An easy access to two epimeric N-substituted (2S)-2-(2'-hydroxypropyl)pyrrolidines

Abstracts

An easy and efficient route for the synthesis of enantiomerically pure beta-aminoketones 5a, 6 and gamma-aminoalcohols 1a, 2a, 3, 4 from L-prolinol 7 and L-proline 15 is described. One of the key steps is the use of Tebbe's reagent allowing the transformation of the ester function to an enol ether without any racemization.

beta-aminoketones; gamma-aminoalcohols; racemization; Tebbe's reagent

Uma fácil e eficiente síntese para obtenção de beta-aminocetonas 5a, 6 e gama-aminoálcoois 1a, 2a, 3, 4 enantiomericamente puros a partir de L-prolinol 7 e L-prolina 15 é descrita. A etapa principal da reação foi o uso do reagente de Tebbe que permitiu a transformação da função éster a um enol éter que após hidrólise formou a cetona sem nenhuma racemização.

ARTICLE

An easy access to two epimeric N-substituted (2S)-2-(2'-hydroxypropyl)pyrrolidines

Maria Joselice e Silva^{I, II}; Louis Cottier^II; Rajendra M. Srivastava^{*, I}; Denis Sinou^II

^IDepartamento de Química Fundamental, Universidade Federal de Pernambuco, Cidade Universitária, 50.740-540 Recife - PE, Brazil

^IILaboratoire de Synthèse Asymétrique, associe au CNRS UMR 5181, ESCPE Lyon, Université Claude Bernard Lyon 1, boulevard du 11 november 1918, 69622, Villeurbanne Cedex, France

ABSTRACT

An easy and efficient route for the synthesis of enantiomerically pure b-aminoketones 5a, 6 and g-aminoalcohols 1a, 2a, 3, 4 from L-prolinol 7 and L-proline 15 is described. One of the key steps is the use of Tebbe's reagent allowing the transformation of the ester function to an enol ether without any racemization.

Keywords: b-aminoketones, g-aminoalcohols, racemization, Tebbe's reagent

RESUMO

Uma fácil e eficiente síntese para obtenção de b-aminocetonas 5a, 6 e g-aminoálcoois 1a, 2a, 3, 4 enantiomericamente puros a partir de L-prolinol 7 e L-prolina 15 é descrita. A etapa principal da reação foi o uso do reagente de Tebbe que permitiu a transformação da função éster a um enol éter que após hidrólise formou a cetona sem nenhuma racemização.

Introduction

In our ongoing research on the total synthesis of glycoheterocyclic compounds, we needed compounds (2S,2'R)- and (2S,2'S)-N-(p-toluenesulfonyl)- and (2S,2'R)- and (2S,2'S)-N-(methoxycarbonyl)-2-(2' -hydroxypropyl)pyrrolidines 1a, 2a 3 and 4 respectively. Before starting the present work, we surveyed the literature and found no record of N-tosyl alcohols 1a and 2a.

There are entries for the racemic alcohols 3 and 4,^1,2 and also of enantiomerically pure 4.³ Our interest developed knowing the fact that pyrrolidine derivatives possess biological activities.^4,5

For obtaining the aforementioned alcohols, our first approach was to prepare ketones 5a and 6 in the enantiomerically pure forms. In fact racemic 5 was prepared earlier in four steps by a tandem S_N2-Michael addition reaction without any description about their optical purity.⁶ Racemic 6 is also known.¹ This contribution therefore gives a detailed account of acquiring compounds 1a, 2a, 3, 4, 5a and 6 starting from (S)-prolinol 7 or (S)-proline 15 (Schemes 1 and ³).

Results and Discussion

We envisaged the synthesis of ketone 5a starting from (S)-prolinol 7 involving a series of steps (Scheme 1). The use of Tebbe's reagent⁷ to transform 10®5a turned out to be interesting because this reagent is used in a non-basic medium. Thus, racemization does not take place on substrates with enolizable chiral centers or other base sensitive groups.

Initially, we decided to ditosylate compound 7⁸ in order to obtain 8 and its transformation to nitrile 9a.⁸ The last product was converted to ester 10. Treatment of 10 with Tebbe's reagent and subsequent hydrolysis of enol ether led to ketone 5a which was reduced to 1a and 2a with sodium borohydride (Scheme 1).

