The stereochemistry of the addition of chlorotitanium enolates of N-acyl oxazolidin-2-ones to 5- and 6- membered N-acyliminium ions

Journal of the Brazilian Chemical Society

Universidade Estadual de Campinas, Campinas, Brazil¹  Böckelmann, Maria Alice¹  Alves, Conceição de Fatima¹  Pilli, Ronaldo A.¹ 

关键词: oxazolidin-2-ones;    titanium (IV) enolates;    cyclic N-acyliminium ions;    2-substituted pyrrolidines and piperidines.;   

DOI  :  10.1590/S0103-50532001000500007

学科分类：化学（综合）

来源: SciELO

【 摘 要 】

The condensation of a carbonyl compound with an amine followed by the addition of a carbon nucleophile to the intermediate iminium species, known as the Mannich reaction, is one of the classical methods for the synthesis of b-aminocarbonyl compounds and nitrogen-containing heterocycles. The use of preformed iminium salts and carbon nucleophiles such as metal enolates, silyl enol ethers, silyl keteneacetals and enamines has greatly expanded the versatility of this reaction allowing the use of milder reaction conditions and the introduction of elements of regioselective control1. Despite the similarity with the aldol reaction much less is known about the structural features controlling the stereochemical outcome of the addition of prochiral carbon nucleophiles to imines or iminium ions when compared to the corresponding addition to aldehydes. Evans and co-workers put forth a topological analysis for the addition of metallic enolates to imines based on the coordination of the nitrogen lone pair to the metallic species giving rise to chelated transition states which may adopt either chair-like or boat-like geometries depending on the interplay of steric and electronic interactions2.The utilization of N-acyliminium ions has attracted much attention particularly in the intramolecular version of the reaction due to their enhanced electrophilic character and the reduced bias towards Grob fragmentation displayed by the corresponding b-aminocarbonyl derivatives3. An open transition state with an antiperiplanar approach of carbon nucleophiles to the electrophilic center of the iminium ion has been proposed4.Inspired by the early work of Fuentes and co-workers who first revealed the feasibility of the addition of boron enolates of chiral oxazolidin-2-ones to chiral 4-acetoxy-2-azetidinones5 and by the work of Nagao and co-workers who described the addition of tin (II) enolates of chiral 3-acyl-1,3-thiazolidine-2-thiones to 4-acetoxy-2-azetidinone and 5-acetoxy-2-pyrrolidinone6, we were attracted to study the effect of the ring size and the nature of the carbamoyl group of the N-acyliminium ion in the reactivity and stereochemical outcome of the addition of boron and chlorotitanium (IV) enolates of oxazolidin-2-ones to prochiral cyclic N-acyliminium ions expecting that diastereoselection would be attained due to the known facial discrimination displayed by the enolates of oxazolidin-2-ones7. Additionally, the results were expected to be of potential interest in the asymmetric synthesis of nitrogen heterocycles such as pyrrolizidine, indolizidine and quinolizidine ring systems8.  Results and Discussion Initially, we investigated the boron enolate addition of achiral oxazolidin-2-one 1 to 2-ethoxypyrrolidine 5, prepared by sodium borohydride reduction of an ethanolic solution of the corresponding lactam9. The boron enolate of achiral oxazolidin-2-one 1 was generated in CH2Cl2 at 0 °C upon treatment with n-Bu2BOTf, according to the procedure by Evans and co-workers10, followed by the addition of 5 (1.0 equiv.) and an additional equivalent of n-Bu2BOTf at 0 °C. The diastereoisomeric ratio for (+/-)-7:(+/-)-8 was shown to be 13:1 after inspection of the 1H NMR spectrum (300 MHz, 55 °C) of the crude product which displayed two doublets at d 1.13 and d 1.18 ppm for the methyl group at C-1' (Scheme1)11. N-Boc-2-substituted pyrrolidine (+/-)-7 was isolated in 50% yield after column chromatography on silica gel. In comparison, the coupling of the N,O-silylketeneacetal derived from N-propionyl oxazolidin-2-one 1, prepared in situ through the addition of 1.2 equiv. of TMSOTf and 1.15 equiv. of Et3N in CH2Cl2 at 0 °C, with 2-ethoxypyrrolidine 5 was also carried out but afforded a 2:1 mixture of (+/-)- 7 and (+/-)-8, in 45% yield (Table 1, entries 1 and 2).      