Studies on the influence of saccharide fragment of urea organocatalysts on the yield and enantioselectivity of aza-Henry reaction

Six new bifunctional ureas bearing a carbohydrate ring and an optically active base for the asymmetric aza-Henry reaction of imines with nitromethane has been developed. The influence of the saccharide urea fragment and the base in organocatalysts, both new and previously prepared by our team, on the yield and enantioselectivity of aza-Henry reactions was demonstrated. The aza-Henry reaction products were obtained in 17-98% yield and ee up to 99%. The highly enantioselective reaction course is likely the result of the synergic action of two urea fragments - saccharide and DACH.


Introduction
Over the past decade, a number of enantioselective transformations of organic compounds promoted by metal-free organocatalysts have been described in the literature.We are still observinge an increase in research on organocatalysts, including sugar derivatives.On the whole, carbohydrate derivatives possess certain distinct advantages.They are inexpensive and readily available natural materials employed as chiral backbones of organocatalysts.  An mple of such a stereocontrolled synthesis catalyzed by sugar derivatives is the aza-Henry reaction, which involves the nucleophilic addition of nitroalkanes to imines, and results in the formation of a new carbon-carbon bond, and, consequently, a β-nitroamine.The resulting β-nitroamines represent interesting and useful synthetic building blocks in organic synthesis.][24][25][26][27][28] This publication summarizes our research on the effect of the saccharide fragment of organocatalysts on enantioselectivity and yield of the aza-Henry reaction.For this purpose, we prepared an additional six new organocatalysts containing different fragments of sugars, and, subsequently, studied their effectiveness in the reaction of the corresponding imine with nitromethane.
The simple synthetic route leading to a series of new organocatalysts is shown in Scheme 1.

Asymmetric aza-Henry reaction catalyzed by carbohydrate ureas L1-L15
0][31][32] Continuing this study, we demonstrate the results obtained in the presence of new ligands in the asymmetric aza-Henry reaction (Table 1).he asymmetric aza-Henry reaction of N-tosyl imine with nitromethane, as the model transformation was carried out under standard conditions -in THF or dichloromethane at room temperature.
Initially, we performed a reaction of methoxy-benzylidene sulfonamide with nitromethane in the presence of urea organocatalyst L1, which did not have a chiral sugar fragment.Such a structure of the organocatalyst will allow us to demonstrate the effect of the sugar moiety or its absence on the yield and enantioselectivity of the tested reaction.
The use of organocatalyst L1 produced 36% and 65% yields of the product in THF and CH 2 Cl 2 , respectively.The obtained enantioselectivity was 14% and 32% ee in favor of the (S)-enantiomer (Table 1, entries 1-2).Subsequently, we analyzed the influence of the sugar moiety of ureas containing the same fragment of diaminocyclohexane derivative (Table 1, entries 3-10).Under identical conditions of aza-Henry reaction, two differently protected glucose derivatives L2 with acetyl and L3 with methyl were not particularly active and gave rise to a final product with low yields, though enantioselectivity for the derivative L2 was satisfactory -ee up to 99% (Table 2, entries 3-6).A significant increase in yield was observed when the cellobiose derivative L4 was used as a catalyst (Table 1, entries 9-10).In turn, the use of the L5 organocatalyst, both in THF and CH 2 Cl 2 , led to a product in excellent yield (98%) and enantioselectivity (99% ee).Such a course of the reaction is likely the result of the synergic action of two urea fragments (saccharide and DACH) of the L5 derivative (Table 1, entries 9-10).
Another group of urea organocatalysts, the activity of which we examined in the aza-Henry reaction, were mono-and disaccharide derivatives containing the proline ring as a second scaffold (Table 1, entries 11-21).In the series of the monosaccharide catalysts L6-L8, the best of the sugar has proven to be glucose derivative L8, with the isopropyl protecting groups: 82% yield and 75% ee in THF (Table 1, entries 15-16).In contrast, the melibiose derivative L9 proved to be less active and resulted in a reaction product in 53% yield and 64% ee.The use of both diastereomeric ligands of proline L10 and L11 led to the formation of chiral amines with the same absolute configuration.Thus, the stereogenic centers located in the proline moieties do not exert a decisive effect on the absolute configuration of the products (Table 1, entries 18-21).
Finally, we decided to investigate the catalytic activity of L12-L15 derivatives.The replacement of the tertiary amine with a diphenylphosphine substituent (weaker base) in the cyclohexane ureas L12, L13, and L14, or the use of an optically inactive (dimethylamino)ethyl group, as in L15, resulted in a drastic decrease in the enantioselectivity of the reaction (Table 1, entries 22-26).Furthermore, urea L12, derived from (1S,2S)-2-(diphenylphosphino)cyclohexane bearing a cellobiosyl scaffold, failed to demonstrate any catalytic activity on the imine with an electron-donating group (Table 1, entry 23).

Conclusions
We presented the synthesis of new urea organocatalysts containing, in addition to an optically active base, a carbohydrate ring as a component of a natural chiral pool.The obtained sugar derivatives proved to be useful and highly effective catalysts for the enantioselective aza-Henry reaction.The best results were obtained for the urea organocatalyst containing structure of melibiose and trans-2-(1-piperidinyl)cyclohexylamine fragments.The highly enantioselective reaction course (ee up to 99%) is likely the result of the synergic action of two urea fragments -saccharide and DACH.

Experimental Section
General.All solvents and reagents (amines 4-6, nitromethane, and imine) were purchased from Sigma-Aldrich and used as supplied, without additional purification.NMR spectra were recorded in CDCl 3 , on a Bruker Avance III (600 MHz for 1 H NMR, 150 MHz for 13 C NMR), and coupling constants are reported in Hz.The optical rotation was measured on a Perkin-Elmer 241 MC polarimeter with a sodium lamp at room temperature.The melting points were determined on a DigiMelt apparatus and remain uncorrected.Chromatographic purification of the compounds was achieved with 230-400 mesh size silica gel.The progress of the reactions was monitored by silica gel thin-layer chromatography plates (Merck TLC Silica gel 60 F 254 ).The IR spectra were recorded on a FT-IR Nexus spectrometer.The enantiomeric ratio was determined by using a HPLC (ProStar Varian) employing a Chiralpak OD-H column (25 cm x 4.6 mm).

General procedure for the synthesis of catalysts L2-7
Triphenylphosphine (865 mg, 3.3 mmol) was added to a solution of azidosaccharide (1.1 mmol) in toluene (8 mL).The resulting solution was stirred at room temperature for 1 h and then flushed with CO 2 .Next, the appropriate amine (1 mmol) was added.The mixture was stirred for 24 h under CO 2 bubbling conditions.After evaporation of the solvent, the residue was purified by flash chromatography on silica gel eluting with ethyl EtOAc/Hexane or EtOAc/MeOH.