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

The head Prof. Sergei G. Zlotin

(mail to: zlotin@ioc.ac.ru)

1. Main areas of research:

• Fine organic synthesis;
• Industry-oriented organic synthesis;
• Green chemistry.

         2. Research objectives

• Development of efficient, sustainable metal-free catalysts (organocatalysts) of stereoselective (enantioselective) organic reactions;
• Elaboration of environment-friendly protocols for organic synthesis in alternative reaction media, including water, ionic liquids, liquefied gases and supercritical fluids;
• Preparation of active pharmaceutical ingredients, energetic materials and other important organic products based on the developed environment-friendly methodologies;

         3. Main results:

Main achievements

In the field of stereoselective organic synthesis:

1. Original bifunctional catalysts containing tertiary amino groups and fragments of squaric acid amides were obtained, which made it possible to significantly expand the scope of asymmetric organocatalysis in the synthesis of biologically active substances. Under developed conditions, previously unknown stable derivatives of benzo[a]phenazin-5-ol (powerful anticancer drug sAJM589) annulated with the tetrahydropyran ring and new enantiomerically pure derivatives of kojic acid, a rice fermentation product having useful biological activities, were synthesized chemo- and enantioselectively (up to 99% ee). Reactions proceed under environment-friendly conditions (in an aqueous and aqueous-alcoholic medium), and catalysts, which are almost insoluble in organic solvents, can be easily regenerated and returned into the catalytic process (Fig. 1).

Figure 1. Asymmetric synthesis of benzo[a]phenazin-5-ol and kojic acid derivatives in the presence of bifunctional catalysts I and II.

2. Methods for the synthesis of new enantiomerically pure C₂-symmetric primary chiral diamines containing fragments of quinoline (III) or squaric acid amides (IV) have been developed. The resulting compounds effectively catalyze the asymmetric addition of 4-hydroxycoumarin and 4-hydroxy-6-methyl-2H-pyran-2-one to α, β-unsaturated ketones. A highly selective synthesis of both enantiomers of the anticoagulant Warfarin and rodent control agent Kumakhlor with practically quantitative yield and an enantiomeric excess of up to 96% was carried out with the use of obtained catalysts (Fig. 2 ). It is important that in the presence of catalyst III, the most active (R)-enantiomer of the drug Warfarin is formed in an aqueous medium from which it can be isolated without chromatography. This fact in combination with the recyclability of the catalyst creates good prerequisites for the practical application of the developed method in the pharmaceutical industry .

Figure 2. Asymmetric catalytic synthesis of the anticoagulant Warfarin and its analogues

3. A new type of immobilized organocatalysts based on chiral tertiary amines modified with ionic groups containing a squaric acid fragment has been developed. The main feature of these catalysts is their ability to carry out effective stereoinduction in heterogeneous reagent – water systems by the formation of stereo-controlling hydrogen bonds. Under developed conditions, a number of Michael adducts were obtained from b-dicarbonyl compounds and a-nitroolefins with almost quantitative yield and enantioselectivity up to 99% ee. Such a high level of stereoinduction is apparently caused by the influence of the amphiphilic ion pair of the catalyst, which protects the transition complex from the racemizing effect of water using hydrophobic and Coulomb interactions (Fig. 3). The catalyst, like natural enzymes, is easily separated from the products and can be introduced into the reaction many times (more than 30 times) without reducing their productivity and selectivity. Some of the compounds obtained are close precursors of the unnatural b-amino acids important for pharmacology and the most active (S)-enantiomer of the pregabalin anticonvulsant used in the clinic (trademark "Lyrica").

Figure 3. Highly stable organocatalyst for non-covalent asymmetric catalysis "on water"

4. A new algorithm for the construction of stable recycled organocatalysts for asymmetric synthesis was proposed. It is based on the combination of two catalytically active fragments in one molecule with the use of a C₂-symmetric (1,2-diaminoethane-1,2-diyl)-bis-(N-methylpyridinium) group, which simultaneously plays the role of a spacer and an ionic “anchor”, preventing the catalyst from "leaching" during extraction of the reaction product. Applying this approach a unique bis-prolinamide catalyst for asymmetric cross-aldol reactions in the absence of solvent was synthesized. This catalyst is characterized by a high level of stereoinduction (up to 99% ee), a wide range of applications (effective in the ketone – ketone, ketone – aldehyde, and aldehyde – aldehyde systems) and a record stability among known aminocatalysts (operating period is more than 830 hours) (Fig. 4). Using quantum chemical calculations, the geometric and energy parameters of possible pre-reaction complexes and transition states were determined. They explain the absolute configuration of the products and the different stereoselectivity of this type of diastereomeric catalysts.

