Synthesis of a New Chiral Pyrrolidine †

The synthesis of a new chiral pyrrolidine has been performed using 2,3-O-iso-propylidene-D-erythronolactol as a suitable starting material.


Introduction
In the last years there has been a growing interest in organocatalysis [1][2][3][4][5][6], a new field which has quickly attracted researchers' attention due to its potential for saving costs, time and energy compared to classic catalysis. Among the many known organocatalysts L-proline is perhaps the one which has been most studied. This fact has led to the appearance of many analogues [7][8][9][10][11][12][13][14]. In the seminal paper of List, Lerner and Barbas III [15], it is described how in the aldol reaction the catalytic activity of L-proline increases using trans-4-hydroxy-L-proline and also how the enantiomeric excess reverses using cis-4-hydroxy-D-proline, (Figure 1 Starting from sulfonylbutadiene 1, pyrrolidines 5 and 6 were obtained through vinyl sulfones 3 and 4, respectively [16][17]. In order to increase the yields, a new route for the synthesis of compound 6 was devised starting from 2,3-O-iso-propylidene-D-erythronolactol (2) through vinylsulfone 4 [18]. This pyrrolidine 6 has been proved to be an organocatalyst for the intramolecular oxa-Michael reaction [19][20]. Moreover, compound 7, which has been reported to catalyze Michael reactions [21], has been synthesized from intermediate vinylsulfone 4 (Scheme 1).

Results and Discussion
In this paper we describe our studies on the synthesis of the epimer at C-2 of pyrrolidine 6, as we are interested in comparing the properties of both diastereoisomers in organocatalytic reactions. In previous studies with PPY-derivatives, we had observed the epimerization of that stereogenic center when it was treated with bases [22]. Taking this into account, we first tried the epimerization at C-2 in compound 8, obtained directly from 4 by treatment with benzylamine. However, although several bases were used, none of them gave the epimerization. Therefore, we devised the following synthesis for the required compound 12 (Scheme 2).

Scheme 2.
Epimerization of C-2 in compound 8. Benzoylation of pyrrolidine 6 gave derivative 10 as outlined in Scheme 2. When this compound was submitted to treatment with n-BuLi, the C-2 epimer 11 was obtained in moderate yield. Once the required stereochemistry at C-2 in 11 was achieved, we proceeded to deprotect the nitrogen to obtain the desired pyrrolidine 12. This step was not as simple as it was thought initially, since the desired direct debenzoylation did not take place under several conditions. Finally, it was necessary to reduce the benzoyl to benzyl group and then deprotect under the usual conditions. Although, the final deprotection took place in good yield, the previous transformation from benzoyl to benzylderivative was only achieved in low yield, making useless this procedure to synthesise 12.   Therefore, we devised a new synthesis of compound 12 starting from 2,3-O-iso-propylidene-Derythronolactol (2). Goti [23][24][25] and Wightman and Closa [26][27][28] have obtained nitrone 13 from compound 2. Besides, Merino and Goti have applied this versatile nitrone to the synthesis of iminocyclitols, pyrrolizidines and indolizidines [29][30], observing that the addition of organometallics to 13 took place to give the trans compounds. With this procedure in mind, we were able to achieve the desired compound 12 in a simple manner, as depicted in Scheme 3.
When compound 13 was treated with lithio(phenylsulfonyl)methane, only hydroxylamine 14 was obtained stereoselectively in moderate yield. The stereochemistry of 14 was established studying its NMR spectra (whose assignment is given in the Experimental section) and by the observation of the nOes that this molecule displays (Scheme 3). The nOes of the enantiomer of compound 6 has already been reported by our research group [16]. Once this compound 14 was synthesized, different reduction conditions to obtain the pyrrolidine ring were tested.
Hydrogenation under different conditions either Pd(OH) 2 or Pd on carbon only leads to the pyrrolidine 6. When 14 was submitted to reduction with stoichiometric indium or with zinc, hydroxylamine 15 with inversion at C-2 was obtained. Thus, it was necessary to choose the adequate conditions to reduce the hydroxylamine to the required pyrrolidine 12 without epimerization at C-2. This was achieved using catalytic indium and stoichiometric Zn [29][30][31] (Table 1, entry 8). Having obtained our desired compounds 6 and 12, they were tested as organocatalysts in Michael addition reactions of cyclohexanone to nitrostyrene, as shown in Table 2. As can be observed, both compounds 6 and 12 are organocatalysts. However, their behaviour is rather different depending on the solvent chosen to carry out the reaction. It is worthy mentioning that compound 12 lead to the opposite enantiomer of 6 in the Michael addition, as a result of the stereochemistry change in C-2 position. The absolute configuration of the addition product was established by comparison of the HPLC data with the ones reported by us [21] and others [32][33].

Conclusions
The synthesis of a new chiral pyrrolidine 12, has been achieved from the same starting material, 2,3-O-iso-propylidene-D-erythronolactol through two different methodologies. In addition, the reduction of the chiral hydroxylamine into pyrrolidine has been studied under different conditions.

General
1 H-NMR and 13 C-NMR spectra were recorded in CDCl 3 at 200 and 400 MHz ( 1 H) or 50 and 100 MHz ( 13 C) on Varian 200 VX and BRUKER DRX 400 instruments, respectively. Multiplicities were determined by DEPT experiments. IR spectra were registered using a BOMEM 100 FTIR spectrophotometer. Optical rotations were determined using a Perkin-Elmer 241 polarimeter in a 1 dm cell and are given in units of 10-1 deg cm 2 g -1 . Concentrations are quoted in g per 100mL. The electron impact (EI) mass spectra were run on a VG-TS 250 spectrometer using a 70 eV ionizing voltage. HRMS were recorded using a VG Platform (Fisons) spectrometer using Chemical Ionization (ammonia as gas) or Fast Atom Bombardment (FAB) techniques. Thin layer chromatography (tlc) was performed on aluminum sheets coated with 60 F254 silica. Sheets were visualized using iodine, UV light or 1% aqueous KMnO 4 solution. Column chromatography (CC) was performed with Merck silica gel 60 (70-230 mesh). Solvents and reagents were generally distilled prior to use: dichloromethane (DCM) from KOH.