Synthesis of New Optically Active 2-Pyrrolidinones

A new class of optically active 2-pyrrolidinones was synthesized, starting from S-pyroglutamic acid, a well known natural chiral synthon. The synthetic design followed led to the insertion of various substituents at positions 1 and 5 of the 2-pyrrolidinone ring, including the imidazole moiety. Some of them possess two or three stereogenic centers, the configuration of which was retained under the mild conditions used. The new compounds also carry an imidazole moiety, which, along with the 2-pyrrolidinone template, may prove pivotal to several biological processes.


OPEN ACCESS
In recent years, we have designed and synthesized 2-pyrrolidinones, starting from the naturally derived S-pyroglutamic acid (2-oxotetrahydropyrrol-5S-carboxylic acid), which is considered as a unique chiral synthon. The asymmetric use of S-pyroglutamic acid is based on its two differentiated carbonyls, the properties of which allow an extended derivatization on the 5-membered ring of the starting compound leading to a plethora of natural products, e.g., (−) domoic acid [6], the neurotoxin anatoxin-a [7], biologically interesting compounds, e.g., an inhibitor of angiotensin-converting enzyme (ACE) [8] for the treatment of hypertension as well as to chemical auxiliaries in asymmetric synthesis [9]. The properties and applications of pyroglutamic acid as a versatile building block in asymmetric synthesis has extensively been reviewed in the literature [10][11][12]. As it was mentioned above, in recent years, we have synthesized optically active pyrrolidinones based on the S-pyroglutamic acid, in which an imidazole ring has also been inserted. Some of them exhibited antihypertensive and anti-inflammatory activity [13][14][15][16]. In this paper we present the synthesis of seven new compounds (Figure 1), containing up to three stereogenic centers, with predetermined absolute configuration derived from the natural amino acid S-pyroglutamic acid, S-histidine and S-serine.