Figure 4. A new type of immobilized prolinamide catalysts for asymmetric synthesis

В области органического синтеза в среде резистентных сжиженных газов и сверхкритических флюидов:

1. An efficient and safe method for nitration of alcohols with nitric (V) oxide in 1,1,1,2-tetrafluoroethane medium has been developed. Products containing up to 6 nitrate groups are formed under mild conditions (temperature 0-10 °C, pressure 0.6-0.8 MPa) with practically quantitative yields (Fig. 5). The process is carried out without the use of toxic organic solvents and is accompanied by the formation of significantly less acid waste (HNO₃) compared with the known methods. The low cost of the required equipment and the ease of fluid recirculation without significant energy costs make the proposed method attractive for the industrial production of high-energy materials and valuable drugs (nitroglycerin, isosorbite dinitrate, etc.). An enzymatic spectrophotometric method revealed quantitative correlations between the number and position of nitrate groups in the synthesized compounds and its NO-donor activity, which determines the effectiveness of their therapeutic effect in the treatment of cardiovascular diseases.

Figure 5. Ecological synthesis of nitroesters in liquefied 1,1,1,2-tetrafluoroethane

2. An effective and safe method for producing nitroesters, including nitroglycerin, diethylene glycol dinitrate, etc., by nitration of the corresponding alcohols with nitric (V) oxide in a flow of liquefied gas (1,1,1,2-tetrafluoroethane) has been developed. Prior to our work, nitration processes in liquefied gases medium have never been carried out before in a flow mode. The unique setup constructed for this purpose (Fig. 6) is two orders of magnitude superior in comparison with the corresponding batch processes in terms of specific productivity. The residence time of the reactants in the active zone of the setup does not exceed one minute, and their simultaneous amount in the reaction zone is minimal, which significantly reduces the explosiveness of the process in comparison with the corresponding reactions in batch mode. The system of condenser-capacitors at the outlet of the reactor unit allows completely capture the spent fluid and again return it to the nitration process, without getting out in the atmosphere, which makes the flow method environment-friendly and economical.

Figure 6. Nitration of alcohols in a flow of liquefied gas.

3. An efficient method for the synthesis of primary N-nitramines has been developed, including nitration of available N, N'-dialkyl oxamides or N-alkyl carbamates with nitric (V) oxide in 1,1,1,2-tetrafluoroethane (TFE) medium and subsequent treatment of nitration products with ammonia in one-pot (Fig. 7). The total yield of the desired N-nitramines at both stages reaches 94%. The method is distinguished by the simplicity of product isolation and environment-friendliness. The only by-products are ammonium nitrate and ethyl carbamate or oxamide, which can be used in agriculture as nitrogen fertilizers. Gaseous TFE can be liquefied again (as it occurs in refrigeration units) and used in the reaction. Such recycling does not lead to significant energy consumption, since the equilibrium pressure of TFE saturated vapor is very low (5.7 bar at 20 °C). From a practical point of view, the method opens up a promising and acceptable for industry way to obtain high-energy materials containing N-nitramine groups.

Figure 7. One-pot synthesis of primary N-nitramines in liquid 1,1,1,2-tetrafluoroethane

4. The first asymmetric catalytic domino reaction in a supercritical fluid (sc-CO₂) was carried out. In the presence of a bifunctional quinine derivative containing a squaric acid amide fragment, o-N-(tosyl)aminophenyl a,b-unsaturated ketones react with a-nitroalkenes under the proposed conditions, resulting in pharmacological valuable polyfunctional chiral tetrahydroquinolines in one step with very high diastereo (dr > 99: 1) and enantioselectivity (up to 98% ee) (Fig. 8). The tetrahydroquinoline fragment is a part of natural alkaloids (angusturein and martinelline) and drugs inhibiting cholesterol synthesis. This result can be used for the development of environment-friendly innovative technologies for obtaining enantiomerically pure drug ingredients.