The ¹H NMR spectra of 1a and 2a are consistent with the proposed structures. Compound 5a was found to be enantiomerically pure by ¹H NMR spectroscopy as verified by the chiral shift reagent, europium tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorate. The same chiral shift reagent was used for obtaining the ¹H NMR spectrum of the racemic mixture 5a,5b.

It is well known that N-alkyl b-amino ketones racemize rapidly in basic medium⁹ and the cleavage of the pyrrolidine ring is favored when the nitrogen atom carries an electron withdrawing group.^10,11 Before the synthesis of 5a employing Tebbe's reagent, we also visualized to prepare ketone 5a in basic medium. For this, compound 9a was allowed to react with MeLi which furnished 5a,5b with 54% enantiomeric excess in favor of the (S) configuration. The ee was determined by measuring the optical rotation of the mixture 5a,5b and comparing with the value of the pure enantiomer 5a. Next, we attempted to obtain 5a from 14 using acidic conditions.¹² This provided racemic 5a,5b, which after reduction with sodium borohydride yielded a mixture of stereoisomers, viz., 1a, 1b and 2a, 2b, respectively (Scheme 2). Each enantiomeric pair was separated by liquid chromatography over silica gel in the ratio of 2.1:1.0 (1a,1b:2a,2b); the fast moving spot 2a,2b crystallized and its X-ray analysis showed them as a racemic mixture consisting of enantiomers (2S,2'S) 2a and its mirror image (2R,2'R) 2b. Since the racemic mixture gave beautiful crystals suitable for X-ray data collection, we analysed it crystallographically. The X-ray structure is depicted in Figure 1.

The single crystal structure analysis shows that the pyrrolidine ring is somewhat deviated and not in an envelope shape. The torsion angles C(4)-N(1)-C(1)-C(2), N(1)-C(1)-C(2)-C(3) and C(2)-C(3)-C(4)-N(1) are -19.7, 34.2 and 24.4 degrees, respectively. It further provides the bond angles C(4)-N(1)-S(1) and C(1)-N(1)-S(1) of 118.7 and 118.8 degrees which is very close to 120 degrees indicating sp² hybridization of the nitrogen atom. The N-S bond distance found in the current work is 1.622Å, both S=O bond distances are: 1.431 and 1.434, respectively. These values are very close to the data reported in the literature for N-tosyl-8-azaspiro(4,5)-deca-1,3-diene, which have N-S = 1.631; S=O = 1.446; S=O = 1.417Å, respectively.¹³ Another interesting observation was found. The dihedral angles N(1)-S(1)-C(5)-C(6) and N(1)-S(1)-C(5)-C(10) are 85.2 and -90.5 degrees showing that the p-tolyl ring is almost perpendicular to N(1)-S(1) bond. Other bond distances and bond angles observed are normal. Both (R) and (S) configurations of 2 can be visualized easily in the diagram (Figure 1).

Next, an alternative route for the synthesis of the known compounds 3 and 4 has been developed by us starting from N-methoxycarbonyl-(S)-proline 16,¹⁴ which in turn was obtained from (S)-proline 15. Homologation of 16 by Arndt-Eistert method¹⁵ gave 17 which was converted to ester 18. The conversion of ester 18 to vinyl ether 19 utilizing Tebbe's reagent, followed by an acidic hydrolysis gave ketone 6 in an excellent yield. Sodium borohydride reduction of 6 afforded 3 and 4 in the ratio of 2.0:1.0 (^{Scheme 3}). Alcohols 3 and 4 were separated in their pure forms by liquid chromatography over silica gel. Their structures and configurations agreed with the data reported earlier.^1-3

Conclusion

In conclusion, we have been able to synthesize ketones 5a and 6 without any epimerization using Tebbe's reagent and also the known diastereoisomers 3 and 4 by an alternative route not elaborated previously. Compounds 6 and 4 may be considered as precursors of (-)-hygrine and (-)-hygroline,^1-3 which are natural alkaloids. A new synthetic procedure has been developed for alcohols 1a, racmic 1a,1b, 2a and racemic 2a,2b starting from (S)-prolinol 7.

