Diastereoselective Synthesis of some pyrrolidin-2-ones azasugars and study of their stereochemistry

The microwave-promoted one-pot multicomponent synthesis of substituted pyrrolidinols using a bifunctional sugar-derived hydroxy-[gamma]-lactone component of amine component or cyanide group is reported. Clean reaction profile, easy work-up procedure, excellent yields and short reaction times are some remarkable features of this method. This modular approach features the in situ-generation of iminium ions intermediate that allows the diastereoselective assembly of the diverse pyrrolidinones efficiently under microwave irradiation has been used.


Introduction
Multicomponent reactions (MCR) take advantage of creating and transforming reactive functionalities in the same reaction vessel without intermediary work-up 1,2 .
Many types of research for the synthesis of biologically active compounds in organic and drug discovery have provided by one-pot multicomponent reactions.These reactions have a highly significant position in comparison with other reactions.
MCRs based on the synthesis of heterocyclic compounds containing a 2-pyrrolidinone gained much importance in organic synthesis.The simplest 2-pyrrolidinone is named 2-pyrrolidone is sometimes referred to as simply pyrrolone (Fig. 1).
2-Pyrrolidinones are important compounds that are found in many pharmaceuticals and active natural products 3 .Some of them are well-known medicines, such us piracetam 2 for patients with seizures, Alzheimer's and other neurological problems 4 , doxapram 3 for patients with respiratory failure 5 .(Fig. 1).

Pyrrolone
Cotinine Rigidiusculamide Recently, novel polyhydroxy-N-alkyl-2pyrrolidinones were prepared and identified as Immunopotentiators by S. R. Bonam et al. 6 .Compound 5e was found to be active in stimulating the production of IL-12 in murine dendritic cells with significant expression of IFN-γ in hPBMCs.
Britton and co-workers developed a highly convergent synthesis of iminosugars that converts a wide range of acetaldehyde derivatives into polyhydroxy pyrrolidines in two or three straightforward reactions 7 .
In 2018, Chandra Pan and co-workers reported an organocatalytic asymmetric cascade reaction for the synthesis of substituted pyrrolidines synthesis.They embarked on a convenient synthesis of substituted pyrrolidines having a stereogenic quaternary centre at the 3-position 8 .

Figure 3. Cyano-pyrrolidines derivatives 5
Accordingly, developing efficient methods for the construction of this type of iminosugars heterocyclic has appealed significant attention of the chemistry community, and many procedures have been developed to offer wide spans in the field of medicinal chemistry 9 .
Considering the importance of clean chemistry, the following study developed a method for the synthesis of substituted pyrrolin-2-ones without solvent under microwave irradiation 10 .
The main step is a condensation of a bifunctional sugar-derived hydroxy--lactone component with an appropriate amine component or cyanide group.This approach features the in situgeneration of an iminium ions intermediate that allows the diastereoselective assembly of the diverse pyrrolidinones efficiently under microwave irradiation.

Results and discussion
Herein we describe the development of a multicomponent reaction (MCR) strategy for the synthesis of C-glycoside iminosugars.Several methods of synthesis have been exploited for the development of iminosugars, but few of them use a one-pot procedure 11 .
The effect of microwave irradiation in accelerating the reactions attracted our attention.Microwave irradiation has widely been used among synthetic organic chemists to improve classical organic reactions, shorting reaction times and/or improving yields, as well as promoting new reactions 8,11 .
To achieve suitable conditions for the synthesis of substituted pyrrolin-2-ones (6 and 7), various reaction conditions were investigated.We first optimized the reaction conditions, such as the effects of solvents, the quantity of nucleophile and microwave irradiation power.
After finding a suitable solvent (CH2Cl2) with the power of (14W) to determine the important role of the microwave, this method was examined with the reaction of an amine or cyanide group and the pool, 3-O-cyclohexylidene-D-erythruronolactonein dichloromethane solvent under microwave irradiation and without microwave irradiation at room temperature (Table 1).