Results and Discussion
The 2-pyrrolidinones shown in Figure 1 possess an N-benzyl-type substituent, the 4-position of which is substituted by a methoxyalkyloxy group. In the case of compound 26 the alkoxy substituent is a chiral α-amino alcohol moiety.
The 5-position of the 2-pyrrolidinone template has retained the absolute configuration of the initial S-pyroglutamic acid, regardless of whether the carbon chain is elongated or not. At the other end of this chain, an imidazole ring (with or without substitution) has been inserted (compounds 11, 14, 15). In the case of compounds 19a-c and 26, the carboxyl group of the starting acid has been coupled to the amino acid S-histidine. Our approach for the synthesis of these 2-pyrrolidinones is depicted in Schemes 1-3. (ix) LiBH 4 , dry THF; 87%; (x) TosCl, Et 3 N in CH 2 Cl 2 ; 72%; (xi) N  As shown in Scheme 1, the S-pyroglutaminol (2), derived from methyl S-pyroglutamate (1) using NaBH 4 in absolute alcohol [17], was protected as the TES ether using TESCl, Et 3 N and DMAP [18] to yield compound 3. N-benzyloxy-carbonylation of 3 with benzyloxycarbonylchloride using NaH in dry THF [19], afforded compound 4. After deprotection of the TES group using TFA in CH 2 Cl 2 [20], the resulting alcohol 5 was subjected to Moffatt oxidation [21] yielding the corresponding aldehyde, using DMSO, water soluble carbodiimide (EDC.HCl), pyridine and a trace of TFA. The aldehyde, without being isolated was immediately reacted with the stabilized ylide, phosphoranylidene methyl acetate [22], under the conditions of the Wittig reaction to give alkene 6. After catalytic hydrogenation, the N-unprotected, saturated methylester 7 was obtained, and its NH group was alkylated by benzylbromide 30 (Scheme 4) using NaH in dry DMF [19], to afford compound 8. The reduction of the ester group of 8 to the corresponding alcohol 9 was accomplished by LiBH 4 in dry THF [23] and the alcohol 9 was converted to the activated tosyl ester 10. The desired products 11-13 were provided in higher yields (~60%) using imidazole or 1H-imidazole-4(5)-carboxylic acid phenylmethyl ester [16] together with Cs 2 CO 3 in dry DMF at 50 °C. It is known that the nucleophilic strength of nitrogen is enhanced via complexes with Cs + , the so called "cesium effect" [24]. After catalytic hydrogenation the final products 14 and 15 were obtained. As shown in Scheme 1, compounds 14 and 15 as well as their precursors 12 and 13 are constitutional isomers in proportion 2:1, depending on which position (4 or 5) on the imidazole ring the substituent is located. In this case the separation of the two isomers was achieved by column chromatography, but we had to identify which isomer corresponds to each isolated compound. In a previous work on similar constitutional isomers [16], we had used 2D NOESY NMR spectroscopy, in order to distinguish whether the carboxyl group is attached on the 4-or 5-carbon of the imidazole ring. According to the 1 H-NMR spectra of isomers 14 and 15 and taking into account the aforementioned studies, the H-4 of isomer 14 with the carboxylic group at the 5-position of the imidazole ring, resonates at lower field (ca. 7.80 ppm) in comparison to H-5 (ca. 7.68 ppm) of isomer 15 with the carboxylic group at the 4-position. In addition, the diastereotopic proton of the methylene group attached to nitrogen that points towards the carboxylate group in the isomer with substitution at 5-position resonates at lower field (ca. 4.71 ppm) in comparison to the corresponding diastereotopic proton that is not deshielded by the carboxylic group in the isomer with substitution at 4-position and resonates at ca. 4.60 ppm.   As shown in Scheme 2, methyl S-pyroglutamate was N-benzylated using bromides 30, 35 and 39 (Schemes 4-6). After alkaline hydrolysis of the methyl ester of compounds 16a-c, the resulting carboxylic group was coupled with properly protected S-histidine (42, Scheme 7) using the water soluble carbodiimide method [25]. The benzylester group and the N-trityl group of the protected amino acid were removed in the end under catalytic hydrogenation.
Bromides 30, 35 and 39 were prepared under the conditions depicted in Schemes 4-6 respectively. Bromides 28 and 37 (Schemes 4 and 6), prepared from the commercially available alcohols 27 and 36 using PBr 3 in Et 2 O, respectively [26], were used to convert 4-hydroxybenzyl alcohol to phenol ethers 29 and 38 using K 2 CO 3 and 18-crown-6 in acetone [27]. Finally, using PBr 3 in Et 2 O the bromide 30 was obtained in 60% yield, whereas bromide 39 was obtained in 42% yield only by the method of TMS-Cl, NaBr in CH 3 CN [28]. We tried to prepare the desired bromide 39 using many other methods like PBr 3 in Et 2 O, Tos-Cl/Et 3 N and NaBr in acetone or DMF [29], MeSO 2 Cl/Et 3 N and NaBr in DMF or LiBr in THF [30], without any success. In the case of bromide 35, we followed a different approach, depicted in Scheme 5, since 3-bromo-propanol was not commercially available. Compound 32 was obtained by the reaction of 4-hydroxy benzaldehyde (31) and 1,3-dibromo propane with K 2 CO 3 in acetone [31]. After conversion of the bromide group of 32 to methyl ether by MeONa [31], the aldehyde 33 was readily subjected to reduction by NaBH 4 in dry THF to afford alcohol 34. The relatively low yield of the preparation of compound 32 can be explained by the fact that a parallel Cannizzaro reaction had occurred, under the alkaline conditions of that synthetic step, as revealed from the characterization of the isolated by-products. Both benzaldehydes 32 and 33 were unstable even if they were stored at −4 °C for more than 2-3 h.   Reagents and Conditions: (i) Bn-Br, Cs 2 CO 3 in DMF; 87%; (ii) Et 2 NH in abs. EtOH, 82%.