Much to our surprise, the experimental protocol described above for the addition of the boron enolate derived from 1 to 2-ethoxypyrrolidine 5 did not provide the corresponding N- Boc- 2- substituted piperidines (+/-)-9:(+/-)-10 when 2-ethoxypiperidine 6 was added to a CH2Cl2 soln. of the boron enolate of oxazolidin-2-one 1, which was recovered in almost quantitative yield, even when the reaction was carried out at room temperature and for longer reaction period. However, the reaction of 2-ethoxypiperidine 6 with the N,O-trimethylsilylketeneacetal of N-propionyl oxazolidin-2-one (1) did proceed to afford a 2:1 mixture of the 2-substituted piperidines corresponding to (+/-)-9 and (+/-)-10, in 36% non-optimized yield after in situ N-Boc deprotection (Table 1, entries 4 and 5).The same reactivity pattern emerged when we employed the boron enolate derived from chiral oxazolidin-2-one ent-2: 1H NMR analysis of the crude mixture revealed that a single 2-substituted pyrrolidine was formed from 5 but no reaction was observed with 2-ethoxypiperidine 6 (Scheme 1, Table 1, entries 7 and 8). N-Boc pyrrolidine (+)-11 was isolated in 55% yield after column chromatography on silica gel and had its structure established by X-ray diffraction analysis7b.As we were facing some difficulties reproducing the yields in the reactions with boron enolates12, we decided to examine the behavior of the chlorotitanium(IV) enolates of oxazolidin-2-one 1 and 2 in the presence of cyclic N-acyliminium ions. Upon addition of a CH2Cl2 soln. of 2-ethoxypyrrolidine 5 to a previously formed solution of the chlorotitanium (IV) enolate corresponding to 1 in CH2Cl2 at –23 °C7b, a gradual fading of the deep burgundy color of the enolate soln. was observed. 1H NMR analysis (in CDCl3 at 55 °C) of the crude product revealed that 2-substituted pyrrolidines (+/-)-7 and (+/-)-8 were produced in a 14:1 ratio (Scheme 1, Table 1, entry 3). Purification by column chromatography on silica gel gave (+/-)-7 in 72% yield. As before, no reaction took place when 2-ethoxypiperidine 6 was employed at –23 °C or at 0 °C (Table 1, entry 6).The puzzling behavior of 2-ethoxypiperidine 6 led us to examine the addition of the chlorotitanium (IV) enolate derived from N-acetyl oxazolidin-2-one 3 which was expected to relieve steric hindrance during the approach of the nucleophile to the intermediate N-acyliminium ion. In fact, 2-substituted piperidine 16 was isolated in 40% yield when the reaction was carried out at –23 °C (Scheme 1 ,Table 1, entry 11). Under the same reaction conditions, 5 afforded 2-substituted pyrrolidine 15 in 46% yield (Scheme 1 ,Table 1, entry 10). In the chiral series, the reaction of chlorotitanium (IV) enolate derived from (-)-4 with 5 and 6 afforded N-2-substituted pyrrolidines 17:18 as a 1:1 mixture and piperidines 19:20 as a 3.5:1 mixture in 70% and 90% yield, respectively (Scheme 1 ,Table 1, entries 12 and 13).At this point, it was evident that the ring size and the nature of nucleofile were modulating the reactivity and the stereochemical outcome of the reaction and an evaluation of the impact of the carbamate group of the N-acyliminium ion on the reaction course seemed in order. The reaction with the chlorotitanium (IV) enolate of achiral oxazolidin-2-one 1 proceeded with moderate to good yields with N-Cbz and N-CO2Me pyrrolidines 21 and 23 and piperidines 22 and 24, but with good diastereoselection only in the pyrrolidine series (Scheme 2, Table 2, entries 1-4). The same trend was observed when the enolate of chiral oxazolidin-2-one 2 (Scheme 2, Table 2, entries 5-8) was employed and the best diastereoselection was achieved with N-Boc-2-ethoxypyrrolidine 5 (table 1, entries 1 and 4).     