Experimental

Melting points were determined on an Electrothermal digital melting points apparatus (model IA9100) and are uncorrected. Specific rotations were measured on a Perkin-Elmer polarimeter model 241. NMR spectra were recorded with a Bruker AM 300MHz for NMR ¹H and 75.5MHz for NMR ¹³C using TMS as an internal standard. Chemical shifts (d) are expressed as ppm and splitting patterns are designated as: s = singlet, bs = broad singlet, d = doublet, dd = double doublet, t = triplet, q = quartet and m = multiplet. Silica gel 60 (230 – 400 mesh) was employed for liquid chromatography. Petroleum ether used in the experiments had boiling range of 40-65 °C.

Ethyl (-)-(S)-N-(p-toluenesulfonyl)-2-pyrrolidinyl acetate (10). (-)-(S)-N-(p-Toluenesulfonyl)-2-pyrrolidinyl acetonitrile 9a (1.0 g, 3.79 mmol) in absolute ethanol (40.0 mL) saturated with gaseous HCl was stirred for 24h at room temperature. Solvent removal under reduced pressure, dissolution of the residue in ice-cold water followed by the treatment with NaHCO₃ furnished an alkaline solution with a pH value of ~ 9.0. Extraction with CH₂Cl₂, drying (Na₂SO₄), filtration and solvent removal left an oil. Liquid chromatography of this material over silica gel using a mixture of petroleum ether and diethyl ether (1:1) gave 0.71 g (60%) of the chromatographically pure product as solid having R_f value of 0.5 (petroleum ether:diethyl ether, 1:1). [a]_D²⁵ -103.2 (c 1.04, CH₂Cl₂). IR(KBr) n_max/cm^-1: 1735 (n C=O), 1250 and 1050 (n C-O). ¹H NMR (300 MHz, CDCl₃): d 1.27 (t, 3H, J 7.1 Hz, aliph.–CH₃), 1.51-1.90 (m, 4H, H-3, H-4), 2.44 (s, 3H, H-12), 2.53 (dd, 1H, J 10.1 Hz, J 16.0 Hz, H-1'), 3.10 (dd, 1H, J 3.9 Hz, J 16.0 Hz, H-1'), 3.11-3.17 (m, 1H, H-5), 3.41-3.48 (m, 1H, H-5), 3.93-3.99 (m, 1H, H-2), 4.14 (2q overlapping, 2H, J 7.1 Hz, -OCH₂-), 7.32 (d, 2H, J 8.2 Hz, H-8, H-10), 7.76 (d, 2H, J 8.2 Hz, H-7, H-11). ¹³C NMR (75.5 MHz, CDCl₃): d 14.5 (aliph.–CH₃), 21.8 (C-12), 24.1 (C-4), 32.0 (C-3), 41.7 (C-5), 49.5 (C-1'), 56.9 (C-2), 60.8 (-OCH₂-), 127.9 (C-8, C-10), 130.1 (C-7, C-11), 134.4 (C-9), 143.9 (C-6), 171.6 (CO). The NMR spectra agreed with the literature data.⁶

