Synthesis of new , optically active 1-( substituted aryl ) pyrrole derivatives via atropisomerism directed diastereosel ctive metalation

Axial chirality directed highly diastereoselective formation of a new stereogenic center in the benzylic position of racemic and optically active 1 -[2-(carboxymethyl)-6-ethylphenyl]-1 Hpyrrole-2-carboxylic acid ( 4) is reported as the very first example of efficien t intramolecular asymmetric induction effect of the atropisomeric 1phenylpyrrole skeleton containing dicarboxylic acid on the metalation, alkylation rea ction sequence. Configuration of a product ((Ra,S)-7a) was determined by single crystal X-ray diffractio n measurements. In addition, stereochemical stability of the new, two chirality elements containing compounds was demonstrated by selective, stepwise transformation of the carboxylic groups into ester and amide functions, respectively.


Introduction
Generation of new chirality elements (central or axial) using chiral catalysts or chiral auxiliaries is the basis for asymmetric synthesis of enantiomerically enriched chiral molecules.The efficiency of the asymmetric induction or chirality transfer is largely dependent on how tight the interaction is between the chirality source and the reacting site. 1 Numerous examples have been published for intermolecular asymmetric inductions where a chiral catalyst determines the configuration of the formed new stereogenic center(s) in the product.3][4][5] There are also examples in the literature for such type of chirality transfer, when the axial chirality of the starting material is used to build up a new stereogenic center of the cyclization product. 68] Directed lateral lithiation of N,N-diisopropyl-2ethyl-naphtalene-1-carboxamide followed by ethyl iodide quench yielded the α-ethyl derivative with a high degree of diastereoselectivity (98/2=syn/anti) due to the CIPE effect and the quasi atropisomeric character of the naphtamide moiety. 9Simpkins et al. also achieved high diastereoselectivity in alkylation and aldol reactions of an atropisomeric anilide in which the nitrogen contained propanoyl and methoxyethoxymethyl groups and the rotation of the amido moiety was controlled by the steric hindrance of an ortho tert-butyl group. 10][13][14] Efficient intramolecular control of enantioselectivity by atropisomeric remote amide conformation has also been studied in SmI 2 -mediated reductive coupling of aldehydes with the crotonates possessing different 2-substituted 8-methoxy-1-naphthamides. 15 Recent developments in the field of intramolecular remote control of stereogenic center(s) formation using asymmetric center or atropisomeric benzamide containing compounds have also been reviewed. 168][19][20] The very first member ((S a )-1) (Scheme 1) of this group was prepared from 1-(2-trifluoromethylphenyl)-1H-pyrrole via selective dimetalation carboxylation reaction sequence.Racemic dicarboxylic acid was resolved into the two stable atropisomers 17,21 and the pure enantiomers were used as starting materials of the synthesis of optically active ligands ((S a )-2) (Scheme 1). 22cheme 1. Optically active 1-phenylpyrrole derivatives.
Dimetalation and consecutive carboxylation of 1-(2-ethyl-6-methylphenyl)-1H-pyrrole (3) has also provided an atropisomeric dicarboxylic acid (rac-4) which was separated into its two enantiomers via diastereoisomeric salt formation using optically active 1-methylbenzylamine ((R)-5, Scheme 2). 20Optically active 4 contains a prochiral benzylic group and enantioselective introduction of a substituent into this position could provide us a new chiral building block with both axial and central chirality elements.However, according to our best knowledge, nobody has studied remote lateral metalation of atropisomeric 1-phenylpyrrole derivatives until now.Therefore we aimed to investigate the asymmetric induction of axial chirality of 4 on the formation of the new stereogenic center in benzylic position and the enantioconservative transformation of the formed product into ester and amide derivatives.

Results and Discussion
Synthesis and optical resolution of the starting material (4) was accomplished according to the literature procedure 20 (Scheme 2).

Scheme 2. Synthesis and resolution of rac-4.
Then metalation alkylation reaction sequence was studied starting from rac-4.The dicarboxylic acid was reacted with three equivalents of potassium tert-butoxide activated lithium diisopropylamide (LiDA-KOR) superbase in tetrahydrofuran at -75 °C (Scheme 3).Clean benzylic metalation occurred under these conditions and the organometallic intermediate (6)  readily reacted with different electrophiles (iodomethane, isobutyl bromide, benzyl bromide and benzaldehyde).The products (7a-d) were isolated, after recrystallization, with good to satisfactory yields (Table 1).It has to mention, that only starting material was recovered when dimethylformamide or benzophenone was added to compound 6.

