PROCESS DEVELOPMENT Peer reviewed Jared Piper Efficient synthesis of a chiral 2-aryl Pyrrolidine JARED L. PIPER1,*, STANLEY P. KOLIS1, CHAOYU XIE1, MARTIAL BERTRAND2, PASCAL BOQUEL2 *Corresponding author 1. Eli Lilly and Company, Lilly Corporate Centre, Chemical Product Research and Development, Indianapolis, IN 46285, USA 2. Eli Lilly & Company, Lilly Development Centre, Chemical Product Research and Development, S.A., Rue Granbonpré 11, Mont-Saint-Guibert, B-1348, Belgium KEYWORDS Asymmetric synthesis; pyrrolidine; iridium catalysts. ABSTRACT 2-aryl pyrrolidine 1 was efficiently prepared in three steps starting from N-vinylpyrrolidinone and ethyl 3,5-dimethylbenzoate. The key steps highlight the use of a rearrangement and an iridium catalysed hydrogenation to afford the desired compound. This methodology was utilised to prepare several differentially 2-aryl-substituted pyrrolidines in good yield and enantiomeric excess, and is complimentary to existing methods to prepare molecules of this type. 38 Scheme 1. First generation synthesis of 1. INTRODUCTION hemical compounds enantioselective reduction, the synthesis had potential limitations. containing the pyrrolidine The Grignard chemistry required long reaction times (>24 hours), Cstructural motif are was difficult to initiate, and failed to reach complete conversion on ubiquitous in nature, and are present larger scale. In addition, multiple impurities were observed for the in both the core of the amino acids reaction, and the rejection of these substances from the product proline and hydroxyproline, and the stream was not trivial. During the cyclization event to form 6, the natural alkaloids nicotine and ficine. retention of stereochemical integrity of 5 during the course of the These heterocycles have been used reaction was unpredictable. Lastly, an early safety assessment also Figure 1. Pyrrolidine of by the pharmaceutical industry in predicted potential difficulties on larger scale, and thus the route was synthetic interest the search for therapeutic agents (1). abandoned (4). Under the best of circumstances, the overall yield for For this reason, methods to synthesize the route was approximately 15 percent. After extensive analysis of de the pyrrolidine skeleton have novo synthetic routes to 1, a route emerged that was more consistent received considerable attention (2). Substituted 2-phenylpyrrolidines with our program design goals, particularly in regards to robustness are also used as intermediates for the preparation of tricyclic on scale, and the rejection of unwanted related substances (5). To systems such as pyrrolo(2,1-a)isoquinolines which can exhibit this end, a cyclization strategy was identified for the preparation of 1 pharmacological activities. A recent requirement to prepare an that utilized a procedure modified by Maryanoff to furnish advanced active pharmaceutical ingredient (API) for evaluation required imine intermediate (Figure 2) (6). Our synthesis started by treating a the synthesis of the 2-aryl substituted pyrrolidine 1 (Figure 1) as a mixture of ester 7 and N-vinylpyrrolidinone 8 with LiHMDS in THF to starting material. Our initial synthesis of 1 is depicted in Scheme 1. furnish β-ketolactam 9 in 81percent yield. It commenced with a Grignard reaction of 1-bromo-3,5- dimethylbenzene (2) and N-Boc-2-pyrrolidinone (3) to provide ketone 4 in 32 percent yield. Corey-Bakshi-Shibata (3) reduction of 4 using (S)-2-methyl-CBS-oxazaborolidine was followed by exposure to methanesulfonylchloride in dichloromethane to provide mesylate 5 in 65 percent yield. The product was treated with potassium tert- butoxide in warm THF to form the pyrrolidine ring in 93 percent yield. Subsequent Boc deprotection in acidic methanol gave rise to the desired product 1 as the hydrochloride salt with >98 percent purity, >98%ee, and 75 percent yield. While the Scheme 1 route Figure 2. Pyrroline formation from aryl-N-vinylpyrrolidinones. allowed stereochemical control of the target using a catalytic, chimica oggi/Chemistry Today - vol. 30 n. 4 July/August 2012 PROCESS DEVELOPMENT There are examples in the literature of imine reductions of this type, and we envisioned that homogeneous catalysis could result in a significant improvement for the overall process (10). As in Table 1, an evaluation of multiple catalysts, ligands, and additives identified a protocol consisting of bis(cyclooctadiene)iridium(I) tetrakis (3,5-bis(trifluoromethyl) phenyl)borate), DM-SEGPHOSTM (14), tetrabutylammonium iodide (TBAI), trifluoroacetic acid (TFA), and di- tert-butyl dicarbonate (Boc2O) in toluene at room temperature and 50 bar hydrogen pressure (11). Several screening exercises were conducted, and analysis of the data indicated that higher pressure (>20 bar) was necessary to achieve reasonable reaction rates. Rhodium based catalysts were effective in our screens, but abandoned after experiments produced multiple impurities (entry 1). We also observed that (Ir(COD)2)BARF