(-)-(S)-N-(p-Toluenesulfonyl)-2-pyrrolidinyl propanone (5a). Tebbe's reagent (2.0 mL, 0.5 mol L^-1 in toluene) was added to ester 10 (0.31 g, 1.0 mmol) dissolved in THF (3.0 mL) at 0 °C, and the mixture was stirred for 30 min at room temperature. Soon after, ether (15.0 mL) and seven drops of 0.1 mol L^-1 NaOH was added to it and stirred for an additional 30 min. Solvent drying over Na₂SO₄, filtration over celite and solvent evaporation under vacuum left the crude product. This was then dissolved in CHCl₃ (15.0 mL) and six drops of a 2.0 mol L^-1 HCl added to it followed by stirring for 1.5h at room temperature. Water was added (30.0 mL) to the solution followed by neutralization with NaHCO₃. Extraction with CH₂Cl₂ (3 x 30.0 mL), drying (Na₂SO₄), filtration and solvent removal provided the crude solid (0.28 g). Column chromatography over silica gel using petroleum ether and ethyl acetate (6:4) gave pure 5a which yielded colorless crystals (0.22 g, 79%) after crystallization from petroleum ether-dichloromethane, mp. 94-96 °C, [a]_D²⁵ -116.9 (c 1, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): d 1.43-1.61 (m, 2H, H-4), 1.72-1.82 (m, 2H, H-3), 2.17 (s, 3H, H-3'), 2.43 (s, 3H, H-12), 2.65 (dd, 1H, J 9.7 Hz, J 17.8 Hz, H-1'), 3.04-3.12 (m, 1H, H-5), 3.25 (dd, 1H, J 3.2 Hz, J 17.8 Hz, H-1'), 3.40-3.47 (m, 1H, H-5), 3.89-3.94 (m, 1H, H-2), 7.33 (d, 2H, J 7.9 Hz, H-8, H-10), 7.72 (d, 2H, J 8.2 Hz, H-7, H-11). ¹³C NMR (75.5 MHz, CDCl₃): d 21.9 (C-12), 24.1 (C-4), 30.9 (C-3'), 32.4 (C-3), 49.5 (C-5), 51.0 (C-1'), 56.2 (C-2), 128.0 (C-8, C-10), 130.1 (C-7, C-11), 134.0 (C-9), 143.9 (C-6), 207.5 (C-2'). The NMR spectra agreed with the literature data.⁶

N-(p-Toluenesulfonyl)-2-pyrrolidinyl propanol-2 (1a and 2a). Sodium borohydride (27mg, 0.71 mmol) was added at 0 °C to compound 5a (0.1 g, 0.36 mmol) dissolved in methanol (8.0 mL) and the contents stirred for 1h at this temperature. After this, a 2.0 mol L^-1 HCl (0.5 mL) was added to the solution and stirred for additional 10 min. Neutralization of this solution with aqueous NaHCO₃, extraction with CH₂Cl₂ and work-up yielded two diastereoisomers which were separated by column chromatography over silica gel using petroleum ether and ethyl acetate (1.5:1.0) to give 1a (66.0 mg) and 2a (31.0 mg) (2.1:1.0). The combined yield was 96%. These compounds were recrystallized from hexane and ethyl acetate (5:1). Compound 1a: mp. 84-85 °C, [a]_D²⁵ -98.0 (c 1.04, CH₂Cl₂), R_f 0.4 (petroleum ether:EtOAc, 6:4). Anal. Calc. for C₁₄H₂₁NO₃S: C, 59.33; H, 7.47. Found: C, 59.26; H, 7.31. ¹H NMR (300 MHz, CDCl₃): d 1.26 (d, 3H, J 6.2 Hz, H-3'), 1.44-2.03 (m, 6H, H-1', H-3, H-4), 2.42 (s, 3H, H-12), 3.14-3.22 (m, 1H, H-5), 3.37-3.45 (m, 1H, H-5), 3.85-3.93 (m, 2H, H-2, H-2'), 7.33 (d, 2H, J 8.1 Hz, H-8, H-10), 7.73 (d, 2H, J 8.2 Hz, H-7, H-11). ¹³C NMR (75.5 MHz, CDCl₃): d 21.9 (C-12), 24.3 (C-4), 24.7 (C-3'), 31.6 (C-3), 46.4 (C-1'), 49.2 (C-5), 58.5 (C-2), 66.6 (C-2'), 128.0 (C-8, C-10), 130.0 (C-7, C-11), 134.8 (C-9), 143.8 (C-6). Compound 2a: mp. 92.5-94 °C, [a]_D²⁵ -20.5 (c 0.83, CH₂Cl₂), R_f 0.5 (petroleum ether:EtOAc, 6:4). Anal. Calc. for C₁₄H₂₁NO₃S: C, 59.33; H, 7.47. Found: C, 59.69; H, 7.72. ¹H NMR (300 MHz, CDCl₃): d 1.23 (d, 3H, J 6.4 Hz, H-3'), 1.31-1.88 (m, 6H, H-1', H-3, H-4), 2.43 (s, 3H, H-12), 3.13-3.22 (m, 1H, H-5), 3.34-3.42 (m, 1H, H-5), 3.46 (bs, 1H, OH), 4.02-4.10 (m, 1H, H-2), 4.16-4.20 (m, 1H, H-2'), 7.33 (d, 2H, J 8.1 Hz, H-8, H-10), 7.73 (d, 2H, J 8.2 Hz, H-7, H-11). ¹³C NMR (75.5 MHz, CDCl₃): d 21.9 (C-12), 23.2 (C-3'), 24.4 (C-4), 31.7 (C-3), 45.8 (C-1'), 48.8 (C-5), 58.1 (C-2), 64.1 (C-2'), 127.9 (C-8, C-10), 130.1 (C-7, C-11), 134.7 (C-9), 144.1 (C-6).

