separated from chiral products and reused up to 15 times in the same or similar reactions without a significant decrease of product yields and enantioselectivity of the reactions (Scheme 2).

 

Scheme 2 Asymmetric aldol, Michael and Michael-initiated domino reactions in the presence of IL-modified organocatalysts

 

  • Chiral ILs have been successfully applied for the first time as organocatalysts of key stereocontrolling transformations which are used for the synthesis of chiral medications and practically important natural compounds or their analogues. Among them, precursors of the most active enantiomers of chiral drugs Phenibut, Baclofen, Rolipram and Paroxetine used in CNS disorders therapy, clinically useful anticoagulant Warfarin, important b-aminoacids (b-phenylalanine, b-tyrosine, and b-DOPA) and compounds containing functionalized syn-aldol fragments, which are integral parts of carbohydrates and some other natural compounds, have been efficiently synthesized in the presence of developed catalysts (Scheme 3).

Scheme 3 Bioactive compounds that can be produced using the developed organocatalysts

 

  • An original approach to the study of deactivation pathways of supported organocatalysts in asymmetric reactions has been proposed, which is based on the combined use of “marked” with ionic group organocatalysts and electrospray ionization mass spectrometry ESI(+). The ESI-MS spectra of recovered ionic catalysts contain mainly peaks of the catalyst and of ionic compounds formed from the catalyst whereas the molecules that do not contain ionic groups gave much lower peaks. As a result, “parasitic” side reactions and undesirable cation intermediates that poisoned the catalyst (O-TMS-a,a-diphenylprolinol derivative) were identified in accordance with their m/z values and an efficient solution to increase the lifetime of the catalyst (> 10 cycles) was suggested. The proposed approach may be used for the study of transformations of other types of organocatalysts modified with ionic groups in various organocatalytic reactions and for the development of novel robust catalysts and processes that would be suitable for large-scale industrial applications (Scheme 4).

    Scheme 4 Chiral ionic liquid/ESI-MS methodology as an efficient tool for the study of transformations of supported organocatalysts

    Recent publications in the field of asymmetric organocatalysis and fine organic synthesis:

    1. R.S. Tukhvatshin, A.S. Kucherenko, Y.V. Nelyubina, S.G. Zlotin. Tertiary Amine-Derived Ionic Liquid-Supported Squaramide as a Recyclable Organocatalyst for Noncovalent “On Water” Catalysis. ACS Catal., 2017, 7, 2981-2989 (doi: 10.1021/acscatal.7b00562).
    2. V.V. Gerasimchuk, A.S. Kucherenko, A.N. Fakhrutdinov, M.G. Medvedev, Y.V. Nelyubina, S.G. Zlotin. Towards sustainable amino acid-derived organocatalysts for asymmetric syn-aldol reactions.Eur. J. Org. Chem., 2017, (doi: 10.1002/ejoc.201700166).
    3. M.G. Vinogradov, O.V. Turova, S.G. Zlotin, New achievements in the chemistry of N-acyliminium ions and their use in stereoselective organic synthesis, Russ. Chem. Rev., 2017, 86, 1–17 (doi: 10.1070/RCR4628) (IF 3.687).
    4. S.G. Zlotin, Hydroxyproline Derivatives as Asymmetric Organocatalysts, in:  Sustainable Catalysis: Without Metals or Other Endangered Elements, M. North (Ed.), Part 1, 2016, 236-261 (ISBN: 978-1-78262-640-4).
    5. A.S. Kucherenko, V.G. Lisnyak, A.A. Kostenko, S.V. Kochetkov, S.G. Zlotin. C2-Symmetric pyrrolidine-derived squaramides as recyclable organocatalysts for asymmetric Michael reactions. Org. Biomol. Chem., 2016, 14, 9751-9759 (doi: 10.1039/c6ob01606e).
    6. A.Yu. Sukhorukov, A.A. Sukhanova, S.G. Zlotin, Stereoselective Reactions of Nitro Compounds in the Synthesis of Natural Compound Analogs and Active Pharmaceutical Ingredients, Tetrahedron, 2016, 72, 6191-6281 (doi: 10.1016/j.tet.2016.07.067).
    7. A. S. Kucherenko,V. V. Perepelkin,G. M. Zhdankina, G. V. Kryshtal,E. Srinivasan,H. Inani, S. G. Zlotin. Ionic liquid supported 4-HO-Pro-Val derived organocatalysts for asymmetric aldol reactions in the presence of water. Mendeleev Commun., 2016, 26, 388-390 (doi: 10.1016/j.mencom.2016.09.007).
    8. A.A. Sukhanova, Y.V. Nelyubina, S.G. Zlotin, Asymmetric synthesis of 3-prenyl-substituted pyrrolidin-2-ones, Mendeleev Commun., 2016, 26, 471–473 (doi: 10.1016/j.mencom.2016.11.003).
    9. A.G. Zavozin, N.I. Simirskaya, Y.V. Nelyubina, S.G. Zlotin, Novel di- and tetra(pyrazolyl)bipyridine ligands and their Co (II)-complexes for electrochemical applications, Tetrahedron, 2016, 72, 7552-7556 (doi: 10.1016/j.tet.2016.10.006).
    10. G.V. Kryshtal, G.M. Zhdankina, N.V. Ignat’ev, M. Schulte, S.G. Zlotin. The orthoester Johnson-Claisen rearrangement of allylic terpenols in the presence of acidic ionic liquid. J. Fluor. Chem., 2016, 183, 23-29 (doi: 10.1016/j.jfluchem.2016.01.005).
    11. V.G. Lisnyak, A.S. Kucherenko, E.F. Valeev, S.G. Zlotin. (1,2-Diaminoethane-1,2-diyl)bis(N-methylpyridinium) salts as a prospective platform for designing recyclable prolinamide-based organocatalysts. J. Org. Chem., 2015, 80, 9570−9577 (doi: 10.1021/acs.joc.5b01555).
    12. A.S. Kucherenko, V.V. Gerasimchuk, V.G. Lisnyak, Y.V. Nelyubina, S.G. Zlotin. Prolinamide-Derived Ionic-Liquid-Supported Organocatalyst for Asymmetric Mono- and Bis-Aldol Reactions in the Presence of Water. Eur. J. Org. Chem., 2015, 5649–5654 (doi: 10.1002/ejoc.201500775).
    13. S.G. Zlotin, S.V. Kochetkov. C2-Symmetric diamines and their derivatives as promising organocatalysts for asymmetric synthesis. Russ. Chem. Rev., 2015, 84, 1077-1099 (doi: 10.1070/RCR4562).
    14. S.V. Kochetkov, A.S. Kucherenko, S.G. Zlotin. Asymmetric aldol reactions in ketone/ketone systems catalyzed by ionic liquid-supported С2-symmetrical organocatalyst. Mendeleev Commun., 2015, 25 (3), 168-170 (doi: 10.1016/j.mencom.2015.05.002).
    15. A.G. Zavozin, N.V. Ignat’ev, M. Schulte, S.G. Zlotin. Synthesis of novel tridentate pyrazole-bipyridine ligands for Co-complexes as redox-couples in dye-sensitized solar cells. Tetrahedron, 2015, 71, 8551-8556 (doi: 10.1016/j.tet.2015.09.032).

      • Some practically useful carbon-carbon and carbon-heteroatom bond forming reactions have been accomplished for the first time in sub- and supercritical (sc) carbon dioxide medium. Among them, the nitration of amines and alcoholes, palladium catalyzed cross-coupling of polychlorinated arenes with arylboronic acids, asymmetric allylation of carbon acids with (E)-1,3-diphenyl allyl acetate and organocatalytic asymmetric additions of carbo- and heteronucleofiles to a-nitroalkenes proceed in carbon dioxide medium efficiently to afford corresponding N- or O-nitro compounds or C-C cross-coupling products in high yields and with high selectivity (enantioselectivity) (Scheme 5). The proposed conditions allow significantly reducing explosion and fire risks and improve environment friendliness of the processes. A significant potential of the supercritical extraction for product isolation and catalyst recovery was demonstrated. The obtained results contribute to green chemistry as they eliminate toxic organic solvents (in particular, CH2Cl2) originated from exhausting hydrocarbon resources and facilitate separation and purification steps that usually have the highest environmental impact in chemical processes.