Figure 8. First asymmetric catalytic domino reaction in sc-CO₂

Selected publications

1. M.N. Zharkov, S.S. Arabadzhi, I.V. Kuchurov, S.G. Zlotin. Continuous nitration of alcohols in a Freon flow. React. Chem. Eng., 2019, 4, 1303–1308 (doi: 10.1039/c9re00035f) (IF 3.395, Q1).
2. R.S. Tukhvatshin, A.S. Kucherenko, Y.V. Nelyubina, S.G. Zlotin. Conjugate Addition of Carbon Acids to β,γ-Unsaturated α‑Keto Esters: Product Tautomerism and Applications for Asymmetric Synthesis of Benzo[a]phenazin-5-ol Derivatives. J. Org. Chem., 2019, 84, 13824-13831 (doi: 10.1021/acs.joc.9b02021) (IF 4.745, Q1).
3. A.S. Kucherenko, A.A. Kostenko, A.N. Komogortsev, B.V. Lichitsky, M.Yu. Fedotov, S.G. Zlotin. C2-Symmetric Chiral Squaramide, Recyclable Organocatalyst for Asymmetric Michael Reactions. J. Org. Chem., 2019, 84, 4304−4311 (doi: 10.1021/acs.joc.9b00252) (IF 4.745, Q1).
4. I.V. Kuchurov, S.S. Arabadzhi, M.N. Zharkov, L.L. Fershtat, S.G. Zlotin, Sustainable synthesis of polynitro esters in the Freon medium and their in vitro evaluation as potential nitric oxide donors, ACS Sustainable Chem. Eng., 2018, 6, 2535-2540 (doi: 10.1021/acssuschemeng.7b04029) (IF 6.140, Q1).
5. A.S. Kucherenko, A.A. Kostenko, G.M. Zhdankina, O.Yu. Kuznetsova, S.G. Zlotin, Green asymmetric synthesis of Warfarin and Coumachlor in pure water catalyzed by quinoline-derived 1,2-diamines, Green Chem., 2018, 20, 754-759 (doi: 10.1039/C7GC03626D) (IF 8.586, Q1).
6. S.V. Kochetkov, A.S. Kucherenko, S.G. Zlotin, Asymmetric synthesis of warfarin and its analogs catalyzed by C2-symmetric squaramide-based primary diamines, Org. Biomol. Chem., 2018, 16, 6423–6429 (doi: 10.1039/c8ob01576g) (IF 3.423, Q1).
7. A. A. Kostenko, A. S. Kucherenko, A. N. Komogortsev, B. V. Lichitsky, S. G. Zlotin, Asymmetric Michael addition between kojic acid derivatives and unsaturated ketoesters promoted by C2-symmetric organocatalysts, Org. Biomol. Chem., 2018, 16, 9314–9318 (doi: 10.1039/C8OB02523A) (IF 3.423, Q1).
8. R. S. Tukhvatshin, A. S. Kucherenko, Y. V. Nelyubina, S. G. Zlotin, Stereoselective Synthesis of Tetrahydroquinolines via Asymmetric Domino Reaction Catalyzed by Recyclable Ionic-Liquid-supported Bifunctional Tertiary Amine, Eur. J. Org. Chem., 2018, 7000–7008 (doi: 10.1002/ejoc.201801423) (IF 2.981, Q1).
9. 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) (IF 10.614, Q1).
10. A. S. Kucherenko, A. A. Kostenko, V. V. Gerasimchuk, S. G. Zlotin. Stereospecific diaza-Cope rearrangement as an efficient tool for the synthesis of DPEDA pyridine analogs and related C₂-symmetric organocatalysts. Org. Biomol. Chem., 2017, 15, 7028-7033 (doi: 10.1039/C7OB01852E) (IF 3.423, Q1).
11. M.G. Vinogradov, O.V. Turova, S.G. Zlotin. Nazarov reaction: current trends and recent advances in the synthesis of natural compounds and their analogs, Org. Biomol. Chem., 2017, 15, 8245–8269 (doi: 10.1039/c7ob01981e) (IF 3.423, Q1).
12. 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 [doi: 10.1055/s-0036-1588616] (IF 2.652, Q2).
13. 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] (IF 2.579, Q1).
14. 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) (IF 3.423, Q1).
15. 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) (IF 4.721, Q1).