N-(p-Toluenesulfonyl)-2-pyrrolidinyl propanone (5a,5b). To a solution of (-)-(S)-N-(p-toluenesulfonyl)-2 -pyrrolidinyl acetonitrile 9a (1.0 g, 3.79 mmol) in dry THF (26.0 mL) at 0 °C, was added 0.75 mol L^-1 MeLi (1 equiv., 5.0 mL) very slowly for 1h under stirring. After this an aqueous solution of 1 mol L^-1 HCl was added at the same temperature and stirred for 3h at rt. The mixture was neutralized with NaHCO₃, extracted with CH₂Cl₂ and dried (Na₂SO₄). Purification by column chromatography over silica gel using CH₂Cl₂ gave 5a,5b (0.213 g, 20%). [a]_D²⁵ -63.1 (c 1.03, CH₂Cl₂), ee 54%. The NMR spectra of 5a,5b agreed with the literature data.⁶ Racemic 9a,9b was recovered (0.14 g),[a]_D²⁵ 0 (c 1, CHCl₃). Data for 12: oil, 66.5 mg (6.6%), R_f 0.32 (petroleum ether:EtOAc, 7:3), IR(film) n_max/cm^-1: 2220 (n CN). ¹H NMR (300 MHz, CDCl₃): d 1.71 (m, 2H, H-2), 2.28 (m, 1H, H-3), 2.38 (m, 1H, H-3), 2.40 (s, 3H, H-13), 2.98 (m, 2H, H-1), 5.34 (m, 2H, NH, H-4), 6.64 (m, 1H, H-5), 7.33 (d, 2H, J 7.9Hz, H-9, H-11), 7.76 (d, 2H, J 7.2Hz, H-8, H-12). ¹³C NMR (75.5 MHz, CDCl₃): d 21.9 (C-13), 27.9 (C-2), 30.3 (C-3), 42.7 (C-1), 101.0 (C-4), 117.6 (C-6), 127.4 (C-9, C-11), 130.2 (C-8, C-12), 137.0 (C-10), 144.0 (C-7), 154.7 (C-5).

(-)-N-(p-Toluenesulfonyl)-2-pyrrolidinyl acetyl diethylmalonate (14). To (-)-(S)-N-(p-toluenesulfonyl)-2-pyrrolidinyl acetic acid 13 (1.0 g, 3.53 mmol) in dichloromethane (10.0 mL) was added two drops of DMF and oxalyl chloride (0.5 mL, ~1.5 equiv.) at 0 °C. The mixture was stirred for 4h at room temperature and concentrated to dryness. Diethylmalonate (2.7 mL, 17.66 mmol) and 60% NaH (0.70 g, 17.66 mmol) in dry THF (10.0 mL) were stirred for 30 min at room temperature. Addition of the generated acid chloride in dry THF (15.0 mL) to this malonate suspension followed by stirring for 4h at 70 °C completed the reaction. Addition of water, extraction with dichloromethane, drying the solution over Na₂SO₄ and solvent removal provided the crude product. Purification by column chromatography over silica gel using 4:1 petroleum ether:EtOAc gave 1.17 g (78%) of an oil caracterized as a 1:1 keto-enolic mixture of 14: TLC (petroleum ether:EtOAc, 4:1): R_f 0.54; [a]_D²⁵ -101.8 (c 1.05, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): d 1.28-1.34 (4t overlapping, 6H, J 6.9 Hz, aliph.–CH₃), 1.45-1.83 (m, 4H, H-3, H-4), 2.43 (s, 1.5H, H-12), 2.44 (s, 1.5H, H-12), 2.66 (dd, 0.5H, J 10.0 Hz, J 13.7 Hz, H-1'), 3.01 (dd, 0.5H, J 9.8 Hz, J 18.2 Hz, H-1'), 3.03-3.10 (m, 1H, H-5), 3.18 (dd, 0.5H, J 4.5 Hz, J 13.7 Hz, H-1'), 3.39 (dd, 0.5H, J 3.1 Hz, J 18.2 Hz, H-1'), 3.41-3.49 (m, 1H, H-5), 3.94-4.01 (m, 1H, H-2), 4.29 (q, 4H, J 7.1 Hz, -OCH₂-), 4.50 (s, 0.5H, H-3'), 7.33 (d, 2H, J 7.9 Hz, H-8, H-10), 7.76 (d, 2H, J 8.2 Hz, H-7, H-11), 13.25 (s, 0.5H, OH). Anal. Calc. for C₂₀H₂₇NO₅S.¼H₂O: C, 55.86; H, 6.44. Found: C, 55.91; H, 6.41.