General
All chemicals and solvents were reagent grade and used without purification. Dry THF and extra dry DMF (99.8%) over molecular sieves were purchased from Acros. Melting points were determined on a Büchi 530 apparatus and are uncorrected. Specific rotations were measured at 25 °C on a Perkin-Elmer polarimeter using a 10 cm cell. Nuclear magnetic resonance spectra were obtained on a Varian Mercury spectrometer ( 1 H-NMR recorded at 200 MHz and 13 C-NMR recorded at 50 MHz and they are referenced in ppm relative to TMS as an internal standard). Mass spectra were recorded on a Finnigan Surveyor MSQ Plus with only molecular ions and major peaks being reported with intensities quoted as percentages of the base peak. TLC plates (Silica Gel 60 F254) were purchased from Merck. Visualization of spots was effected with UV light and/or phosphomolybdic acid in EtOH stain. All target compounds possessed 95% purity as determined by combustion analysis.

General Procedure for the Preparation of Compounds 28, 30, 35, 37
To an ice cooled solution of appropriate alcohol 27, 29, 34, 36 (10 mmol) in Et 2 O (25 mL), PBr 3 (1.41 mL, 15 mmol) was added dropwise under argon. The mixture was stirred at room temperature for 3-7 h and the reaction was quenched by the addition of H 2 O (15 mL) in small portions at 0 °C. The aqueous phase was removed and the organic layer was washed with H 2 O, dried over Na 2 SO 4 and evaporated in vacuo. In the case of products 30 and 35, purification was achieved by column chromatography using the appropriate solvent systems as it will be defined in each case below. In the case of bromides 28, 37, the oily products were not visible either in UV-light or in iodine stain. They were characterized by NMR and used in the next step without further purification. For this reason the yields of their preparation must be considered as crude yields. (28). Prepared from the commercially available alcohol 27; Yield: 58% (colorless oil). 1 (30

General Procedure of for the Preparation of Compounds 4, 8, 16a-c, 20
To a cooled solution of methyl (S)-pyroglutamate (1), O-protected-S-pyroglutaminol (3), or methylester 7 (1 mmol) in dry THF (5 mL) NaH (60% in paraffin oil, 1.5 mmol) was added in small portions, followed by the addition of the appropriate benzyl bromide (or benzyloxycarbonylchloride in case of compound 4) (1.1 mmol). The stirring was continued for 15 min at 0 °C, and for 24 h at rt under argon. The reaction was quenched by the addition of a saturated solution of NH 4 Cl at 0 °C, the organic solvent was evaporated and the residue was dissolved in ethyl acetate. The organic layer was washed with brine, dried over Na 2 SO 4 and evaporated under reduced pressure. The product was purified by column chromatography (Silica Gel 60) using the appropriate solvent systems as defined in each case below.    (20). Prepared from methyl-S-pyroglutamate (1) and 1-(benzyloxy)-4-(bromomethyl) benzene [32]. Eluent EtOAc -petroleum ether (bp. 40-60 °C), 7:3. The product was obtained as a colorless oil in 47% yield.  (5). To a stirred solution of compound 4 (1.20 g, 3.30 mmol) in DCM (20 mL), TFA was added (2.02 mL, 26.4 mmol) at room temperature. Once the reaction was finished (45 min), the solvent was evaporated to dryness. The residue was dissolved in toluene and the solvent was evaporated (twice) for the removal of the acid. Finally the residue was dissolved in ethyl acetate and the organic phase was washed with brine to neutral pH. After drying over Na 2 SO 4 and evaporation of the solvent under reduced pressure, the product was obtained as a pure white solid. Yield  (6). Alcohol 5 (0.22 g, 0.882 mmol) was dissolved in a mixture of dry toluene (5 mL) and dry DMSO (2.5 mL), followed by the addition of EDC·HCl (0.51 g, 2.64 mmol), the dropwise addition of dry pyridine (0.25 mL, 3.04 mmol) and finally TFA (33.2 μL, 0.441 mmol) under argon. After stirring at rt for 1.5 h the reaction was quenched by the addition of CHCl 3 and the solution was washed with brine and H 2 O. The organic layer was dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. The resulting crude aldehyde was subjected to Wittig reaction without further purification. More specifically, it was dissolved in dry THF (6 mL), methyl (triphenylphosphoranylidene)acetate (0.32 g, 0.95 mmol) was added and the mixture was refluxed under argon for 1 h. The reaction was quenched by the addition of saturated solution of NH 4 Cl. The solvent was evaporated under reduced pressure and the residue dissolved in EtOAc was successively washed with NH 4 Cl, H 2 O and brine. The organic layer was dried over Na 2 SO 4, filtered and evaporated under reduced pressure. After purification by column chromatography using EtOAc as eluent, the product was obtained in 60% yield (0.16 g) as a colorless oil. Rf 0.63 in EtOAc; [α] (9). To a two necked flask, LiBH 4 (14 mg, 0.656 mmol) was suspended in dry THF (0.5 mL) under argon at rt. A solution of compound 8 (0.110g, 0.656 mmol) in dry THF (1.5 mL) was added dropwise and the reaction mixture was stirred for 10 h. The reaction was quenched by the addition of a 20% aq. solution of AcOH at 0 °C until gas production ceased. The excess of acetic acid was neutralized by the addition of a small quantity of Na 2 CO 3 . The organic solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc. The organic phase was then washed with brine, dried over Na 2 SO 4 and evaporated under reduced pressure. After purification with column chromatography using EtOAc-MeOH 9:1 as eluent, the product was obtained as a colorless oil in 87% yield (87 mg). Rf 0.34 in EtOAc-