Scheme 1. Synthesis of substituted pyrrolidinols
As shown in Table 1, when the reactions were carried out with the conventional method, these seem to take a comparatively long time and resulted in lower yields; whereas when the same reactions were performed under the influence of microwave conditions, they gave higher yields in shorter reaction times.Generally, a similar effect was observed in all reactions, and we found that microwave irradiation was very effective and suitable in this research, since the products could be synthesized in a short time with excellent yields.
The method remains effective as it is carried out in a single step, mainly, when the cyano-iminosugars is described in the literature as synthesized according to several stages 12 .
The 2,3-O-isopropylidene-D-gulonolactone derivative was synthesized from D-gulunolactone in 95% yield by the procedure described by Borcherdinf et all 13 .
Table 1.Comparison of the times and yields of the reactions with or without irradiation for the synthesis of substituted pyrrolidinols.The suggested mechanism for the synthesis of substituted pyrrolidinols (7 and 8) is illustrated in Scheme 2. Showing that the first step in the reaction may proceed via the formation of an amine.This is activated by intramolecular protonation to lead to a more electrophilic iminium ion (I.1).The cyanide group (or excess of amine) adds up on the electrophilic iminium ion, thus forming the intermediate (I.2), then the intermediate (I.3) is formed, after an attack of the carbonyl by the doublet of nitrogen and elimination of a molecule of water, pyrrolidine is formed.Reaction yield is satisfactory passing from 40 to 80 yields, and good diastereoselectivities were obtained (25:75 dr).
The configuration at the epimeric center was assigned on the base of their spectroscopic properties.The stereochemistry of compounds 6a-d (and 7a-f) deserves comment.
The aim is to establish without ambiguity the stereochemistry (cis, trans) of epimers tentatively noted α and β.
• The configuration retention of carbons C-3 and C-4 is known since they are obtained from precursors whose geometry is perfectly established 3 J H3-H4 (cis) ~ 6Hz.
• The assignment of the δ of the different protons in the two epimers.This point has been elucidated using correlation NMR.The study of the HETCOR spectra of pairs of epimers 6 makes it possible to produce the following Table: From this designation corresponding to the two epimers, the measure of J should allow the distinction between the forms α and β.
A stereo-chemical study of analogous heterocycles are mentioned in the literature REF.
In the first example Zhou et all.show that, while the vicinal coupling constants (J H4, H5>6.0 Hz) for cisdiastereomers 8 and J H4-H-5,= 0-4. 4 Hz for transdiastereomers 09, (example 1) are commonly used to determine the 4,5-relative stereo-chemistries of 4,5disubstituted -lactams 14 .JH3-H4: The relative configuration of carbons 3 and 4 is well known, it is identical with both epimers.The measurement of the 3 JH3-H4 coupling constant is of the order of 6 Hz.This result is also confirmed in example 2.

• 3
J H4-H5: The stripping of the 1H NMR spectra of heterocyclic compounds 6and 7 shows very delicate because of the proximity of the signals of the different cyclic hydrogens and the numerous couplings.All the hydrogens resonate in a range of 1 ppm between 4 and 5 ppm.It is known that the shape of an H NMR spectrum depends on the evaluation of the Δν/J ratio.Indeed, the small value of the differences in resonant frequencies concerning the coupling constant J complicates the appearance of the spectra.
• It is noted that the proton H-5 appears in the form of a doublet due to the coupling with H-4 in the compounds α, against in series β, it is in singlet, which indicates that the coupling with H-4 disappears (Scheme 3).STOP This result is not surprising since the constant J depends on the dihedral angle of the two coupled protons.The same phenomenon is observed in Example 2 (J H7-H11 = 0 Hz).Scheme 3. Assignment of the stereochemistry of α and β compounds.
Very low or even zero coupling constants indicate dihedral angles between 90 ° and 100 °.Also, it is known that the pyrrolidinone ring is not plane, it can exist in enveloped forms.The differences between the measured 3 J H-4.H-5 and the approximate values of the dihedral angles are large enough to allow correct assignments.At the end of the reaction, four products that are difficult to separate by column were obtained.We conclude that it is difficult to control the reactivity of iminium ions.The same diastereoselectivity has been observed for additions of nucleophilic reagents to 2,3-O-isopropylidene-D-erythruronolactone dr (25:75).
In all three cases, complex mixtures (TLC analysis) are obtained and are difficult to separate.However, the desired products have been isolated but with low yields, (Scheme 7).
The compounds 12 (a, b, c, d) are characterized by mass spectroscopy, peaks m/z = 305 and m/ z = 353 corresponding to the proton form of the molecular peak MH + .

Conclusion
In this work, the reported method offers a simple and efficient way for the one-pot microwave chemical synthesis of substituted pyrrolidnols.Some important advantages of this method are due to the short reaction time, without solvent, easy work-up, high yields.
The advantage of this method and its application to a substrate, 2,3-O-isopropylidene-D-erythruronolactone has provided the corresponding substituted pyrrolidinols , giving a good yields and with the same diastereoselectivity dr (75: 25).
The configurations of the newly introduced chiral centers in 6 and 7 have been supported by NMR spectroscopic data and confirmed by mass spectroscopy.