N-(p-Toluenesulfonyl)-2-pyrrolidinyl propanone (5a,5b). (-)-N-(p-toluenesulfonyl)-2-pyrrolidinyl acetyl diethylmalonate 14 (1.10 g, 2.59 mmol) in 4 mol L H₂SO₄ (55.0 mL) was stirred for 12h at 100 °C. The mixture was neutralized with sat. aq. NaHCO₃ and extracted with CH₂Cl₂. The extract was washed with water (3 x 100 mL), dried (Na₂SO₄) and concentrated to yield the crude product. Purification by column chromatography over silica gel using petroleum ether:EtOAc (7:3) gave 5a,5b which after crystallization from petroleum ether:CH₂Cl₂ yielded colorless crystals (575 mg, 79%): [a]_D²⁵ 0 (c 1, CH₂Cl₂). The NMR spectra agreed with the literature data.⁶

N-(p-Toluenesulfonyl)-2-pyrrolidinyl propanol-2 (1a, 1b and 2a,2b). Starting from ketone 5a, 5b and following the procedure described above, we obtained 1a,1b and 2a,2b (2.1:1). Yield 96%. Compound 1a,1b: mp. 76-78°C, [a]_D²⁵ 0 (c 1.05, CH₂Cl₂). Compound 2a,2b: mp. 87-89°C, [a]_D²⁵ 0 (c 1, CH₂Cl₂). The ¹H NMR and ¹³C NMR spectra agreed with the compounds 1a and 2a above.

(-)-(S)-N-Methoxycarbonyl-L-proline (16). L-proline 15 (1.0 g, 8.7 mmol) in THF (15.0 mL) was put in a round-bottom flask at 0 °C and NaHCO₃ (3.65 g) in water (4.0 mL) was added to it. Afterwards, methyl chloroformate (3.4 mL, 43.5 mmol) was poured into the flask and the contents stirred for 16h at room temperature. Acidification of the solution with dilute HCl, extraction with CH₂Cl₂ and usual work-up gave the crude product which could be purified by column chromatography over silica using CH₂Cl₂ and ethyl acetate (1:1) as eluent. The work-up yielded 16 (1.2 g, 80%) as light yellow oil. [a]_D²⁵ -100.4 (c 1.16, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): d 2.10 (m, 2H, H-4), 2.31 (m, 2H, H-3), 3.60 (m, 2H, H-5), 3.69, 3.74 (2s, 3H, H-7), 4.42 (m, 1H, H-2), 10.29 (s, 1H, OH). ¹³C NMR (75.5 MHz, CDCl₃): d 23.7, 24.6 (C-4), 29.9, 31.2 (C-3), 46.8, 47.2 (C-5), 53.2, 53.3 (C-7), 59.0, 59.5 (C-2), 155.7, 156.6 (C-6), 176.9, 177.9 (C-1'). Certain proton and carbon atoms of this compound produced two signals because of the existence of two rotamers at room temperature.