Recent publications in the field of organic synthesis (in particular, enantioselective) in sub- or supercritical fluids

  1. M.N. Zharkov, I.V. Kuchurov, I.V. Fomenkov, V.A. Tartakovsky, I.V. Fedyanin, S.G. Zlotin. Safe and Convenient Synthesis of Primary N-Nitramines in the Freon Media. Synthesis, 2017, 49, 1103-1108 [http://dx.doi.org/10.1055/s-0036-1588616].
  2. E.V. Filatova, O.V. Turova, I.V. Kuchurov, A.A. Kostenko, A.G. Nigmatov, S.G. Zlotin. Asymmetric catalytic synthesis of functionalized tetrahydroquinolines in supercritical fluids. J. Supercrit. Fluids, 2016, 109, 35-42 (doi: 10.1016/j.supflu.2015.11.004).
  3. S.G. Zlotin, A.M. Churakov, O.A. Luk’yanov, N.N. Makhova, A.Yu. Sukhorukov, V.A. Tartakovsky. Novel approaches to pharmacology-oriented and energy rich organic nitrogen–oxygen systems. Mendeleev Commun., 2015, 25, 399-409 (doi: 10.1016/j.mencom.2015.11.001).
  4. M.N. Zharkov, I.V. Kuchurov, I.V. Fomenkov, S.G. Zlotin, V.A. Tartakovsky. Nitration of glycoluryl derivatives in liquid carbon dioxide. Mendeleev Commun., 2015, 25 (1), 15-16 (doi: 10.1016/j.mencom.2015.01.004).
  5. A.A. Guskov, I.V. Kuchurov, S.G. Zlotin. Relative Permittivity of Monocomponent and Binary Solutions of N2O5 in Liquid CO2 and Their Activity in Nitration of Cellulose.Russian Journal of Physical Chemistry B, 2015, 9 (8), 1130–1136(ISSN 1990-7931).

 

  • Novel “green-chemistry” syntheses of various classes of organic compounds (polyunsaturated compounds, furan, tetrahydropyran and thiazole derivatives) in ionic liquid medium have been developed. Intermediates for the synthesis of therapeutically useful (CNS-disorders) g-aminobutiric acid analogues, derivatives of d-aminolevulinic acid, which is used in photodynamic therapy of cancer and exhibits anti-bacterial properties, vitamin A analogues, carotinoids, heterocyclic anticancer compounds, and furan-2-one derivatives incorporating a butenolide fragment, which is an integral part of a number of natural products, have been prepared by the developed procedures. A majority of the studied reactions run in the ionic liquid medium at high rate and with better selectivity than in organic solvents, and the solvents can be easily recovered and multiply used (Scheme 6).

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Important events:

Professor Mario Pargliaro Lecturing at Zelinsky Institute Prof Mario Pagliaro (Palermo Italy) gave two talks on June 8th and 9th.
Selective In-Situ Metal Azide Reactions Alexey Sukhorukov, N. D. Zelinsky Institute of Organic Chemistry, Moscow, Russia, and colleagues studied the selective reactions of in-situ generated metal azides on N,N-bis(oxy)enamines. By combining readily generated bis(oxy)enamine substrates with sodium azide and one of a variety of metal salts (including Mg, Cu, Zn, Co, and Ni), the researchers showed that the metal cation selectively alters the mechanism to favor the formation of specific organoazide products.
On February 1st, Prof. Gleb Sukhorukov from the School of Engineering and Materials Science, Queen Mary, University of London, gave a lecture “Remote Controlled Delivery Nanosystems” at ZIOC.
“We can record up to one thousand spectra per day” Director of Zelinsky Institute about Devising New Molecules
Steep and Thorny Way of a Scientist in Russia Prof. Valentine Ananikov participated in the plenary panel discussion HR Challenge for the Society held in the framework of VII Russian National Congress of Young Scientists and Specialists on November 30 – December 1 2016 in MEPhI.
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