The unambiguous assignements of the absolute configuration of the major 2-substituted pyrrolidine (-)-117b and piperidine (-)-357b were achieved after X-ray diffraction analyses. The relative configurations of (+/-)-7 and (+/-)-27 were established as 2SR, 1'SR after their conversion to the racemic form of carboxylic acids (-)-41 (authentic sample prepared from (-)-11) and 42 (authentic sample prepared from a 1.8:1 mixture of 35:36), respectively (Scheme 3).   The relative configuration of the major products (+/-)- 25 and (+/-)- 29 formed from achiral oxazolidin-2-one 1 was confirmed to be 2SR, 1'SR after conversion of (+/-)- 7 and (+/-)-25 to the same pyrrolidine (+/-)-43 which upon carboxymethylation was converted to (+/-)-29 (Scheme 4). The same protocol was employed to correlate 2-substituted piperidines (+/-)-27 and (+/-)-39, after hydrogenolysis and N-carboxymethylation.    The relative configuration 2RS, 1'SR of the minor isomer (+)-12 formed in the reaction of the chiral chlorotitanium (IV) enolate derived from 2 and 2-ethoxypyrrolidine 5 was established after its conversion to carboxylic acid (+)-44 (LiOH, H2O2, THF, H2O, 0°C) which proved to be diastereoisomeric to carboxylic acid (-)-41 (Scheme 5). When the major isomer (-)-11 was treated with a THF soln. of LDA at –78oC it underwent partial epimerization at C-1' to afford (-)-45, a diastereoisomer of both the minor isomer (+)-12 and the major isomer (-)-11, together with N-acyl urea 46 resulting from the nucleophilic attack of LDA to the endocyclic carbonyl of (-)-11. (Scheme 6).      Basic hydrolysis of (-)-45 afforded carboxylic acid (-)-44 which was shown to be enantiomeric to the carboxylic acid (+)- 44 obtained from the basic hydrolysis of (+)-12 thus confirming the 2R, 1'S stereochemistry of the later carboxylic acid. (Schemes 5 and 6)The absolute configuration of the major and minor pyrrolidines in the mixture 33:34 was assigned after conversion of a 9:1 mixture of 11:12 into a 9:1 mixture of 33:34 which involved Boc removal (CF3CO2H, CH2Cl2, rt) and nitrogen protection (ClCO2Bn, K2CO3, CH2Cl2). The stereochemistries of pyrrolidines 37 and 38 were determined accordingly. In the piperidine series, X-ray diffraction analysis established the stereochemistry of the major adduct (-)-357b, and the absolute configuration of the minor isomer (-)-36 was eventually established as 2R, 1'S after its conversion to piperidine derivative (+)-49, enantiomeric to the piperidine derivative obtained from (-)-35 (Scheme 7).   Inspection of the 13C NMR spectra in the 2-substituted piperidines series revealed a downfield shift of C-2 in the major isomers when compared with the minor ones (Dd 1.4-1.7 ppm) which may be diagnostic of their relative stereochemistry. The absolute configuration of 39:40 was confirmed after conversion of a 1.8:1 mixture of (-) -35 and (-)-36 of known configuration to the corresponding mixture of 39:40 (i. H2, Pd/C, MeOH, rt; ii. MeOCOCl, K2CO3, acetone, rt) and comparison by HPLC analysis.Finally, the major isomer (-)-19 formed in the addition of the chlorotitanium (IV) enolate derived from oxazolidin-2-one (-)-4 to 2-ethoxy piperidine 6 was shown to have 2S configuration after its conversion to the known methyl ester (-)-51 (Scheme 8)13.   