(S)-N-Methoxycarbonyl-2-pyrrolidinyl acetic acid (17). To N-methoxycarbonyl-L-proline 16 (0.77 g, 4.45 mmol) in dry CH₂Cl₂ (16.0 mL) was added (COCl)₂ (0.6 mL) and one drop of DMF at 0 °C. The mixture was stirred for 4h at room temperature. Solvent evaporation left a yellow oil which was dissolved in dry ether and then diazomethane was added at 0 °C. The contents were stirred at 0 °C for 5h followed by solvent removal which furnished the crude product. Dissolution of this product in dioxane (10.0 mL), followed by the addition of water (10.0 mL) and Ag₂O (0.10 g) and stirring at 90 °C for 6h completed the reaction. Filtration over celite, solvent removal and purification by column chromatography over silica using CH₂Cl₂ and ethyl acetate (1.5:1) afforded 0.38 g (46%) of 17 as light yellow oil. ¹H NMR (300 MHz, CDCl₃): d 1.94 (m, 3H, 2 H-4, 1 H-3), 2.14 (m, 1H, 1 H-3), 2.40 (dd, 1H, H-1'), 3.03 (dd, 1H, H-1'), 3.40 (m, 2H, H-5), 3.69 (s, 3H, H-7), 4.19 (m, 1H, H-2), 8.76 (bs, 1H, OH).

Methyl (-)-(S)-N-methoxycarbonyl-2-pyrrolidinyl acetate (18). To (S)-N-methoxycarbonyl-2-pyrrolidinyl acetic acid 17 (0.35 g, 1.87 mmol) in dry ether at 0 °C, was added diazomethane in excess and the mixture was stirred for 1.5h at this temperature. After, solvent removal, the crude product was purified by column chromatography over silica gel using petroleum ether and ethyl acetate (1.5:1) as eluent. The work-up yielded 0.38 g (100%) of 18 as light yellow oil. [a]_D²⁵ -50.0 (c 1.1, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): d 1.91 (m, 3H, 2 H-4, 1 H-3), 2.11 (m, 1H, 1 H-3), 2.37 (dd, 1H, H-1'), 2.98 (dd, 1H, H-1'), 3.43 (m, 2H, H-5), 3.68, 3.69 (2s, 3H, H-3'), 3.69 (s, 3H, H-7), 4.19 (m, 1H, H-2). ¹³C NMR (75.5 MHz, CDCl₃): d 23.1, 23.9 (C-4), 30.9, 31.7 (C-3), 38.5, 39.4 (C-1'), 46.7, 47.1 (C-5), 51.9 (C-3'), 52.5, 52.7 (C-7), 54.3, 54.9 (C-2), 155.7 (C-6), 172.2 (C-2').

(-)-(S)-N-Methoxycarbonyl-2-pyrrolidinyl propanone (6). Tebbe's reagent (2.88 mL, 0.5 mol L^-1 in toluene) was added to ester 18 (0.29 g, 1.44 mmol) dissolved in tetrahydrofuran (3.0 mL) at 0 °C, and the mixture was stirred for 30 min at room temperature. Soon after, ether (15.0 mL) and two drops of NaOH (~ 10% aqueous solution) was added to it and stirred for an additional 20 min. After this, 12 drops of an aqueous hydrochloric acid solution (1.0 mol L^-1) was added and the contents stirred for 1.5h at room temperature. Water (30.0 mL) addition to the flask, neutralization with NaHCO₃, extration with dichloromethane (3 x 30.0 mL), drying the solvent over Na₂SO₄, filtration and solvent evaporation under reduced pressure gave an oil. Purification by liquid chromatography over silica gel using petroleum ether and ethyl acetate (1.5:1.0) provided pure 6 (0.22 g, 83%) as light yellow oil. [a]_D²⁵ -66.1 (c 1, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): d 1.28-1.34 (4t overlapping, 6H, J 6.9 Hz, aliph.–CH₃), 1.45-1.83 (m, 4H, H-3, H-4), 2.43 (s, 1.5H, H-12), 2.44 (s, 1.5H, H-12), 2.66 (dd, 0.5H, J 10.0 Hz, J 13.7 Hz, H-1'), 3.01 (dd, 0.5H, J 9.8 Hz, J 18.2 Hz, H-1'), 3.03-3.10 (m, 1H, H-5), 3.18 (dd, 0.5H, J 4.5 Hz, J 13.7 Hz, H-1'), 3.39 (dd, 0.5H, J 3.1 Hz, J 18.2 Hz, H-1'), 3.41-3.49 (m, 1H, H-5), 3.94-4.01 (m, 1H, H-2), 4.29 (q, 4H, J 7.1 Hz, -OCH₂-), 4.50 (s, 0.5H, H-3'), 7.33 (d, 2H, J 7.9 Hz, H-8, H-10), 7.76 (d, 2H, J 8.2 Hz, H-7, H-11), 13.25 (s, 0.5H, OH). Some carbons gave two peaks because the compound exists as rotamers at room temperature.