Experiment
The CEM Discover microwave allows irradiating in two modes: either an assigned power with continuous measure of the resulting temperature by an IR captor, or an assigned temperature with continuous adjustment of the irradiation power.We chose the second mode, in solvent-free conditions with assigned temperature to avoid degradation of sugars by browning reactions.Chemicals were purchased from Aldrich, Acros organics and Fluka and used without further purification.Solvents distilled with appropriate drying agents.All reactions performed under anhydrous conditions employing routine drying techniques unless otherwise indicated.Reactions were monitored by thin-layer chromatography (TLC) performed on E. Merck glass plates silica gel sheets (Silica Gel F254) and stained with vanillin acidaqueous H2SO4 solution.Column chromatography carried out on silica gel (E.Merck 230-400 mesh).Nuclear Magnetic Resonance (NMR) data ( 1 H or 13 C) were obtained on an AC-Brucker 300 machine chemical shifts are reported in parts per million relatives to tetramethylsilane in deuterated solvents.Assignments of 1 H and 13 C were assisted by 2D 1 H COSY and 2D 1 H- 13 C CORR experiments.Optical rotations were determined with a Jasco Dip 370 electronic micropolarimeter (10 cm cell).High-Resolution Electro sprays Mass Spectra (ESI-HRMS) in the positive ion mode were obtained on a Q-TOF Ultima Global hybrid quadrupole time-of-flight instrument (Waters-Micro mass), equipped with a pneumatically assisted electro spray (Z-spray) ionization source and an additional sprayer (Lock Spray) for the reference compound.

General Procedure for Synthesis of (6 a-d).
To a mixture of 2,3-O-isopropylidene-Derythruronolactone (0.86 mmol) and a primary amine (excess), 5 mL of CH2Cl2 were added.The mixture was stirred for 12h at rt.After concentration under reduced pressure, the resulting was purified by chromatography (CH2Cl2/MeOH, 95/5).The characterization of each compound was obtained using NMR and mass spectrometry as reported below.

Synthesis of substituted pyrrolidinols 6 a-d under microwave irradiation
A mixture of 2,3-O-isopropylidene-Derythruronolactone (0.86 mmol of sugar) and primary amine (excess) was thoroughly mixed in an open Pyrex flask.The flask placed in the MW reactor (CEM Discover) and irradiated.After irradiation, the crude reaction mixture was cooled down to room temperature, and solvent of CH2Cl2 (20 ml) was added, the resulting mixture was concentrated in vacuum, purified by chromatography (CH2Cl2/MeOH, 95/5).

A representative procedure for the synthesis of 7 (a-f)
To a mixture of 2,3-O-isopropylidene-Derythruronolactone (0.86 mmol of sugar) and 1.2 eq of amine, 5mL of CH2Cl2 was added, after 10 minutes of reaction, trimethylsilyl cyanide was added.The mixture was stirred for 12 h at room temperature.After concentration under reduced pressure, the resulting was purified by chromatography (EtOAc /cyclohexane, 70/30).

Synthesis of substituted pyrrolidinols 7 (a-f) under microwave irradiation
A mixture of 2,3-O-isopropylidene-Derythruronolactone (0.86 mmol of sugar) and primary amine (1.2) were thoroughly mixed in an open Pyrex flask.The flask placed in the MW reactor (CEM Discover) and irradiated for 10 mn.Trimethylsilyl cyanide was added.The mixture was irradiated for 15 mn.After concentration under reduced pressure, the resulting was purified by chromatography (EtOAc /cyclohexane, 70/30).

Example 1 . 11 Example 2 .
Attribution of stereochemistry according to ZhouIn the second example Pinhey et al. show that the coupling constant for the cis isomer is greater than the trans isomer15 .10Attribution of stereochemistry according to Pinhey Stereo-chemistry is progressively assigned by studying the different couplings of the cyclic protons.•3

Scheme 4 . 3 J
Scheme 4. The two possible enveloping forms of pyrrolidinone

Figure I Figure II Scheme 5 .Scheme 6 .
Figure I Figure II Scheme 5. Representation in the space of epimers α and β Finally, it is concluded that the configuration at the newly generated chiral center in compounds 7 and 8 were determined by NMR analysis.The coupling constants between H-4 and H-5 of 4.02, 4.60 , 5.27 and 5.48 Hz, indicate that the amine or cyanide function has been introduced is in a cis-relationship to the hydroxyl group at position C-5.Scheme 6.

Table 2 .
Correlations observed on the HSQC spectra for compounds 6a/b.