Novel Synthesis of 1-substituted meso-3,4-dihydroxypyrrolidines with a RuCl3-catalyzed Key Reaction

meso-1-Substituted-3,4-dihydroxypyrrolidines were synthesized in three steps from (Z)-but-2-ene-1,4-diol involving RuCl3-catalyzed cis-dihydroxylation of (Z)-but-2-ene-1,4-diyl dimethanesulfonate. In this key step RuCl3-catalysis allowed us to avoid the use of more toxic OsO4. The final cyclization reaction was performed with three different aromatic amines to yield the desired 3,4dihydroxypyrrolidines.

Our aim was to develop a convenient method for the cisdihydroxylation step using a cheaper, less hazardous and less toxic catalyst.Use of ruthenium catalysts has been reported already in cis-dihydroxylations of olefins to produce cis-diols selectively in rapid reactions with medium to good yields [14][15][16][17].In the most cases, RuO 4 was generated in situ in the reactions from RuCl 3 and NaIO 4 , and hydrolysis of the rutheniumdiester formed from the olefins with this RuO 4 catalyst gave the cis-diol [15,16].The most frequent side reaction in this process is overoxidation resulting in formation of aldehydes and ketones from the olefins [15][16][17].The side reactions could be suppressed by addition of Lewis acids to the system to promote the hydrolysis of the Ru-diester [15,16].A study on the effects of various Lewis acids showed that CeCl 3 as additive in the dihydroxylations of olefins resulted in high yields and the best diol-aldehyde ratio [16].Ru nanoparticles immobilized on hydroxyapatite [18], or a polymer incarcerated ruthenium catalyst [19] allowed recovery of the catalyst and rendered the reactions easy-to-perform and more economical.Moreover, heterogenization of Ru-catalysts opened up the way for carrying out the reactions in continuous-flow reactor.
Our goal in this study was to develop a novel synthetic route to 1-substituted meso-3,4-dihydroxypyrrolidines involving Ru-catalzed cis-dihydroxylation as the key reaction.

Results and discussion
For synthesis of the desired meso-3,4-dihydroxypyrrolidines, our first approach was the cis-dihydroxylation of N-substituted-3-pyrrolidines (Route A in Fig. 1) by analogy of Plietker's method (use of catalytic amounts of RuCl 3 and CeCl 3 as Lewis acid) which was successfully applied to cyclic olefins [16].
The reaction conditions for cyclization of meso-diol (6) were investigated using aniline (3a) as aromatic amine (Table 1).In the course of the first synthetic trial (Route A, Fig. 1), cyclization of (Z)-but-2-ene-1,4-diyl dimethanesulfonate (2) was performed in dichloromethane.However in the case of the meso-diol (6), it was not soluble in dichloromethane under argon.Thus, solvent was changed to acetonitrile (Entries 1,2).At room temperature no product formation was observed even using one week reaction time.At reflux temperature without inert atmosphere only negligible amount of product (5a) was formed.Next, when only 1.2 equivalents of aniline (3a) and triethylamine as antacid were used (Entries 3-5), 5a formed in low yield after even 7 h reflux (Entry 3).Although by increasing the triethylamine/acetonitrile ratio the yields were increased (Entry 3-5), substantial degree of side reactions were observed on TLC after a few hours reflux excluding the possibility of prolongation of the cyclization under these conditions.When the reaction was performed in neat triethylamine, similarly low amount of product (5a) was formed (Entry 6).Significant increase of the yield could be achieved by addition of 2 equiv. of KI (promoting the SN1 reaction) or KI and TEBACl (Entries 7, 8).Next, to enhance the solubility of the starting material (6), solvent was changed to ethanol, which is also favorable for SN1 reactions (Entries 9-12).Because in ethanol the reaction could be prolonged without any side reaction, the yield of the desired product (5a) increased significantly.In these cases, KI or KI and TEBACl could be used as well.Finally, the reaction was carried out also in isopropanol as a higher boiling alcohol to test whether the higher temperature can favor the reaction (Entry 13) but no further increase in the yield was observed.

Materials and methods
All chemicals and starting materials were purchased from Sigma-Aldrich (Saint Louis, MO, USA) and Alfa Aesar Europe (Karlsruhe, Germany) and used without further purification.Prior to use, solvents from Merck KGaA (Darmstadt, Germany) were dried and/or freshly distilled.
TLC was carried out using Kieselgel 60 F254 (Merck) sheets.Spots were visualized under UV light (254 nm and 365 nm) or by treatment with 5% ethanolic phosphomolybdic acid solution and heating of the dried plates.The NMR spectra were recorded on a Bruker DRX-300 spectrometer operating at 300 MHz for 1H and 75 MHz for 13C, and signals are given in ppm on the δ scale.Infrared spectra were recorded on a Bruker ALPHA FT-IR spectrometer and wavenumbers of bands are listed in cm -1 .

Conclusion
New and convenient methods were developed for preparation of drug-like meso-3,4-dihydroxypyrrolidines involving cis-dihydroxylation as a key step.In the key step leading to the (Z)-2,3-dihydroxybut-1,4-diyl dimethanesulfonate in good yield, RuCl 3 was applied in catalytic amounts instead of the expensive and very toxic OsO 4 .The optimized reaction conditions of the cyclization of the dihydroxylated dimethanesulfonate with aniline (KI and TEBACl promoting the S N 1 reaction in ethanol, 48 h, reflux) proved to be applicable with other amines as well.

Table 1
Conditions for cyclization of meso-diol(6)with aniline (3a) b Yield after preparative TLC c Yield after vacuum chromatography