General Procedure for the Preparation of Compounds 17a-c, 23
To a stirred solution of methylester (compounds 16a-c, 22) (1 mmol), in MeOH (3 mL), an aq. solution of 2N NaOH (0.5 ml, 1 mmol) was added and the reaction mixture was left stirring at rt for 2-3 h. Upon completion of the reaction, the MeOH was evaporated under reduced pressure and the residual product was diluted with H 2 O and extracted with Et 2 O (1 × 10 mL). The aqueous phase was acidified with 1 N HCl aq. solution at pH 2 and extracted with EtOAc (2 × 10 mL). The combined organic phases were neutralized by washing with brine and H 2 O, dried over Na 2 SO 4 and evaporated under reduced pressure to afford the carboxylic products in quantitative yield and high purity.

General Procedure for the Preparation of Compounds 18a-c, 24
To a stirred solution of carboxylic acids (compounds 17a-c, 23) (1 mmol) in CH 2 Cl 2 (10 mL) at 0 °C, 1-hydroxybenzotriazole (HOBt) (0.135 g, 1 mmol), freshly prepared benzyl 3-trityl-L-histidinate (42) (0.537 g, 1.1 mmol), Et 3 N (0.154 mL, 1.1 mmol) and N-ethyl-N-dimethylaminopropylcarbodiimide hydrochloride (EDC.HCl) (0.210 g, 1.1 mmol) were added consecutively. The reaction mixture was left stirring at 0 °C for 1 h and then warmed to room temperature and left stirring for 18 h. The solvents were evaporated under reduced pressure and the crude product was dissolved in EtOAc (20 mL). The organic layer was washed with 5% aq. H 2 SO 4 , H 2 O, 5% aq. NaHCO 3 , and brine. After drying over Na 2 SO 4 and evaporation of the solvent in vacuo, the crude ester was purified using column chromatography with the appropriate solvent systems as it will be defined in each case below.

Conclusions
In this paper the synthesis of new, optically active 2-pyrrolidinones starting from the natural chiral synthon of S-pyroglutamic acid is described.