N-Methoxycarbonyl-2-pyrrolidinyl propanol-2 (3 and 4). To (-)-(S)-N-methoxycarbonyl-2-pyrrolidinyl propanone 6 (0.21 g, 1.14 mmol) in methanol (10.0 mL) at 0 °C was added NaBH₄ (86 mg, 2.27 mmol) under stirring and the agitation continued for 1h more maintaining this temperature. After this, an aqueous solution of HCl (2.0 mL, 1.0 mol L^-1) was added to it and stirred for an additional 10 min. Neutralization of this solution with aqueous NaHCO₃, extraction with dichloromethane and work-up yielded two diastereoisomers which were separated by column chromatography over silica gel using petroleum ether and ethyl acetate (1:1), both as light yellow oils. The yields of 3 (125 mg) and 4 (66 mg) together turned out to be 90%. Compound 3: R_f 0.36 (petroleum ether:EtOAc, 1:1), [a]_D²⁵ -73.5 (c 1.13, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): d 1.14 (d, 3H, J 6.0Hz, H-3'), 1.35-1.96 (m, 6H, 2 H-1', 2 H-3, 2 H-4), 3.31 (m, 2H, H-5), 3.62 (s, 3H, H-7), 3.79 (m, 1H, H-2), 3.98 (m, 1H, H-2'). ¹³C NMR (75.5 MHz, CDCl₃): d 24.1 (C-4), 24.4 (C-3'), 31.8 (C-3), 44.9 (C-1'), 46.4 (C-5), 52.6 (C-7), 56.1 (C-2), 66.3 (C-2'), 156.4 (C-6). Compound 4: R_f 0.44 (petroleum ether:EtOAc, 1:1), [a]_D²⁵ -3.0 (c 0.72, CH₂Cl₂). Lit:³ [a]_D²⁵ -2.0 (c 0.7, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): d 1.18 (d, 3H, J 6.4Hz, H-3'), 1.36-1.62 (m, 3H, 1 H-3, 2 H-4), 1.90-2.04 (m, 3H, 2 H-1', 1 H-3), 3.38 (m, 2H, H-5), 3.65-3.83 (m, 1H, H-2), 3.71 (s, 3H, H-7), 4.22 (m, 1H, H-2'), 4.77 (bs, 1H, OH). ¹³C NMR (75.5 MHz, CDCl₃): d 22.9 (C-3'), 23.9 (C-4), 31.5 (C-3), 45.8 (C-1'), 46.6 (C-5), 53.0 (C-2), 55.0 (C-7), 64.0 (C-2'), 157.9 (C-6).

Supplementary Information

Crystallographic data (excluding structure factors) for racemic 2a,2b reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 244859. Copies of the data can be obtained, free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK ; fax: [phone]; or e-mail: [e-mail]).

Acknowledgments

The authors express their gratitude to both CAPES and CNPq of Brazil and CNRS (France) for financial help. One of us (MJeSilva) is thankful to CAPES/COFECUB for a fellowship. We would like to thank Dr. Bogdan Doboszewski for his nice suggestions at the initial stage of this work. We also thank Dr. Alain Thozet and Dr. Monique Perrin, Laboratoire de Cristallographie, Université Claude Bernard Lyon 1, Villeurbanne, France, for obtaining the crystallographic data.

Received: November 11, 2004

Published on the web: August 3, 2005

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Publication Dates

• Publication in this collection
  09 Nov 2005
• Date of issue
  Oct 2005

History

• Accepted
  03 Aug 2005
• Received
  11 Nov 2004