In order to extend the study of the influence of the nature of the nucleophile in the stereochemical outcome of the reaction, chlorotitanium (IV) enolates derived from oxazolidin-2-ones 52 and 53 were employed (Scheme 9). Our choice was additionally guided by the potential usefulness of the corresponding adducts in the asymmetric synthesis of (2R, 2'R)-methylphenidate hydrochloride7c and in the total synthesis of pyrrolizidine and indolizidine alkaloids6.   As depicted in Table 3 the formation of 2-substituted pyrrolidine derivatives occurred with excelent diastereoselection (>95:5, entries 1, 4 and 5) while moderate to good selectivity was observed in the piperidines series (entries 2, 3 and 6), superior to the diastereoisomeric ratio observed with chlorotitanium enolates from oxazolidin-2-ones 1-4 (Table 1 and 2). The absolute configuration for 54, 60 and 62 was tentatively assigned as (2R, 1'R) based on our previous results for the addition of chlorotitanium enolates derived from 2 to a-alkoxy pyrrolidines 5, 21 and 23.    Inspection of the 13C NMR spectra of the mixture 64:65 revealed that the major isomer 64 displayed its C-2 shift downfield (1.4 ppm) in comparison with the minor isomer 65, as observed earlier for 2-substituted piperidines depicted in Table 2. Based on that evidence (2R, 1'R) and (2R, 1'S) configuration were assigned to 64 and 65, respectively.The absolute configuration of the majors isomers 56 and 58 was established after their conversion to (2R, 2'R) methylphenidate hydrochloride (66). Methylphenidate is a mild psychostimulant and is widely prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) in children, a condition that is manifested by impulsivity, hyperactivity, and inattention. It is marketed as its racemic form despite the fact that the 2R, 2'R-isomer is several times more active than the corresponding enantiomer14-16.Basic hydrolysis of the mixture 56/57 allowed the efficient recovery of the chiral auxiliary (>90% yield), and provided carboxylic acid 67 wich was converted to methyl ester 68 in 81% overall yield, as a 12:1 mixture with its 2'S epimer. Hydrogenolysis followed by treatment with ethanolic HCl, and recrystallization from EtOH/Et2O afforded (+)-(2R, 2'R)-methylphenidate hydrochloride 66 in 76% yield from 67.Alternatively, basic hydrolysis of 58 allowed recovery of the chiral auxiliary (90% yield), and afforded carboxylic acid 69 in 90% yield. Carbamate deprotection was accomplished with in situ prepared trimethylsilyl iodide and it was followed by esterification and treatment with ethanolic HCl to provide (2R, 2'R)-methylphenidate hydrochloride 66 in 63% yield from 69.Overall, (2R, 2'R)-methylphenidate hydrochloride 66 was prepared in 4 steps and 43% overall yield from 22 and in 5 steps and 37% overall yield from 24 (Scheme 10).   The absolute configuration (2S, 1'R) for the minors isomers 57 and 59 was assigned based on our previous studies (Scheme 2, Table 2) in agreement with the results by Matsumura et al7c.From the body of information described above it emerges that the oxazolidin-2-one moiety is efficiently discriminating its approach to the N-acyliminium ion: in every case, both major and minor isomers displayed 1'S stereochemistry when (R)-4-benzyl oxazolidin-2-one was employed as chiral auxiliary revealing the preferential approach of the Re face of the corresponding chlorotitanium (IV) enolate. A Z-configured internally coordinated chlorotitanium (IV) enolate, as depicted in Scheme 11, is proposed to be the nucleophilic species in the reactions above and either an antiperiplanar or a synclinal approach of the nucleophile to the N-acyliminium ion seems to be available.   For bulky carbamates such as 5-6 (Scheme 1) the stereochemical outcome will be dictated by the relief of steric interactions involving the Boc group: while this seems to be the

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