as the iridium precursor consistently provided greater conversion than Scheme 2. Second generation synthesis of 1. the (Ir(COD)Cl)2 (entries 3, 6). In general, lower selectivities were observed for reactions using the ligands C3-TUNEPHOSTM (12) and The Claisen product could be purified via crystallisation (7), but was DIFLUORPHOSTM (13). The addition of TBAI and TFA proved necessary instead processed directly without purification. Exposure of 9 to for the reaction to proceed with high conversion. We concluded that concentrated HCl and heat led to rapid loss of the vinyl protecting the additives may be involved in the formation of an active “hydrido” group, followed by decarboxylation and cyclization to afford imine species, resulting in an addition of iodine and hydrogen to the iridium, 10 in 92 percent yield (8). Hydrogenolysis using Pearlman’s catalyst (9) forming the active species. Such a system has been reported in in isopropyl alcohol under 3 bar of hydrogen atmosphere provided the literature, but we have yet to isolate or characterise the active amine 11 as a racemic mixture that could be resolved using catalyst present in our system (12). D-tartaric acid to provide 1 as a crystalline tartrate salt in good yield Finally, we found that adding a stoichiometric amount of Boc2O was (30 percent overall), purity (98.0 percent) and enantiomeric excess necessary to achieve lower catalyst loadings by sequestering the (84%ee). Recrystallization from aqueous mixtures of acetone, THF, or formed product during the course of the reaction and presumably acetonitrile proved effective at upgrading the enantiomeric excess preventing poisoning of the active catalyst (13). In conclusion, we of 1 from 84%ee to >98%ee. have demonstrated an efficient and enantioselective synthesis of 1 that highlights the use of a rearrangement and subsequent iridium mediated catalytic hydrogenation. This method can be used to ASYMMETRIC HYDROGENATION prepare a variety of 2-aryl substituted pyrrolidines of synthetic interest, thus expanding both the substrate scope of the rearrangement as Following our initial success in developing an efficient and robust route well as the iridium mediated asymmetric reduction. to 1 using the tartrate salt resolution, we next examined a catalytic Optimization of the iridium catalysed reduction to prepare 1 resulted 39 system capable of reducing imine 10 with high enantioselectivity. in low catalyst loadings (0.5 mol%) under these conditions. PROCESS DEVELOPMENT Further development of this methodology and results from the 5. T.Y. Zhang, Chem. Rev., pp. 2583-2595 (2006). application of this technology on larger scale will be reported in due 6. a) S. Brandange, L. Lindblom, Acta Chem. Scand. Ser. B, p. 93 (1976); b) P. course. Jacob, J. Org. Chem., pp. 4165-4167 (1982); c) K.L. Sorgi, C. Maryanoff et al., J. Am. Chem. Soc., pp. 3567-3579 (1990); d) K.L. Sorgi, C.A. Maryanoff et al., Org. Synth., pp. 215-222 (1998). [Header] 7. 20% EtOAc/heptanes was an effective solvent for the recrystallization of β-ketoamide 9. 8. Experimental procedure for the preparation of 10: To a 2-L 3-neck round bottom flask equipped with an overhead stirrer, addition funnel and thermocouple was added conc. HCl (307 mL), and the solution was heated to 100 °C. 9 (51.2 g, 210.4 mmol) from the previous reaction in toluene (270 mL) was added to the hot acid over 30 minutes, and the toluene was removed by distillation during the addition. After stirring for 18 hours at 100°C, the reaction was deemed complete by HPLC analysis, and the dark brown reaction mixture was cooled to room temperature. Toluene (150 mL) was added, the layers separated, and the organic layer discarded. The organic layer was free of product, but removed the majority of color from the reaction mixture. There is evidence that varying levels of polymerization occur during the reaction, but the toluene extraction served as an efficient puridication. The water layer containing product was adjusted to pH~12 by the addition of 2.0 N NaOH, and the aqueous phase was extracted with ethyl acetate (2 x 150 mL). The combined organic extracts were concentrated to dryness, and 30% EtOAc/Heptanes (200 mL) was added to the crude residue. The solution was filtered over silica gel (30.0 g) and concentrated to provide 33.5 g 10 (92 percent) as a pale yellow oil (typically, the crude product was carried forward into subsequent steps as a solution in isopropanol without formal 1 isolation): H NMR (400 MHz, CDCl3): δ 7.45 (s, 2 H), 7.04 (s, 1 H), 4.06-3.98 (m, 2 H), 2.92-2.84 (m, 2 H), 2.33 (s, 3 H), 2.03-1.94 (m, 2 H). 13C NMR (100 Mz, CDCl3): δ 173.5, 137.9, 134.5, 131.9, 125.4, 61.4, 34.9, 22.6, 21.2. FT-IR (KBr) -1 2918, 1598, 1343, 852, 696 cm . HR-MS (EI): calcd. for C12H16N (M + H) = 173.1205, found 173.1208. 9. Palladium hydroxide (10 wt% on carbon) was a superior catalyst in our experiments. Significant levels of by-products were observed when using [Footer] palladium on carbon.