Three-Component Synthesis of Polysubstituted Homoproline Analogs

Tetrasubstituted pyrrolidines representing analogs of homoproline were synthesized by three-component condensation of aryl(heteroaryl)aldehydes, asparagine and N-methylmaleimide (NMM). Compounds with (1S*, 3R*, 3aS*, 6aR*)-configuration at the corresponding carbon positions of the bicyclic pyrrolidine ring could be isolated on a preparative scale.


Results and Discussion
1,3-Dipolar cycloaddition of dipolarophiles to azomethine ylides generated from the corresponding imines is a widely used method of pyrrolidine synthesis [9]. Decarboxylation of α-arylideneamino acids upon heating is one of the approaches to generate ylide 2. If aspartic acid or asparagine (3) is used as amino acid component in this approach the formation of homoproline 1 could be predicted. To the best of our knowledge there is a single example of utilization of aspartic acid in combination with pyruvic acid and NMM for synthesis of bicyclic structure containing homoproline fragment [10]. We also observed consuming of starting materials under heating of equimolar amounts of veratraldehyde, aspartic acid and NMM in DMF at 120°C, but were not able to isolate individual stable material from this mixture. It was decided to employ asparagine as an amino acid component for 1,3-dipole generation to lower the side interactions of free carboxylic functionality. Heating of aryl(heteroaryl)aldehydes, asparagine and NMM at 120°C in DMF in inert atmosphere led to formation of homogeneous brownish mixture from which racemic homoproline analogs 5 and 6 were isolated with moderate yields (scheme 2, table 1). Chromatographic and NMR analyses of crude reaction mixtures have shown formation of these and other isomers, seemingly all four possible isomers [11], but predominantly products of endo-cycloaddition of NMM to the sterically favorite dipole 2 could be isolated in pure isomeric form. Accenting our research on preparative method for the synthesis of polysubstituted homoprolines all inseparable fractions of isomeric pyrrolidines were discarded.  Table 1. Condensation products of asparagine, NMM and aryl(heteroaryl)aldehydes.

Aldehyde Ar Major isomer (%*) Minor isomer (%*)
Stereochemistry of synthesized compounds was thoroughly analyzed by 1D and 2D NMR spectroscopy. Observed 3 J H-H coupling constants and their correlation with molecular modeling results for 5b ( Figure 1, Table 2) indicated a cis-configuration of H3 -H3a and H3a -H6a proton pairs. H1 hydrogen atom is in trans-position to other heterocyclic skeletal protons.  Later these suppositions were unequivocally confirmed by X-ray analysis of 5b (Figure 2) [12]. Molecules of 5b form endless chains due to hydrogen bonds of pyridyl nitrogen of one molecule with one of amide hydrogens of other molecule. Compounds 5a, 5c and 5d have proton shifts and coupling constants similar to 5b in NMR experiments. These facts allowed us to conclude the identity of space structure of homoprolines 5a, 5b, 5c and 5d with different aryl(heteroaryl) substituents at the α-position of pyrrolidine ring. Correlation of observed and calculated proton coupling constants for compound 6a ( fig. 3, table 3) prompted us to perform ROESY experiments ( fig. 3). Cross peaks of H3 and methylene group protons evidenced their positioning from the same side of pyrrolidine ring. Space interaction of H1 and b and f protons of dimethoxyphenyl substituent expressed in appropriate cross peaks also confirmed their relative positions. Formation of 6a may be considered as exo-cycloaddition of NMM to the dipole 2.  The synthesis of compound 5b was reproduced on 50 mmol scale and the desired compound was easily isolated as a white solid in 1 H-NMR pure form upon treatment of the concentrated reaction mixture with methanol.

Conclusions
We have performed the synthesis of polysubstituted homoproline analogs by three-component condensation of aryl(heteroaryl) aldehydes, asparagine and NMM. Proposed approach allowed to obtain homoprolines with aryl(heteroaryl) substituent at α-position of pyrrolidine ring. Hydrolysis or desymmetrization of the imide moiety of synthesized compounds is determining an additional diversity of accessible structures.

Experimental
General 1 H-and 13 C-NMR spectra were recorded on Bruker WM-250 and Bruker DRX-500 spectrometers.
All reagents and chemicals were obtained from commercial sources (Lancaster, Aldrich) and purified by standard procedures. Molecular modeling calculations were performed with programme Tinker (version 3.0) using the MM3 power field. Aryl(heteroaryl)aldehyde (4.5 mmol), D,L-asparagine (4.5 mmol) and NMM (4.5 mmol) were heated at 120°C in DMF (24 mL) under an inert atmosphere during 3-4 hours. After cooling to room temperature the reaction mixture was concentrated on a rotary evaporator. The residue was subjected to column chromatography separation with subsequent recrystallization of the obtained fractions.