Scheme 3. Preparation of compounds 7a-d (M = K (or Li)).
Beside the axial chirality, compounds 7a-d contain a new asymmetric carbon atom in benzylic position, therefore two diastereoisomeric pairs should be formed from the racemic starting material (rac-4).However, according to the 1 H-NMR spectra of compounds 7a-d, only one diastereoisomer was formed in each case.Consequently, the axial chirality of the starting material (rac-4) completely determined the stereochemical outcome of the metalation/alkylation reaction sequence.a Product distribution was determined from the 1 H-NMR spectra of the crude product.b The crude product was purified by recrystallization from ethyl acetate.c Calculated to the amount of the starting material 4.
In order to prove this supposition, the methylation reaction was repeated with (R a )-(-)-4 as starting material.A single enantiomer was isolated as the only product ((+)-7a) and it was suitable to preparation of single crystals (grown from ethanol/diethyl ether mixture).Hence, Xray diffraction measurements were carried out to determine the absolute configuration of the new asymmetric carbon atom in (+)-7a (Figure 1).In previous studies 20 we have determined the absolute configuration of (R a )-(-)-4.This axial chirality did not change during the introduction of the methyl group into the benzylic position.It is also evident from the determined molecular structure, that the absolute configuration of the new asymmetric carbon atom (C12 in Figure 1) is S.This high stereoselectivity can be rationalised if one take into account that methyl group could only join to the benzylic carbon atom from the Si face of the organometallic intermediate 6, because the other side of the reaction center was shadowed by the alkali carboxylate moiety connected to the α-position of the pyrrole ring like the proposed model structure 8 (Scheme 4).Scheme 4. Synthesis of (R a ,S)-(+)-7a (possible diisopropyl amine and THF ligands of the metal cations (M + ) are not depicted in 8 for clarity).
We suppose that structure of 8 is stabilized by the Coulomb interactions among the two alkali cations and the negatively charged oxygen atoms of the two carboxylate groups, respectively.This way the axial chirality of 4 strictly determines the configuration of the new asymmetric center.
Optically active (R a ,S)-(+)-7a can serve as a useful intermediate of new chiral ligands and organocatalyst, therefore selective, stepwise transformations of the two carboxylic groups were also investigated.Highly selective monoesterification of (S)-1-[2-carboxy-6-(trifluoromethyl)phenyl]-pyrrole-2-carboxylic acid ((S)-1) has been published by our laboratory. 22After stirring the dicarboxylic acid (S)-1 for 48 hours at room temperature in methanol, in the presence of 7 equivalents thionyl chloride, the carboxylic group connected to the phenyl ring was selectively esterified.In that case the effects of the electron withdrawing trifluoromethyl group of the benzene ring and the electron donating effect of the pyrrole ring toward the carbonyl group caused significant difference between the reactivities of the two carboxylic groups of (S)-1.As a consequence, the monoester could be prepared selectively even a large excess of thionyl chloride was used in methanolic solution for esterification. 22he situation is different in the case of (R a ,S)-(+)-7a because electron donating alkyl groups are connected to the benzene ring and the benzylic carbon atom, respectively, which decrease the reactivity of the connected carboxylic group in such esterification reaction.In order to test the residual reactivity difference between the two carboxylic functions in (-)-4 and (+)-7a, both optically active compounds were treated with an excess of thionyl chloride in dry ethanol.In principle, during the esterification process three products may be formed: two monoesters (9 and 10) and the diester (11) (Scheme 5).When (R a )-(-)-4 dicarboxylic acid was esterified in presence of two equivalents of thionyl chloride with ethanol for 22 hours at room temperature, mainly the monoester ((R a )-(-)-9b) was formed together with a small amount of diester 11b.This selectivity decreased considerably when (R a ,S)-(+)-7a was used as starting material because, according to the chromatographic and 1 H-NMR investigations, the crude product mixture contained considerably more the diester ((R a ,S)-(+)-11a) together with the major product (R a ,S)-(+)-9a.Decreasing of regioselectivity in case of (R a ,S)-(+)-7a may be explained by the above mentioned electronic effect of the methyl group.

Scheme 6. Two highly selective methods for preparation of optically active (R a ,S)-(+)-9a monoester.
A simpler, but far more sensitive method for preparation of (R a ,S)-(+)-9a monoester is the direct esterification of (R a ,S)-(+)-7a by using 1.5 equivalents of thionyl chloride in ethanol.To avoid diesterification, the progress of the esterification reaction should be monitored by TLC or other suitable methods.According to the 1 H-NMR and 13 C-NMR spectra of the products obtained after the selective hydrolysis and the selective monoesterification, respectively, (R a ,S)-(+)-9a monoester formed in both cases.These experimental results may be rationalised if one take into consideration that esterification is governed by the acidity difference of the two carboxylic groups while basic hydrolysis occurs more easily on the sterically less hindered site of the molecule.
In order to determine the exact structure of (R a ,S)-(+)-9a, two dimensional 1 H, 13 C-HMBC spectroscopic measurements were performed.These measurements confirmed without doubt that the ethoxycarbonyl group is connected to the carbon atom of the benzylic -CH(CH The carboxylic groups of (R a ,S)-(+)-9a and (R a )-(-)-9b were transformed into the corresponding acid chlorides in toluene at 70 o C before the addition of N,N-diethylamine and, in spite of the applied high temperature, the products were isolated without any loss of their enantiomeric purities.The above mentioned experimental data (half ester and amide formation reactions) confirmed that the prepared new optically active compounds are stereochemically stable, they axial and the central chirality remained intact under the applied conditions.

