An Easy Access to Two Epimeric N-Substituted ( 2 S )-2-( 2 ́-Hydroxypropyl ) pyrrolidines

There are entries for the racemic alcohols 3 and 4, and also of enantiomerically pure 4. Our interest developed knowing the fact that pyrrolidine derivatives possess biological activities. 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 N 2-Michael addition reaction without any description about their optical purity. Racemic 6 is also known. 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).

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. 4,5or 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 N 2-Michael addition reaction without any description about their optical purity. 6acemic 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 reagent 7 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 7 8 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 1 H NMR spectra of 1a and 2a are consistent with the proposed structures.Compound 5a was found to be enantiomerically pure by 1 H NMR spectroscopy as verified by the chiral shift reagent, europium tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorate.
The same chiral shift reagent was used for obtaining the 1 H NMR spectrum of the racemic mixture 5a,5b.
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 method 15 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.[3]

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 1 H and 75.5MHz for NMR 13 C using TMS as an internal standard.Chemical shifts (δ) 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.

(S)-N-Methoxycarbonyl-2-pyrrolidinyl acetic acid (17).
To N-methoxycarbonyl-L-proline 16 (0.77g, 4.45 mmol) in dry CH 2 Cl 2 (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 Ag 2 O (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 CH 2 Cl 2 and ethyl acetate (1.5:1) afforded 0.38 g (46%) of 17 as light yellow oil. 1

(-)-(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 NaHCO 3 , extration with dichloromethane (3 x 30.0 mL), drying the solvent over Na 2 SO 4 , 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.