Conclusions
Experimental results of the metalation alkylation reaction sequence of racemic and optically active 1-[2-(carboxymethyl)-6-ethylphenyl]-1H-pyrrole-2-carboxylic acid (4) let us to conclude that the chiral information of the atropisomeric 1-phenylpyrrole skeleton containing dicarboxylic acid can be completely transmitted to the intramolecular benzylic position.Diastereoselectivity of the metalation could be explained by the complex formation of the pyrrole connected carboxylate anion with the metal ion of the metalated carboxymethyl moiety of the molecule as shown in structure 8. Steric arrangement of this complex is strictly determined by the axial chiraltity of the molecule, thus only one side is free for the reaction with the electrophilic reagents.Single crystal X-ray diffraction measurements have confirmed the above mentioned model structure and provided us the absolute configuration of the new asymmetric carbon atom.According to reactivity difference between the two carboxylic groups, two methods have also been developed for selective monoestericication of dicarboxylic acids (R a )-(-)-4 and (R a ,S)-(+)-7a.The monoesters were transformed into the optically active half ester-half amide derivatives ((R a ,S)-(+)-12a and (R a )-(-)-12b).These reactions confirmed the supposed stereochemical stabilities of the investigated compounds.Consequently, the synthetized new optically active 1phenylpyrrole derivatives may be used as building blocks of new chiral ligands and organocatalysts.

General method for the synthesis of acid amides 12a and 12b
Thionyl chloride (2 equiv.) was added dropwise at 0 °C to a solution of the optical active monoester (7a or 7b, 1 equiv.) in dry toluene (15 ml), in the presence of 2-3 drop of dry dimethylformamide.The mixture was stirred at 70 °C for 2 hours.The solvent and the excess of thionyl chloride were evaporated in vacuo.To remove traces of thionyl chloride, the residue was dissolved in toluene and again evaporated.The residue containing the acid chloride was dissolved in dry toluene (10 ml), and then a solution of diethylamine (3 equiv.) in dry toluene (5 ml) was added at 0 °C.The mixture was stirred at room temperature (TLC control, eluent: hexane/ethyl acetate = 1/1) for 30 minutes.Toluene was evaporated in vacuo and the residue was dissolved in ethyl acetate (15 ml).The solution was acidified with 5% aqueous hydrochloric acid solution (15 ml).The phases were separated; the organic phase was washed with saturated NaHCO 3 -solution, water and brine.The organic phase was dried over sodium sulphate and concentrated in vacuo to give the 12a or 12b amides.(R a ,S)-(-)-N,N

Single crystal X-ray diffraction measurement of (R a ,S)-(+)-7a
Crystal data: C 16 H 17 NO 4 , Fwt.: 287.31, colourless, prism, size: 0.45 x 0.45 x 0.30 mm, orthorhombic, space group P 2 1 2 1 2 1 , a = 8.1717( 6 A crystal of (R a ,S)-(+)-7a was mounted on a loop.Cell parameters were determined by leastsquares using 15344 (3.00 ≤ θ ≤ 25.67°) reflections.Intensity data were collected on a(n) Rigaku R-AXIS-RAPID diffractometer (monochromator Mo-Kα radiation, λ = 0.71075 Å) at 295(2) K in the range 3.00 ≤ θ ≤ 22.21 24 .A total of 21813 reflections were collected of which 1935 were unique [R(int) =0.0423, R(σ) =0.0235]; intensities of 1609 reflections were greater than 2σ(I).Completeness to θ = 0.997.A numerical absorption correction 25 was applied to the data (the minimum and maximum transmission factors were 0.962 and 0.983).The structure was solved by direct methods 26 (and subsequent difference syntheses).Anisotropic full-matrix least-squares refinement 26 on F 2 for all non-hydrogen atoms yielded R 1 = 0.0415 and wR 2 = 0.1017 for 1332 [I>2σ( I)] and R 1 = 0.0511 and wR 2 = 0.1058 for all (1935) intensity data, (number of parameters = 192, goodness-of-fit = 1.060, the maximum and mean shift/esd is 0.000 and 0.000).The maximum and minimum residual electron density in the final difference map was 0.1 and -0.1 e.Å -3 .The weighting scheme applied was w = 1/[σ 2 (F o 2 )+(0.0639P) 2 +0.0176P]where P = (F o 2 +2F c 2 )/3.Hydrogen atomic positions were calculated from assumed geometries H1O and H4O.Hydrogen atoms were included in structure factor calculations but they were not refined.The isotropic displacement parameters of the hydrogen atoms were approximated from the U(eq) value of the atom they were bonded to.ORTEP style molecular structure diagram can be found in Figure 1, further data are given in the supplement.Crystallographic data (including structure factors) for the structure in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication nos.CCDC 1032325.The compound number in these files is: BBEB09.Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: ţ44-(0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).